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.

Exam domain	One-glance essentials
Definition / diagnosis	*Clonal neoplasm of B-, T- or NK-lineage lymphoid cells, usually presenting in lymphoid tissue* ^[1] Hodgkin lymphoma is defined pathologically by characteristic Reed-Sternberg–type cells; NHL comprises the remaining diverse entities ^[2]
Epidemiology / risks	Infections: EBV (Burkitt, PTLD, NK/T, some HL), H. pylori (gastric MALT), HTLV-1 (ATLL), HHV-8 (primary effusion) ^[1] HIV/immunosuppression and autoimmune disease increase risk; *NK/T lymphoma is particularly relevant in Asian populations* ^[1]
Core mechanism	Antigen-receptor rearrangement creates clonality; oncogene translocations drive survival/proliferation ^[1] *t(14;18)→BCL2 follicular; t(8;14)→MYC Burkitt; t(11;14)→cyclin D1 mantle cell* ^[1]
Clinical picture	Painless progressive firm/rubbery lymphadenopathy ± extranodal mass ^[2] B symptoms: fever > 38°C, drenching night sweats, > 10% weight loss in 6 months ^[2] HL tends to contiguous spread; NHL is often non-contiguous/extranodal ^[2]
Investigations	*Excisional lymph-node biopsy is preferred; FNA alone is insufficient because architecture is essential* ^[2] Classify with histology + immunophenotype + cytogenetic/molecular tests ^[2] Stage FDG-avid disease with PET-CT/Ann Arbor; check CBC, LDH, renal/liver function and viral serology ^[2]
Management	Management depends on subtype, stage and fitness ^[2] cHL: ABVD-based; DLBCL: *R-CHOP*; localised gastric MALT: H. pylori eradication when appropriate ^[3] Some asymptomatic indolent NHL can be observed; high-grade lymphoma is aggressive but potentially curable ^[3]
Complications	TLS, SVCO, cord compression, marrow failure, infection and organ obstruction/infiltration ^[3] Indolent disease may transform to DLBCL: rapid node growth, new B symptoms, rising LDH → re-biopsy ^[3] Late effects: cardiopulmonary toxicity, infertility and second malignancies ^[3]
Prevention / follow-up	Before rituximab: *screen HBsAg, anti-HBc and anti-HBs* and provide antiviral prophylaxis when indicated ^[3] TLS prophylaxis for bulky/high-grade disease; baseline echo before anthracycline and PFTs before bleomycin ^[2] Discuss fertility preservation before gonadotoxic treatment ^[2]
Exam traps	*Reactive lymphadenopathy is polyclonal; lymphoma is monoclonal—tissue remains decisive ^[1] Classical HL: CD15+/CD30+/usually CD20−*; B-NHL commonly CD20+ ^[2] Do not give steroids before biopsy of suspected primary CNS lymphoma; tissue may become non-diagnostic ^[3]

References

^[1] Lecture slides: Molecular Pathology Seminar 4_MALIGNANT LYMPHOMA.pdf (clonality, translocations and infection associations) ^[2] Senior notes: Block A - Generalised Lymphadenopathy_ Differential diagnosis and principle of management.pdf (lymphoma diagnosis, staging and treatment principles) ^[3] Senior notes: Ryan Ho Haemtology.pdf (Hodgkin and non-Hodgkin lymphoma management and complications, p.93–99)

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:
- NK-cell lymphoma: predominantly occurs in Asians (very rare in the West), associated with EBV ^[2]
- T-cell lymphomas (e.g., HTLV-1 associated adult T-cell leukaemia-lymphoma): prevalent in Japan, Taiwan, and Caribbean ^[2]
- Gastric MALT lymphoma is common in regions with high H. pylori prevalence ^[5]

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]

HHV-8 (also causes Kaposi sarcoma) → viral proteins (v-FLIP, v-cyclin) promote cell survival and proliferation
Associated with primary effusion lymphoma ^[2]^[3] — presents as body cavity effusions without a solid tumour mass

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)

Palatal ulcer/perforation: pathognomonic for NK/T-cell lymphoma (nasal type) ^[2]^[9]
Abdominal mass: may be palpable in abdominal lymphoma (Burkitt, DLBCL)
Testicular mass: painless, firm enlargement
Neurological signs: if CNS involvement

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

Most common site for extranodal NHL ^[5]
H. pylori eradication can lead to regression in early-stage, HP-positive, t(11;18)-negative tumours ^[5]
Staging: EUS-guided biopsy for diagnosis + CT thorax/abdomen + bone marrow biopsy for staging + HP testing and FISH for t(11;18) ^[5]

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:

Thyroid lymphoma (DLBCL): R-CHOP + EBRT, median survival 9 years ^[6]
Anaplastic thyroid CA: chemoirradiation ± debulking, median survival < 6 months ^[6] The management and prognosis are radically different — you must get tissue before committing to a treatment plan.

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

Treatment options ^[3]^[32]:

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

R-CHOP + external beam radiotherapy (EBRT) as standard therapy ^[6]
Prognosis: better than anaplastic thyroid CA; median survival 9 years ^[6]

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.

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].

Risk factors ^[15]^[34]:

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

Pleural effusion in up to 10% at diagnosis ^[3]^[38]
Pericardial effusion → tamponade (rare but serious)
Ascites (abdominal/pelvic lymphoma)
Primary effusion lymphoma: body cavity effusions without solid mass, a/w HHV-8 ^[2]

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]

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

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

Lymphoma

References

Lymphoma

1. Definition

2. Epidemiology

2.1 Hodgkin Lymphoma (HL)

2.2 Non-Hodgkin Lymphoma (NHL)

2.3 Paediatric Considerations

3. Risk Factors

3.1 Hodgkin Lymphoma Risk Factors

3.2 Non-Hodgkin Lymphoma Risk Factors

3.3 Specific Hong Kong / Asian Considerations

4. Anatomy and Function of the Lymphoid System (Relevant to Lymphoma)

4.1 Primary Lymphoid Organs

4.2 Secondary Lymphoid Organs

4.3 Normal B-cell Development and Lymphoma Origin

5. Etiology and Pathophysiology

5.1 General Principles of Lymphomagenesis

5.1.1 Oncogene Activation

5.1.2 Tumour Suppressor Gene Inactivation

5.1.3 Aberrant Somatic Hypermutation

5.1.4 Epigenetic Dysregulation

5.2 Role of Infections

5.2.1 Epstein-Barr Virus (EBV)

5.2.2 H. pylori and Gastric MALT Lymphoma

5.2.3 HTLV-1 and Adult T-cell Leukaemia-Lymphoma (ATLL)

5.2.4 HHV-8 and Primary Effusion Lymphoma

5.3 Role of Immunodeficiency

5.4 Autoimmune Disease and Lymphoma

6. Classification

6.1 Overview

6.2 Hodgkin Lymphoma Classification

6.3 Non-Hodgkin Lymphoma Classification

6.3.1 By Cell Lineage

6.3.2 By Grade/Behaviour

6.3.3 Key NHL Subtypes (High Yield)

7. Clinical Features

7.1 General Presentation: Symptoms

7.1.1 Lymphadenopathy (Most Common Presenting Feature)

7.1.2 B Symptoms (Constitutional Symptoms)

7.1.3 Symptoms of Local Compression / Organ Involvement

7.1.4 Symptoms of Cytopaenias (Bone Marrow Involvement)

7.1.5 Pruritus

7.1.6 Fatigue and Malaise

7.2 General Presentation: Signs

7.2.1 Lymphadenopathy on Examination

7.2.2 Hepatosplenomegaly

7.2.3 Waldeyer's Ring Involvement

7.2.4 Superior Vena Cava Obstruction (SVCO) Signs

7.2.5 Skin Signs

7.2.6 Extranodal Disease Signs

7.2.7 Signs Related to Autoimmune Phenomena

7.3 Hodgkin vs Non-Hodgkin: Clinical Feature Comparison

7.4 Low-Grade vs High-Grade NHL: Clinical Feature Comparison

8. Immunophenotyping and Molecular Markers (Key for Diagnosis)

8.1 Flow Cytometry Markers

8.2 Molecular/Genetic Testing

9. Pathology – The Reed-Sternberg Cell and Other Histological Features

9.1 Reed-Sternberg (RS) Cell (Hodgkin Lymphoma)

9.2 Burkitt Lymphoma Histology

9.3 Follicular Lymphoma Histology

10. Important Special Subtypes and Clinical Scenarios

10.1 Primary CNS Lymphoma

10.2 Gastric MALT Lymphoma

10.3 Post-Transplant Lymphoproliferative Disorder (PTLD)

10.4 Thyroid Lymphoma

10.5 Tumour Lysis Syndrome (TLS)

Active Recall - Lymphoma (Definition to Clinical Features)

References

Differential Diagnosis of Lymphoma

1. Clinical Approach to the Differential Diagnosis

2. Differential Diagnosis by Clinical Presentation

2.1 Differential Diagnosis of Lymphadenopathy (the Most Common Presenting Feature of Lymphoma)

2.2 Differential Diagnosis of Specific Lymphoma Presentations

2.2.1 Mediastinal Mass

2.2.2 Splenomegaly Without Prominent Lymphadenopathy

2.2.3 Bone Pain and Anaemia in an Elderly Patient

2.2.4 Extranodal Presentations

3. Distinguishing Between Lymphoma Subtypes

3.1 Hodgkin vs Non-Hodgkin Lymphoma