Lymphomas — Hodgkin & Non-Hodgkin

Lymphomas are clonal malignancies of lymphocytes that present as solid tumours of lymphoid tissue (nodal or extranodal). They are broadly split into Hodgkin lymphoma (HL) — characterised by Reed–Sternberg (RS) cells in an inflammatory background — and Non-Hodgkin lymphoma (NHL), a heterogeneous group of B-cell (≈85%) and T/NK-cell neoplasms. This is a high-yield Medicine + Pathology overlap topic where staging, immunophenotype, and the named chemotherapy regimens are the most repeatedly tested points.

Definition & classification

A useful mental model: leukaemia = bone-marrow/blood predominant, lymphoma = solid lymphoid-mass predominant, though there is overlap (e.g., CLL/SLL is the same disease in different compartments).

• Hodgkin lymphoma — neoplastic RS cells comprise <1% of the tumour; the bulk is reactive lymphocytes, eosinophils, and plasma cells.
  • Classical HL (95%): RS cells CD15+, CD30+, CD20–, PAX5 weak. Four subtypes.
  • Nodular lymphocyte-predominant HL (NLPHL, 5%): "popcorn"/LP cells, CD20+, CD45+, CD15–, CD30– — behaves more like an indolent B-cell NHL.
• Non-Hodgkin lymphoma — classified by the WHO scheme into indolent (low-grade) and aggressive (high/intermediate-grade) categories based on cell of origin and behaviour.

High-yield: Classical RS cell is CD15+/CD30+/CD20–; NLPHL "popcorn" cell is the reverse — CD20+/CD30–/CD15–. This single contrast is the most repeated immunophenotype question.

Classical Hodgkin subtypes

Subtype	Frequency	Key features	Prognosis
Nodular sclerosis	Most common (~70%)	Young women, mediastinal mass, lacunar cells, collagen bands	Good
Mixed cellularity	~20%	Older/HIV, EBV+, many RS cells, eosinophils	Intermediate
Lymphocyte-rich	~5%	Few RS cells, many lymphocytes	Best (classical)
Lymphocyte-depleted	<1%	Elderly, HIV, abdominal/retroperitoneal	Worst

High-yield: Nodular sclerosis is commonest overall; lymphocyte-rich = best prognosis among classical types; lymphocyte-depleted = worst and is associated with HIV/EBV.

Common NHL subtypes

Subtype	Origin	Genetics / marker	Behaviour
Diffuse large B-cell (DLBCL)	Mature B	BCL6, BCL2, MYC ("double/triple hit"); CD20+	Aggressive, commonest NHL
Follicular	Germinal centre B	t(14;18) → BCL2 overexpression	Indolent
Burkitt	B	t(8;14) → c-MYC; Ki-67 ~100%	Highly aggressive
Mantle cell	Mantle-zone B	t(11;14) → cyclin D1 (BCL1)	Aggressive, poor
MALT (marginal zone)	Mucosa B	H. pylori, t(11;18)	Indolent
Small lymphocytic (SLL/CLL)	Mature B	CD5+, CD23+	Indolent
Adult T-cell leukaemia/lymphoma	T	HTLV-1, hypercalcaemia	Aggressive
Mycosis fungoides / Sézary	CD4 T (skin)	CD4+, cerebriform nuclei	Indolent → aggressive

High-yield: DLBCL is the single most common NHL. Translocation triad to memorise — Follicular t(14;18), Burkitt t(8;14), Mantle cell t(11;14).

Etiology & pathophysiology

• Hodgkin lymphoma
  • Bimodal age distribution: peak in young adults (15–35 y) and a second peak >55 y.
  • EBV implicated, especially in mixed-cellularity and HIV-associated HL (LMP-1 protein).
  • The RS cell is a germinal-centre B cell that has lost surface immunoglobulin; it secretes cytokines (IL-5 → eosinophilia, TGF-β → fibrosis), producing the reactive infiltrate and B symptoms.
• Non-Hodgkin lymphoma — driven by translocations that dysregulate proto-oncogenes (BCL2 anti-apoptosis, MYC proliferation, cyclin D1 cell-cycle).
  • Infections: EBV (Burkitt, post-transplant), HTLV-1 (ATLL), H. pylori (gastric MALT), HCV (splenic marginal zone), HHV-8 (primary effusion lymphoma), Chlamydia psittaci (ocular adnexal MALT), Borrelia (cutaneous), Campylobacter jejuni (IPSID/small-bowel MALT).
  • Immunodeficiency: HIV (DLBCL, primary CNS lymphoma, Burkitt), transplant immunosuppression (PTLD), autoimmune disease (Sjögren → MALT; Hashimoto → thyroid lymphoma; coeliac → enteropathy-associated T-cell lymphoma).

High-yield: Endemic (African) Burkitt → jaw/mandible, EBV-driven; Sporadic Burkitt → abdominal/ileocaecal. Both share t(8;14) c-MYC and a classic "starry-sky" histology (tingible-body macrophages engulfing apoptotic debris).

Clinical features

• Painless lymphadenopathy — rubbery, firm; HL classically spreads contiguously node-to-node, whereas NHL spreads non-contiguously and is more often disseminated/extranodal at presentation.
• B symptoms (defined for staging):
  1. Fever >38°C (Pel–Ebstein fever — cyclical, classic for HL)
  2. Drenching night sweats
  3. Weight loss >10% of body weight over 6 months
• Alcohol-induced nodal pain — rare but specific for HL.
• Pruritus — common in HL (but NOT a staging B symptom).
• Mediastinal mass (nodular sclerosis HL, primary mediastinal B-cell lymphoma) → SVC obstruction, cough.
• Extranodal disease (NHL): GI (commonest extranodal site), Waldeyer's ring, skin (CTCL), CNS, testis.
• Oncological emergencies: tumour lysis syndrome (Burkitt, on starting therapy), SVC syndrome, spinal cord compression.

High-yield: Pel–Ebstein fever (cyclical, days of fever alternating with afebrile periods) and alcohol-induced pain are pointers to Hodgkin lymphoma.

Diagnosis & investigation of choice

Diagnostic approach (flow):

Persistent/unexplained lymphadenopathy → Excisional lymph-node biopsy (NOT FNAC) → Histology + Immunohistochemistry → PET-CT for staging → Bone-marrow biopsy (if indicated) → Risk stratify (IPS / IPI)

• Excisional biopsy is the investigation of choice — architecture is essential to diagnose lymphoma; FNAC cannot reliably distinguish subtype or assess nodal architecture.
• Immunohistochemistry / flow cytometry establishes lineage and subtype (CD15/CD30 for HL; CD20, CD10, BCL2, BCL6, cyclin D1, Ki-67 for NHL).
• PET-CT (FDG) — staging modality of choice for both HL and most NHL; also used for interim response (Deauville score) and end-of-treatment assessment.
• Bone-marrow biopsy — for staging; increasingly omitted in HL when PET-CT shows no marrow uptake.
• LDH — surrogate for tumour burden; component of IPI.
• Baseline ECHO (anthracycline cardiotoxicity) and PFTs (bleomycin lung toxicity) before chemotherapy; HIV, HBV, HCV serology; fertility counselling.

Ann Arbor staging (with Cotswold modification)

Stage	Definition
I	Single lymph-node region (or single extralymphatic site, IE)
II	≥2 regions on the same side of the diaphragm
III	Nodal regions on both sides of the diaphragm (III S = spleen involved)
IV	Diffuse extralymphatic involvement (e.g., marrow, liver, lung)

Suffixes: A = no B symptoms; B = B symptoms present; E = localised extranodal extension; X = bulky disease (mediastinal mass >1/3 thoracic width or node >10 cm).

High-yield: The spleen is treated as lymphoid tissue (so splenic involvement alone is III S, not stage IV). The liver and bone marrow are extralymphatic, so their involvement = stage IV.

Prognostic scores

International Prognostic Score (IPS) — advanced Hodgkin lymphoma (7 factors)

Each adverse factor reduces survival by ~7–8% per point:

1. Albumin <4 g/dL
2. Haemoglobin <10.5 g/dL
3. Male sex
4. Age ≥45 years
5. Stage IV disease
6. Leucocytosis (WBC ≥15,000)
7. Lymphocytopenia (<600 or <8% of WBC)

International Prognostic Index (IPI) — aggressive NHL (DLBCL)

Mnemonic "APLES": Age >60, Performance status (ECOG ≥2), LDH raised, Extranodal sites >1, Stage III/IV (Ann Arbor).

High-yield: IPS is for Hodgkin (7 factors); IPI/"APLES" is for NHL. Do not mix them — a classic distractor pairing.

Management / drug of choice

Hodgkin lymphoma

• ABVD is the standard regimen — Adriamycin (doxorubicin), Bleomycin, Vinblastine, Dacarbazine.
  • Early-stage favourable: short ABVD (2–4 cycles) + involved-site radiotherapy.
  • Advanced: 6 cycles ABVD; PET-adapted escalation/de-escalation (interim PET-2 negative → drop bleomycin → "AVD").
• Escalated BEACOPP — for high-risk advanced disease; more toxic.
• Brentuximab vedotin (anti-CD30 antibody–drug conjugate) and PD-1 inhibitors (nivolumab, pembrolizumab) for relapsed/refractory; autologous stem-cell transplant for relapse.
• NLPHL (CD20+): rituximab-based approaches.

High-yield: Mnemonic for ABVD toxicities — "A breaks the heart, B the lungs": Adriamycin → cardiomyopathy; Bleomycin → pulmonary fibrosis; Vinblastine → neuropathy/myelosuppression. Hence baseline ECHO + PFTs.

Non-Hodgkin lymphoma

• DLBCL → R-CHOP — Rituximab + Cyclophosphamide, Hydroxydaunorubicin (doxorubicin), Oncovin (vincristine), Prednisolone. Usually 6 cycles; curable in many.
• Follicular lymphoma (indolent): watch-and-wait if asymptomatic/low burden; rituximab ± bendamustine or R-CHOP when treatment is indicated.
• Burkitt lymphoma: intensive multi-agent chemo (e.g., R-CODOX-M/IVAC or DA-EPOCH-R) with CNS prophylaxis and aggressive tumour-lysis prophylaxis (rasburicase, hydration).
• Mantle cell: aggressive, often R-CHOP/cytarabine + transplant; BTK inhibitors (ibrutinib).
• Gastric MALT lymphoma: H. pylori eradication (triple therapy) alone induces remission in the majority — treatment of choice when H. pylori-positive and t(11;18)-negative.
• CNS prophylaxis (intrathecal methotrexate) for Burkitt, testicular, and high-risk DLBCL.

High-yield: R-CHOP is the answer for DLBCL; H. pylori eradication is first-line for early gastric MALT lymphoma — a favourite single-best-answer.

Complications

• Treatment-related: tumour lysis syndrome (hyperuricaemia, hyperkalaemia, hyperphosphataemia, hypocalcaemia, AKI), bleomycin-induced pneumonitis, anthracycline cardiomyopathy, vincristine neuropathy, infertility, secondary malignancies (AML, solid tumours, breast cancer after mantle/mediastinal radiotherapy), hypothyroidism after neck RT.
• Disease-related: marrow failure (cytopenias), SVC obstruction, spinal cord compression, paraneoplastic phenomena, immune dysfunction with opportunistic infection (especially HL — defective cell-mediated immunity → herpes zoster, fungal infections).
• Richter transformation: CLL/SLL transforming into aggressive DLBCL — sudden clinical deterioration, rising LDH.

High-yield: Rapidly enlarging node + soaring LDH in a known CLL patient → suspect Richter transformation to DLBCL.

Key differentials

• Reactive lymphadenopathy / infections: TB lymphadenitis (caseating granuloma, very common in India), infectious mononucleosis (EBV — atypical lymphocytes can mimic lymphoma), toxoplasmosis, HIV.
• Other malignancy: metastatic carcinoma to nodes, leukaemic infiltration.
• HL vs NHL: contiguous spread, B symptoms, RS cells, mediastinal mass favour HL; extranodal/disseminated disease and older age favour NHL.
• Granulomatous disease: sarcoidosis (bilateral hilar lymphadenopathy, non-caseating granuloma) vs lymphoma mediastinal mass.
• Castleman disease (HHV-8/IL-6 driven angiofollicular hyperplasia) — mimics lymphoma.

Feature	Hodgkin	Non-Hodgkin
Spread	Contiguous, orderly	Non-contiguous, scattered
Extranodal at onset	Uncommon	Common
Age	Bimodal (young + old)	Increases with age
B symptoms	More frequent	Less frequent
Hallmark cell	Reed–Sternberg	Varies by subtype
Bone-marrow involvement	Uncommon	Common
Curability	Often curable even when advanced	Variable (aggressive often curable; indolent rarely)

Recently asked / exam angle

• Immunophenotype matching: "RS cell positive for which markers?" → CD15, CD30. "Popcorn cell?" → CD20.
• Translocation → disease: t(14;18) follicular (BCL2), t(8;14) Burkitt (c-MYC), t(11;14) mantle cell (cyclin D1), t(11;18) MALT.
• Staging interpretation: spleen = lymphoid (III S), liver/marrow = extralymphatic (IV); identify what counts as a "B symptom" (fever, night sweats, >10% weight loss — pruritus and fatigue are NOT staging B symptoms).
• Investigation of choice: excisional biopsy (not FNAC); staging modality = PET-CT.
• Regimen recall: ABVD (HL) vs R-CHOP (DLBCL); component-toxicity pairs (bleomycin–lung, doxorubicin–heart).
• Prognostic-score allocation: IPS = Hodgkin (7 factors), IPI = NHL.
• MALT + H. pylori eradication as first-line; Pel–Ebstein and alcohol-induced pain as HL pointers.
• Burkitt: starry-sky, Ki-67 ~100%, highest tumour-lysis risk; endemic = jaw, sporadic = abdomen.
• Best vs worst prognosis subtype of classical HL (lymphocyte-rich best, lymphocyte-depleted worst).

Rapid revision

• Reed–Sternberg cell = "owl-eye" binucleate cell; CD15+, CD30+, CD20–.
• Nodular sclerosis = commonest HL; young women + mediastinal mass + lacunar cells.
• Lymphocyte-depleted = worst HL prognosis; lymphocyte-rich = best.
• DLBCL = commonest NHL overall; treat with R-CHOP.
• Follicular t(14;18) BCL2; Burkitt t(8;14) c-MYC; Mantle t(11;14) cyclin D1; MALT t(11;18).
• Burkitt = starry-sky, Ki-67≈100%, highest tumour-lysis risk; endemic → jaw (EBV), sporadic → abdomen.
• B symptoms = fever + drenching night sweats + >10% weight loss; Pel–Ebstein fever is classic HL.
• Spleen = lymphoid (stage III S); liver/marrow = extralymphatic (stage IV).
• Excisional biopsy is diagnostic gold standard (never FNAC); PET-CT is the staging modality of choice.
• ABVD for HL — bleomycin → lung fibrosis, doxorubicin → cardiomyopathy (do PFTs + ECHO first).
• IPS = Hodgkin (7 factors), IPI "APLES" = NHL (age, performance status, LDH, extranodal sites, stage).
• Gastric MALT → eradicate H. pylori first; Richter transformation = CLL → DLBCL.