Hodgkin lymphoma

Overview

Hodgkin lymphoma (HL), formerly known as Hodgkin’s disease, is a distinct neoplasm of lymphoid tissue characterized by the presence of malignant Reed-Sternberg (RS) cells within a reactive inflammatory microenvironment. It represents approximately 10–15% of all lymphomas diagnosed annually in Western countries. Unlike most cancers, HL exhibits a bimodal age distribution, with a first peak in young adulthood (ages 15–35) and a second peak in older adulthood (over 55 years).

The disease is unique in oncology for its exceptionally high cure rates, even in advanced stages, owing to the exquisite sensitivity of RS cells to chemotherapy and radiotherapy. Modern management strategies focus not only on eradicating the disease but on minimizing long-term toxicities—such as secondary malignancies, cardiovascular disease, and infertility—associated with curative treatment.

Etiology and Risk Factors

The precise etiology of Hodgkin lymphoma remains multifactorial and incompletely understood. It arises from a complex interplay between genetic susceptibility, environmental triggers, and immune dysregulation.

1. Infectious Agents

• Epstein-Barr Virus (EBV): The strongest established environmental risk factor. EBV genomic material is detected in the RS cells of approximately 30–40% of classical HL cases in Western countries (higher in mixed cellularity subtype and pediatric cases, lower in nodular sclerosis). The virus likely contributes to oncogenesis through latent membrane proteins (LMP1, LMP2A) mimicking CD40 and B-cell receptor signaling, providing constitutive survival signals to the malignant clone.
• HIV Infection: Individuals with HIV have a 5- to 20-fold increased risk of developing HL. Paradoxically, HL often presents at a higher CD4+ count compared to non-Hodgkin lymphomas and may even occur during immune reconstitution inflammatory syndrome (IRIS) after starting antiretroviral therapy (ART).

2. Immune Dysregulation

• Primary Immunodeficiencies: Rare congenital syndromes (e.g., Ataxia-telangiectasia, Wiskott-Aldrich syndrome, Common Variable Immunodeficiency) confer elevated risk.
• Iatrogenic Immunosuppression: Solid organ transplant recipients on chronic immunosuppression have an increased incidence, though Non-Hodgkin Lymphoma (PTLD) is far more common in this population.
• Autoimmune Diseases: Conditions such as rheumatoid arthritis, systemic lupus erythematosus (SLE), and Sjögren’s syndrome are associated with a modestly increased risk, potentially driven by chronic antigenic stimulation or immunosuppressive therapies (e.g., TNF-alpha inhibitors, methotrexate).

3. Genetic and Familial Factors

• Family History: First-degree relatives of HL patients have a 3- to 9-fold increased risk. Monozygotic twins show a significantly higher concordance rate (~100-fold risk) compared to dizygotic twins, implicating a strong heritable component.
• Genome-Wide Association Studies (GWAS): Have identified susceptibility loci in the HLA region (Class II genes), confirming the role of antigen presentation. Variants in KLHDC8B, REL, GATA3, and PVT1 have also been implicated.

4. Demographics and Lifestyle

• Age: Bimodal distribution (peaks 15–35 and >55).
• Sex: Slight male predominance overall (M:F ~1.2:1), though the young adult peak shows a female predominance in the nodular sclerosis subtype.
• Geography/Ethnicity: Higher incidence in North America, Northern Europe, and Australia; lower in Asia. Higher socioeconomic status in childhood is associated with increased risk (the “hygiene hypothesis” – delayed exposure to common infections).
• Smoking: Some meta-analyses suggest a modest association with cigarette smoking, particularly for the nodular sclerosis subtype.

Classification: The WHO 2022 / ICC 2022 Framework

Modern classification separates HL into two distinct disease entities with different biology, clinical behavior, and management.

1. Classical Hodgkin Lymphoma (cHL)

Accounts for 95% of cases. Defined by the presence of classic Reed-Sternberg cells and variants in a characteristic inflammatory background. cHL is further subdivided into four histologic subtypes:

2. Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL)

Accounts for ~5% of cases. Recognized as a distinct entity, biologically closer to B-cell non-Hodgkin lymphomas (specifically T-cell/histiocyte-rich large B-cell lymphoma).

• Malignant Cell: “Popcorn cells” (LP cells / L&H cells) – multilobated nuclei, small nucleoli.
• Immunophenotype: CD20+, CD45+, CD79a+, PAX5+, BCL6+, CD15-, CD30- (usually), EMA+.
• Microenvironment: Nodular proliferation of B-cells with follicular dendritic cell meshworks; rosetting of T-cells (CD57+) around LP cells.
• Clinical Course: Indolent, frequent late relapses, risk of transformation to aggressive diffuse large B-cell lymphoma (DLBCL) (~5–10% over 10 years). Management often differs (e.g., rituximab integration, watch-and-wait for early stage).

Pathophysiology: The Reed-Sternberg Cell and Its Microenvironment

The hallmark of cHL is the Reed-Sternberg (RS) cell (binucleated/multinucleated, “owl-eyed” nuclei with prominent eosinophilic nucleoli) and its mononuclear variant, the Hodgkin (H) cell. These cells constitute only 0.1% to 2% of the total tumor mass. The vast majority of the tumor bulk comprises a reactive infiltrate of T-cells, B-cells, eosinophils, plasma cells, fibroblasts, and macrophages recruited by the malignant clone.

The Cellular Origin

RS cells originate from mature germinal center B-cells that have undergone somatic hypermutation (SHM) and class-switch recombination (CSR). However, they have lost their B-cell phenotype (“failed germinal center B-cells”).

• Crippling Mutations: Inactivating mutations in BCL6 translocations, SPIB, PU.1, OCT2, BOB.1 lead to downregulation of the B-cell receptor (BCR) and B-cell specific genes (CD19, CD20, CD79a).
• Survival Without BCR: Normally, a B-cell without a functional BCR undergoes apoptosis. RS cells evade this via constitutive activation of NF-κB and JAK/STAT pathways.

Key Molecular Pathways

1. NF-κB Pathway: Constitutively active via multiple mechanisms: REL amplification (chromosome 2p gain), mutations in NFKBIA (IκBα), TNFAIP3 (A20) inactivation, and signaling from CD30, CD40, RANK, and BAFF-R.
2. JAK/STAT Pathway: Activated by mutations in SOCS1 (negative regulator), STAT6, and cytokine signaling (IL-13, IL-21). Drives proliferation and Th2 polarization.
3. Immune Evasion (The “Invisible” Tumor):

• 9p24.1 Amplification: Leads to overexpression of PD-L1 (CD274) and PD-L2 (PDCD1LG2). This engages PD-1 on tumor-infiltrating T-cells, causing T-cell exhaustion.
• MHC Class I/II Downregulation: Via mutations in B2M, CIITA, HLA genes, and epigenetic silencing, impairing antigen presentation to CD8+ and CD4+ T-cells.
• Secretion of Cytokines: RS cells secrete CCL5, CCL17 (TARC), CCL22, IL-5, IL-10, TGF-β, and Galectin-1 to recruit immunosuppressive Tregs, Th2 cells, and macrophages (M2 phenotype), creating a “protective” niche.

How Does It Look? (Pathology, Imaging, and Gross Appearance)

This section details the visual and structural characteristics of Hodgkin lymphoma across macroscopic, microscopic, and radiological domains.

1. Gross Pathology (Macroscopic Appearance)

• Lymph Nodes: Typically enlarged, firm, and rubbery. They are usually non-tender and freely mobile (not fixed to underlying structures early on).
• Cut Surface:
• NSCHL: Distinctive nodular appearance with broad, white/tan fibrous bands dividing the node into pale nodules (replaced germinal centers). Cystic degeneration or necrosis may be seen in large mediastinal masses.
• MCCHL / LDCHL: Homogeneous, fleshy, tan-white cut surface, often obscuring the normal corticomedullary distinction. Necrosis is more frequent in LDCHL.
• NLPHL: Resembles reactive hyperplasia; nodules may be visible but lack the dense fibrosis of NSCHL.
• Spleen: Splenomegaly may show milky spots (white nodules) on the capsule and cut surface, representing nodular involvement.
• Extranodal Sites: Rare at diagnosis (<5%). Liver involvement appears as pale nodules; bone lesions are osteolytic (“punched out”) or ivory (sclerotic); lung shows nodules or interstitial infiltrates.

2. Microscopic Pathology (Histology & Immunohistochemistry)

Diagnosis requires an excisional or incisional biopsy (core needle biopsy is often insufficient for subtyping due to architectural distortion). Fine Needle Aspiration (FNA) is not diagnostic for primary diagnosis.

Classical HL Diagnostic Criteria (Immunophenotype)

NLPHL Diagnostic Criteria

• LP Cells (Popcorn): CD20+, CD79a+, PAX5 (Strong), BCL6+, EMA+.
• Negative: CD15, CD30 (usually), CD10.
• Microenvironment: Nodules with CD21/CD23+ follicular dendritic cell meshworks. CD57+ T-cell rosettes surrounding LP cells (highly characteristic).

3. Radiological Appearance (Imaging)

Imaging is critical for staging (Lugano Classification), response assessment (Deauville Score), and radiation planning.

A. Computed Tomography (CT) – Neck, Chest, Abdomen, Pelvis

• Lymphadenopathy:
• Size: Nodes > 1.5 cm (long axis) generally considered abnormal. In mediastinum, any discrete mass is abnormal.
• Shape: Usually ovoid/round, preserving fatty hilum initially (vs. metastatic nodes which lose hilum).
• Enhancement: Homogeneous enhancement. Necrosis/central low attenuation suggests large tumor burden or specific subtypes (LDCHL) or TB co-infection.
• Calcification: Rare at presentation; common after treatment (radiotherapy/chemo).
• Mediastinal Involvement (NSCHL hallmark):
• Anterior/superior mediastinal mass.
• “Bulky Disease” Definition: Mediastinal ratio (Max transverse diameter of mass / Max transverse diameter of thorax at T5–T6) ≥ 0.33 (1/3). Absolute size ≥ 10 cm also used in some protocols (e.g., German Hodgkin Study Group).
• May compress trachea, SVC, or invade lung/pericardium.
• Splenic Involvement:
• Splenomegaly (>13 cm craniocaudal length).
• Focal lesions: Hypodense nodules (milky spots) – highly specific.
• Note: Homogeneous splenomegaly alone is non-specific (congestion, portal hypertension).
• Hepatic Involvement: Focal hypodense lesions (rare as sole site).
• Bone: Lytic lesions (CT better than PET for cortical breach assessment).

B. Positron Emission Tomography / CT (PET-CT) – Gold Standard for Staging & Response

• Physiology: RS cells have high metabolic rate (Warburg effect) → Intense FDG-avidity (High SUVmax). Typically SUVmax > 10–15 in bulky disease.
• Staging Sensitivity: Superior to CT for detecting splenic micronodules, bone marrow involvement (avoiding biopsy if PET+), and small volume nodal disease.
• Deauville 5-Point Scale (Response Assessment):

• Threshold for “Negative” End-of-Treatment PET: Deauville 1–3 (Deauville 3 is generally considered negative in modern trials like RATHL, HD18).

C. Magnetic Resonance Imaging (MRI)

• Indicated for: Spinal cord compression (epidural extension), brachial/lumbosacral plexus involvement, or CNS evaluation (rare primary CNS HL, but needed for neurological symptoms).
• Superior soft tissue contrast for neural foramina invasion.

D. Ultrasonography

• Role: Initial assessment of superficial nodes (neck, axilla, groin).
• Features: Loss of fatty hilum, rounded shape (short/long axis ratio > 0.5), chaotic/hilar vascularity on Doppler (vs. peripheral in reactive nodes).
• Guidance: US-guided core biopsy for accessible nodes.

Symptoms: Clinical Presentation

The clinical presentation of HL is highly variable, ranging from an incidental finding on imaging to life-threatening compressive syndromes or systemic “B symptoms.”

1. Lymphadenopathy (The Cardinal Sign)

• Frequency: > 80–90% of patients at diagnosis.
• Characteristics:
• Painless: The vast majority are non-tender.
• Alcohol-Induced Pain: A pathognomonic but rare feature (< 5–10%). Sharp, aching pain in involved nodes within minutes of alcohol ingestion. Mechanism unknown (vasodilation? capsule stretch?).
• Distribution:
• Cervical / Supraclavicular: Most common site (60–80%).
• Mediastinal: Often asymptomatic initially; found on chest X-ray. NSCHL hallmark.
• Axillary / Inguinal: Less common as isolated presentation.
• Contiguity: HL spreads contiguously to adjacent nodal groups (e.g., cervical → supraclavicular → mediastinal → hilar → para-aortic → iliac/inguinal). “Skip lesions” are rare (< 5%).

2. B Symptoms (Systemic Symptoms) – Prognostic Significance

Defined by the Ann Arbor / Cotswolds criteria. Presence upstages the disease (e.g., Stage IIB vs IIA) and mandates more intensive therapy in most protocols.

• Fever: Temperature > 38°C (100.4°F). Often Pel-Ebstein fever (cyclical high fevers lasting days/weeks alternating with afebrile periods), though this classic pattern is rare today.
• Drenching Night Sweats: Profuse sweating requiring change of bedclothes/sheets. Not just “feeling warm.”
• Unintentional Weight Loss: > 10% of baseline body weight within 6 months prior to diagnosis (not attributable to diet/exercise).
• Pruritus (Itching): Historically considered a “B symptom” equivalent. Severe, generalized, often intractable pruritus without rash. Associated with eosinophilia and advanced stage. Mediated by IL-31, TARC, histamine.

3. Symptoms from Local Compression / Organ Infiltration

Due to the contiguous spread and propensity for bulky mediastinal disease (NSCHL):

4. Paraneoplastic Syndromes & Rare Presentations

• Neurological: Paraneoplastic cerebellar degeneration (anti-Yo/Hu), limbic encephalitis, sensory neuropathy. Rare but documented.
• Hematological:
• Autoimmune Hemolytic Anemia (AIHA) / ITP: Coombs-positive hemolysis or immune thrombocytopenia (more common in NLPHL).
• Eosinophilia: Peripheral blood eosinophilia (> 1500/µL) – cytokine driven (IL-5), associated with MCCHL.
• Neutropenia: Rare, immune-mediated.
• Endocrine: Syndrome of Inappropriate ADH (SIADH), Hypercalcemia (rare, usually osteoclast-activating factors).
• Nephrotic Syndrome: Minimal change disease or membranous nephropathy (rare, usually NLPHL).

5. Asymptomatic / Incidental Presentation

Increasingly common due to widespread imaging. Asymptomatic mediastinal mass on chest X-ray/CT for trauma/cough, or incidental nodal uptake on PET-CT for another malignancy. These patients still require full staging and treatment.

Staging: The Lugano Classification (2014)

Staging integrates anatomic extent (Ann Arbor) with metabolic activity (PET-CT). It dictates prognosis and treatment intensity.

Critical Staging Nuances:

• Stage IV vs IE/IIE: Isolated lung nodules or pleural effusion positive for lymphoma = Stage IV. Direct extension from node to lung = Stage IIE.
• Bone Marrow: PET-CT positive = Stage IV (biopsy not mandatory if PET+). PET negative = Biopsy not routinely required in early stage; recommended in advanced stage (III/IV) or if cytopenias exist.
• Bulky Disease: Defined per protocol (e.g., Mediastinal Ratio ≥ 0.33 or Max Diameter ≥ 10 cm). Upstages early favorable to early unfavorable.

Risk Stratification (Early Stage: I/II)

Used to tailor therapy intensity (Combined Modality vs Chemo alone vs Radiotherapy alone).

International Prognostic Score (IPS) for Advanced Stage (III/IV)

1 point each for 7 adverse factors at diagnosis:

1. Albumin < 4.0 g/dL
2. Hemoglobin < 10.5 g/dL
3. Male Sex
4. Stage IV Disease
5. Age ≥ 45 years
6. WBC ≥ 15,000 / µL
7. Lymphocyte count < 600 / µL OR < 8% of WBC

Risk Groups: 0–1 (Favorable), 2–3 (Intermediate), 4–7 (Unfavorable). 5-year PFS: ~90%, ~80%, ~60% respectively (historical ABVD data; modern PET-adapted better).

Diagnostic Workup Algorithm

1. History & Physical: Detailed B-symptom assessment, alcohol pain query, full nodal exam (Waldeneyer’s ring, epitrochlear, popliteal), hepatosplenomegaly, neurological exam.
2. Excisional Biopsy: Gold Standard. Submit fresh tissue for flow cytometry (to rule out NHL) and formalin for H&E + IHC panel (CD30, CD15, CD45, PAX5, CD20, CD3, ALK, EMA, CD21/CD23, CD57, Ki-67, EBER-ISH).
3. Laboratory Baseline:

• CBC with Differential (Cytopenias? Eosinophilia? Lymphopenia?).
• ESR / CRP (Inflammatory markers, prognostic).
• LDH (Tumor burden, prognostic).
• Liver/Renal Function: ALT, AST, Bilirubin, Creatinine, GFR (Cisplatin/Carboplatin dosing, Bleomycin contraindication if renal impairment).
• Albumin (Prognostic/IPS).
• Viral Serology: HIV, Hepatitis B (HBsAg, Anti-HBc, Anti-HBs – Reactivation Risk!), Hepatitis C, EBV/CMV (baseline).
• Pregnancy Test (Females of childbearing potential).
• Fertility Counseling Referral (Mandatory pre-treatment).

1. Imaging:

• PET-CT (Skull base to mid-thigh): Standard for staging & response.
• Diagnostic CT Chest/Abdomen/Pelvis (with contrast): If PET-CT not available, or for anatomical detail/Radiation planning.
• MRI Brain/Spine: Only if neurological symptoms.

1. Cardiopulmonary Baseline (Pre-ABVD/Bleomycin):

• Echocardiogram / MUGA: LVEF baseline (Anthracycline cardiotoxicity).
• Pulmonary Function Tests (PFTs): DLCO, FEV1, FVC (Bleomycin pulmonary toxicity risk). Note: Some modern protocols omit routine PFTs if Bleomycin omitted (e.g., AVD, BrECADD).

1. Bone Marrow Biopsy: Indicated for Stage III/IV, B symptoms, cytopenias, or PET+ marrow signal. Bilateral posterior iliac crest trephine + aspirate.

Treatment Strategies: Modern Risk-Adapted Approach

Treatment is curative in >85–90% overall. Strategy balances Cure Rate vs Late Toxicity (Cardiotoxicity, Secondary Malignancies, Infertility, Hypothyroidism, Pulmonary Fibrosis).

1. Early Stage (I/II) – Classical HL

Early Favorable (IA/IIA Non-Bulky, Limited Nodal Sites)

• Standard (GHSG HD16/HD17 / NCCN Preferred):
• 2 cycles ABVD → PET-CT (Interim).
• PET Negative (Deauville 1–3): 2 more cycles ABVD (Total 4 cycles ABVD). No Radiotherapy (RT). Non-inferior survival, significantly less toxicity.
• PET Positive (Deauville 4–5): 2 cycles escalated BEACOPP → Consolidation RT (30 Gy) to involved sites.
• Alternative (EORTC H10F / UK RAPID): 3 cycles ABVD → PET. PET-neg → Randomized to RT vs Observation. Observation non-inferior for PFS but higher relapse rate; RT reduces relapse but adds toxicity.
• NLPHL Early Stage: Involved Site Radiotherapy (ISRT) 30 Gy alone is standard for Stage IA. Rituximab + Chemo (or Rituximab alone) for Stage II/bulky.

Early Unfavorable (B symptoms, Bulky, >3 sites, E lesion)

• Standard (GHSG HD14 / HD18):
• 2 cycles ABVD → PET (iPET).
• PET Negative: 2 more ABVD + Consolidation RT (30 Gy) to initially involved sites (ISRT). Total 4 ABVD + RT.
• PET Positive: Escalation to 4 cycles eBEACOPP (or 2 eBEACOPP + 2 ABVD) + RT.
• Alternative (NCCN / US Practice): 4–6 cycles ABVD + RT (historically). Modern trend: PET-adapted ABVD x 4–6 + RT, or escalation to A(A)VD (Brentuximab Vedotin + AVD) based on BREACH trial data (though BV approved for Stage III/IV frontline, used off-label/clinical trial in early unfavorable).
• RT Technique: ISRT (Involved Site RT) – targets initially involved nodal regions only, sparing uninvolved organs (breast, heart, lung, thyroid). Dose: 30 Gy (20 Gy if complete metabolic response pre-RT in some protocols).

2. Advanced Stage (III/IV) – Classical HL

Standard of Care (Historical): ABVD x 6 cycles (or 8 if PET+ interim).

• RATHL Trial: 2 ABVD → iPET. PET-neg → 4 ABVD (Total 6, No Bleomycin cycles 3–6). PET-pos → Escalate to eBEACOPP (or continue ABVD + RT). Omitting Bleomycin after negative iPET drastically reduces pulmonary toxicity.

New Standard of Care (Since 2022/2023): Brentuximab Vedotin (BV) + AVD (BrECADD / ECHELON-1 / HD21)

• ECHELON-1 (Stage III/IV): BV + AVD (brentuximab vedotin, doxorubicin, vinblastine, dacarbazine) x 6 cycles vs ABVD x 6.
• Result: Significant improvement in Modified PFS (88.2% vs 82.8% at 5 yrs). Less Peripheral Neuropathy (counter-intuitively, due to no bleomycin/less vincristine? No, BV causes neuropathy; but less severe pulmonary/cardiac toxicity). Actually, ECHELON-1 showed higher Grade 3+ neuropathy (67% vs 43%) but much lower pulmonary toxicity (1% vs 4%) and no bleomycin deaths.
• FDA/EMA Approved: Frontline Stage III/IV cHL.
• GHSG HD21 Trial (BrECADD): BV + eBEACOPP (dose-reduced: no bleomycin, no vincristine, no procarbazine, reduced cyclophosphamide/etoposide) vs eBEACOPP.
• Result: BrECADD superior efficacy (higher PFS) AND significantly lower toxicity (neutropenia, infections, neuropathy, alopecia, infertility risk).
• Emerging New Standard: BrECADD (4–6 cycles) is rapidly replacing ABVD and eBEACOPP for fit advanced stage patients in Europe/Germany. NCCN lists as Category 1 Preferred.

PET-Adapted Strategy (Advanced Stage)

• Baseline PET → 2 Cycles → Interim PET (iPET).
• Deauville 1–3: Continue same regimen (de-escalate Bleomycin if ABVD; continue BrECADD/BV-AVD).
• Deauville 4–5: Escalate therapy (e.g., switch to eBEACOPP or BV+AVD if on ABVD) + Consolidation RT to residual PET+ sites (Deauville 4–5) at end of treatment.

Special Populations

• Elderly / Frail (>60–65 yrs or Comorbidities): ABVD poorly tolerated (Bleomycin lung, Vinblastine neuropathy, Doxorubicin heart).
• Options: BV monotherapy (approved relapsed, used off-label frontline), AVD (Omit Bleomycin), BV + Bendamustine, PD-1 Inhibitor (Pembrolizumab/Nivolumab) + AVD (Clinical trials/Compassionate use), ChlVPP/EVA (Non-anthracycline/non-bleomycin).
• HIV+: ABVD + ART (start ART immediately if not on it). G-CSF support mandatory. Cure rates equivalent to HIV-negative with modern supportive care.
• Pregnancy:
• 1st Trimester: Delay if possible (RT contraindicated, Chemo teratogenic). Vinblastine single agent if urgent.
• 2nd/3rd Trimester: ABVD (A, B, V, D relatively safe after organogenesis). Avoid RT, BV, Checkpoint inhibitors. Delivery at 35–37 weeks if feasible.

3. Relapsed / Refractory (R/R) Disease

• Definition: Relapse after frontline; Primary Refractory (Deauville 4–5 at end of frontline or progression during).
• Salvage Chemotherapy (Bridge to Transplant):
• Standard: ICE (Ifosfamide, Carboplatin, Etoposide), DHAP, GDP (Gemcitabine, Dexamethasone, Cisplatin), BV-based (BV+Nivo, BV+AVD).
• Goal: Achieve PET-negative (Deauville 1–3) status before Autologous Stem Cell Transplant (ASCT).
• High-Dose Chemotherapy + ASCT (HDT-ASCT): Standard of Care for Chemosensitive Relapse (CR/PR to salvage).
• Conditioning: BEAM (Carmustine, Etoposide, Cytarabine, Melphalan) or BuCy (Busulfan/Cyclophosphamide).
• Outcome: 5-yr PFS ~50–60% for chemosensitive; < 10% for refractory.
• Post-ASCT Consolidation: Brentuximab Vedotin (BV) x 16 cycles (AETHERA trial) improves PFS in high-risk patients (refractory, early relapse <12mo, extranodal).
• Novel Agents for Post-ASCT Failure or Transplant-Ineligible:
• PD-1 Inhibitors (Pembrolizumab, Nivolumab): ORR ~65–70%, CRR ~20–25%. Durable responses in subset. Risk: Allogeneic transplant after PD-1 → High risk of severe GVHD / Hepatic VOD. Washout period required.
• BV Monotherapy: ORR ~75%, CRR ~34%.
• CAR-T Cell Therapy (CD30-directed or CD19 – HL is CD19 negative usually): CD30-CAR-T in trials. CD19-CAR-T generally ineffective for cHL (RS cells lack CD19). Exception: NLPHL / Transformed DLBCL.
• Antibody-Drug Conjugates (ADCs): New targets (CD25, CD30-bispecifics).

4. NLPHL Specific Management

• Early Stage (IA): ISRT 30 Gy alone (Excellent local control, >90% 10-yr PFS).
• Advanced / Bulky / B-symptoms: Rituximab + Chemo (ABVD or CHOP) or Rituximab maintenance (2 years).
• Relapse: Rituximab +/- Chemo. Watch-and-Wait acceptable for asymptomatic limited relapse. Transformation to DLBCL: Treat as DLBCL (R-CHOP).

Supportive Care & Toxicity Management

Survivorship and Long-Term Follow-Up

Survivorship care begins at diagnosis. The “Cost of Cure” is the defining feature of HL management.

Follow-Up Schedule (Typical)

• Years 1–2: Every 3–4 months (History, Exam, Labs: CBC, ESR/CRP, LDH, TSH, Creatinine).
• Years 3–5: Every 6 months.
• Year 5+: Annually (Transition to Survivorship Clinic / Primary Care with Survivorship Care Plan).
• Imaging:
• Routine Surveillance PET-CT / CT is NOT RECOMMENDED for asymptomatic patients in remission (High false positive rate, radiation exposure, cost, anxiety).
• Imaging only for: New symptoms, abnormal labs, suspicious exam findings.
• Exception: High-risk patients (e.g., prior refractory disease) or clinical trials.

Key Late Effects Screening

Prognosis and Survival Statistics

• Overall 5-Year Relative Survival (SEER 2013–2019): ~89%.
• Stage I: > 92–95%.
• Stage II: > 90–94%.
• Stage III: > 80–85%.
• Stage IV: > 75–80% (Improving rapidly with BV-AVD/BrECADD).
• NLPHL: 10-year OS > 90% (indolent course, but late relapses/transformation).

Prognostic Factors (Adverse):

• Advanced Stage (III/IV).
• B Symptoms.
• Bulky Disease (>10 cm or Mediastinal Ratio ≥ 0.33).
• Age > 45 (or > 60).
• Male Sex.
• Low Albumin (< 4.0), Low Hb (< 10.5), Low Lymphocytes (< 600/µL or < 8%), High WBC (> 15k).
• Interim PET Positivity (Deauville 4–5): Strongest predictor of early failure.
• EBV Negative (in older adults) / EBV Positive (in some pediatric contexts – complex).

Frequently Asked Questions (FAQ)

Q: Is Hodgkin lymphoma hereditary?

A: It is not strictly “inherited” in a Mendelian pattern, but there is a strong familial aggregation. First-degree relatives have a 3–9x higher risk. This is likely due to shared genetic susceptibility loci (especially HLA class II) and shared environment/infections. Genetic testing for family members is not routinely recommended.

Q: Can I have children after treatment?

A: Yes, many patients do. However, alkylating chemotherapy (BEACOPP, BEAM, Cyclophosphamide) and pelvic radiation pose significant risks to ovarian reserve and spermatogenesis. Fertility preservation (sperm banking, egg/embryo freezing) MUST be discussed BEFORE treatment starts. GnRH agonists during chemo offer some ovarian protection. Modern regimens (ABVD, BV-AVD, BrECADD) have significantly lower gonadotoxicity than BEACOPP.

Q: Does a PET-positive scan after 2 cycles mean I won’t be cured?

A: No. A positive interim PET (Deauville 4–5) indicates higher risk, but treatment intensification (switching to eBEACOPP or adding BV) and consolidation radiotherapy can still achieve cure rates of 70–80%. It mandates a change in strategy, not a terminal diagnosis.

Q: Why is Bleomycin being removed from regimens?

A: Bleomycin causes pulmonary fibrosis in ~3–5% of patients, which can be fatal (especially with high oxygen during surgery later in life). The RATHL trial proved that for PET-negative early responders, omitting Bleomycin for the remaining cycles maintains identical survival with drastically lower lung toxicity. New regimens (BV-AVD, BrECADD) replace Bleomycin entirely with more effective, less lung-toxic agents.

Q: What is the difference between Hodgkin and Non-Hodgkin Lymphoma?

A: They are distinct diseases.

• HL: Reed-Sternberg cells (B-cell origin, crippled phenotype), contiguous spread, bimodal age, very high cure rate, defined by CD30+/CD15+/CD45-.
• NHL: Diverse group (>60 subtypes) of B, T, NK cell origin. Non-contiguous spread common. Variable prognosis (indolent to aggressive). CD20+ common (B-cell NHL). Treated differently (e.g., R-CHOP for DLBCL).

Q: Can I get the COVID-19 / Flu / Shingles vaccine during treatment?

A: Inactivated vaccines (Flu, COVID mRNA, Pneumococcal, Shingles recombinant/Shingrix): Recommended. Best given ≥ 2 weeks before chemo or ~3–6 months post-chemo/ASCT (when B-cells recover). Response may be blunted during active treatment/anti-CD20 (Rituximab) therapy, but safety is established. Live vaccines (MMR, Varicella Zoster live, Yellow Fever, Oral Typhoid): CONTRAINDICATED during chemo and for ≥ 3–6 months post-chemo/ASCT (until immune reconstitution).

References

• Al-Kali, A. and Ansell, S.M. (2021) ‘Hodgkin Lymphoma’, Mayo Clinic Proceedings, 96(1), pp. 194–210. doi:10.1016/j.mayocp.2020.09.014.
• Ansell, S.M. (2023) ‘Hodgkin Lymphoma: 2023 Update on Diagnosis, Risk Stratification, and Management’, American Journal of Hematology, 98(1), pp. 154–167. doi:10.1002/ajh.26789.
• Barrington, S.F. et al. (2014) ‘Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group’, Journal of Clinical Oncology, 32(27), pp. 3048–3058. doi:10.1200/JCO.2013.53.5229.
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