Lymphoma
Lymphoma is a group of hematologic malignancies arising from the clonal proliferation of lymphocytes within lymphoid tissues, broadly classified into Hodgkin and non-Hodgkin types.
Lymphoma
Lymphoma is a clonal neoplasm of lymphoid cells (B-cells, T-cells, or NK-cells) at various stages of differentiation [1][2]. The word itself breaks down simply: "lymph-" = lymphoid tissue, "-oma" = tumour. Unlike leukaemias, which primarily involve the bone marrow and peripheral blood, lymphomas predominantly present as solid tumours of lymphoid tissue (lymph nodes, spleen, mucosa-associated lymphoid tissue), though there is significant overlap — many lymphomas can have a leukaemic phase, and some leukaemias (e.g., ALL) can present as lymphoblastic lymphoma.
All cells in a lymphoma are descended from one single mutated cell, which has usually undergone V(D)J rearrangement (immunoglobulin [IG] genes in B-cell lymphoma, T-cell receptor [TCR] genes in T-cell lymphoma). Therefore, all cells in a lymphoma share the same VDJ rearrangement [1]. This clonality is the fundamental feature distinguishing lymphoma from reactive (polyclonal) lymphoid proliferations. It is this shared clonal rearrangement that we exploit diagnostically — by PCR for clonal IGH or TCR gene rearrangement.
Key Concept – Clonality
Lymphoma = monoclonal proliferation of lymphoid cells → all tumour cells share the identical antigen receptor gene rearrangement. This is in contrast to reactive lymphadenopathy, where lymphocytes are polyclonal (many different rearrangements). Demonstrating monoclonality via PCR or flow cytometry is a core diagnostic principle.
The two major categories are:
- Hodgkin lymphoma (HL): a specific type of B-cell lymphoma characterised by the presence of Reed-Sternberg (RS) cells on histology [2][3]
- Non-Hodgkin lymphoma (NHL): everything else — the vast majority of lymphomas, encompassing B-cell, T-cell, and NK-cell subtypes [2][3]
2. Epidemiology
- Accounts for ~10% of all lymphomas [3]
- Incidence: 2–3/100,000/year [3]
- Demographics: bimodal age distribution — peak in late adolescence/young adulthood (15–35 years) and a second peak in older age (> 55 years), M > F [3]
- In Hong Kong: relatively uncommon compared to Western populations; the classical bimodal pattern may be less pronounced in Asian populations
- Incidence in HK: 13.6/100,000/year (9th overall cancer, 8th in males, 10th in females) [3]
- Mortality in HK: 5.3/100,000/year (8th overall) [3]
- Demographics: M > F (slight), median age 65–70 years (incidence increases with age) [3]
- NHL is far more common than HL (roughly 90% vs 10% of all lymphomas)
- Certain subtypes have distinct geographic patterns relevant to Hong Kong:
- Lymphoma is the 3rd most common childhood malignancy (after leukaemias and brain tumours)
- In children, NHL tends to be high-grade (Burkitt lymphoma, lymphoblastic lymphoma, diffuse large B-cell lymphoma) and HL tends to present in adolescence
- ALL is the most common cancer in children (~25%) — when presenting with lymphatic tissue involvement, it is also called lymphoblastic lymphoma [4]
3. Risk Factors
These risk factors are high yield and commonly examined.
| Category | Details |
|---|---|
| Genetics | HLA-A1, -B5, -B8, -B18 associations [3] |
| Family history | 3–5× risk in close relatives, especially for NLPHL subtype [3] |
| EBV infection | Most commonly associated with mixed cellularity (MCCHL) and lymphocyte-depleted (LDCHL) subtypes; but only 1/1000 risk of HL after EBV infection (risk markedly ↑ if HIV/AIDS or immunosuppression) [3] |
| Immunosuppression | HIV (5–25× risk), solid organ transplant, HSCT, immunosuppressant use [3] |
| Socioeconomic factors | ↑ nodular sclerosis (NSCHL) + ↑ in young adults, ↓ in elderly in developed countries [3] |
| Lifestyle | Obesity, smoking (↑ risk); aspirin use (protective) [3] |
| Other infections | HHV-6 (controversial) [3] |
| Category | Details |
|---|---|
| Genetics / Cytogenetics | t(14;18) → follicular lymphoma (dysregulated BCL2); t(8;14) → Burkitt lymphoma (c-MYC); t(11;14) → mantle cell lymphoma (cyclin D1) [2][3] |
| Infections | HIV (100× risk, ~10% of all HIV-related malignancies); EBV (post-transplant NHL, Burkitt, NK-cell lymphoma); HHV-8 (primary effusion lymphoma); HTLV-1 (adult T-cell leukaemia-lymphoma); H. pylori (gastric MALT lymphoma) [2][3] |
| Immunodeficiency states | Congenital cell-mediated immunodeficiencies; post-transplant (PTLD) [2][3] |
| Other factors | Carcinogen exposure (pesticides, hair dyes, dioxins); autoimmune disease (e.g., Sjögren's, RA, coeliac disease); mixed cryoglobulinaemia; multicentric Castleman disease [2][3] |
- NK/T-cell lymphoma (nasal type): predominantly Asian, strongly EBV-associated, classically affects the nose and may result in palatal ulcer/perforation [2]
- Nasopharyngeal-type EBV-driven lymphomas more common in southern Chinese populations
- Hashimoto's thyroiditis → 60× risk of thyroid lymphoma (usually DLBCL) [6]
High Yield – Infection–Lymphoma Associations
| Infection | Associated Lymphoma |
|---|---|
| EBV | Burkitt (endemic), post-transplant NHL, NK/T-cell lymphoma, classical HL (MCCHL, LDCHL), PTLD |
| HIV | 100× ↑ NHL risk; also ↑ HL risk |
| H. pylori | Gastric MALT lymphoma |
| HTLV-1 | Adult T-cell leukaemia-lymphoma |
| HHV-8 | Primary effusion lymphoma |
| HCV | Splenic marginal zone lymphoma, DLBCL |
4. Anatomy and Function of the Lymphoid System (Relevant to Lymphoma)
Understanding where lymphomas arise requires understanding the normal lymphoid system.
- Bone marrow: site of B-cell development (early stages) and haematopoiesis
- Thymus: site of T-cell maturation and selection
- Lymph nodes: organised structures with cortex (B-cell follicles), paracortex (T-cells), and medulla
- Follicles: germinal centres are where B-cells undergo somatic hypermutation and class-switch recombination → many lymphomas arise from germinal centre (GC) or post-GC B-cells
- Mantle zone: surrounding the GC, contains naive B-cells (mantle cell lymphoma arises here)
- Marginal zone: between follicle and paracortex (marginal zone lymphoma arises here)
- Spleen: white pulp (periarteriolar lymphoid sheath = T-cells; follicles = B-cells); red pulp (filtration)
- Mucosa-associated lymphoid tissue (MALT): Peyer's patches, tonsils, bronchial and gastric lymphoid tissue → MALT lymphomas arise here
This is conceptually critical because the stage of B-cell differentiation at which the malignant transformation occurs determines the type of lymphoma.
- Pre-GC lymphomas: mantle cell lymphoma (naive B-cells)
- GC lymphomas: follicular lymphoma, Burkitt lymphoma, DLBCL (centroblasts/centrocytes)
- Post-GC lymphomas: marginal zone/MALT lymphoma, lymphoplasmacytic lymphoma
- Plasma cell neoplasms: multiple myeloma, Waldenström's macroglobulinaemia
For T-cells: T-cell lymphomas can arise from precursor T-cells (T-lymphoblastic lymphoma/leukaemia) or mature/peripheral T-cells (peripheral T-cell lymphomas, ATLL, etc.)
5. Etiology and Pathophysiology
5.1 General Principles of Lymphomagenesis
The aetiology of cancer is an interplay of three factors: oncogenes, tumour suppressor genes, and DNA repair mechanisms [8]. Lymphomas arise through a multistep accumulation of genetic hits that dysregulate cell proliferation, survival, and differentiation in lymphoid cells.
The hallmark genetic events in many lymphomas are chromosomal translocations that juxtapose an oncogene next to a strong promoter/enhancer element (typically the immunoglobulin heavy chain locus on chromosome 14, which is highly active in B-cells):
| Translocation | Oncogene | Lymphoma | Mechanism |
|---|---|---|---|
| t(14;18)(q32;q21) | BCL2 | Follicular lymphoma | BCL2 overexpression → blocks apoptosis → cells that should die during GC selection survive [2][3] |
| t(8;14)(q24;q32) | c-MYC | Burkitt lymphoma | c-MYC overexpression → drives massive cell proliferation (MYC is a master transcription factor for cell cycle progression) [2][3] |
| t(11;14)(q13;q32) | Cyclin D1 | Mantle cell lymphoma | Cyclin D1 overexpression → accelerated G1→S cell cycle transition [2][3] |
| t(11;18)(q21;q21) | MALT1 | MALT lymphoma | Constitutive NF-κB activation → anti-apoptosis |
| t(2;5) | ALK | Anaplastic large cell lymphoma | ALK fusion protein → constitutive kinase signalling |
Why chromosome 14? Because the IGH locus at 14q32 has extremely powerful enhancer elements — these are needed to drive high-level immunoglobulin production in B-cells. When an oncogene lands next to these enhancers via translocation, it gets "hijacked" into overexpression.
- TP53 mutations: common in aggressive/transformed lymphomas (e.g., Richter transformation of CLL → DLBCL)
- RB1, CDKN2A deletions: cell cycle checkpoint loss
- ATM mutations: impaired DNA damage response (common in mantle cell lymphoma)
During the germinal centre reaction, activation-induced cytidine deaminase (AID) introduces mutations into immunoglobulin genes for affinity maturation. Occasionally, AID targets proto-oncogenes instead → aberrant somatic hypermutation → contributes to DLBCL and other GC-derived lymphomas.
- Mutations in chromatin-modifying enzymes (EZH2, KMT2D, CREBBP) are common in follicular lymphoma and DLBCL
- These alter the histone code → aberrant gene silencing/activation
5.2 Role of Infections
EBV is the most important viral association in lymphomagenesis [7].
Mechanism:
- EBV infects B-cells via CD21 receptor
- The virus drives B-cell proliferation via latent membrane proteins (LMP1 mimics CD40 signalling; LMP2A mimics BCR signalling) → constitutive survival and proliferation signals
- In immunocompetent individuals, EBV-infected B-cells are kept in check by cytotoxic T-cells
- In immunodeficient states (HIV, post-transplant), loss of T-cell surveillance → unchecked EBV-driven B-cell proliferation → lymphoma
EBV-encoded small RNAs (EBER) detected by in-situ hybridisation (ISH) is the gold standard for demonstrating EBV in tissue [9].
EBV-associated lymphomas:
- Endemic Burkitt lymphoma (near 100% EBV+)
- Post-transplant lymphoproliferative disorder (PTLD)
- NK/T-cell lymphoma (nasal type) — nearly 100% EBV+
- Classical HL (mixed cellularity, lymphocyte-depleted subtypes)
- EBV+ DLBCL of the elderly
- Primary CNS lymphoma in HIV
Mechanism:
- H. pylori causes chronic gastritis → stimulates development of lymphoid aggregates in the stomach (which normally lacks organised lymphoid tissue) [5]
- Chronic antigenic stimulation drives B-cell proliferation in these MALT aggregates
- Initially, the lymphoma is antigen-dependent (will regress with H. pylori eradication)
- Over time, accumulation of genetic hits (e.g., t(11;18)) renders the lymphoma antigen-independent → no longer responds to H. pylori eradication
t(11;18) (MALT1 translocation) predicts poor response to H. pylori eradication therapy [5]
- HTLV-1 integrates into host genome → Tax protein activates NF-κB → T-cell proliferation
- Long latency (20–30 years); only ~5% of carriers develop ATLL
- Prevalent in Japan, Taiwan, and Caribbean [2]
Immunodeficiency states are a major risk factor for lymphoma — this applies to both congenital and acquired immunodeficiency [2][3].
Why does immunodeficiency → lymphoma?
- Loss of immune surveillance: Cytotoxic T-cells normally eliminate aberrant/EBV-infected B-cells. When T-cell function is impaired, these cells proliferate unchecked
- Chronic immune stimulation: In autoimmune disease, persistent antigenic stimulation drives lymphoid proliferation → ↑ chance of acquiring transforming mutations
- Direct effects of immunosuppressive drugs: Some agents (e.g., azathioprine, cyclosporine) may have direct oncogenic potential
Key immunodeficiency-related lymphomas:
- Post-transplant lymphoproliferative disorder (PTLD): driven by EBV in the setting of iatrogenic immunosuppression; risk correlates with cumulative immunosuppression dose [3][10]
- HIV-associated lymphoma: DLBCL, Burkitt, primary CNS lymphoma, primary effusion lymphoma
- Congenital immunodeficiencies: Wiskott-Aldrich syndrome, ataxia-telangiectasia, CVID, severe combined immunodeficiency → all ↑ lymphoma risk [11]
- Sjögren's syndrome: progressive B-cell activation from polyclonal → oligoclonal → monoclonal → lymphoma (usually low-grade B-cell NHL). Persistent major salivary gland swelling > 12 weeks should prompt concern for NHL [12]
- Hashimoto's thyroiditis → 60× risk of thyroid lymphoma (usually DLBCL) [6]
- Coeliac disease → enteropathy-associated T-cell lymphoma (EATL)
- Rheumatoid arthritis → ↑ lymphoma risk (partially from disease activity, partially from immunosuppressive therapy)
6. Classification
The WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (5th edition, 2022 / ICC 2022) is the standard. For exam purposes, the key frameworks are:
- HL vs NHL (the fundamental split)
- Cell lineage (B-cell vs T-cell vs NK-cell)
- Grade/behaviour (indolent/low-grade vs aggressive/high-grade)
- Stage of differentiation (precursor vs mature/peripheral)
Classical HL (95%) [3]:
| Subtype | Frequency | Key Features |
|---|---|---|
| Nodular sclerosis (NSCHL) | ~70% | Most common; young adults; mediastinal mass; collagen bands; lacunar RS cells |
| Mixed cellularity (MCCHL) | ~20% | Older adults; EBV+; mixed inflammatory background; classic RS cells |
| Lymphocyte-rich (LRCHL) | ~5% | Excellent prognosis |
| Lymphocyte-depleted (LDCHL) | < 5% | Rare; HIV patients; worst prognosis among cHL; abundant RS cells, few lymphocytes |
Nodular lymphocyte-predominant HL (NLPHL) (~5%) [3]:
- Distinct entity, NOT classical HL
- Characterised by "popcorn" cells (lymphocyte-predominant cells / LP cells) rather than classic RS cells
- Slow-growing indolent subtype; usually chronic asymptomatic lymphadenopathy; uncommonly organ involvement or B symptoms [3]
- CD20+ (unlike cHL which is CD15+/CD30+) → can be treated with rituximab
- Risk of transformation to DLBCL (T-cell/histiocyte-rich type)
6.3 Non-Hodgkin Lymphoma Classification
| Lineage | Frequency | Notes |
|---|---|---|
| B-cell lymphoma | ~85% | Most common type of lymphoma [2] |
| T-cell lymphoma | ~10-15% | Quite uncommon, associated with HTLV-1 (prevalent in Japan, Taiwan, Caribbean) [2] |
| NK-cell lymphoma | ~1-2% | Predominantly Asians, associated with EBV; classically affects nose → palatal ulcer/perforation; highly aggressive with unfavourable prognosis [2] |
This is a critical clinical classification:
| Feature | High-Grade NHL (60–65%) | Low-Grade NHL (35–40%) |
|---|---|---|
| Behaviour | High histological grade, rapid proliferation | Low histological grade, slow proliferation |
| Clinical presentation | Acute/subacute (weeks) with rapidly growing masses and prominent systemic B symptoms | Chronic (months–years) with slowly progressive painless lymphadenopathy; B symptoms less common |
| Natural history | Rapidly fatal if untreated (weeks–months) | Indolent course over years; may wax and wane |
| Curability | Potentially curable with chemoimmunotherapy | Generally incurable with conventional therapy (exceptions exist); aim is disease control |
| Examples | DLBCL, Burkitt lymphoma, mantle cell lymphoma (aggressive variant), T-lymphoblastic lymphoma | Follicular lymphoma, marginal zone/MALT lymphoma, small lymphocytic lymphoma (CLL/SLL), lymphoplasmacytic lymphoma (Waldenström's) |
Paradox of Lymphoma Grade
The "lymphoma paradox": High-grade lymphomas are more aggressive but more curable (because rapidly dividing cells are more susceptible to chemotherapy). Low-grade lymphomas are less aggressive but generally incurable (slowly dividing cells escape chemo-kill, and the disease inevitably relapses). This is a favourite exam concept.
B-cell NHL:
| Subtype | Key Features |
|---|---|
| Diffuse large B-cell lymphoma (DLBCL) | Most common NHL worldwide (~30-40%); high-grade; rapidly growing mass; CD20+; treated with R-CHOP; ~60% curable |
| Follicular lymphoma | 2nd most common NHL; low-grade; t(14;18)/BCL2; gradual painless lymphadenopathy; may transform to DLBCL (~3%/year) |
| Burkitt lymphoma | Very high-grade; t(8;14)/c-MYC; "starry sky" pattern on histology; endemic (EBV+, jaw mass in African children), sporadic (abdominal mass), or immunodeficiency-associated; one of fastest growing human tumours (doubling time ~24h); high risk of tumour lysis syndrome |
| Mantle cell lymphoma | t(11;14)/cyclin D1; typically elderly males; aggressive despite "low-grade" appearance; GI involvement (lymphomatous polyposis) |
| Marginal zone lymphoma / MALT lymphoma | Low-grade; associated with chronic antigenic stimulation (H. pylori → gastric, Hashimoto's → thyroid, Sjögren's → salivary); may regress with treatment of the underlying cause |
| Small lymphocytic lymphoma (SLL) / CLL | Low-grade; SLL and CLL are the same disease (SLL = predominantly nodal, CLL = predominantly blood/marrow) |
T/NK-cell NHL:
| Subtype | Key Features |
|---|---|
| Peripheral T-cell lymphoma, NOS | Most common T-cell lymphoma; aggressive; poor prognosis |
| Anaplastic large cell lymphoma (ALCL) | ALK+ (better prognosis, younger patients) vs ALK−; CD30+ |
| Extranodal NK/T-cell lymphoma, nasal type | Predominantly Asian; EBV+; nasal/palatal destruction; CD56+, EBER+ [9]; aggressive |
| Adult T-cell leukaemia-lymphoma (ATLL) | HTLV-1; endemic in Japan/Caribbean; skin involvement, hypercalcaemia, "flower cells" |
| Enteropathy-associated T-cell lymphoma (EATL) | Associated with coeliac disease |
7. Clinical Features
7.1 General Presentation: Symptoms
- Painless, progressive enlargement of lymph nodes — this is the cardinal symptom
- Pathophysiology: clonal proliferation of lymphoid cells within the lymph node architecture → nodal expansion
- HL: typically contiguous spread (one nodal group to the next adjacent group) → often presents as isolated cervical/supraclavicular or mediastinal lymphadenopathy
- NHL: often non-contiguous spread → may present with widespread/generalised lymphadenopathy
- Consistency: typically firm, rubbery, non-tender (cf. tender nodes in infection, hard/fixed nodes in metastatic carcinoma)
- Matted nodes: may suggest lymphoma (or TB)
High Yield – Painful Lymph Nodes in HL
A classic (but rare) feature: lymph node pain after alcohol consumption in Hodgkin lymphoma. Mechanism is unclear but may relate to eosinophil degranulation or vascular changes induced by alcohol in affected nodes. It is a classic exam question!
B symptoms are specifically defined for staging purposes and have prognostic significance:
| Symptom | Definition | Pathophysiology |
|---|---|---|
| Fever | Unexplained fever > 38°C | Cytokines (IL-1, IL-6, TNF-α) produced by tumour cells and reactive immune cells → hypothalamic thermoregulatory set point elevation |
| Night sweats | Drenching night sweats (requiring change of bedclothes) | Same cytokine-mediated mechanism; why predominantly at night is not fully understood but may relate to circadian cortisol nadir |
| Weight loss | > 10% of body weight in the preceding 6 months, unexplained | Tumour-derived cytokines (TNF-α = "cachectin") → increased catabolism, anorexia, altered metabolism |
- B symptoms are more prominent in high-grade NHL [2] and advanced HL
- In low-grade NHL, B symptoms are less common at presentation [2]
- The absence of B symptoms is denoted "A" in staging (e.g., Stage IIA vs Stage IIB)
- Pel-Ebstein fever: a rare pattern of cyclical fever (1–2 weeks on, 1–2 weeks off) classically associated with HL
The specific symptoms depend on the site(s) involved:
| Site | Symptom | Pathophysiology |
|---|---|---|
| Mediastinum | Cough, dyspnoea, stridor, chest pain, SVCO (facial/arm swelling, headache, distended neck veins) | Mediastinal mass compressing airways, SVC; very common in nodular sclerosis HL and T-lymphoblastic lymphoma |
| Abdomen | Abdominal pain, bloating, early satiety, bowel obstruction | Mesenteric/retroperitoneal nodal masses, hepatosplenomegaly, or GI tract involvement |
| Bone | Bone pain | Lymphomatous infiltration of bone marrow/cortex |
| CNS | Headache, confusion, focal neurological deficits, meningism | Primary CNS lymphoma (DLBCL, a/w immunodeficiency) or leptomeningeal disease |
| Skin | Skin nodules, plaques, erythroderma | Cutaneous T-cell lymphoma (mycosis fungoides/Sézary syndrome) or secondary skin involvement |
| GI tract | Dyspepsia, GI bleeding, perforation, obstruction | GI lymphoma (MALT, DLBCL, Burkitt, EATL, mantle cell lymphomatous polyposis) |
| Nasopharynx / nasal cavity | Nasal obstruction, epistaxis, palatal ulceration/perforation, facial swelling | NK/T-cell lymphoma (nasal type) — classically destroys midline facial structures [2] |
| Testis | Painless testicular swelling | Testicular lymphoma (usually DLBCL; most common testicular tumour in men > 60y) |
| Thyroid | Rapidly enlarging goitre, compressive symptoms (dysphagia, stridor) | Thyroid lymphoma (usually DLBCL); associated with Hashimoto's thyroiditis [6] |
- Fatigue, pallor → anaemia (marrow infiltration ± autoimmune haemolytic anaemia)
- Recurrent infections → neutropaenia (marrow infiltration or treatment-related)
- Bruising, petechiae, mucosal bleeding → thrombocytopaenia (marrow infiltration, splenic sequestration, or immune-mediated)
- Generalised pruritus without primary skin lesion is a recognised symptom, especially in HL
- Pathophysiology: cytokines (especially IL-5, IL-13) and histamine released by eosinophils in the tumour microenvironment → stimulation of cutaneous itch receptors
- Not classified as a B symptom but has prognostic significance
- Non-specific but very common
- Pathophysiology: multifactorial — cytokine-mediated (same pro-inflammatory cytokines), anaemia, metabolic derangement
7.2 General Presentation: Signs
All lymphoid organs must be systematically examined — cervical, supraclavicular, axillary, epitrochlear, inguinal, popliteal lymph nodes + tonsils + testes [4]:
- Character: firm, rubbery, non-tender, may be matted
- Distribution:
- HL: often localised (cervical > mediastinal > axillary); tends to spread contiguously
- NHL: often widespread/generalised; may involve peripheral and central/deep nodal groups
Red flag features for malignant lymphadenopathy: > 2 cm, non-tender, firm/rubbery, fixed/matted, supraclavicular location, progressive enlargement over weeks, associated B symptoms
- Hepatosplenomegaly in up to 50% (especially ALL/lymphoblastic lymphoma) [4]
- Splenomegaly:
- Pathophysiology: lymphomatous infiltration of splenic white pulp ± splenic congestion
- Can cause massive splenomegaly in some NHL subtypes (e.g., splenic marginal zone lymphoma, hairy cell leukaemia)
- Splenic involvement is classified as Stage III in both HL and NHL staging
- Hepatomegaly:
- Pathophysiology: portal/parenchymal infiltration by lymphoma cells
- Tonsillar and pharyngeal lymphoid tissue enlargement
- More common in NHL than HL
- May present as sore throat, dysphagia, or asymmetric tonsillar enlargement
- Facial plethora, periorbital oedema, distended neck veins (non-pulsatile), collateral veins on chest wall, upper limb oedema
- Pathophysiology: mediastinal mass compressing the SVC → impaired venous drainage from head, neck, and upper limbs
- Commonest in: nodular sclerosis HL, T-lymphoblastic lymphoma, primary mediastinal large B-cell lymphoma
- Specific skin infiltration: nodules, plaques, tumours (cutaneous lymphoma or secondary skin involvement)
- Non-specific: pruritus-related excoriations, erythroderma (Sézary syndrome), herpes zoster scars (immunocompromised state)
- Autoimmune haemolytic anaemia (AIHA): jaundice, pallor
- Immune thrombocytopaenia (ITP): petechiae, purpura
- These are more common in low-grade B-cell NHL (CLL/SLL, follicular lymphoma)
| Feature | Hodgkin Lymphoma | Non-Hodgkin Lymphoma |
|---|---|---|
| Age | Bimodal (young adult + elderly) | Median 65–70y |
| Lymphadenopathy | Usually localised, cervical/mediastinal | Often widespread, may be extranodal |
| Spread | Contiguous (predictable, node to adjacent node) | Non-contiguous (unpredictable, skips nodal groups) |
| B symptoms | Common (~40% at presentation) | Variable (more common in high-grade) |
| Extranodal disease | Uncommon at presentation | Common (~40% extranodal at presentation) |
| Bone marrow involvement | Uncommon (~5%) | Common (~20–40%, depending on subtype) |
| Mediastinal involvement | Very common (~60–70% in NS subtype) | Less common (except primary mediastinal DLBCL, T-LBL) |
| Pruritus | Characteristic | Less common |
| Alcohol-induced pain | Classic (rare but specific) | Not typical |
| Curability | High (~80–90% overall cure rate) | Variable (high-grade: ~50–60% curable; low-grade: generally incurable) |
| Feature | Low-Grade NHL | High-Grade NHL |
|---|---|---|
| Onset | Chronic (months to years) | Acute/subacute (weeks) [2] |
| Lymphadenopathy | Slowly progressive, painless, may wax and wane | Rapidly growing masses [2] |
| B symptoms | Less common | Prominent [2] |
| Marrow involvement | Common at diagnosis | Less common at diagnosis |
| Transformation | Can transform to high-grade (e.g., follicular → DLBCL) | N/A |
| Response to chemo | Low proliferation → less chemosensitive | High proliferation → more chemosensitive |
| Curability | Generally incurable | Potentially curable |
8. Immunophenotyping and Molecular Markers (Key for Diagnosis)
Understanding the immunophenotype is essential for classification and is heavily tested:
Flow cytometry is used to identify cell surface markers on lymphoma cells for classification [13]:
| Marker | Significance |
|---|---|
| CD20 | Pan-B-cell marker; positive in most B-cell NHL and NLPHL; negative in classical HL (important distinction!); target for rituximab |
| CD19 | Pan-B-cell marker |
| CD3 | Pan-T-cell marker; positive in T-cell lymphomas [9] |
| CD5 | Normally on T-cells; aberrantly expressed in CLL/SLL and mantle cell lymphoma |
| CD10 | Germinal centre marker; positive in follicular lymphoma, Burkitt |
| CD23 | Positive in CLL/SLL; negative in mantle cell lymphoma (helps distinguish) |
| CD56 | NK-cell marker; positive in NK/T-cell lymphoma [9] |
| CD15, CD30 | Positive in classical HL (Reed-Sternberg cells); CD30 also positive in ALCL |
| Cyclin D1 | Positive in mantle cell lymphoma (product of t(11;14)) |
| BCL2 | Overexpressed in follicular lymphoma (product of t(14;18)) |
| Ki-67 | Proliferation marker; high Ki-67 (>90%) in Burkitt lymphoma |
| Test | Application |
|---|---|
| Clonal IGH gene rearrangement (PCR) | Confirms B-cell clonality → diagnostic of B-cell lymphoma [1][9] |
| Clonal TCR gene rearrangement (PCR) | Confirms T-cell clonality → diagnostic of T-cell lymphoma [1][9] |
| FISH for specific translocations | t(14;18), t(8;14), t(11;14), t(11;18), ALK rearrangement |
| EBER ISH (EBV-encoded small RNA in-situ hybridisation) | Gold standard for detecting EBV in tissue [7][9] |
| MYC/BCL2/BCL6 FISH | "Double-hit" or "triple-hit" lymphoma (high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements) — very aggressive, poor prognosis |
High Yield – Immunophenotypic Distinction of Key Lymphomas
| Lymphoma | CD20 | CD3 | CD5 | CD10 | CD15 | CD23 | CD30 | CD56 | Cyclin D1 | Other |
|---|---|---|---|---|---|---|---|---|---|---|
| CLL/SLL | + (dim) | − | + | − | − | + | − | − | − | |
| Mantle cell | + | − | + | − | − | − | − | − | + | |
| Follicular | + | − | − | + | − | − | − | − | − | BCL2+ |
| DLBCL | + | − | ± | ± | − | − | ± | − | − | |
| Burkitt | + | − | − | + | − | − | − | − | − | Ki-67 ~100% |
| Classical HL | − | − | − | − | + | − | + | − | − | RS cells |
| NK/T-cell | − | ± | − | − | − | − | − | + | − | EBER+ |
| ALCL | − | − | − | − | − | − | + | − | − | ALK ± |
9. Pathology – The Reed-Sternberg Cell and Other Histological Features
- The hallmark of classical Hodgkin lymphoma [3][9]
- Large cell with bilobed or multilobed nucleus, each lobe containing a large nucleolus ("owl-eye" appearance) [9]
- RS cells are actually B-cell derived (have clonal IGH rearrangement) but have lost most B-cell markers → CD20−, CD15+, CD30+
- RS cells are typically a minority of the tumour mass (~1–2%); the rest is a reactive inflammatory infiltrate (lymphocytes, eosinophils, histiocytes, plasma cells, fibroblasts)
- This explains the clinical features: B symptoms and pruritus are driven by the reactive inflammatory milieu, not the RS cells themselves
- Variants: lacunar cells (NSCHL), mononuclear Hodgkin cells, "popcorn" / LP cells (NLPHL — these are NOT classic RS cells)
- "Starry sky" pattern: sheets of monotonous medium-sized lymphoid cells with scattered tingible-body macrophages (the "stars" = macrophages phagocytosing apoptotic tumour cells against a "sky" of dark tumour cells)
- Reflects the extremely high proliferative rate (Ki-67 ~100%) with equally high apoptotic rate
- Nodular (follicular) pattern of neoplastic follicles lacking the normal mantle zone and polarisation
- Centrocytes and centroblasts (but unlike reactive GCs, these are BCL2+)
- Grading: based on number of centroblasts per high-power field (Grade 1–3)
10. Important Special Subtypes and Clinical Scenarios
- Usually DLBCL
- Risk factors: EBV, immunosuppression [14]
- Location: periventricular white matter, may be multifocal
- Diagnosis: brain biopsy (must NOT give steroids before biopsy as they can cause transient tumour regression → non-diagnostic biopsy)
- Treatment: high-dose methotrexate-based regimen (crosses blood-brain barrier); whole-brain RT
- Spectrum from reactive polyclonal proliferation to aggressive monomorphic B-cell lymphoma [10]
- Driven by EBV reactivation in the setting of T-cell immunosuppression
- Management: reduction of immunosuppression first → rituximab ± chemotherapy
- 5% of all thyroid cancers; usually > 50y; M:F = 1:2 [6]
- Risk factors: history of lymphoma elsewhere, Hashimoto's thyroiditis (60× risk) [6]
- Pathology: usually DLBCL (non-Hodgkin) [6]
- Presentation: rapidly enlarging hard goitre with compressive symptoms (over 2–3 months) [6]
- Treatment: R-CHOP + external beam radiotherapy (EBRT) [6]
- Prognosis: better than anaplastic thyroid carcinoma; median survival 9 years [6]
High-risk malignancies for TLS: Burkitt lymphoma, acute leukaemia (ALL, AML, CML in blast crisis), SCLC [15].
- Pathophysiology: massive tumour cell breakdown → release of intracellular contents (K⁺, phosphate, uric acid, nucleic acids) → hyperkalaemia, hyperphosphataemia, hyperuricaemia, hypocalcaemia (calcium-phosphate precipitation), AKI
- Prophylaxis: adequate hydration (3–4L/day), urate-lowering drugs before chemotherapy (allopurinol — check HLA-B*5801; febuxostat; ± rasburicase if high risk) [15]
High Yield Summary
Definition: Lymphoma = clonal neoplasm of B-cells, T-cells, or NK-cells at various stages of differentiation; all tumour cells share the same VDJ rearrangement (monoclonal)
Epidemiology: NHL >> HL (~90:10); NHL median age 65–70y; HL bimodal; NK/T-cell lymphoma predominantly Asian
Key Risk Factors:
- HL: EBV, HIV, immunosuppression, FHx
- NHL: t(14;18)/t(8;14)/t(11;14), HIV (100×), EBV, HTLV-1, HHV-8, H. pylori, immunodeficiency, autoimmune disease
Classification:
- HL: Classical (NS > MC > LR > LD) vs NLPHL
- NHL: B-cell (85%) > T-cell > NK-cell; High-grade (aggressive, curable) vs Low-grade (indolent, incurable)
- "Lymphoma paradox": high-grade = more aggressive but more curable; low-grade = less aggressive but incurable
Clinical Features:
- Hallmark: painless, progressive lymphadenopathy (firm, rubbery)
- B symptoms: fever > 38°C, drenching night sweats, > 10% weight loss in 6 months
- HL: contiguous spread, mediastinal mass, pruritus, alcohol-induced pain
- NHL: non-contiguous, extranodal disease common, organomegaly
- High-grade: acute onset, rapidly growing, prominent B symptoms
- Low-grade: chronic, slowly progressive, may wax and wane
- Special subtypes: NK/T-cell → nasal/palatal destruction; MALT → H. pylori; thyroid lymphoma → Hashimoto's
Key Pathology:
- HL: Reed-Sternberg cells (CD15+/CD30+/CD20−)
- Follicular: t(14;18)/BCL2, nodular pattern
- Burkitt: t(8;14)/c-MYC, starry sky, Ki-67 ~100%
- Mantle cell: t(11;14)/cyclin D1
Key Immunophenotype: CD20 for B-cell, CD3 for T-cell, CD56 for NK-cell; clonal IGH/TCR rearrangement confirms clonality
Active Recall - Lymphoma (Definition to Clinical Features)
[1] Lecture slides: Molecular Pathology Seminar 4_MALIGNANT LYMPHOMA.pdf (definition slides, clonality, VDJ rearrangement) [2] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 426–427, lymphoma classification and NHL) [3] Senior notes: Ryan Ho Haemtology.pdf (p. 93–96, HL and NHL epidemiology, risk factors, classification, treatment) [4] Senior notes: Ryan Ho Haemtology.pdf (p. 60, ALL clinical features, lymphoid organ examination) [5] Senior notes: Ryan Ho GI.pdf (p. 82, 90, gastric MALT lymphoma) [6] Senior notes: Ryan Ho Endocrine.pdf (p. 38, thyroid lymphoma) [7] Lecture slides: Molecular Pathology Seminar 4_EPSTEIN-BARR VIRUS.pdf [8] Paediatrics lecture slides: Block C - A child with cancer_ paediatric cancers.pdf (p. 8–9, etiology of cancer) [9] AOS material: AOS - Pathology.pdf (p. 38–40, lymphoma phenotyping and molecular diagnosis) [10] Senior notes: Block A - Renal Replacement Therapies.pdf (p. 39, PTLD) [11] Senior notes: Jerry's immunodeficiencies.pdf (p. 1, CVID and lymphoid malignancies) [12] Senior notes: Ryan Ho Rheumatology.pdf (p. 88, Sjögren's syndrome and lymphoma risk) [13] Lecture slides: Laboratory Diagnostic Investigations Seminar_Flow cytometry in haematology.pdf [14] Senior notes: Maksim Surgery Notes.pdf (p. 361, brain tumours including primary CNS lymphoma) [15] Senior notes: Maksim Medicine Notes.pdf (p. 48, tumour lysis syndrome)
Differential Diagnosis of Lymphoma
The differential diagnosis of lymphoma is really the differential diagnosis of two clinical presentations: (1) lymphadenopathy (localised or generalised), and (2) the systemic picture (B symptoms, cytopaenias, organomegaly). The key task is distinguishing lymphoma from its mimics, and then — once lymphoma is suspected — distinguishing between the major subtypes.
Let's work through this systematically.
When a patient presents with lymphadenopathy ± B symptoms ± organomegaly, the differential spans four broad categories. This framework comes directly from the GC lecture material:
Differential diagnoses for generalised lymphadenopathy [16]:
- Neoplastic — leukaemias, lymphomas/lymphoproliferative disorders
- Infective (with predilection to involvement of the reticuloendothelial system) — viral (EBV, CMV), bacterial, mycobacterial, parasitic, dimorphic fungi
- Autoimmune
- Drugs
This is a high-yield GC lecture slide framework for approaching any patient with lymphadenopathy and should be your starting scaffold [16].
2. Differential Diagnosis by Clinical Presentation
The mnemonic "MIAMI" can help you organise differentials for lymphadenopathy:
- Malignancy
- Infection
- Autoimmune
- Miscellaneous / Medications
- Iatrogenic (post-vaccination, serum sickness)
| Category | Differential Diagnoses | Key Distinguishing Features from Lymphoma |
|---|---|---|
| Malignant — Haematological | Leukaemias (ALL, CLL, AML), lymphomas, other lymphoproliferative disorders (PTLD, Castleman disease) [16] | ALL: circulating blasts, younger patients. CLL: incidental lymphocytosis in older patient, smudge cells on PBS [17]. AML: rarely causes prominent lymphadenopathy (more marrow failure). |
| Malignant — Solid tumours | Metastatic carcinoma (head and neck SCC, lung, breast, gastric, melanoma) | Lymph nodes typically hard, fixed, non-tender (cf. firm and rubbery in lymphoma). Often localised to draining nodal basin. |
| Infective — Viral | EBV (infectious mononucleosis), CMV, HIV (acute seroconversion or persistent generalised lymphadenopathy), adenovirus, measles, rubella, HSV, HHV-6 | Atypical lymphocytosis on PBS — NOT neoplastic, not to be mistaken as blasts or lymphoma cells [18]. Tender nodes, fever, pharyngitis, splenomegaly. Self-limiting. |
| Infective — Bacterial | Staphylococcal/streptococcal lymphadenitis, cat-scratch disease (Bartonella henselae), brucellosis, syphilis (2° stage) | Usually tender, warm, overlying erythema (suppurative). Localised. |
| Infective — Mycobacterial | TB lymphadenitis (scrofula), atypical mycobacteria | Matted, non-tender nodes, may form cold abscess/sinus tract. Caseating granulomata on biopsy. Critical DDx in Hong Kong where TB is still prevalent. |
| Infective — Parasitic / Fungal | Toxoplasmosis, leishmaniasis, histoplasmosis, coccidioidomycosis | Travel history important. Dimorphic fungi in immunocompromised. |
| Autoimmune / Inflammatory | SLE, rheumatoid arthritis (Felty syndrome), Sjögren's syndrome, sarcoidosis, Kikuchi disease, Rosai-Dorfman disease, IgG4-related disease | SLE: multisystem involvement, ANA+. Sarcoidosis: bilateral hilar LAD, non-caseating granulomata. Kikuchi disease: young Asian females, fever, cervical LAD, necrotising lymphadenitis — important DDx in HK. Self-limiting. |
| Drug-related | Phenytoin, carbamazepine, allopurinol, sulfonamides (drug-induced pseudolymphoma / DRESS) | Temporal relationship with drug initiation. Eosinophilia, rash, organ involvement in DRESS. |
| Reactive / Non-specific | Non-specific reactive hyperplasia, dermatopathic lymphadenopathy | Bilateral inguinal nodes < 1 cm in adults are often normal. Dermatopathic LAD in chronic skin diseases (e.g., cutaneous lymphoma vs eczema/psoriasis — must biopsy if uncertain [19]). |
High Yield – EBV Infectious Mononucleosis vs Lymphoma
This is a classic exam trap. Both EBV infectious mononucleosis and lymphoma can present with fever, lymphadenopathy, splenomegaly, and atypical lymphocytes on PBS. Key distinguishing points:
- IM: Atypical lymphocytes are reactive, NOT neoplastic — polyclonal [18]. Self-limiting within 2–4 weeks.
- Lymphoma: Monoclonal population on flow cytometry/PCR. Progressive, does not self-resolve.
- Always perform flow cytometry if lymphoma is clinically suspected — morphology alone is insufficient!
2.2 Differential Diagnosis of Specific Lymphoma Presentations
A mediastinal mass in a young adult raises a specific differential — the classic "4 Ts" of anterior mediastinal masses:
- Thymoma
- Teratoma (and other germ cell tumours)
- Terrible lymphoma (HL — nodular sclerosis, or primary mediastinal large B-cell lymphoma, or T-lymphoblastic lymphoma/ALL)
- Thyroid (retrosternal goitre)
Mediastinal mass is characteristic of T-ALL (50–75%) [4] and nodular sclerosis HL.
Consider:
- Splenic marginal zone lymphoma (low-grade B-cell NHL)
- Hairy cell leukaemia (pancytopaenia + splenomegaly + "hairy" cells on PBS)
- CLL/SLL [17]
- Hepatosplenic T-cell lymphoma (young males, aggressive)
- Myeloproliferative neoplasms (CML, myelofibrosis — massive splenomegaly)
- Non-haematological: portal hypertension, infections (malaria, kala-azar, EBV), storage diseases
Pressure symptoms of splenomegaly: abdominal fullness, early satiety, symptoms related to pancytopaenia due to greater blood pooling in spleen [20].
The differential here is lymphoma vs:
- Multiple myeloma — paraprotein on SPEP, lytic bone lesions, renal impairment, hypercalcaemia (CRAB criteria) [21]
- Metastatic carcinoma to bone
- Myelofibrosis (leukoerythroblastic blood film)
| Site | Lymphoma Subtype | Key Differentials |
|---|---|---|
| Stomach | Gastric MALT lymphoma, gastric DLBCL | Gastric adenocarcinoma, gastric GIST, peptic ulcer |
| Nasopharynx / nasal cavity | NK/T-cell lymphoma (nasal type) — palatal ulcer/perforation, CD56+, EBER+ [9] | Nasopharyngeal carcinoma (EBV+, but epithelial), Wegener's granulomatosis (GPA), midline destructive disease |
| Skin | Mycosis fungoides, Sézary syndrome, primary cutaneous DLBCL | Eczema, psoriasis, cutaneous lymphoma, pityriasis rubra pilaris [19]. Mycosis fungoides can mimic chronic dermatitis for years. |
| Brain | Primary CNS lymphoma (DLBCL) | GBM, brain metastasis, toxoplasmosis (in HIV — ring-enhancing lesions in both), progressive multifocal leukoencephalopathy |
| Testis | Testicular DLBCL (most common testicular tumour in men > 60y) | Seminoma, non-seminomatous germ cell tumours (younger patients, AFP/β-hCG elevated) |
| Thyroid | Thyroid lymphoma (usually DLBCL; 60× risk with Hashimoto's) [6] | Anaplastic thyroid carcinoma (both rapidly enlarging, both elderly, but anaplastic = median survival < 6 months vs lymphoma median survival 9 years). Biopsy is essential. |
| Tonsils / tongue base | Lymphoma — tonsils and tongue base may be the presenting site for a lymphoma [22] | Tonsillar SCC (HPV-related), minor salivary gland tumour |
| Small intestine | Burkitt lymphoma, EATL, DLBCL, mantle cell (lymphomatous polyposis) | Small bowel adenocarcinoma, carcinoid, Crohn's disease |
High Yield – Thyroid Lymphoma vs Anaplastic Thyroid Carcinoma
Both present as a rapidly enlarging thyroid mass in an elderly patient with compressive symptoms. Biopsy is absolutely essential:
3. Distinguishing Between Lymphoma Subtypes
Once you've established that the patient has lymphoma, the next critical step is subtype classification. This drives management entirely.
All 3 features are needed for appropriate classification of lymphoma: (1) histological appearance, (2) immunophenotyping (flow cytometry / immunohistochemistry), (3) cytogenetics / molecular genetics [23].
| Feature | Hodgkin Lymphoma | Non-Hodgkin Lymphoma |
|---|---|---|
| Hallmark cell | Reed-Sternberg cell (bilobed nucleus, "owl-eye" nucleoli) | Varies by subtype |
| Immunophenotype | CD15+, CD30+, CD20− (classical HL) | CD20+ (B-cell NHL), CD3+ (T-cell NHL), CD56+ (NK-cell NHL) [9] |
| Spread | Contiguous (orderly anatomical fashion) [23] | Non-contiguous (can skip nodal regions) |
| Extranodal disease | Uncommon | Common (~40%) |
| Bone marrow | ~5% at diagnosis | ~20–40% |
| Curability | ~80–90% | Varies (high-grade ~50–60% curable; low-grade generally incurable) |
The distinction between high-grade and low-grade NHL is clinically critical: [2]
| Feature | High-Grade NHL | Low-Grade NHL |
|---|---|---|
| Presentation | Acute/subacute (weeks), rapidly growing masses, prominent B symptoms | Insidious (months), slow-growing LN or organomegaly, may present with cytopaenia [2] |
| Prognosis if untreated | Death in weeks/months | Death in years [2] |
| Curability | Potentially curable | Generally incurable |
| Examples (B-cell) | DLBCL (most common), mantle cell lymphoma, Burkitt lymphoma, precursor B-LBL | Follicular lymphoma (most common), SLL/CLL, marginal zone/MALT, lymphoplasmacytic lymphoma [2] |
| Scenario | Lymphoma A vs B | Key Distinguishing Feature |
|---|---|---|
| ALL vs Burkitt lymphoma | Both very aggressive, can have similar morphology | Immunophenotyping + cytogenetics/molecular: Burkitt = mature B-cell (surface Ig+, TdT−, t(8;14)/c-MYC); ALL = precursor lymphoblasts (TdT+, surface Ig−) [4][18] |
| CLL/SLL vs mantle cell lymphoma | Both CD5+ B-cell | CLL: CD23+, cyclin D1−. Mantle cell: CD23−, cyclin D1+, t(11;14) |
| Follicular lymphoma vs reactive follicular hyperplasia | Both show follicular pattern | Follicular lymphoma: BCL2+ (follicles), monoclonal IgH rearrangement, t(14;18). Reactive: BCL2− in GC, polyclonal |
| DLBCL vs classical HL | Both large cells | DLBCL: CD20+, CD15−, CD30 variable. cHL: CD20−, CD15+, CD30+, RS cells in reactive background |
| Reactive lymphocytosis vs CLL/lymphoma | Both can show lymphocytosis | Reactive: atypical lymphocytes, polyclonal. CLL: smudge cells, monoclonal B-cells (CD5+/CD19+/CD23+) [17][18] |
CLL may transform to aggressive large cell lymphoma (Richter transformation), most commonly DLBCL [17]. This should be suspected when a CLL patient develops:
- Rapidly enlarging lymph node(s)
- New or worsening B symptoms
- Rising LDH
- Biopsy is required to confirm transformation — this changes management entirely (from indolent CLL approach to aggressive chemoimmunotherapy)
Hong Kong-Specific DDx Points
- TB lymphadenitis is a critical DDx for lymphoma in HK — cervical lymphadenopathy with matted, non-tender nodes. Always send tissue for AFB culture and granuloma assessment.
- Kikuchi disease (histiocytic necrotising lymphadenitis) — young Asian females, self-limiting cervical lymphadenopathy + fever. Can mimic lymphoma or SLE histologically. Biopsy shows necrotising lymphadenitis without neutrophils.
- NK/T-cell lymphoma (nasal type) — predominantly Asian, EBV+, CD56+. Must differentiate from NPC (epithelial, also EBV+) and GPA (vasculitis, ANCA+) [9].
- NPC metastatic to cervical nodes — very common in southern Chinese. Posterior triangle lymphadenopathy in a middle-aged Chinese patient should raise suspicion for NPC before lymphoma.
- Reactive lymphocytosis from EBV/IM — very common in young adults; do NOT mistake atypical lymphocytes for lymphoma cells [18].
| Condition | Node Character | Systemic Features | PBS Findings | Definitive Test |
|---|---|---|---|---|
| Hodgkin lymphoma | Firm, rubbery, localised (cervical/mediastinal) | B symptoms, pruritus | Often normal; eosinophilia | Biopsy: RS cells, CD15+/CD30+ |
| High-grade NHL | Rapidly growing, widespread | Prominent B symptoms | May show circulating lymphoma cells | Biopsy + immunophenotyping + molecular |
| Low-grade NHL | Slowly progressive, waxing/waning | Mild or absent B symptoms | Lymphocytosis (CLL), smudge cells | Biopsy + flow cytometry |
| Reactive / EBV | Tender, soft, bilateral cervical | Fever, pharyngitis, rash | Atypical lymphocytes (polyclonal) [18] | Monospot / EBV serology |
| TB | Matted, non-tender, cervical | Low-grade fever, weight loss, night sweats | Normal or monocytosis | AFB culture, biopsy with caseating granulomata |
| Metastatic carcinoma | Hard, fixed, non-tender | Depends on primary | Usually normal | Biopsy: epithelial markers (CK+) |
| Kikuchi disease | Tender cervical LN, young Asian female | Fever, skin rash | Leucopaenia, atypical lymphocytes | Biopsy: necrotising lymphadenitis without neutrophils |
| Multiple myeloma | Usually no significant LAD | Bone pain, anaemia, renal failure | Rouleaux formation | SPEP (paraprotein), BM biopsy > 10% plasma cells |
High Yield Summary – Differential Diagnosis of Lymphoma
- Framework for LAD DDx: Neoplastic (leukaemia/lymphoma) > Infective (EBV, CMV, TB, parasites) > Autoimmune (SLE, sarcoidosis, Kikuchi) > Drugs
- Lymphoma vs reactive: Monoclonal (lymphoma) vs polyclonal (reactive) — confirmed by flow cytometry or PCR for clonal IGH/TCR rearrangement
- HL vs NHL: RS cells + CD15/CD30 = HL; CD20+ = B-NHL; CD3+ = T-NHL; CD56+/EBER+ = NK/T-cell NHL
- High-grade vs low-grade NHL: Rapid onset + B symptoms + curable = high-grade; Insidious + indolent + incurable = low-grade
- CLL → Richter transformation (to DLBCL): suspect if rapidly enlarging nodes + ↑LDH + new B symptoms in known CLL
- HK-specific DDx: TB lymphadenitis, Kikuchi disease, NPC metastasis, NK/T-cell lymphoma, EBV/IM
- Extranodal DDx: Thyroid lymphoma vs anaplastic CA (both rapid goitre, vastly different prognosis); gastric MALT vs gastric adenocarcinoma; primary CNS lymphoma vs GBM/toxoplasmosis; NK/T-cell lymphoma vs NPC vs GPA
- ALL vs Burkitt: TdT+ = ALL; TdT−, surface Ig+, t(8;14) = Burkitt
Active Recall - Differential Diagnosis of Lymphoma
References
[2] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 426, NHL classification, high vs low grade) [4] Senior notes: Ryan Ho Haemtology.pdf (p. 60–61, ALL clinical features, D/dx, diagnosis) [6] Senior notes: Ryan Ho Endocrine.pdf (p. 38, thyroid lymphoma vs anaplastic CA) [9] AOS material: AOS - Pathology.pdf (p. 26, 38–40, phenotyping and molecular diagnosis of lymphoma, NK-cell lymphoma and EBV) [16] Senior notes: Block A - Generalised Lymphadenopathy_ Differential diagnosis and principle of management.pdf (p. 1–2, DDx of generalised lymphadenopathy) [17] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (p. 24, CLL, Richter transformation) [18] Senior notes: Ryan Ho Haemtology.pdf (p. 47, atypical lymphocytosis vs blasts/lymphoma cells); Ryan Ho Fundamentals.pdf (p. 390, same) [19] Senior notes: Block A - Dermatology PBL 1.pdf (p. 18, erythroderma DDx including cutaneous lymphoma) [20] Senior notes: Block A - Splenomegaly_ common causes of splenomegaly; myeloproliferative diseases.pdf (p. 11, clinical features of splenomegaly) [21] Senior notes: Block A - An old man with bone pain and anaemia_ multiple myeloma; monoclonal gammopathy.pdf (p. 12, myeloma spectrum) [22] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai).pdf (p. 255, tonsil/tongue base as presenting site for lymphoma) [23] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p. 751–752, classification of lymphoma, HL vs NHL)
Diagnostic Criteria, Diagnostic Algorithm, and Investigation Modalities for Lymphoma
Before diving into specific investigations, it is essential to understand why we investigate the way we do. Lymphoma diagnosis is never made on clinical grounds alone — you must have tissue. The overarching framework can be summarised as:
Investigations for lymphomas have three aims [16]:
- Establish the diagnosis — confirm lymphoma and determine the exact subtype
- Stage the disease — determine the extent of disease spread (which guides treatment intensity)
- Assess the patient — evaluate fitness for treatment (organ function, comorbidities, viral carrier status)
All 3 features are needed for appropriate classification of lymphoma [23]:
- Histological appearance
- Immunophenotyping (flow cytometry / immunohistochemistry)
- Cytogenetics / Molecular genetics
This is the MCICM framework: Morphology, Cytochemistry, Immunophenotype, Cytogenetics, Molecular genetics [18][24].
High Yield – Why Can't You Diagnose Lymphoma on FNA Alone?
Fine needle aspiration (FNA) gives you individual cells but destroys the tissue architecture. Lymphoma classification depends on the pattern of lymph node involvement (nodular vs diffuse vs follicular), which can only be assessed on an intact tissue section. Furthermore, flow cytometry on a small FNA sample may miss heterogeneous cell populations. An excisional biopsy (or at minimum a core needle biopsy) is mandatory.
2. Diagnostic Criteria
Unlike some conditions (e.g., SLE with formal ACR/EULAR criteria, or myeloma with IMWG criteria), lymphoma does not have a single set of "diagnostic criteria" that you tick off. Instead, the diagnosis is pathological — it requires biopsy-proven evidence of a clonal lymphoid neoplasm, classified by the WHO system. However, certain principles are absolute:
| Requirement | Rationale |
|---|---|
| Tissue biopsy (excisional LN biopsy preferred) | Architecture preservation is essential for pattern recognition; FNA alone is insufficient |
| Morphological assessment on H&E-stained sections | Identifies cell size, growth pattern (nodular/diffuse/follicular), and characteristic cells (e.g., Reed-Sternberg cells in HL) |
| Immunophenotyping (flow cytometry and/or immunohistochemistry) | Determines cell lineage (B/T/NK), maturation stage, and specific markers for subtype classification [23][25] |
| Clonality assessment (IGH/TCR gene rearrangement by PCR) | Confirms monoclonality — the sine qua non of lymphoma. Every cell from the lymphoma is derived from one neoplastic cell, so only ONE single rearrangement pattern can be seen [1][25] |
| Cytogenetics (karyotyping/FISH) | Identifies specific chromosomal translocations (e.g., t(14;18), t(8;14), t(11;14)) → subtype-specific and prognostically important |
- Presence of Reed-Sternberg cells — large cells with bilobed nucleus, prominent nucleoli with surrounding clear space ("owl-eye" appearance) [23]
- RS cells in a background of non-neoplastic inflammatory cells (lymphocytes, eosinophils, plasma cells, histiocytes, fibroblasts) [23]
- Immunophenotype of RS cells: CD15+, CD30+, CD20− (negative or weakly positive), CD45− [25]
- The pattern and composition of the reactive background determine the histological subtype (NS/MC/LR/LD)
Each subtype has its own morphological and immunophenotypic profile. The universal requirement is:
- Monoclonal lymphoid population confirmed by flow cytometry (light chain restriction for B-cell) or molecular studies (clonal IGH or TCR rearrangement)
- Specific immunophenotype matching a defined WHO entity
For reference, key subtype-specific diagnostic patterns:
| Subtype | Morphology | Immunophenotype | Cytogenetics |
|---|---|---|---|
| DLBCL | Large B-cells in diffuse sheets | CD20+, CD10±, BCL6±, MUM1± | Variable; check for MYC/BCL2/BCL6 rearrangements |
| Follicular lymphoma | Nodular (follicular) growth pattern; centrocytes + centroblasts | CD20+, CD10+, BCL2+ (abnormal in GC), BCL6+ | t(14;18) / IGH-BCL2 |
| Burkitt lymphoma | Medium-sized cells, "starry sky" pattern, Ki-67 ~100% | CD20+, CD10+, BCL6+, BCL2−, TdT− | t(8;14) / IGH-MYC |
| Mantle cell lymphoma | Small-to-medium lymphocytes, diffuse or vaguely nodular | CD20+, CD5+, CD23−, Cyclin D1+ | t(11;14) / IGH-CCND1 |
| CLL/SLL | Small mature lymphocytes, pseudofollicles (proliferation centres) | CD19+, CD20+ (dim), CD5+, CD23+, surface Ig (dim) [26] | del(13q), del(11q), del(17p), trisomy 12 |
| NK/T-cell lymphoma | Medium-sized cells, necrosis, angiocentric/angiodestructive pattern | CD56+, CD3 (cytoplasmic)+, EBER+ (EBV) [9] | No consistent translocation |
Diagnosis of CLL requires BOTH [26]:
- Absolute B-lymphocyte count in peripheral blood ≥ 5 × 10⁹/L with predominantly mature-appearing small lymphocytes
- Flow cytometry showing monoclonal B-cells with: CD19+, CD20+ (dim), CD5+, CD23+, dim surface immunoglobulin with light chain restriction (κ or λ but not both)
If absolute lymphocyte count < 5 × 10⁹/L with no other disease manifestation → monoclonal B-cell lymphocytosis (MBL), not CLL [26].
The following algorithm represents the step-by-step approach from clinical suspicion to definitive diagnosis and staging:
4. Investigation Modalities — Detailed Breakdown
4.1 Tissue Diagnosis (The Most Important Step)
This is the gold standard for lymphoma diagnosis.
- Why excisional? Because you need the entire node to assess:
- Histological pattern of lymph node involvement: nodular / follicular / diffuse [25]
- Architecture (is it effaced? preserved? partially involved?)
- Relationship between different cell types
- Technique: select the most abnormal/largest accessible node. Avoid inguinal nodes if possible (often reactive/fibrotic)
- Specimen handling: part of the node should be sent fresh (for flow cytometry and cytogenetics), and part fixed in formalin (for H&E and IHC)
- Acceptable alternative when excisional biopsy is not feasible (e.g., deep-seated retroperitoneal nodes, mediastinal mass)
- Provides tissue architecture (unlike FNA) but limited sample → may miss heterogeneous areas
- Image-guided (CT or US-guided) for deep lesions
| Site | Indication |
|---|---|
| Bone marrow aspirate + trephine biopsy | If presenting with cytopaenias without accessible nodes; also part of staging |
| Extranodal tissue biopsy | GI endoscopy with biopsy for gastric MALT; skin biopsy for cutaneous lymphoma; brain biopsy for primary CNS lymphoma |
| Splenectomy | Suspected splenic lymphoma when only a space-occupying lesion is found in the spleen. Concept of spleen biopsy generally does not exist due to high vascularity and risk of bleeding [27] |
High Yield – No Spleen Biopsy!
The concept of spleen biopsy does not exist — since the spleen is highly vascular, there is great risk of bleeding [27]. If splenic lymphoma is suspected and there is no other accessible tissue, splenectomy serves as both a diagnostic and therapeutic procedure. However, nowadays if pathology is very close to the cortex/surface, image-guided biopsy can be attempted [27].
Assess morphology of individual tumour cells that comprise the LN infiltrate and identify pattern of lymph node involvement (nodular / follicular / diffuse) [25].
| Finding | Interpretation |
|---|---|
| Reed-Sternberg cells in reactive background | Classical Hodgkin lymphoma |
| "Popcorn" cells (LP cells) | NLPHL |
| Nodular/follicular pattern with BCL2+ follicles | Follicular lymphoma |
| Diffuse sheets of large cells | DLBCL |
| "Starry sky" pattern (tingible body macrophages) | Burkitt lymphoma |
| Small mature lymphocytes with pseudofollicles | CLL/SLL |
| Necrosis with angiocentric pattern | NK/T-cell lymphoma |
4.3 Immunophenotyping
Two complementary techniques [25]:
- Performed on fresh, unfixed single-cell suspensions [25]
- Detects surface immunoglobulin light chains — very helpful in determining clonality of B-cell proliferation [25]
- Superior to IHC due to ability to detect two or more markers simultaneously, rapid turnaround time, greater quantitative capacity, and higher sensitivity for certain markers [25]
- Key principle: B-cell clonality = light chain restriction (all cells express either κ or λ, but not both → monoclonal). Normal B-cells show a κ:λ ratio of approximately 2:1; significant deviation indicates clonality.
- Performed on sections of fixed or fresh frozen tissues [25]
- Expression of cell surface lymphoid differentiation antigens used to distinguish B cells and T cells at various developmental stages [25]
- Essential when flow cytometry material is not available (e.g., only formalin-fixed paraffin-embedded tissue available)
- Also used for EBER in-situ hybridisation (ISH) to detect EBV
This marker table is high yield for exams [25]:
| Group | Lineage | Markers |
|---|---|---|
| WBC | General | CD45 (weak in blasts) |
| Lymphoid | B cell | CD19, CD20, CD22, CD79a |
| Lymphoid | T cell | CD2, CD3, CD4, CD5, CD7, CD8, TCR |
| Lymphoid | NK cell | CD11a, CD56, CD57, CD94 |
| Myeloid | Granulocytic | CD13, CD33, myeloperoxidase |
| Myeloid | Monocytic | CD11c, CD14, CD64 |
| Immaturity | CD34, terminal deoxynucleotidyl transferase (TdT) |
Yellow-highlighted markers are lineage-specific, whereas others are lineage-associated only [25].
4.4 Cytogenetics and Molecular Genetics
- Detection of chromosomal abnormalities [25]
- FISH is targeted (you need to know what you're looking for) and can be performed on interphase cells → faster
- Key translocations to request:
| Request | When |
|---|---|
| t(14;18) / BCL2 | Suspected follicular lymphoma |
| t(8;14) / MYC | Suspected Burkitt lymphoma |
| t(11;14) / CCND1 | Suspected mantle cell lymphoma |
| t(11;18) / MALT1 | Gastric MALT lymphoma → predicts poor response to H. pylori eradication [5] |
| MYC + BCL2 ± BCL6 | "Double/triple hit" high-grade B-cell lymphoma |
| ALK rearrangement | Suspected ALCL |
Immunoglobulin (IgH) gene rearrangement by PCR [25]:
- Determines clonality of B lymphocytes
- Every normal B-lymphocyte carries one or two rearranged immunoglobulin heavy genes with unique DNA sequence — in lymphoma, all cells share the same rearrangement → single band on PCR
T-cell receptor (TCR) gene rearrangement by PCR [25]:
- Determines clonality of T lymphocytes
These rearrangement studies are confirmatory of clonality but are not subtype-specific — they tell you "this is a clonal B/T-cell population" but not "this is follicular lymphoma."
4.5 Staging Investigations
Once diagnosis is confirmed, staging determines the extent of disease and guides treatment intensity.
The Ann Arbor staging system is the standard for lymphoma staging [16]:
| Stage | Definition |
|---|---|
| I | Single lymph node region or single extranodal site |
| II | Two or more lymph node regions on the SAME side of the diaphragm |
| III | Lymph node regions on BOTH sides of the diaphragm (splenic involvement = Stage III) |
| IV | Diffuse or disseminated involvement of one or more extranodal organs (e.g., bone marrow, liver parenchyma, lung parenchyma) |
Suffixes:
- A = absence of B symptoms
- B = presence of B symptoms (fever > 38°C, drenching night sweats, > 10% weight loss in 6 months)
- E = localised extranodal extension from an adjacent nodal site (not stage IV)
- X = bulky disease (> 10 cm or > ⅓ mediastinal diameter)
- S = splenic involvement
- Standard of care for staging FDG-avid lymphomas (most HL and aggressive NHL — DLBCL, Burkitt, mantle cell, follicular grade 3b)
- FDG = fluorodeoxyglucose → taken up by metabolically active cells → lymphoma cells have high glucose metabolism
- Also used for response assessment during and after treatment
Deauville score — standard for lymph node uptake on PET/CT [3]:
| Score | Uptake | Interpretation |
|---|---|---|
| 1 | No uptake | Negative |
| 2 | ≤ mediastinal blood pool | Negative |
| 3 | > mediastinal blood pool but ≤ liver | Interpret with clinical context |
| 4 | Moderately > liver | Positive |
| 5 | Markedly > liver | Positive |
Rationale: compare lymph node uptake against mediastinal blood pool and liver as internal reference standards [3].
- Used when PET-CT is not available, or for low-grade NHL that may not be FDG-avid (some indolent lymphomas — marginal zone, SLL/CLL — may have low FDG uptake)
- Identifies enlarged lymph nodes (≥ 1.5 cm short axis for cervical/axillary; ≥ 1 cm for other sites), organomegaly, extranodal disease
- Indicated: part of standard staging workup in most lymphoma subtypes
- Not mandatory in early-stage HL with a negative PET-CT (PET/CT has replaced BM biopsy for HL staging in many centres)
- Remains important in NHL, especially low-grade subtypes where BM involvement is common (follicular: 60–80%, CLL/SLL: virtually all)
- Aspirate: for cytology, flow cytometry, and genetic studies [24]
- Trephine biopsy: for histological examination — assesses marrow cellularity, architectural details, marrow fibrosis, bone structure and immunohistochemistry [24]
- Pattern of lymphocyte infiltration informs prognosis (e.g., in CLL: diffuse infiltration associated with progressive course vs non-diffuse (interstitial, nodular) associated with more indolent course) [26]
| Investigation | Key Findings / Interpretation |
|---|---|
| CBC + differential | Cytopaenias (marrow involvement, hypersplenism); lymphocytosis (CLL, leukaemic phase); eosinophilia — most crucial cause is tumour → body's reaction towards the tumour, classical Hodgkin lymphoma and T-cell lymphoma [28] |
| PBS | Smudge cells → CLL; atypical lymphocytes (reactive, NOT lymphoma); circulating lymphoma cells; leukoerythroblastic picture (marrow infiltration) [17][18] |
| LDH | Elevated = high tumour burden, rapid cell turnover; important for prognosis (IPI score for DLBCL, IPS for HL) |
| β2-microglobulin | Elevated in lymphoma; prognostic marker; also elevated in myeloma and CKD |
| Uric acid | Elevated in high-turnover lymphomas; risk factor for tumour lysis syndrome |
| Albumin | Low albumin = poor prognostic marker (IPS for HL); also assess liver synthetic function |
| LFT | Hepatic involvement; baseline before hepatotoxic chemotherapy |
| RFT + electrolytes | Baseline renal function; hypercalcaemia (ATLL, some NHL); urate nephropathy risk |
| ESR | Prognostic marker in HL (elevated ESR = unfavourable) |
| Serum protein electrophoresis (SPEP) | Paraprotein may be present in lymphoplasmacytic lymphoma (Waldenström's), some DLBCL, and to exclude myeloma |
| Immunoglobulins | Hypogammaglobulinaemia in CLL (↓ IgG, IgA, IgM → infection risk) [26]; immunoparesis in myeloma |
This is not optional — it is mandatory before starting lymphoma treatment:
| Virus | Why Test |
|---|---|
| HBV (HBsAg, anti-HBc, anti-HBs, HBV DNA) | Rituximab (anti-CD20) and other immunosuppressive therapies can reactivate occult HBV. Reactivation can be FATAL. Must start entecavir prophylaxis if HBsAg+ or anti-HBc+ before rituximab [29] |
| HCV | Can be associated with certain lymphomas (splenic MZL); may affect treatment decisions |
| HIV | HIV is a major risk factor for lymphoma (100× for NHL, 5–25× for HL); affects treatment intensity and opportunistic infection prophylaxis |
| EBV | Relevant for Burkitt, PTLD, NK/T-cell lymphoma; EBV viral load monitoring may be needed |
High Yield – HBV Reactivation with Rituximab
Rituximab (anti-CD20) causes profound B-cell depletion lasting ~1 year. When B-cells recover, they prime T-cells → immune reconstitution → hepatic flare → fulminant liver failure [29]. This can occur up to 11 months after the last cycle of rituximab [29].
First report: reactivation of occult HBV (even anti-HBs positive) in lymphoma patient treated with rituximab [29].
Action: Check HBV serology in ALL lymphoma patients before rituximab. If HBsAg+ or anti-HBc+ → start entecavir ± monitor HBV DNA. Cover for at least 12 months after last rituximab dose.
| Clinical Scenario | Investigation |
|---|---|
| CNS involvement suspected | Lumbar puncture with CSF cytology + flow cytometry; MRI brain with contrast |
| Gastric lymphoma | EUS-guided biopsy for diagnosis + CT thorax/abdomen + BM biopsy for staging + H. pylori testing + FISH for t(11;18) [5] |
| Testicular lymphoma | Testicular ultrasound; contralateral testis assessment |
| Mediastinal mass (T-ALL/LBL) | CXR / contrast CT thorax for all T-ALL for evaluation of mediastinal mass [4] |
| Orbital/sinus involvement | MRI orbits |
| Assessment | Purpose |
|---|---|
| Echocardiography | Baseline LVEF before anthracycline-based chemotherapy (doxorubicin in CHOP is cardiotoxic) |
| Pulmonary function tests | Baseline DLCO before bleomycin (in ABVD for HL) — bleomycin causes pulmonary fibrosis |
| Fertility counselling + cryopreservation | Fertility issue should be discussed before instituting potentially gonadotoxic chemotherapy [3] — sperm banking or oocyte cryopreservation |
| G6PD level | Required before rasburicase (for TLS prophylaxis) — rasburicase is contraindicated in G6PD deficiency [15] |
| Cardiac risk factors | Hypertension, diabetes, dyslipidaemia → cardiovascular risk modification before cardiotoxic chemo |
5. Prognostic Scoring Systems
These are used after diagnosis and staging to guide treatment intensity:
| Factor (1 point each) | Unfavourable |
|---|---|
| Age | > 60 years |
| Stage | III–IV |
| LDH | Above upper limit of normal |
| ECOG performance status | ≥ 2 |
| Number of extranodal sites | > 1 |
Score: 0–1 = low risk, 2 = low-intermediate, 3 = high-intermediate, 4–5 = high risk.
Seven factors (1 point each): age ≥ 45, male sex, stage IV, Hb < 10.5, WBC ≥ 15, lymphocyte count < 0.6 or < 8%, albumin < 4.0.
Five factors: age > 60, stage III–IV, Hb < 12, number of nodal sites > 4, LDH elevated.
| Step | What You Do | Why |
|---|---|---|
| 1. Clinical assessment | Hx, P/E, identify red flags | Determine if biopsy is needed |
| 2. Tissue biopsy | Excisional LN biopsy (preferred) | Gold standard; architecture essential |
| 3. MCICM workup | Morphology, Cytochemistry, Immunophenotype, Cytogenetics, Molecular [18][24] | Establish exact diagnosis and subtype |
| 4. Staging | PET-CT (or CT T+A+P), BM biopsy, blood tests | Determine disease extent → Ann Arbor stage |
| 5. Pre-treatment | Viral serology (HBV/HCV/HIV), echocardiography, PFTs, fertility counselling, G6PD | Ensure patient safety during treatment |
| 6. Prognostic scoring | IPI, IPS, FLIPI as appropriate | Guide treatment intensity |
High Yield Summary – Diagnosis and Investigations
- Lymphoma diagnosis = tissue diagnosis. Excisional LN biopsy is the gold standard; FNA alone is NEVER sufficient.
- MCICM framework: Morphology → Cytochemistry → Immunophenotype → Cytogenetics → Molecular genetics. All three of histology, immunophenotyping, and cytogenetics/molecular are needed for classification.
- Flow cytometry detects surface markers and light chain restriction (clonality); IHC works on fixed tissue; PCR for IGH/TCR confirms clonality at the molecular level.
- Key markers: CD20 (B-cell), CD3 (T-cell), CD56 (NK-cell), CD15/CD30 (HL), CD5/CD23 (CLL), Cyclin D1 (mantle cell), TdT (precursor/blast).
- Staging: Ann Arbor I–IV with A/B suffix. PET-CT is standard for FDG-avid lymphomas. Deauville score (1–5) for response assessment.
- Pre-treatment essentials: HBV serology (rituximab → HBV reactivation risk), echo (anthracycline), PFTs (bleomycin), fertility counselling, G6PD (rasburicase).
- Spleen biopsy does not exist — splenectomy for suspected splenic lymphoma.
- CLL diagnosis: ≥ 5 × 10⁹/L monoclonal B-lymphocytes with CD5+/CD19+/CD20+(dim)/CD23+/light chain restriction.
Active Recall - Diagnosis and Investigations of Lymphoma
References
[1] Lecture slides: Molecular Pathology Seminar 4_MALIGNANT LYMPHOMA.pdf (clonality, VDJ rearrangement) [3] Senior notes: Ryan Ho Haemtology.pdf (p. 96, Deauville score, peri-treatment issues, fertility) [4] Senior notes: Ryan Ho Haemtology.pdf (p. 60–61, ALL laboratory features, diagnosis, pre-treatment evaluation) [5] Senior notes: Ryan Ho GI.pdf (p. 90, gastric MALT lymphoma investigations and t(11;18)) [9] AOS material: AOS - Pathology.pdf (p. 26, 38–40, NK-cell lymphoma, phenotyping) [15] Senior notes: Maksim Medicine Notes.pdf (p. 48, TLS prophylaxis, rasburicase, G6PD) [16] Senior notes: Block A - Generalised Lymphadenopathy_ Differential diagnosis and principle of management.pdf (p. 16–17, principles of diagnosis, staging, investigations for lymphomas) [17] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (p. 24, CLL, smudge cells) [18] Senior notes: Ryan Ho Fundamentals.pdf (p. 390–391, MCICM workup, PBS interpretation, marrow examination) [23] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p. 751, classification requires histology + immunophenotyping + cytogenetics/molecular) [24] Senior notes: Ryan Ho Fundamentals.pdf (p. 391, marrow examination techniques — aspirate vs trephine) [25] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p. 1426–1428, specific investigations — histology, immunophenotyping markers table, flow cytometry vs IHC, cytogenetics, molecular genetics) [26] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p. 1411–1413, CLL diagnostic criteria); Ryan Ho Haemtology.pdf (p. 67, CLL findings and diagnosis) [27] Senior notes: Block A - Splenomegaly_ common causes of splenomegaly; myeloproliferative diseases.pdf (p. 19, splenectomy for diagnosis, no spleen biopsy concept) [28] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf (p. 3, eosinophilia and tumour association — cHL and T-cell lymphoma) [29] Senior notes: Block A - I am a hepatitis B carrier.pdf (p. 68–69, rituximab and HBV reactivation, entecavir prophylaxis)
Management Algorithm and Treatment Modalities for Lymphoma
Before we discuss specific regimens, you need to understand why lymphoma management is structured the way it is. The treatment strategy is driven by three axes:
- Subtype (HL vs NHL; high-grade vs low-grade; B-cell vs T-cell vs NK-cell)
- Stage (Ann Arbor I–IV, A/B, bulky vs non-bulky)
- Patient fitness (age, performance status, comorbidities, organ function)
Treatment principles of lymphomas and major modalities of treatment of lymphomas are explicit learning objectives of the GC Lymphadenopathy lecture [16].
The fundamental treatment modalities are:
| Modality | Role |
|---|---|
| Chemotherapy | Cytotoxic backbone — kills rapidly dividing cells |
| Monoclonal antibody against CD20 [16] | Immunotherapy targeting B-cell surface antigen (rituximab, obinutuzumab) |
| Radiotherapy | Localised disease control; consolidation; palliation |
| Haematopoietic stem cell transplantation | Rescue after myeloablative therapy; graft-versus-lymphoma effect (allogeneic) |
| Targeted / novel agents | BTK inhibitors, BCL-2 inhibitors, checkpoint inhibitors, CAR-T cell therapy |
| Supportive care | Transfusion support, infection prophylaxis, TLS prevention, HBV prophylaxis |
Key Principle – The Lymphoma Treatment Paradox Revisited
High-grade lymphomas are aggressive but potentially curable with intensive chemoimmunotherapy (because rapidly dividing cells are more susceptible to cytotoxic drugs). Low-grade lymphomas are indolent but generally incurable with conventional therapy — the goal is disease control, not cure. This paradox fundamentally shapes the management approach.
3. Management of Hodgkin Lymphoma
3.1 Classical Hodgkin Lymphoma (cHL)
- Standard: ABVD × 2–4 cycles + involved-site radiotherapy (ISRT) [3]
- ABVD = Adriamycin (doxorubicin) + Bleomycin + Vinblastine + Dacarbazine
- Why these drugs? Each targets a different mechanism — doxorubicin (topoisomerase II inhibitor/intercalator), bleomycin (free radical-mediated DNA strand breaks), vinblastine (microtubule inhibitor → blocks mitosis), dacarbazine (alkylating agent)
- Can consider omitting bleomycin and RT if PET-CT negative after 2 cycles of ABVD [3] — this is response-adapted therapy to reduce long-term toxicity
Risk factors include: bulky mediastinal mass (≥ ⅓ mediastinal width or ≥ 10 cm), ≥ 3 nodal sites, elevated ESR (≥ 50 if A, ≥ 30 if B), extranodal extension
- Standard: ABVD × 4–6 cycles + ISRT, OR escalated BEACOPP × 2 + ABVD × 2 + ISRT
- Standard: ABVD × 6 cycles OR escalated BEACOPP × 6 cycles
- Newer option: BV-AVD (brentuximab vedotin + AVD — omits bleomycin and dacarbazine; replaces with anti-CD30 antibody-drug conjugate) — shown to be superior to ABVD in ECHELON-1 trial
- RT may be considered for sites of initial bulk or residual PET-positive disease
- Salvage chemotherapy (e.g., ICE, DHAP, GDP) followed by autologous HSCT if chemosensitive
- Brentuximab vedotin (anti-CD30 ADC): for relapse post-ASCT or ≥ 2 prior therapies
- Checkpoint inhibitors: nivolumab, pembrolizumab (anti-PD-1) — HL has high PD-L1 expression on RS cells due to 9p24.1 amplification → highly responsive to checkpoint blockade
- Allogeneic HSCT: for relapsed lymphoma, young patients [30]
- Slow-growing indolent subtype [3]
- Involved-site RT (ISRT) or active surveillance for non-bulky early stage (I–II) [3]
- Chemoimmunotherapy (R-CHOP, R-CVP, ABVD) for bulky or non-contiguous or symptomatic early stage [3]
- Chemoimmunotherapy, rituximab monotherapy, or active surveillance for advanced disease depending on symptoms [3]
- Why rituximab? NLPHL LP cells are CD20+ (unlike classical HL RS cells which are CD20−) → consider rituximab as part of treatment since most NLPHL RS cells are CD20+ [23]
Blood product support: must be irradiated to prevent transfusion-associated GvHD (TA-GvHD) — uniformly fatal [3]
Indications for irradiated blood products [3]:
- Intrauterine transfusion or premature neonates
- Congenital cell-mediated immunodeficiencies
- Potent immunosuppressants (e.g., purine analogues, ATG)
- HSCT recipients
- HL of any stage
Why specifically HL of any stage? Because HL patients have inherent T-cell dysfunction (the disease is characterised by an immunosuppressive microenvironment around RS cells) → cannot eliminate transfused donor lymphocytes → risk of TA-GvHD.
Disease monitoring by ESR and PET/CT [3]:
- Deauville score as standard — compare uptake against mediastinal blood pool and liver [3]
- Treatment decision: can consider omitting bleomycin and RT if negative after 2 × ABVD [3]
Drug toxicity to monitor [3]:
- Neuropathy (vinblastine, brentuximab vedotin)
- Interstitial pulmonary fibrosis (bleomycin) — check PFTs (DLCO) at baseline and during therapy
- Cardiotoxicity (doxorubicin) — cumulative dose-dependent; monitor LVEF by echocardiography
Fertility: must be discussed before instituting potentially gonadotoxic chemotherapy [3]
4. Management of Non-Hodgkin Lymphoma — By Subtype
The most common NHL; treated with curative intent.
-
Standard regimen: R-CHOP × 6–8 cycles [16]
- R = Rituximab (anti-CD20 monoclonal antibody) [16]
- C = Cyclophosphamide (alkylating agent — crosslinks DNA)
- H = Hydroxydaunorubicin / doxorubicin (topoisomerase II inhibitor)
- O = Oncovin / vincristine (vinca alkaloid — microtubule inhibitor)
- P = Prednisolone / prednisone (glucocorticoid — lympholytic, reduces tumour-associated oedema)
-
± Consolidation RT for initially bulky disease or residual PET-positive sites
-
CNS prophylaxis: intrathecal methotrexate or high-dose systemic methotrexate for high-risk patients (testicular DLBCL, breast DLBCL, high IPI score with ≥ 2 extranodal sites, kidney/adrenal involvement)
-
Relapsed/refractory: salvage chemo (R-ICE, R-DHAP, R-GDP) → autologous HSCT if chemosensitive; CAR-T cell therapy (e.g., axicabtagene ciloleucel, lisocabtagene maraleucel) for refractory disease
-
Prognosis: ~60% curable with R-CHOP
High Yield – Rituximab (Anti-CD20)
Rituximab is a chimeric monoclonal antibody against CD20 [16], a surface protein expressed on most B-cell lymphomas (but NOT classical HL RS cells, NOT plasma cells).
Mechanism: Binds CD20 → cell death via:
- Antibody-dependent cellular cytotoxicity (ADCC)
- Complement-dependent cytotoxicity (CDC)
- Direct induction of apoptosis
Key side effects:
- Infusion reactions (first dose — premedicate with paracetamol, antihistamine, steroid)
- HBV reactivation — can be FATAL [29] (see below)
- Hypogammaglobulinaemia → recurrent infections
- Progressive multifocal leukoencephalopathy (PML) — rare but serious (JC virus reactivation)
- Late-onset neutropaenia
Newer anti-CD20: Obinutuzumab (fully humanised, type II → more direct cell death, used in some FL and CLL regimens)
- One of the fastest-growing human tumours (doubling time ~24 hours) → oncological emergency
- High risk for tumour lysis syndrome [15] → prophylaxis mandatory: hydration + urate-lowering agents (allopurinol — check HLA-B5801; febuxostat; ± rasburicase if high risk)* [30]
- Treatment: intensive, short-duration chemoimmunotherapy
- R-hyper-CVAD (rituximab + hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with high-dose methotrexate/cytarabine)
- DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin + rituximab)
- R-CODOX-M/IVAC
- CNS prophylaxis is mandatory (high risk of CNS involvement): intrathecal methotrexate + cytarabine
- Role of HSCT: generally not needed in first complete remission if adequate intensive chemo given; reserved for relapse
- Young/fit patients: intensive induction (R-CHOP alternating with R-DHAP or R-hyper-CVAD) → consolidation with autologous HSCT → rituximab maintenance
- Older/unfit patients: BR (bendamustine + rituximab) or R-CHOP ± rituximab maintenance
- Ibrutinib (BTK inhibitor): highly effective in relapsed mantle cell
- Prognosis: generally poor compared to other NHL; median survival ~5–7 years
Follicular lymphoma illustrates the "incurable but manageable" paradigm of low-grade NHL [3].
| Stage | Management |
|---|---|
| Stage I (localised) | Curative RT — one of the few situations where low-grade NHL can be truly cured [3] |
| Stage II–IV asymptomatic | Watch and wait — no survival benefit to early treatment; monitor for transformation [3] |
| Stage II–IV symptomatic | Chemoimmunotherapy: BR (bendamustine + rituximab), R-CHOP, or R-CVP [3] |
| Grade 3b | Treat as high-grade NHL (R-CHOP) — behaves like DLBCL [3] |
- Anti-CD20: rituximab (1st line), obinutuzumab should be part of regimen [3]
- Chemo options: bendamustine (similar efficacy but fewer side effects), CHOP, CVP (lower response rate and PFS) [3]
- Other options: salvage chemo + autologous HSCT in early treatment failure; rituximab monotherapy in late failure [3]
- Rituximab maintenance (every 2–3 months for 2 years post-induction) — prolongs progression-free survival
- Histological transformation (~1–2%/year) into high-grade NHL (usually DLBCL) — requires biopsy to confirm → treat as DLBCL [3]
- H. pylori eradication: causes regression in ~80% of early-stage, HP-positive, t(11;18)-negative tumours [31]
- RT and/or rituximab and/or chemotherapy if early-stage HP-negative or late-stage tumours [5]
- t(11;18) predicts poor response to HP eradication [5] → these patients need primary chemo/RT
- Close endoscopic surveillance after HP eradication (complete regression may take 6–12 months)
CLL has a variable clinical course → avoid early treatment — may shorten life expectancy if instituted early for indolent disease [3][26].
| Setting | Management |
|---|---|
| Binet A / Rai 0–I (early, asymptomatic) | Observe — close follow-up only [3][26][32] |
| Localised SLL (Ann Arbor stage I) | Local RT [3] |
| Advanced/symptomatic CLL | Systemic treatment [3][26] |
Indications for treatment of CLL [32]:
- Advanced stage: Rai III/IV
- Symptomatic: severe B symptoms, bulky lymphadenopathy/splenomegaly
- Active disease progression: lymphocytosis ≥ 50% increase over 2 months or doubling time ≤ 6 months
- Disease-related complications: refractory AIHA/ITP, recurrent infections, Richter's transformation
| Setting | Regimen |
|---|---|
| Young, fit | FCR (fludarabine + cyclophosphamide + rituximab) [3][32] or bendamustine-based [32] |
| Older, frail | Chlorambucil ± rituximab (least side effects) [3][32] |
| del(17p) / TP53 mutation | Ibrutinib (BTK inhibitor) — especially effective [3]; venetoclax (BCL-2 inhibitor) [32] |
| Newer agents | Ibrutinib, idelalisib (PI3K blocker), venetoclax, rituximab/obinutuzumab (anti-CD20) [3][32] |
Ibrutinib: "ibrut-inib" → Bruton's tyrosine kinase (BTK) inhibitor → BTK is essential for B-cell receptor signalling and B-cell survival → inhibition → B-cell apoptosis. Now regarded as standard option for both young and old patients [3]. Side effects: bleeding (inhibits platelet function via off-target effects), atrial fibrillation, hypertension.
Venetoclax: "vene-to-clax" → BCL-2 inhibitor → BCL-2 is the anti-apoptotic protein overexpressed in CLL (and follicular lymphoma) → blocking it restores apoptosis. Risk of TLS → requires dose ramp-up.
4.7 T-Cell and NK-Cell Lymphomas
- CHOP-based chemotherapy ± autologous HSCT consolidation in first complete remission for eligible patients
- Prognosis generally poorer than B-cell NHL
- No rituximab — T-cells do not express CD20
- L-asparaginase-based regimen + concurrent radiotherapy (e.g., SMILE protocol: dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide)
- Why L-asparaginase? NK/T-cell lymphoma cells lack asparagine synthetase → cannot synthesise asparagine endogenously → L-asparaginase depletes circulating asparagine → tumour cell death by amino acid starvation
- Early concurrent RT is important — nasal NK/T-cell lymphoma is radiosensitive
- Prognosis: poor for advanced disease, better for localised disease with combined modality treatment
- Aggressive subtypes: CHOP-like chemotherapy → generally poor response; consider allogeneic HSCT
- Indolent subtypes: watch and wait
- High-dose methotrexate-based regimen (crosses blood-brain barrier) ± whole-brain RT
- Do NOT give steroids before biopsy — can cause transient tumour regression → non-diagnostic biopsy
- Add rituximab (R-MPV: rituximab, methotrexate, procarbazine, vincristine) for CD20+ tumours
- Consolidation: cytarabine or autologous HSCT in younger patients
5. Haematopoietic Stem Cell Transplantation (HSCT) in Lymphoma
| Type | Autologous HSCT | Allogeneic HSCT |
|---|---|---|
| Source | Own HSC harvested and cryopreserved | Donor HSC (related or unrelated) [33] |
| Purpose | Allow more intensive myeloablative therapy without worrying about myelosuppression | Replace diseased marrow + graft-versus-lymphoma (GvL) effect [33] |
| Indications in lymphoma | Relapsed DLBCL, mantle cell (consolidation), relapsed HL, follicular (early failure) [33] | Relapsed lymphoma, young + aggressive CLL, selected high-risk or relapsed cases [30][33] |
| Risks | Lower morbidity (no GvHD); no GvL effect | GVHD (acute and chronic), higher TRM, infections |
Generally for haematopoietic malignancies [30]:
- AML/ALL — high risk at first remission or relapsed
- CML — T315I mutation, accelerated/blast phase
- Relapsed lymphoma
- High-risk MDS
- Aplastic anaemia
6. Supportive Care in Lymphoma Treatment
High risk: Burkitt lymphoma, ALL, high tumour burden [15][30]
| Component | Details |
|---|---|
| Monitoring | Daily bloods for moderate risk; Q8–12h for high risk — RFT, calcium/phosphate, urate, potassium [34] |
| Hydration | Aggressive hydration 3–4L/day ± diuretics to maintain urine output > 150 mL/h [15] |
| Urate lowering | Allopurinol (check HLA-B5801 first!), febuxostat (no renal adjustment needed unless severe, C/I in IHD), ± rasburicase if high risk* [15] |
| Rasburicase | Recombinant urate oxidase — converts uric acid to allantoin (soluble). Check G6PD level first — contraindicated in G6PD deficiency [15] |
| Electrolyte correction | Treat hyperK, hyperPO4, hyperuricaemia. Do NOT replace calcium unless symptomatic (risk of nephrocalcinosis) [15] |
| Dialysis | If refractory AKI despite above measures |
What must be done for every single patient before starting allopurinol? → Check for HLA-B5801 → risk of SJS/TEN* [30].
- Immediate empirical broad-spectrum antibiotics (e.g., piperacillin-tazobactam, meropenem) [30]
- Antifungal prophylaxis in patients with prolonged and profound neutropenia [30]
- Proper nursing care: reverse isolation, face mask, hand hygiene, low-bacteria diet [30]
- G-CSF: can be considered in septic shock, fungal infection, or severe pneumonia; stop when ANC returns to 1 × 10⁹/L [34]
Mandatory pre-treatment screening: Check HBsAg, anti-HBs, anti-HBc [29]
| HBV Status | Action |
|---|---|
| HBsAg +ve | Start prophylactic entecavir/TDF irrespective of baseline HBV DNA [29] |
| HBsAg −ve, anti-HBc +ve | Check HBV DNA; start entecavir when HBV DNA becomes detectable; studies show will completely control reactivations [29] |
| Duration | Continue antiviral for at least 12 months after last rituximab cycle (B-cell recovery takes ~1 year) [29] |
| If baseline HBV DNA > 2000 IU/mL | Long-term antiviral therapy [29] |
Presence of anti-HBs appears to have some benefit in protecting against HBV reactivation (68.3% vs 34.4%) [29].
- All blood products for HL patients (any stage) must be irradiated [3]
- Also irradiate for: HSCT recipients, congenital cell-mediated immunodeficiency, patients on potent immunosuppressants (purine analogues, ATG) [3]
- Why? TA-GvHD occurs when live donor lymphocytes engraft into an immunocompromised recipient → marrow aplasia → uniformly fatal as there is no treatment [3]
- If irradiated products not immediately available in an emergency: ask blood bank for the oldest bag of blood (lymphocytes die after > 14 days of storage) [35]
| Issue | Management |
|---|---|
| Hypercalcaemia (e.g., in ATLL, some lymphomas) | IV hydration → IV bisphosphonate (if eGFR > 35); glucocorticoids if endogenous calcitriol overproduction (chronic granulomatous disease, lymphoma) [36]; denosumab if refractory/CKD |
| Hyperviscosity (Waldenström's) | Plasmapheresis [15] |
| Leukostasis (WBC > 100) | Urgent leukapheresis + hydroxyurea [30] |
| Fertility preservation | Sperm banking / oocyte cryopreservation before gonadotoxic chemotherapy [3] |
These are high yield, especially for HL where patients survive decades post-treatment [3]:
| Complication | Mechanism / Details |
|---|---|
| Cardiotoxicity | Doxorubicin (anthracycline) — cumulative dose-dependent cardiomyopathy; monitor LVEF [3] |
| Pulmonary fibrosis | Bleomycin — dose-dependent IPF; monitor DLCO [3] |
| Peripheral neuropathy | Vinca alkaloids (vincristine, vinblastine), brentuximab vedotin [3] |
| Gonadotoxicity | Cyclophosphamide, nitrogen mustard, procarbazine — infertility [3] |
| Second malignancies | Risk 1.5–4.5× for solid tumours; sites: breast, lung, colon, AML (peaks 5–9 years) [3] |
| Cardiovascular disease | Risk 2.5×, remains elevated for ≥ 25 years [3] |
| Hypothyroidism | Post neck/mediastinal RT [3] |
| Anti-TNF use (in autoimmune conditions) | Lymphoma risk, particularly in young, male patients [37] |
| Subtype | Stage / Setting | First-Line Treatment | Key Notes |
|---|---|---|---|
| cHL, early favourable | I–IIA | ABVD × 2–4 + ISRT | PET-adapted: omit bleomycin/RT if PET −ve |
| cHL, advanced | III–IV | ABVD × 6 or esc-BEACOPP or BV-AVD | Monitor for bleomycin lung toxicity |
| cHL, relapsed | — | Salvage chemo → auto-HSCT; BV; nivolumab/pembrolizumab | HL highly responsive to checkpoint inhibitors |
| NLPHL | I–II | ISRT or watch and wait; R-CHOP if symptomatic | CD20+ → rituximab works |
| DLBCL | All stages | R-CHOP × 6–8 ± RT | ~60% curable; CNS prophylaxis if high-risk |
| Burkitt | All stages | R-hyper-CVAD or DA-EPOCH-R | TLS prophylaxis mandatory; CNS prophylaxis |
| Follicular | I–II | Curative RT | Only low-grade NHL potentially cured by RT |
| Follicular | III–IV asymp | Watch and wait | No survival benefit from early Tx |
| Follicular | III–IV symp | BR or R-CHOP/R-CVP ± rituximab maintenance | Treat grade 3b as high-grade |
| Gastric MALT | Early, HP+ | H. pylori eradication | 80% regression; t(11;18) predicts failure |
| CLL/SLL | Early asymp | Watch and wait | Early Tx may shorten survival |
| CLL/SLL | Advanced/symp | FCR, ibrutinib, venetoclax | Ibrutinib now standard for all ages |
| Mantle cell | All stages | R-CHOP / R-DHAP → auto-HSCT (young); BR (old) | Ibrutinib for relapse |
| NK/T-cell | Localised | L-asparaginase-based + concurrent RT | Radiosensitive; no CD20 → no rituximab |
| Thyroid lymphoma | — | R-CHOP + EBRT | 60× risk with Hashimoto's |
| Primary CNS | — | HD-MTX-based ± RT | Do NOT give steroids before biopsy |
High Yield Summary – Lymphoma Management
- HL: ABVD is the backbone; response-adapted therapy using PET-CT (Deauville score); irradiate ALL blood products; excellent prognosis (~80–90% cure)
- DLBCL: R-CHOP × 6–8; rituximab revolutionised outcomes; ~60% curable
- Burkitt: intensive chemo + CNS prophylaxis; TLS prophylaxis mandatory (allopurinol/rasburicase + hydration)
- Follicular: cure possible ONLY in stage I (RT); otherwise watch and wait if asymptomatic, BR/R-CHOP if symptomatic; transformation to DLBCL ~1–2%/year
- Gastric MALT: H. pylori eradication first; t(11;18) predicts failure of HP eradication
- CLL: observe early/asymptomatic; treat with FCR (young), ibrutinib/venetoclax (all ages, especially del(17p))
- Rituximab: anti-CD20; check HBV status before starting — HBV reactivation can be fatal; entecavir prophylaxis for ≥ 12 months post-last dose
- Supportive care: TLS prevention (check HLA-B*5801 before allopurinol, G6PD before rasburicase), neutropenic fever protocols, irradiated blood for HL/HSCT/immunosuppressed
- HSCT: autologous for relapsed DLBCL/HL/mantle cell; allogeneic for relapsed lymphoma/high-risk CLL/refractory disease
- Late effects: second malignancies (1.5–4.5×), cardiovascular disease (2.5× for ≥ 25 years), hypothyroidism, infertility, pulmonary fibrosis
Active Recall - Management of Lymphoma
References
[3] Senior notes: Ryan Ho Haemtology.pdf (p. 93–96, HL classification, ABVD, peri-treatment issues, Deauville score, irradiated blood, drug toxicity, fertility, late complications; p. 99, follicular lymphoma management; p. 68, CLL management principles) [5] Senior notes: Ryan Ho GI.pdf (p. 90, gastric MALT lymphoma management, t(11;18)) [6] Senior notes: Ryan Ho Endocrine.pdf (p. 38, thyroid lymphoma treatment — R-CHOP + EBRT) [15] Senior notes: Maksim Medicine Notes.pdf (p. 48, TLS prophylaxis and management, hyperviscosity) [16] Senior notes: Block A - Generalised Lymphadenopathy_ Differential diagnosis and principle of management.pdf (p. 1, 12, 18, treatment principles, monoclonal antibody against CD20) [23] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p. 752, NLPHL CD20+ and rituximab) [26] Senior notes: Ryan Ho Haemtology.pdf (p. 67–68, CLL management, Binet staging) [29] Senior notes: Block A - I am a hepatitis B carrier.pdf (p. 69–70, rituximab and HBV reactivation, entecavir prophylaxis, duration of cover, anti-HBs protective) [30] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (p. 9, 20, 23, 28, supportive treatment, HSCT indications, HLA-B*5801, ALL treatment, haematological emergencies) [31] Senior notes: Maksim Surgery Notes.pdf (p. 73, gastric lymphoma treatment — HP eradication 80% regression) [32] Senior notes: Maksim Medicine Notes.pdf (p. 177, CLL management — indications, regimens, newer agents) [33] Senior notes: Ryan Ho Haemtology.pdf (p. 153, HSCT overview — types, indications, purpose) [34] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 424, TLS monitoring frequency, G-CSF indications) [35] Senior notes: Block A - Fever after a blood transfusion_ transfusion and related problems.pdf (p. 22, oldest bag of blood if irradiated not available) [36] Senior notes: Block A - Confused and dehydrated_ hypercalcaemia; hypocalcaemia.pdf (p. 11–12, glucocorticoids for lymphoma-related hypercalcaemia, denosumab) [37] Senior notes: Block A - Chronic diarrhoea_ irritable bowel syndrome and inflammatory bowel disease.pdf (p. 48, anti-TNF risk of lymphoma)
Complications of Lymphoma
Complications of lymphoma can be organised into three broad categories: (1) disease-related complications (from the lymphoma itself), (2) treatment-related complications (from chemotherapy, radiotherapy, immunotherapy, HSCT), and (3) late complications (long-term sequelae in lymphoma survivors). Understanding each complication from first principles — why does it happen? — is essential.
1. Disease-Related Complications
These arise directly from tumour biology: mass effect, immune dysregulation, metabolic derangement, or bone marrow infiltration.
1.1 Oncological Emergencies
TLS is the most important metabolic emergency in lymphoma — especially in Burkitt lymphoma [2][15][34].
Mechanism from first principles:
- Massive breakdown of tumour cells (spontaneous or chemotherapy-triggered) → release of intracellular contents:
- K⁺ → hyperkalaemia → cardiac arrhythmias (peaked T waves, widened QRS, VF)
- Nucleic acids → catabolised to uric acid → hyperuricaemia → crystallisation in renal tubules → uric acid nephropathy → AKI
- PO₄³⁻ → hyperphosphataemia → binds calcium → calcium-phosphate precipitation in tissues (nephrocalcinosis) → hypocalcaemia → tetany, arrhythmias
- Lactate → metabolic acidosis
- Result: "PAN-HIGH except calcium" — hyperK, hyperPO₄, hyperuricaemia, hypoCa [34]
High-risk malignancies for TLS: Burkitt lymphoma, ALL (WCC ≥ 100), AML (WCC ≥ 50) [34][15].
- Tumour factors: high tumour burden (↑LDH), high proliferative index, high chemosensitivity, bulky disease > 10 cm
- Patient factors: pre-treatment hyperuricaemia, pre-existing nephropathy, dehydration, old age
TLS prophylaxis: hydration 3–4L/day, allopurinol (check HLA-B5801* first), febuxostat, ± rasburicase (check G6PD first) [15][30]. TLS management: IV hydration to maintain urine output > 70 mL/h, correct electrolytes, do NOT replace calcium unless symptomatic (risk of nephrocalcinosis), haemodialysis if refractory [15].
- Mechanism: mediastinal mass (nodular sclerosis HL, T-lymphoblastic lymphoma/ALL, primary mediastinal DLBCL) compresses the SVC → impaired venous return from head, neck, and upper limbs
- Signs: facial plethora, periorbital oedema, distended non-pulsatile neck veins, upper limb oedema, collateral veins on chest wall
- Danger: can progress to airway compromise, cerebral oedema
- Management: urgent tissue diagnosis (if safe); if airway/cerebral compromise → empirical dexamethasone + urgent chemotherapy or RT; mediastinal stenting in refractory cases
- Mechanism: epidural tumour extension or vertebral body collapse from lymphomatous infiltration → compression of the spinal cord or cauda equina
- Signs: back pain, lower limb weakness, sensory level, bowel/bladder dysfunction
- Management: emergency MRI whole spine; high-dose dexamethasone (reduces peri-tumour oedema); urgent RT or chemo (lymphomas are highly chemosensitive, unlike most cord compression from solid tumours where surgery is first-line)
- Relevant to: Waldenström's macroglobulinaemia (lymphoplasmacytic lymphoma producing monoclonal IgM), rarely other NHL
- Mechanism: excessive monoclonal immunoglobulin → ↑ serum viscosity → impaired microcirculation
- Symptoms: headache, visual disturbance (retinal haemorrhages, "sausage-shaped" retinal veins), confusion, bleeding (mucosal), SOB
- Management: plasmapheresis [15] to acutely reduce viscosity; then definitive chemoimmunotherapy
- When lymphoma has a leukaemic phase (ALL/LBL) with WBC > 100 × 10⁹/L
- Mechanism: blast cells are large and "sticky" → occlude microvasculature → tissue hypoxia → organ damage (lung, brain)
- Management: urgent leukapheresis + hydroxyurea for cytoreduction [30]
- CBC/D: ~60% abnormal, cytopaenias strongly associated with BM involvement [3][38]
- Anaemia: fatigue, pallor, dyspnoea → mechanism: marrow replacement by lymphoma cells → reduced erythropoiesis
- Neutropaenia: recurrent/severe infections → mechanism: marrow crowding displaces normal granulopoiesis
- Thrombocytopaenia: bruising, petechiae, mucosal bleeding → mechanism: marrow infiltration ± splenic sequestration
Low-grade B-cell lymphomas (especially CLL/SLL) are commonly associated with autoimmune cytopaenias because the dysregulated B-cell clone produces autoantibodies or disrupts immune tolerance:
| Complication | Mechanism | Clinical |
|---|---|---|
| Autoimmune haemolytic anaemia (AIHA) | Warm-type IgG autoantibodies against RBC surface antigens | Jaundice + pallor + ↑reticulocytes + positive DAT |
| Immune thrombocytopaenia (ITP) | IgG autoantibodies against platelet glycoproteins | Bruising, petechiae, mucosal bleeding |
| Pure red cell aplasia (PRCA) | Autoantibodies/T-cells against erythroid precursors | Severe anaemia with absent reticulocytes |
Lymphoma itself causes immunodeficiency through multiple mechanisms:
- Hypogammaglobulinaemia: especially in CLL/SLL (↓IgG, IgA, IgM → recurrent sinopulmonary infections) [26]
- T-cell dysfunction: inherent in HL (immunosuppressive microenvironment around RS cells → impaired cell-mediated immunity → susceptibility to herpes zoster, fungal infections, Pneumocystis jirovecii)
- Splenic dysfunction: from splenic infiltration or splenectomy → risk of encapsulated bacterial infections (S. pneumoniae, N. meningitidis, H. influenzae)
- Most commonly seen in ATLL (adult T-cell leukaemia-lymphoma) and some aggressive NHL
- Mechanism: tumour cells produce PTHrP (parathyroid hormone-related peptide) or calcitriol (1,25-dihydroxyvitamin D) → ↑ bone resorption + ↑ renal calcium reabsorption + ↑ GI calcium absorption
- For lymphoma-related hypercalcaemia due to endogenous calcitriol overproduction → glucocorticoids are specifically indicated (mechanism: reduce calcitriol production by activated mononuclear/lymphoma cells) [36]
- Signs: confusion, dehydration, polyuria, constipation, shortened QT
| Organ | Complication | Mechanism |
|---|---|---|
| CNS | Leptomeningeal disease; primary CNS lymphoma | Direct infiltration; high risk in DLBCL (testicular, breast, high IPI), Burkitt, ALL/LBL |
| GI tract | Perforation, obstruction, bleeding | Transmural lymphomatous infiltration; especially Burkitt (ileocaecal), NK/T-cell, EATL |
| Kidneys | AKI from urate nephropathy, bilateral ureteric obstruction, direct infiltration, light chain deposition | TLS, retroperitoneal mass, parenchymal infiltration |
| Nose/palate | Palatal ulceration/perforation | NK/T-cell lymphoma (nasal type) — angiocentric, angiodestructive [2] |
This is a disease-related complication specific to low-grade NHL:
- Follicular lymphoma → DLBCL (~1–2% per year) [3]
- CLL/SLL → DLBCL (Richter transformation, 3–7%) [3]
- CLL → prolymphocytic leukaemia (2%), Hodgkin lymphoma (0.5–2%), or rarely multiple myeloma (0.1%) [3]
- Clinical clue: rapid clinical deterioration — rapidly enlarging node(s), new B symptoms, ↑LDH in a previously indolent disease
- Always requires new biopsy to confirm — management changes completely to aggressive chemoimmunotherapy
- Paraneoplastic pemphigus (PNP): painful mucocutaneous blistering and erosions, associated with NHL (especially follicular lymphoma), CLL, Castleman disease, Waldenström's, thymoma [39]
- Poor prognosis from bronchiolitis obliterans (BOS) [39]
- Anti-skin antibodies detectable
- Eosinophilia: body's reaction towards the tumour — classical Hodgkin lymphoma and T-cell lymphoma [28]
- Nephrotic syndrome: HL → minimal change disease (MCD); NHL → membranous nephropathy [40]
2. Treatment-Related Complications
| Complication | Drug(s) Responsible | Mechanism |
|---|---|---|
| Neutropenic fever | All myelosuppressive chemo | Bone marrow suppression → ANC < 0.5 → inability to mount immune response against endogenous flora → medical emergency requiring blood cultures + empirical broad-spectrum antibiotics within 1 hour [30] |
| Nausea/vomiting | Cisplatin, cyclophosphamide, doxorubicin | Stimulation of chemoreceptor trigger zone and vagal afferents |
| Mucositis | Cytarabine, methotrexate, conditioning regimens | Damage to rapidly dividing mucosal epithelial cells |
| Alopecia | Doxorubicin, cyclophosphamide, etoposide | Damage to rapidly dividing hair follicle matrix cells |
| Tumour lysis syndrome | Burkitt/ALL chemo | Massive tumour cell lysis (see above) |
| DIC | Rarely in lymphoma (more in APML) | Release of procoagulants |
| Extravasation injury | Doxorubicin (vesicant) | Direct tissue necrosis if leaks from IV |
These are directly from the lecture material and are heavily tested [3]:
| Drug | Toxicity | Mechanism | Monitoring |
|---|---|---|---|
| Doxorubicin (anthracycline) | Cardiotoxicity | Cumulative dose-dependent cardiomyopathy via free radical damage to cardiomyocytes + topoisomerase IIβ-mediated DNA damage in cardiomyocytes | Echocardiogram (LVEF) at baseline and periodically; cumulative dose limit ~450–550 mg/m² |
| Bleomycin | Pulmonary fibrosis (IPF) | Bleomycin hydrolase (which inactivates bleomycin) is deficient in lung tissue → lungs are selectively damaged; free radical-mediated damage to pneumocytes | Pulmonary function tests (DLCO) at baseline and during therapy [3]; avoid high FiO₂ (exacerbates toxicity) |
| Vincristine / Vinblastine | Peripheral neuropathy | Disruption of axonal microtubules → impaired axonal transport | Clinical assessment; dose reduction/omission if symptomatic |
| Cyclophosphamide | Gonadotoxicity, haemorrhagic cystitis, secondary malignancies | Direct DNA damage to germ cells; acrolein metabolite damages bladder epithelium | Adequate hydration; mesna (binds acrolein in urine); fertility counselling |
| Brentuximab vedotin | Peripheral neuropathy | MMAE (monomethyl auristatin E) payload disrupts microtubules — similar to vinca alkaloids | Clinical assessment |
| Methotrexate | Mucositis, myelosuppression, hepatotoxicity, nephrotoxicity (high-dose) | Folate antagonist → impairs DNA synthesis in all rapidly dividing cells; crystallises in renal tubules at high doses | Leucovorin rescue; alkaline hydration for high-dose MTX |
| Rituximab | HBV reactivation (can be FATAL), infusion reactions, hypogammaglobulinaemia, PML | Profound B-cell depletion → loss of immune surveillance of HBV/JC virus; cytokine release during first infusion | HBV serology before treatment; entecavir prophylaxis ≥ 12 months post-last dose [29] |
High Yield – Bleomycin Pulmonary Toxicity
Bleomycin is metabolised by bleomycin hydrolase, which is present in most tissues except the lung and skin. This is why the lung (and to a lesser extent skin) is selectively vulnerable. Risk factors for bleomycin pneumonitis: cumulative dose > 400 units, older age, renal impairment (↓ clearance), concurrent RT, high FiO₂ exposure. Clinically: dry cough, dyspnoea, bibasal crackles, reticular infiltrates on CXR. Can progress to fatal pulmonary fibrosis. Always check baseline DLCO!
| Complication | Mechanism | Timeline |
|---|---|---|
| Second malignancy | RT-induced DNA damage in normal tissues → carcinogenesis; risk highest in irradiated field (e.g., breast cancer after mantle RT in young women with HL) | Years to decades |
| Cardiac disease | Radiation-induced coronary artery disease, pericarditis, valvular disease, cardiomyopathy | Years |
| Hypothyroidism | Radiation damage to thyroid gland (neck/mediastinal RT) | Months to years |
| Pulmonary fibrosis | Radiation pneumonitis → fibrosis in irradiated lung parenchyma | Months |
| PVD, muscular atrophy | Vascular endothelial damage, fibrosis of irradiated soft tissues | Years |
2.4 HSCT-Related Complications
HSCT complications span the entire post-transplant timeline [33]:
| Complication | Details |
|---|---|
| Cytopaenia-related | Anaemia, bleeding (26% in first year, 9% life-threatening — sites: lung 16%, GI 14%, CNS 12%), neutropenic infections (bacterial and fungal) [33] |
| Oral mucositis | Due to conditioning regimen; managed with ice cubes, pre-treatment laser, IV palifermin ± TPN [33] |
| Veno-occlusive disease (VOD) of liver | Mechanism: conditioning damages hepatic venous endothelium → S/S: painful hepatomegaly, ascites, jaundice ± fulminant failure → Mx: ursodeoxycholic acid/heparin for prophylaxis, defibrotide + supportive treatment [33] |
| Graft rejection (host-versus-graft) | Residual host immune cells destroy donor cells |
| Acute graft-versus-host disease (aGVHD) | Donor T-cells attack recipient tissues (skin → rash, GI → diarrhoea, liver → jaundice); grading I–IV |
| Complication | Details |
|---|---|
| Cardiovascular disease | 5% at 5 years, 9% at 15 years; most common cause of morbidity/non-relapse mortality [33] |
| Endocrine dysfunction | T2DM (3× risk post-allo-HSCT), hypothyroidism, hypogonadism, infertility, osteoporosis/AVN (steroid use) [33] |
| Second malignancy | PTLD, post-treatment MDS/acute leukaemia, solid organ tumours (e.g., SCC of skin/oral cavity) [33] |
| Chronic GVHD | Sclerodermatous skin changes, sicca syndrome, bronchiolitis obliterans, hepatic dysfunction |
| Cataract | From total body irradiation [33] |
| Infections | Prolonged immunosuppression → viral reactivation (CMV, VZV, EBV), fungal, encapsulated bacteria |
3. Late Complications of Lymphoma Survivors
These are especially important for HL survivors, who are typically young at diagnosis and survive decades [3]:
Risk: 1.5–4.5× for solid tumours; increased risk for AML and NHL [3]
| Type | Sites / Timing |
|---|---|
| Solid tumours | Breast (after mantle RT — screen from 8 years post-RT or age 25, whichever is later), lung, colon, thyroid [3] |
| AML (therapy-related) | Peaks 5–9 years post-treatment; related to alkylating agents (cyclophosphamide, procarbazine) and topoisomerase II inhibitors (etoposide, doxorubicin) [3] |
| NHL | Can develop in HL survivors |
| PTLD | Post-transplant; EBV-driven; B-cell lymphoma — PTLD is a recognised long-term complication of renal transplant and HSCT [10][33] |
Second malignancy is the leading cause of late death in HL survivors who achieve remission.
Risk: 2.5×, remains elevated for ≥ 25 years [3]
- Mechanisms: anthracycline cardiotoxicity + mediastinal RT → accelerated coronary atherosclerosis, cardiomyopathy, valvular disease, pericarditis
- Requires lifelong cardiovascular risk factor management and surveillance echocardiography
Late pulmonary complications: IPF, bronchiectasis, pleural effusion [3]
- Bleomycin + RT synergistically damage lung parenchyma
- Monitor PFTs long-term
Endocrine/metabolic: hypothyroidism, DM, infertility [3]
- Hypothyroidism: especially after neck/mediastinal RT — monitor TSH annually
- Infertility: especially from cyclophosphamide, procarbazine (BEACOPP more gonadotoxic than ABVD) — fertility must be discussed before treatment [3]
- Premature menopause in women
- DM: from steroid use, metabolic syndrome post-treatment
Neuromuscular: muscular atrophy, neuropathy [3]
- Chronic peripheral neuropathy from vinca alkaloids or brentuximab vedotin
- May be irreversible
- Anxiety, depression, fear of recurrence, "chemobrain" (cognitive dysfunction)
- Impact on employment, relationships, quality of life
- Requires psychosocial support and rehabilitation
70% of children with cancer will survive, but have a lot of long-term complications [41].
- Biology: almost 100% of childhood lymphomas are aggressive (vs 60% of adult lymphomas are indolent) [41]
- Paradox: aggressive childhood lymphomas have better outcomes than adult counterparts [41] — due to higher chemosensitivity + fewer comorbidities + better treatment tolerance
- Growth retardation: from RT (especially craniospinal), chronic steroid use
- Neurocognitive deficits: from cranial RT and/or intrathecal chemotherapy
- Second malignancies: longer survival time → longer at-risk period → cumulative risk higher than adults
- Cardiac: anthracycline cardiomyopathy may not manifest for decades
| Category | Complications |
|---|---|
| Disease — metabolic | TLS (Burkitt, ALL), hypercalcaemia (ATLL), hyperuricaemia |
| Disease — compressive | SVCO, cord compression, ureteric obstruction, airway obstruction |
| Disease — infiltrative | Marrow failure (cytopaenias), CNS involvement, GI perforation/obstruction, nasal/palatal destruction (NK/T) |
| Disease — immune | AIHA, ITP, PRCA, hypogammaglobulinaemia, paraneoplastic pemphigus |
| Disease — transformation | Follicular → DLBCL, CLL → Richter (DLBCL), CLL → HL |
| Treatment — acute | Neutropenic fever, mucositis, nausea, TLS, infusion reactions |
| Treatment — organ-specific | Cardiotoxicity (doxorubicin), pulmonary fibrosis (bleomycin), neuropathy (vinca/BV), HBV reactivation (rituximab), haemorrhagic cystitis (cyclophosphamide) |
| Treatment — HSCT | GVHD (acute/chronic), VOD, infections, graft failure |
| Late — second malignancy | Solid tumours (breast, lung, colon, thyroid), t-AML/MDS, PTLD |
| Late — cardiovascular | 2.5× risk for ≥ 25 years |
| Late — endocrine | Hypothyroidism, infertility, premature menopause, DM, osteoporosis |
| Late — other | Pulmonary fibrosis, neurocognitive deficits, psychosocial |
High Yield Summary – Complications of Lymphoma
- TLS: "PAN-HIGH except calcium" — most dangerous in Burkitt/ALL; prophylaxis = hydration + allopurinol (check HLA-B*5801) ± rasburicase (check G6PD); do NOT replace Ca unless symptomatic
- SVCO: mediastinal mass → facial plethora, distended neck veins; urgent if airway compromise
- Histological transformation: follicular → DLBCL (~1–2%/yr); CLL → Richter/DLBCL (3–7%) — always re-biopsy
- Drug toxicities: doxorubicin → heart; bleomycin → lungs; vincristine → nerves; cyclophosphamide → fertility + bladder; rituximab → HBV reactivation (FATAL)
- HBV reactivation with rituximab: check serology pre-treatment; entecavir prophylaxis ≥ 12 months post-last dose; can occur up to 11 months after stopping
- Irradiated blood products: mandatory for ALL HL patients (any stage), HSCT recipients, congenital immunodeficiency, potent immunosuppressants — prevents TA-GvHD (uniformly fatal)
- Late effects (especially HL survivors): second malignancy (leading cause of late death; 1.5–4.5×), CVD (2.5× for ≥ 25 years), hypothyroidism, infertility
- Childhood paradox: aggressive but better outcomes; long survivorship → long-term complications (growth, neurocognitive, cardiac, second malignancy)
- Paraneoplastic: pemphigus (NHL, CLL, Castleman), eosinophilia (HL, T-cell lymphoma), MCD (HL)
- Autoimmune cytopaenias: AIHA, ITP in CLL/SLL — due to dysregulated B-cell clone
Active Recall - Complications of Lymphoma
References
[2] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 426, lymphoma classification, NK-cell lymphoma palatal destruction, HHV-8 association) [3] Senior notes: Ryan Ho Haemtology.pdf (p. 96, HL peri-treatment issues — irradiated blood, drug toxicity, late complications table — second malignancies 1.5–4.5×, CVD 2.5× for ≥ 25y, endocrine/metabolic, neuromuscular; p. 98, initial evaluation — CBC abnormal 60%, pleural effusion 10%; p. 68, CLL transformation — Richter 3–7%, PLL 2%, HL 0.5–2%) [10] Senior notes: Block A - Renal Replacement Therapies.pdf (p. 36, 39, PTLD as long-term complication of renal transplant, EBV-related B-cell lymphoma) [15] Senior notes: Maksim Medicine Notes.pdf (p. 48, TLS — high-risk malignancies, risk factors, prophylaxis, management, hyperviscosity/plasmapheresis) [26] Senior notes: Ryan Ho Haemtology.pdf (p. 67, CLL — hypogammaglobulinaemia) [28] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf (p. 3, eosinophilia — tumour reaction in cHL and T-cell lymphoma) [29] Senior notes: Block A - I am a hepatitis B carrier.pdf (p. 68–69, rituximab HBV reactivation, fatal fulminant liver failure, entecavir prophylaxis, duration of cover) [30] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (p. 9, supportive treatment — neutropenic sepsis, TLS, leukostasis, HLA-B*5801; p. 28, HSCT indications — relapsed lymphoma) [33] Senior notes: Ryan Ho Haemtology.pdf (p. 153, 156, HSCT complications — early and late, VOD, GVHD, CVD 5% at 5y/9% at 15y, endocrine, second malignancy, cataract from TBI) [34] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 424, TLS — causes, pathophysiology "PAN-HIGH except calcium", monitoring frequency, supportive therapy) [36] Senior notes: Block A - Confused and dehydrated_ hypercalcaemia; hypocalcaemia.pdf (p. 11, glucocorticoids for lymphoma-related hypercalcaemia — reduce calcitriol production) [38] Senior notes: Ryan Ho Haemtology.pdf (p. 98, initial evaluation — blood test findings, complications workup) [39] Lecture slides: Derm General Clerkship 2026 Part2.pdf (p. 28, paraneoplastic pemphigus — NHL, CLL, Castleman, poor prognosis from BOS) [40] Senior notes: Ryan Ho Urogenital.pdf (p. 77, MCD secondary to haematologic malignancy — HL, NHL) [41] Paediatrics lecture slides: Block C - A child with cancer_ paediatric cancers.pdf (p. 2, 70% survival but long-term complications, 100% aggressive biology in childhood lymphoma)
High Yield Summary
Definition: Lymphoma = clonal neoplasm of B-cells, T-cells, or NK-cells at various stages of differentiation; all tumour cells share the same VDJ rearrangement (monoclonal)
Epidemiology: NHL >> HL (~90:10); NHL median age 65–70y; HL bimodal; NK/T-cell lymphoma predominantly Asian
Key Risk Factors:
- HL: EBV, HIV, immunosuppression, FHx
- NHL: t(14;18)/t(8;14)/t(11;14), HIV (100×), EBV, HTLV-1, HHV-8, H. pylori, immunodeficiency, autoimmune disease
Classification:
- HL: Classical (NS > MC > LR > LD) vs NLPHL
- NHL: B-cell (85%) > T-cell > NK-cell; High-grade (aggressive, curable) vs Low-grade (indolent, incurable)
- "Lymphoma paradox": high-grade = more aggressive but more curable; low-grade = less aggressive but incurable
Clinical Features:
- Hallmark: painless, progressive lymphadenopathy (firm, rubbery)
- B symptoms: fever > 38°C, drenching night sweats, > 10% weight loss in 6 months
- HL: contiguous spread, mediastinal mass, pruritus, alcohol-induced pain
- NHL: non-contiguous, extranodal disease common, organomegaly
- High-grade: acute onset, rapidly growing, prominent B symptoms
- Low-grade: chronic, slowly progressive, may wax and wane
- Special subtypes: NK/T-cell → nasal/palatal destruction; MALT → H. pylori; thyroid lymphoma → Hashimoto's
Key Pathology:
- HL: Reed-Sternberg cells (CD15+/CD30+/CD20−)
- Follicular: t(14;18)/BCL2, nodular pattern
- Burkitt: t(8;14)/c-MYC, starry sky, Ki-67 ~100%
- Mantle cell: t(11;14)/cyclin D1
Key Immunophenotype: CD20 for B-cell, CD3 for T-cell, CD56 for NK-cell; clonal IGH/TCR rearrangement confirms clonality
High Yield Summary – Differential Diagnosis of Lymphoma
- Framework for LAD DDx: Neoplastic (leukaemia/lymphoma) > Infective (EBV, CMV, TB, parasites) > Autoimmune (SLE, sarcoidosis, Kikuchi) > Drugs
- Lymphoma vs reactive: Monoclonal (lymphoma) vs polyclonal (reactive) — confirmed by flow cytometry or PCR for clonal IGH/TCR rearrangement
- HL vs NHL: RS cells + CD15/CD30 = HL; CD20+ = B-NHL; CD3+ = T-NHL; CD56+/EBER+ = NK/T-cell NHL
- High-grade vs low-grade NHL: Rapid onset + B symptoms + curable = high-grade; Insidious + indolent + incurable = low-grade
- CLL → Richter transformation (to DLBCL): suspect if rapidly enlarging nodes + ↑LDH + new B symptoms in known CLL
- HK-specific DDx: TB lymphadenitis, Kikuchi disease, NPC metastasis, NK/T-cell lymphoma, EBV/IM
- Extranodal DDx: Thyroid lymphoma vs anaplastic CA (both rapid goitre, vastly different prognosis); gastric MALT vs gastric adenocarcinoma; primary CNS lymphoma vs GBM/toxoplasmosis; NK/T-cell lymphoma vs NPC vs GPA
- ALL vs Burkitt: TdT+ = ALL; TdT−, surface Ig+, t(8;14) = Burkitt
High Yield Summary – Diagnosis and Investigations
- Lymphoma diagnosis = tissue diagnosis. Excisional LN biopsy is the gold standard; FNA alone is NEVER sufficient.
- MCICM framework: Morphology → Cytochemistry → Immunophenotype → Cytogenetics → Molecular genetics. All three of histology, immunophenotyping, and cytogenetics/molecular are needed for classification.
- Flow cytometry detects surface markers and light chain restriction (clonality); IHC works on fixed tissue; PCR for IGH/TCR confirms clonality at the molecular level.
- Key markers: CD20 (B-cell), CD3 (T-cell), CD56 (NK-cell), CD15/CD30 (HL), CD5/CD23 (CLL), Cyclin D1 (mantle cell), TdT (precursor/blast).
- Staging: Ann Arbor I–IV with A/B suffix. PET-CT is standard for FDG-avid lymphomas. Deauville score (1–5) for response assessment.
- Pre-treatment essentials: HBV serology (rituximab → HBV reactivation risk), echo (anthracycline), PFTs (bleomycin), fertility counselling, G6PD (rasburicase).
- Spleen biopsy does not exist — splenectomy for suspected splenic lymphoma.
- CLL diagnosis: ≥ 5 × 10⁹/L monoclonal B-lymphocytes with CD5+/CD19+/CD20+(dim)/CD23+/light chain restriction.
High Yield Summary – Lymphoma Management
- HL: ABVD is the backbone; response-adapted therapy using PET-CT (Deauville score); irradiate ALL blood products; excellent prognosis (~80–90% cure)
- DLBCL: R-CHOP × 6–8; rituximab revolutionised outcomes; ~60% curable
- Burkitt: intensive chemo + CNS prophylaxis; TLS prophylaxis mandatory (allopurinol/rasburicase + hydration)
- Follicular: cure possible ONLY in stage I (RT); otherwise watch and wait if asymptomatic, BR/R-CHOP if symptomatic; transformation to DLBCL ~1–2%/year
- Gastric MALT: H. pylori eradication first; t(11;18) predicts failure of HP eradication
- CLL: observe early/asymptomatic; treat with FCR (young), ibrutinib/venetoclax (all ages, especially del(17p))
- Rituximab: anti-CD20; check HBV status before starting — HBV reactivation can be fatal; entecavir prophylaxis for ≥ 12 months post-last dose
- Supportive care: TLS prevention (check HLA-B*5801 before allopurinol, G6PD before rasburicase), neutropenic fever protocols, irradiated blood for HL/HSCT/immunosuppressed
- HSCT: autologous for relapsed DLBCL/HL/mantle cell; allogeneic for relapsed lymphoma/high-risk CLL/refractory disease
- Late effects: second malignancies (1.5–4.5×), cardiovascular disease (2.5× for ≥ 25 years), hypothyroidism, infertility, pulmonary fibrosis
High Yield Summary – Complications of Lymphoma
- TLS: "PAN-HIGH except calcium" — most dangerous in Burkitt/ALL; prophylaxis = hydration + allopurinol (check HLA-B*5801) ± rasburicase (check G6PD); do NOT replace Ca unless symptomatic
- SVCO: mediastinal mass → facial plethora, distended neck veins; urgent if airway compromise
- Histological transformation: follicular → DLBCL (~1–2%/yr); CLL → Richter/DLBCL (3–7%) — always re-biopsy
- Drug toxicities: doxorubicin → heart; bleomycin → lungs; vincristine → nerves; cyclophosphamide → fertility + bladder; rituximab → HBV reactivation (FATAL)
- HBV reactivation with rituximab: check serology pre-treatment; entecavir prophylaxis ≥ 12 months post-last dose; can occur up to 11 months after stopping
- Irradiated blood products: mandatory for ALL HL patients (any stage), HSCT recipients, congenital immunodeficiency, potent immunosuppressants — prevents TA-GvHD (uniformly fatal)
- Late effects (especially HL survivors): second malignancy (leading cause of late death; 1.5–4.5×), CVD (2.5× for ≥ 25 years), hypothyroidism, infertility
- Childhood paradox: aggressive but better outcomes; long survivorship → long-term complications (growth, neurocognitive, cardiac, second malignancy)
- Paraneoplastic: pemphigus (NHL, CLL, Castleman), eosinophilia (HL, T-cell lymphoma), MCD (HL)
- Autoimmune cytopaenias: AIHA, ITP in CLL/SLL — due to dysregulated B-cell clone