Hodgkin Lymphoma

Pathological Hallmarks

 Hodgkin/Reed-Sternberg Cells

• Large abnormal lymphoid cells with one or more nuclei and prominent nucleoli.
• Comprise a minor proportion of the tumour mass.
• The bulk of the tumour consists of reactive inflammatory cells including lymphocytes, eosinophils, histiocytes, plasma cells, and fibroblasts.

Immunophenotype

• Classic HRS cells typically express CD30 and CD15.
• Negative for CD45.
• Show reduced or absent expression of B-cell markers such as CD20.
• In contrast, L&H cells found in nodular lymphocyte-predominant HL (NLPHL) are CD20 and CD45 positive, CD15 and CD30 negative.

Subtypes of Hodgkin Lymphoma

1. Classical Hodgkin Lymphoma (cHL) (≈95% of cases)

 Nodular sclerosis (NSHL)

• Most common subtype (≈70%).
• Characterised by lacunar-type HRS cells and fibrous bands dividing lymphoid tissue into nodules.
• Predominantly affects young adults.
• Often involves the mediastinum.

Mixed cellularity (MC)

• Accounts for 20–25% of cases.
• Features classic HRS cells amidst a mixed inflammatory infiltrate.
• More common in older adults.
• Associated with immunosuppression or Epstein-Barr virus (EBV) infection.

Lymphocyte-rich (LR)

• Comprises ≈5% of cases.
• Predominance of small lymphocytes and scarce HRS cells.
• Tends to have a favourable prognosis.

Lymphocyte-depleted (LD)

• Rarest form (<1%).
• Abundant HRS cells in a background with few reactive lymphocytes.
• Often seen in immunocompromised individuals.
• Associated with a poor prognosis.

2. Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL) (≈5% of cases)

• Features distinct “popcorn” or L&H cells in a nodular background of small B lymphocytes and follicular dendritic cells.
• Typically indolent.
• Often presents with localised disease in peripheral lymph nodes.
• Usually spares the mediastinum.
• Now reclassified by some authorities as a form of B-cell non-Hodgkin lymphoma due to clinical and biological distinctions.

• A significant body of evidence suggests an infectious aetiology in a proportion of HL cases, particularly involving Epstein-Barr virus (EBV)
• EBV antigens are detectable in Reed-Sternberg cells in approximately 20–40% of HL cases.
• The association is strongest in the mixed cellularity and lymphocyte-depleted subtypes of classical HL, while it is rare in nodular lymphocyte-predominant HL.
• A prior history of infectious mononucleosis is linked with an increased risk of EBV-positive HL, with an estimated risk of around 1 in 1000 following infection.
• The precise mechanism by which EBV contributes to oncogenesis is not fully elucidated, but proposed pathways include the evasion of immune surveillance and the provision of proliferative signals via viral proteins (e.g., LMP1, LMP2A, EBNA1).

Immunodeficiency and HIV Infection

• HIV-positive individuals have a substantially increased risk of developing HL—estimated to be 5–25 times higher than the general population.
• HL in HIV-positive patients is typically EBV-positive, exhibits more aggressive clinical behaviour, and frequently presents with advanced-stage disease and extranodal involvement.
• Other immunosuppressive states—such as post-organ transplantation, haematopoietic stem cell transplantation, and long-term immunosuppressive therapy—also confer increased susceptibility to HL.

Autoimmune Disease and Immune Dysregulation

• A history of autoimmune diseases (e.g., Sjögren’s syndrome, systemic lupus erythematosus, rheumatoid arthritis) is associated with a higher risk of HL.
• This association may reflect chronic immune activation, altered immune surveillance, or the impact of immunosuppressive treatment.

Genetic and Familial Factors

• A familial predisposition is observed in approximately 1–5% of HL cases:
  • First-degree relatives of affected individuals have a 3-fold increased risk.
  • Monozygotic twins of HL patients exhibit a nearly 100-fold increased risk; dizygotic twins have a 7-fold increase.
• Genetic susceptibility appears especially relevant in nodular sclerosis HL (NSHL), where familial clustering and twin concordance are most evident.
• Specific human leukocyte antigen (HLA) class II alleles (e.g., HLA-DRB1, HLA-DQB1) and single-nucleotide polymorphisms (SNPs) in the 6p21.32 locus have been consistently linked to increased HL risk.
• These genetic markers may influence host immune responses to viral infections or other environmental triggers.

Other Viral Agents

• While EBV is the only virus strongly implicated in HL pathogenesis, the role of other viruses has been examined without consistent evidence. Human herpesvirus 6 (HHV-6) and cytomegalovirus (CMV), among others, have not been shown to have a definitive causal link to HL.

Gene–Environment Interaction

• Evidence suggests that HL may arise from the interplay of genetic susceptibility and environmental exposure, particularly viral infections. For instance, individuals with a genetic predisposition may develop HL in response to an atypical or dysregulated immune reaction to an infectious trigger such as EBV.

Cellular Origin of HRS Cells

• HRS cells are derived from germinal centre (GC) B lymphocytes but have lost key B-cell features such as immunoglobulin expression.
• They exhibit clonal immunoglobulin gene rearrangements and somatic hypermutation, confirming their B-cell origin.
• Despite this origin, they typically do not express surface immunoglobulins or B-cell markers like CD20 and CD45, while consistently expressing CD30 and often CD15.
• Constitute only a minor fraction of the total tumour mass (often 1–2%) but they drive the disease pathogenesis through a complex network of molecular, immunological, and cellular interactions.

Cytogenetic and Molecular Abnormalities

• Genetic profiling has identified various mutations and chromosomal aberrations that contribute to HRS cell survival and proliferation.
• These include copy number gains at chromosome 9p24.1, resulting in overexpression of PD-L1 and PD-L2, which promote immune evasion.
• Other recurrent mutations include alterations in TNFAIP3, SOCS1, and ITPKB, all of which are involved in signalling and immune regulation.

Aberrant Intracellular Signalling

• Key signalling pathways are constitutively activated in HRS cells:
  • NF-κB: Promotes cell survival, proliferation, and cytokine production.
  • JAK/STAT: Enhances resistance to apoptosis and modulates the tumour microenvironment.
  • NOTCH and AP-1: Contribute to cytokine dysregulation and immune cell recruitment.
• These signalling disruptions result in the secretion of various chemokines (e.g., CCL5, CCL17, CCL22, IL-8), which modulate the immune landscape.

Tumour Microenvironment (TME)

• The TME is composed of diverse immune and stromal cells including CD4+ T cells, T regulatory cells (Tregs), macrophages, mast cells, eosinophils, neutrophils, plasma cells, and fibroblasts.
• HRS cells manipulate the TME to promote their survival:
  • Recruitment of Immunosuppressive Cells: CCL17 and CCL22 attract CCR4+ Tregs; CCL5 recruits mast cells and macrophages; IL-8 attracts neutrophils.
  • Secretion of Immunomodulatory Cytokines: IL-10 and TGF-β1 inhibit cytotoxic T lymphocytes (CTLs) and antigen-presenting cells (APCs).

Immune Evasion Mechanisms

• HRS cells survive in a milieu rich in immune effector cells by employing several evasion strategies:
  • Loss of Antigen Presentation:
    • Downregulation or mutation of β2-microglobulin (B2M) disrupts MHC class I expression.
    • Inactivation of CIITA impairs MHC class II expression.
  • Checkpoint Activation:
    • Overexpression of PD-L1 and PD-L2 leads to interaction with PD-1 on T cells, promoting T-cell exhaustion and impaired anti-tumour immunity.
  • Immunosuppressive Secretions:
    • Factors like galectin-1, prostaglandins, and IL-10 further inhibit CTL and APC function.

Resistance to Apoptosis

• HRS cells, unlike normal B cells lacking surface immunoglobulin expression, evade apoptosis by activating survival pathways.
• Key contributors include NF-κB, JAK/STAT, and MAPK/ERK signalling cascades, which upregulate anti-apoptotic proteins and suppress pro-apoptotic signals.

Viral Contributions

• In EBV-positive HL, latent viral proteins such as LMP1, LMP2A, and EBNA1 mimic constitutive signalling to promote cell proliferation, inhibit apoptosis, and subvert immune detection.
• EBV-associated HL typically exhibits a more inflammatory TME with an increased presence of macrophages and neutrophils.

Molecular Subtypes and Emerging Classifications

• Recent studies using circulating tumour DNA have proposed molecular subtypes of classical HL, with distinct pathogenic and clinical features:
  • Inflammatory–Immune Escape Subtype:
    • High copy-number variation, particularly of PD-L1 locus.
    • Prominent inflammatory infiltrate and strong immune suppression.
  • Virally-Driven Subtype:
    • EBV or human herpesvirus 6 associated.
    • Inflammatory TME with macrophages and neutrophils.
    • Low tumour mutational burden.
  • Oncogene-Driven Subtype:
    • High tumour mutational burden with mutations in driver genes like TNFAIP3 and SOCS1.
    • Minimal immune infiltration ("cold" TME).

Pathological Subtypes of HL

 Classical Hodgkin Lymphoma (cHL)

• Includes nodular sclerosis (NSHL), mixed cellularity (MCHL), lymphocyte-rich (LRHL), and lymphocyte-depleted (LDHL).
• All subtypes show HRS cells within a reactive inflammatory background.

Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL)

• Distinct entity featuring L&H or "popcorn" cells.
• These are CD20-positive and lack CD15/CD30, in contrast to cHL.
• The TME is composed predominantly of benign B cells and follicular dendritic cells.

Global Incidence and Trends

• In high-income countries such as the United States and across Europe, HL has an incidence of approximately 2 to 3 cases per 100,000 people annually.
• UK data from 2016–2018 reported a crude incidence of 3.2 per 100,000, with a higher rate in males (3.8) compared to females (2.7).
• The US National Cancer Institute reported an age-adjusted annual incidence of 2.5 per 100,000 for 2017–2021. Incidence has been decreasing by about 2.3% annually over the past decade, while mortality remains low and stable at 0.3 per 100,000 per year.
• The American Cancer Society projects 8570 new cases and 910 deaths from HL in the US in 2024.

Age Distribution

• HL exhibits a bimodal age distribution:
  • The first peak occurs in adolescents and young adults (ages 15–35).
  • A second, smaller peak appears in older adults over the age of 55–65.
• In adolescents aged 15–19, HL is the most common cancer, comprising two-thirds of lymphoma cases in this age group.
• The median age at diagnosis in the US is 39 years.

Sex Differences

• HL is more common in males than in females. In the US, male incidence is approximately 2.8 per 100,000 compared to 2.2 in females.
• This male predominance is particularly evident in childhood and in certain histological subtypes such as mixed cellularity (MC) and lymphocyte-depleted (LD) cHL.
• Nodular sclerosis (NS) cHL shows a more balanced sex distribution.

Ethnic and Racial Variation

• Non-Hispanic White individuals exhibit the highest incidence, while the lowest rates are observed among Native American, Alaska Native, and Asian/Pacific Islander populations.
• Hispanic Americans show intermediate rates but with some variation:
  • In one SEER analysis, the peak incidence occurred at older ages in Hispanic populations.
  • Hispanic children demonstrated a higher risk of HL than non-Hispanic White children, especially for MC subtype.

Geographic Variation

• Southern Europe reports the highest incidence rates globally.
• Differences in subtype distribution are also observed:
  • NS cHL predominates in urbanised and economically developed regions.
  • MC and LD subtypes are more frequently encountered in lower-resource settings, often in association with Epstein-Barr virus (EBV) and HIV infection.
• In transitional economies, a mixed pattern is noted, with peaks in both childhood and adolescence.

Socioeconomic Factors

• Socioeconomic status is associated with both incidence rates and subtype prevalence:
  • NS cHL is more common in higher-income, urbanised areas.
  • MC and LD cHL are prevalent in lower socioeconomic and rural populations.
• Crowding, family size, housing conditions, and birth order have been linked to HL risk patterns, possibly reflecting differences in early-life exposures to infections.
• A study from Brazil showed NS predominating in urban areas, while MC was more common in rural regions. In Israel, Israeli-born individuals had a higher risk of NS cHL compared to immigrants, potentially reflecting socioeconomic influences.

Subtype Distribution

• In developed settings, the relative distribution of cHL subtypes is as follows:
  • Nodular sclerosis (NS): 70%
  • Mixed cellularity (MC): 20–25%
  • Lymphocyte-rich (LR): 5%
  • Lymphocyte-depleted (LD): <1%
• The prevalence of EBV-associated HL correlates with subtype and geographic region:
  • EBV positivity is highest in MC and LD subtypes, particularly in settings with high HIV prevalence and lower socioeconomic status.

Lymphadenopathy

• Painless, persistent lymphadenopathy is the most common presenting symptom.
• Frequently involves the cervical and supraclavicular lymph nodes (in 60–80% of patients).
• Axillary involvement is seen in up to 30% and inguinal nodes in around 10%.
• Mediastinal lymphadenopathy is common but often asymptomatic; when symptomatic, it may cause:
  • Cough
  • Shortness of breath
  • Chest discomfort
• Abdominal lymphadenopathy may cause nonspecific abdominal pain.

Constitutional "B" Symptoms

• B symptoms are present in approximately 30–40% of patients and are associated with more advanced disease and worse prognosis:
  • Fever: Persistent temperature >38°C, often worse in the evening; Pel-Ebstein fever (intermittent, cyclic fever) is rare but characteristic.
  • Drenching night sweats, often requiring a change of bedclothes.
  • Unexplained weight loss >10% of body weight over 6 months
• Note: B symptoms can occasionally precede detectable lymphadenopathy.

Pruritus and Other Systemic Complaints

• Pruritus (generalised or localised) occurs in 10–15% and may precede diagnosis by months.
• Fatigue is common but nonspecific.
• Alcohol-induced pain: Rare but specific to HL; pain occurs at sites of disease (e.g., lymph nodes, bones) within minutes of alcohol consumption.

Respiratory and Thoracic Symptoms

• Symptoms are generally due to mediastinal involvement:
  • Dyspnoea
  • Dry cough
  • Retrosternal chest pain
• Superior vena cava syndrome (SVCS) is a rare but serious presentation, causing:
  • Orthopnoea
  • Facial/upper extremity oedema
  • Dilated neck veins

Abdominal Symptoms

• Splenomegaly or hepatomegaly may cause:
  • Abdominal fullness or pain
  • Nausea, anorexia
  • Early satiety
• Retroperitoneal nodal involvement may cause flank pain or ureteral obstruction.
• Rarely, ascites or liver dysfunction (including vanishing bile duct syndrome) may occur.

Bone and Bone Marrow-Related Symptoms

• Bone pain, especially in weight-bearing areas, may reflect osseous involvement.
• May be associated with elevated alkaline phosphatase or calcium levels.
• Bone marrow involvement, more common in advanced disease or immunosuppressed patients, may present with:
  • Cytopenias (anaemia, leukopenia, thrombocytopenia)
  • Unexplained fatigue or infection

Neurologic and Paraneoplastic Syndromes

• Cerebellar degeneration
• Limbic encephalitis
• Neuromyotonia
• Peripheral neuropathy
• Stiff-person syndrome

Renal and Endocrine Symptoms

• Nephrotic syndrome, particularly minimal change disease, may precede or occur with HL.
• Hypercalcaemia, typically driven by increased calcitriol production, can present with nausea, confusion, or constipation.

Dermatologic Manifestations

• May include:
  • Ichthyosis
  • Urticaria
  • Hyperpigmentation
  • Paraneoplastic syndromes like acrokeratosis or erythema nodosum

Risk Factors to Identify in History

• Age: Peak incidence in 15–35 years and >55 years.
• Family history: Particularly in first-degree relatives and monozygotic twins.
• History of Epstein-Barr virus (EBV) infection: Especially infectious mononucleosis.
• Socioeconomic status: Higher incidence in young adults from higher socioeconomic backgrounds, particularly for nodular sclerosis subtype.
• Genetic factors: A family history of HL or certain human leukocyte antigen (HLA) types.
• Ethnic background: Jewish ancestry and certain ethnic groups have increased risk.
• Immunosuppression: HIV infection, post-transplant immunosuppression.

Lymphadenopathy

• Cervical and supraclavicular nodes: Most commonly involved; palpable in 60–80% of patients.
• Axillary lymph nodes: Present in 20–30% of cases.
• Inguinal lymph nodes: Involved in 6–20% of patients.
• Nodes are typically painless, firm, rubbery, and non-tender.
• Lymphadenopathy may be bilateral or unilateral, and nodal involvement often follows a contiguous pattern.
• Waldeyer’s ring, occipital, and epitrochlear nodes are rarely involved.

Mediastinal and Thoracic Findings

• A mediastinal mass is often not evident on examination but may be suspected in the presence of:
  • Dyspnoea
  • Tachypnoea
  • Distended neck veins
  • Reduced breath sounds or dullness to percussion
• Superior vena cava syndrome (SVCS) may present with:
  • Facial and upper limb oedema
  • Orthopnoea
  • Cyanosis
  • Venous distension in the neck and upper chest

Hepatosplenomegaly

• Splenomegaly and/or hepatomegaly may be present in advanced disease.
  • May manifest as a palpable edge below the costal margin.
  • Can be associated with abdominal distension or discomfort.
• Massive splenomegaly is uncommon but may indicate advanced disease or hypersplenism.

Dermatological Signs

• Though rare, skin involvement may be detected, including:
  • Hyperpigmentation
  • Excoriations due to intense pruritus
  • Urticaria, erythema nodosum, ichthyosis, or infiltrative lesions
• Skin manifestations may precede diagnosis and can be paraneoplastic.

Neurological Findings

• Neurological abnormalities are rare but may indicate paraneoplastic syndromes such as:
  • Cerebellar degeneration: Ataxia, dysarthria
  • Peripheral neuropathy: Weakness, sensory deficits
  • Limbic encephalitis, chorea, or Guillain-Barré-like syndrome
• CNS involvement due to direct infiltration is very rare but should be suspected in the presence of focal deficits or altered consciousness.

Other Paraneoplastic and Systemic Signs

• Oedema of the lower extremities or ascites may indicate intra-abdominal lymphatic obstruction.
• Bone tenderness may suggest osseous involvement or marrow infiltration.
• Abdominal masses or tenderness may reflect bulky retroperitoneal lymphadenopathy or hepatosplenomegaly.

General Examination Observations

• Fever may be documented during evaluation or inferred from history.
• Cachexia or significant weight loss may be evident in advanced disease.
• Pallor may indicate anaemia; bruising or petechiae suggest thrombocytopenia from marrow involvement.
• Clubbing, cyanosis, or pleural signs may suggest thoracic involvement or effusions.

Less Common Examination Findings

• Signs of nephrotic syndrome (e.g., periorbital oedema, proteinuria) as a paraneoplastic feature.
• Jaundice or hepatic stigmata in the rare case of liver involvement or vanishing bile duct syndrome.
• Peripheral lymphadenopathy without other systemic signs may occur in indolent disease.

Haematological and Biochemical Investigations

Full Blood Count (FBC) with Differential

• May reveal normocytic anaemia, which could reflect chronic disease, marrow infiltration, or haemolysis.
• Leukocyte and platelet abnormalities (e.g. leukocytosis, lymphopenia, thrombocytopenia) may also occur.
• Anaemia with haemoglobin <10.5 g/dL is associated with poorer prognosis.

Biochemical Profile

• A panel evaluating liver and kidney function is required prior to initiating therapy.
• Elevated lactate dehydrogenase (LDH) levels may suggest high tumour burden.
• Increased alkaline phosphatase can indicate hepatic or skeletal involvement.
• Hypoalbuminaemia (<4.0 g/dL) is an unfavourable prognostic feature.

Inflammatory Markers

• Erythrocyte sedimentation rate (ESR) can be raised and is incorporated in several prognostic scoring systems.
• An ESR >50 mm/hour without B symptoms or >30 mm/hour with B symptoms is considered a negative prognostic sign.

Viral Screening

• Testing for HIV, hepatitis B, and hepatitis C is standard, as viral infections influence management and outcomes.
• Co-infections may require treatment modifications and prophylactic measures.

Thyroid Function

• Especially important in patients scheduled to receive neck irradiation, as radiotherapy can precipitate thyroid dysfunction.

Imaging for Staging and Response Assessment

Chest Radiograph (CXR)

• May demonstrate mediastinal widening or a large mediastinal mass.
• A mass occupying more than one-third of the thoracic diameter at the T5–T6 level qualifies as bulky disease.

Positron Emission Tomography–Computed Tomography (PET/CT)

• Integral to baseline staging and interim or end-of-treatment response evaluation.
• Detects metabolically active disease using fluorodeoxyglucose (FDG).
• PET findings are interpreted using the Deauville five-point scale, which compares uptake in lesions to that in the mediastinum and liver.
• A score of 1–3 suggests complete metabolic remission.
• If PET/CT is available and shows no marrow involvement, a bone marrow biopsy is generally unnecessary.

Computed Tomography (CT) Scans

• Helpful in identifying anatomical involvement if PET is unavailable.
• Visualises nodal enlargement, splenic/hepatic involvement, and extranodal sites.

Gallium Scintigraphy

• Now largely replaced by PET; less sensitive and more cumbersome.
• Can still be used if PET is unavailable, though it delivers a higher radiation dose and results are delayed.

Histological Confirmation

Excisional Lymph Node Biopsy

• Offers optimal architecture for assessing classical Reed-Sternberg cells or lymphocytic and histiocytic (L&H) cells.
• Essential to distinguish between classical HL (cHL) and nodular lymphocyte-predominant HL (NLPHL).
• Fine-needle aspiration is not diagnostic and should be avoided.

Core Needle Biopsy

• Acceptable when excisional biopsy is not feasible, but may limit histological subtyping.

Immunohistochemistry

• Confirms diagnosis and classifies HL subtype:
  • cHL: CD30+, usually CD15+, CD20–, CD45–
  • NLPHL: CD20+, CD45+, CD15–, CD30–

Additional and Specialised Tests

Bone Marrow Biopsy

• Typically reserved for patients with unexplained cytopenias or if PET/CT is unavailable.
• More common in older patients or those with advanced-stage disease.

Cardiac Evaluation (Echocardiogram or MUGA Scan)

• Mandatory for those receiving anthracyclines (e.g., doxorubicin) to assess left ventricular function.
• Decreased ejection fraction may necessitate regimen adjustment.

Pulmonary Function Testing

• Conducted before use of bleomycin or mediastinal radiotherapy.
• Identifies pre-existing pulmonary compromise and risk of toxicity.

Lumbar Puncture or CNS Imaging

• Rarely indicated; reserved for patients with neurological symptoms or suspected CNS involvement.
• CNS infiltration is exceedingly rare in HL.

Serum Cytokines and Soluble Markers

• Elevated levels of IL-6, IL-10, and soluble CD25 may correlate with tumour burden and systemic symptoms.
• These are primarily used in research or clinical trials, not routine practice.

Staging Systems

Staging is primarily guided by the Ann Arbor classification with Cotswolds modification

• Stage I: Single lymph node region or single extralymphatic site.
• Stage II: Multiple lymph node regions on the same side of the diaphragm.
• Stage III: Lymph node involvement on both sides of the diaphragm.
• Stage IV: Disseminated involvement of one or more extralymphatic organs.

Suffixes further refine staging

• A/B: Denote absence or presence of B symptoms.
• E: Indicates direct extension from nodal disease to adjacent tissue.
• X: Used to designate bulky disease (e.g. mass >10 cm or large mediastinal mass).

Reactive and Infectious Causes

Reactive Lymphadenopathy

• Lymphadenopathy due to viral or bacterial infections (e.g. EBV, cytomegalovirus, toxoplasmosis) may mimic HL, particularly when accompanied by fever or weight loss.
• Lymph node architecture remains preserved, and diagnostic Hodgkin/Reed-Sternberg (HRS) cells are absent.
• Fine-needle aspiration is insufficient for differentiation; excisional biopsy is essential.

Infectious Mononucleosis (EBV)

• Common in adolescents and young adults, typically presents with tender cervical lymphadenopathy, fever, fatigue, and pharyngitis.
• EBV infection is a known risk factor for HL but often precedes it by years.
• EBV-positive mononucleosis may transiently mimic HL histologically, but lacks the characteristic immunophenotype of HRS cells.
• Serological testing (e.g. EBV-VCA IgM, heterophile antibody test) aids in diagnosis.

EBV-positive Mucocutaneous Ulcer

• Presents as isolated, superficial ulcers often in the oropharynx or GI tract, especially in the elderly or immunosuppressed.
• Histology may show EBV-infected B cells resembling HRS cells but lacks systemic spread.
• Distinguished by self-limited course and response to conservative management.

Other Lymphomas

Nodular Lymphocyte-Predominant HL (NLPHL)

• May closely resemble lymphocyte-rich classical HL (LR-cHL).
• NLPHL features "popcorn cells" (L&H cells), strong CD20 and CD45 positivity, and absence of CD15 and CD30.
• Usually EBV-negative and displays a nodular B-cell–rich background.

Non-Hodgkin Lymphoma (NHL)

• Typically involves non-contiguous nodal or extranodal sites (e.g. gastrointestinal tract, bone marrow).
• Waldeyer ring and extranodal involvement more common than in HL.
• Lymphadenopathy in NHL may be less symmetrical and occurs at varied anatomic sites.
• Diagnosis relies on morphology and immunophenotyping.

Anaplastic Large Cell Lymphoma (ALCL)

• Can resemble lymphocyte-depleted HL, especially when accompanied by fibrosis or inflammatory infiltrates.
• ALCL typically shows CD30 positivity but differs by expression of T-cell markers and ALK positivity (in ALK-positive ALCL).
• PAX5 expression, usually weak in HL, helps distinguish HL from ALCL.

Primary Mediastinal Large B Cell Lymphoma (PMBL)

• Shares clinical features with nodular sclerosis HL, including frequent occurrence in young adults with mediastinal masses.
• PMBL cells typically express CD20 and CD79a, and show weak or absent CD15 expression.
• Strong CD30 expression is common in HL but only weak or patchy in PMBL.
• EBV is rarely implicated in PMBL, unlike in some HL subtypes.

Mediastinal Grey Zone Lymphoma (MGZL)

• Displays overlapping features of cHL and PMBL, often with discordant immunophenotypic markers.
• Presents most often in young males with bulky mediastinal masses.
• Tumours may express both CD30 and B-cell markers, complicating classification.
• MGZL tends to have a more aggressive course and inferior outcomes compared to cHL or PMBL.

T cell Histiocyte-Rich Large B Cell Lymphoma (THRLBCL)

• Composed predominantly of reactive T cells and histiocytes with sparse malignant B cells.
• May mimic HL due to low tumour cell content and inflammatory milieu.
• Distinguished by positive staining for pan-B cell markers and absence of CD15/CD30 expression.

Other Malignancies

Metastatic Solid Tumours

• Malignancies such as head and neck squamous cell carcinoma, breast cancer, or gastrointestinal cancers may present with regional lymphadenopathy.
• Distribution tends to follow expected anatomical drainage patterns.
• Histology and immunohistochemistry (e.g. cytokeratins) clarify the diagnosis.

General Principles

• Combination chemotherapy and radiotherapy are the backbone of curative treatment in HL.
• PET-adapted strategies have enabled response-based tailoring of treatment intensity.
• Older patients (typically >60 years) have increased treatment-related toxicity and may require modified regimens.
• Bleomycin, though effective, is often restricted or omitted due to pulmonary toxicity risks, especially in older or comorbid patients.

Early-Stage Classical Hodgkin Lymphoma (Stage I–II)

Risk Stratification

• Patients are categorised as favourable or unfavourable based on factors such as:
  • ≤2 nodal sites
  • No B symptoms
  • ESR <50 mm/h (or <30 mm/h with B symptoms)
  • Mediastinal mass ratio <0.33
  • Absence of extranodal involvement

Treatment Approaches

• ABVD chemotherapy (doxorubicin, bleomycin, vinblastine, dacarbazine) followed by involved-site radiotherapy (ISRT).
• ISRT limits radiation exposure to only the involved lymph node areas, reducing long-term toxicity.

Chemotherapy Alone

• Considered for patients where radiotherapy is contraindicated or to minimise risk (e.g. young women, prior malignancy).
• Slightly increased relapse risk, but overall survival remains comparable.

PET-Adapted Treatment

• Interim PET/CT after 2 cycles of ABVD guides further therapy:
  • Deauville 1–3: Suggests complete response; fewer chemo cycles and/or omission of radiotherapy may be appropriate.
  • Deauville 4–5: Suggests residual disease; further ABVD or biopsy considered.

Unfavourable Early-Stage cHL

• Treated with ABVD ± radiotherapy depending on bulk and PET response.
• PET-guided intensification may include escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone) for those with poor response.

Advanced-Stage Classical Hodgkin Lymphoma (Stage III–IV)

Initial Therapy

• ABVD or brentuximab vedotin plus AVD are standard.
• Escalated BEACOPP offers improved disease control but greater toxicity and no survival benefit over ABVD in most patients.
• Brentuximab vedotin + AVD shows improved survival but requires caution in older adults and those with neuropathy.

PET-Guided Therapy

• After 2 cycles of ABVD:
  • Deauville 1–3: Continue AVD (omit bleomycin to avoid toxicity).
  • Deauville 4–5: Escalation to BEACOPP or salvage therapy depending on age and comorbidities.

Consolidation Radiotherapy

• Not routinely required if end-of-treatment PET/CT is negative.
• May be used for residual PET-positive sites or bulky disease post-chemotherapy.

Refractory or Relapsed Classical HL

Salvage Strategy

• Biopsy confirmation is required.
• Goal is cure through high-dose chemotherapy and autologous stem cell transplant (ASCT) after tumour debulking.
• Common salvage regimens include:
  • BeGEV (bendamustine, gemcitabine, vinorelbine)
  • ICE, DHAP, IGEV, GVD

Immunotherapy-Based Combinations

• Used before ASCT or in relapsed settings:
  • Brentuximab vedotin + bendamustine
  • Brentuximab vedotin + nivolumab
  • Pembrolizumab + GVD

Post-ASCT Maintenance

• Brentuximab vedotin recommended for high-risk patients post-transplant (e.g. early relapse, extranodal disease).

Nodular Lymphocyte-Predominant HL (NLPHL)

Early-Stage Disease

• Radiotherapy alone (30–36 Gy ISRT) is preferred in asymptomatic, non-bulky stage IA/IIA disease.
• Observation is an option after complete excision or in those with radiotherapy contraindications.

Bulky or Symptomatic Early-Stage

• Rituximab-based chemoimmunotherapy (e.g. R-ABVD, R-CHOP, R-CVbP) followed by ISRT.

Advanced-Stage NLPHL

• Observation may be appropriate in asymptomatic patients.
• Symptomatic disease warrants rituximab + chemotherapy, with or without radiotherapy.

Relapsed NLPHL

• Requires biopsy to exclude transformation.
• Managed with rituximab monotherapy or rituximab-based salvage regimens (e.g. R-ICE, R-DHAP).
• ASCT considered in aggressive or high-risk relapse.

Overall Survival and Stage-Based Prognosis

• Based on Surveillance, Epidemiology, and End Results (SEER) data from 2014–2020, the overall 5-year relative survival for HL across all stages is 88.9%.
• Survival rates by stage:
  • Stage I: 92.0%
  • Stage II: 94.8%
  • Stage III: 87.1%
  • Stage IV: 81.2%
  • Unstaged: 82.6%

Prognosis in Early-Stage Classical HL (Stage I–II)

• Long-term disease control exceeds 80–90% when treated with combined-modality therapy (chemotherapy + involved-site radiotherapy).
• Recurrences within the first 15 years tend to be due to HL itself, whereas long-term mortality beyond this period is often due to secondary malignancies and cardiovascular disease, highlighting the importance of minimising treatment-related toxicity.
• Use of involved-site radiotherapy (ISRT) over traditional involved-field radiotherapy (IFRT) has reduced radiation-related complications without compromising disease control.

Prognosis in Advanced-Stage Classical HL (Stage III–IV)

• Advanced disease presents more heterogeneously; outcomes depend heavily on disease burden and host factors.
• Long-term control is achieved in approximately 60–80% of patients using chemotherapy-based strategies, including regimens such as ABVD, brentuximab vedotin + AVD, or escalated BEACOPP.
• PET-guided therapy allows adaptation based on interim treatment response, improving long-term outcomes while reducing overtreatment in responders.

Prognosis in Nodular Lymphocyte-Predominant HL (NLPHL)

• NLPHL generally follows a favourable clinical course, especially in early-stage (I–II) disease.
• Long-term control with radiotherapy or chemoimmunotherapy reaches 80–90%.
• Late relapses can occur, but the disease tends to remain indolent and highly treatable.
• Prognosis is less favourable in cases of transformation to aggressive B-cell lymphoma or in advanced-stage NLPHL with symptomatic progression.

Prognostic Indices: The International Prognostic Score (IPS)

Seven adverse prognostic factors

• Serum albumin <4 g/dL
• Haemoglobin <10.5 g/dL
• Male sex
• Age ≥45 years
• Stage IV disease
• WBC count >15,000/mm³
• Absolute lymphocyte count <600/mm³ or <8% of total WBC
• Each factor scores 1 point.

5-year overall survival by IPS score

• 0 points: 84%
• 1 point: 77%
• 2 points: 67%
• 3 points: 60%
• 4 points: 51%
• ≥5 points: 42%

Factors Influencing Prognosis

• Beyond stage and IPS, several factors affect prognosis:
  • Presence of B symptoms (fever, weight loss, night sweats) signals higher tumour burden.
  • Elevated ESR, bulky disease, and extranodal involvement are linked with poorer outcomes.
  • Age >60 years is associated with increased treatment-related mortality and comorbidity burden.
  • Treatment response, especially as assessed by interim PET/CT, is one of the strongest predictors of outcome.

Long-Term Considerations

• Patients cured of HL face long-term risks, including:
  • Secondary malignancies (e.g. breast, lung, thyroid cancers)
  • Cardiovascular disease
  • Infertility and endocrine dysfunction, particularly after alkylating agents or pelvic radiotherapy
• Ongoing surveillance and management of late effects are crucial for survivorship care.

Endocrine Complications

Thyroid Dysfunction

• Hypothyroidism is the most common endocrine complication, affecting up to 50% of patients receiving neck or mediastinal radiotherapy.
• Other thyroid-related issues include Graves’ disease, benign nodules, and thyroid cancer.
• Lifelong monitoring with thyroid function tests is advised in at-risk patients.

Ovarian Dysfunction

• Risk increases with age and intensity of therapy.
• ABVD regimens are associated with a lower risk compared to escalated BEACOPP or pelvic irradiation.
• Infertility is more likely in women over 35 years.
• PET-adapted therapy and fertility preservation strategies should be discussed upfront.

Testicular Dysfunction

• Temporary azoospermia is common with ABVD.
• Escalated BEACOPP and radiotherapy (even at low doses of 1–2 Gy) carry a greater risk of permanent infertility.
• Leydig cell function (testosterone production) is generally preserved with appropriate shielding.
• Fertility preservation (e.g. sperm banking) should be offered before treatment.

Secondary Malignancies

Solid Tumours

• The risk of secondary cancers (especially breast and lung) increases with time, and is strongly linked to radiotherapy exposure, particularly in younger patients.
• Smaller fields (e.g., involved-site radiotherapy) and lower doses aim to mitigate this risk.
• Breast cancer screening (mammography and MRI) is essential for women treated with thoracic radiation before age 30.
• Lung cancer risk is magnified by smoking—cessation should be strongly encouraged.

Haematological Malignancies

• Acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) are associated with alkylating agents, especially in escalated BEACOPP regimens.
• ABVD carries a lower risk.
• Secondary leukaemias often occur within 5–10 years post-treatment.

Cardiovascular Complications

• Radiotherapy to the mediastinum increases the risk of:
  • Pericarditis
  • Valvular heart disease
  • Coronary artery disease
• Anthracyclines (e.g., doxorubicin) contribute to cardiomyopathy, especially at cumulative doses >300 mg/m².
• Cardiac effects may present earlier than in the general population.
• Use of modern radiotherapy techniques (e.g., ISRT) and cardioprotective measures (e.g., dose limits, dexrazoxane) reduce risk.
• Cardiovascular risk factors (e.g., hypertension, hyperlipidaemia) should be monitored and aggressively managed.

Pulmonary Toxicity

• Bleomycin-induced lung injury affects ~20% of patients treated with ABVD.
• Manifests as dry cough, dyspnoea, or pulmonary fibrosis.
• Risk increases with age, renal dysfunction, high oxygen exposure, or concurrent radiotherapy.
• Monitoring of lung diffusing capacity (DLCO) is essential during therapy.
• Bleomycin should be discontinued if significant toxicity arises.

Immunosuppression and Infection Risk

• HL itself and its treatments impair cell-mediated immunity.
• Post-treatment, patients may have a blunted antibody response, placing them at risk of opportunistic infections.
• Reactivation of varicella zoster, Pneumocystis jirovecii, and fungal infections are concerns.
• Vaccination, antimicrobial prophylaxis in high-risk individuals, and prompt evaluation of febrile episodes are essential.

Fertility and Gonadal Toxicity

• Infertility affects over 50% of patients undergoing intensive therapy or pelvic irradiation.
• Fertility preservation (e.g., oocyte cryopreservation, ovarian suppression, sperm banking) should be discussed prior to initiating therapy.
• PET-guided de-escalation strategies may reduce gonadal toxicity in responsive patients.

Psychosocial and Quality-of-Life Issues

• Survivors may experience:
  • Depression and anxiety
  • Peripheral neuropathy
  • Disturbed sexual functioning
  • Body image issues
  • Strained interpersonal or family relationships
• Multidisciplinary support involving mental health professionals, fertility specialists, and survivorship clinics is beneficial.

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