Definition/General
Introduction:
Hodgkin lymphoma (HL) is a unique lymphoid malignancy characterized by Reed-Sternberg cells or lymphocyte and histiocyte cells
It accounts for 10% of all lymphomas
It has distinctive biological behavior and excellent curability
It shows characteristic contiguous spread pattern.
Origin:
Originates from mature B-cells in most cases
Classical HL arises from germinal center or post-germinal center B-cells
NLPHL arises from germinal center B-cells
Shows clonal immunoglobulin gene rearrangements
Neoplastic cells represent minority of tumor mass.
Classification:
WHO classification recognizes 2 major types
Classical Hodgkin lymphoma (95% of cases)
Nodular lymphocyte predominant HL (5% of cases)
Classical HL has 4 subtypes
Ann Arbor staging system used
Cotswolds modification incorporates bulk disease.
Epidemiology:
Bimodal age distribution in classical HL (peaks at 25-30 and >55 years)
Male predominance overall (M:F = 1.4:1)
EBV association in 40% of classical HL
Higher incidence in developed countries
Excellent prognosis with >90% cure rate in early stages.
Clinical Features
Presentation:
Painless lymphadenopathy (85-90% of cases)
Mediastinal involvement common (60% in nodular sclerosis)
B-symptoms in 25-30% (fever, night sweats, weight loss)
Alcohol-induced pain in affected nodes (rare but pathognomonic)
Superior vena cava syndrome possible.
Symptoms:
Painless lymph node enlargement (most common)
B-symptoms: fever >38°C, drenching night sweats, weight loss >10%
Chest symptoms (cough, dyspnea, chest pain)
Pruritus (15-30% cases)
Fatigue and weakness
Performance status usually preserved.
Risk Factors:
EBV infection (especially in developing countries and immunocompromised)
Immunosuppression (HIV, organ transplant)
Family history (genetic predisposition)
Higher socioeconomic status (young adult classical HL)
Previous mononucleosis
Male gender.
Screening:
No routine screening available
Diagnosis requires tissue biopsy
Staging with CT and PET scans
Bone marrow biopsy not routinely required
Pulmonary function tests if mediastinal disease
Cardiac assessment before anthracyclines.
Master Hodgkin Lymphoma Pathology with RxDx
Access 100+ pathology videos and expert guidance with the RxDx app
Gross Description
Appearance:
Enlarged lymph nodes with intact capsule
Cut surface shows gray-white to tan appearance
Nodular sclerosis shows thick fibrous bands
Fish-flesh appearance less common than NHL
Areas of necrosis may be present.
Characteristics:
Lymph node size typically 2-10 cm
Firm consistency
Sclerotic bands visible in nodular sclerosis subtype
Capsular thickening possible
Adjacent nodes may be matted together
Extracapsular extension uncommon.
Size Location:
Cervical and mediastinal nodes most commonly involved
Axillary and para-aortic nodes frequent
Contiguous spread pattern characteristic
Waldeyer ring involvement rare
Extranodal involvement uncommon at presentation (<10%).
Multifocality:
Contiguous spread from node group to node group
Skip lesions uncommon (unlike NHL)
Mediastinal involvement common in young adults
Retroperitoneal involvement in advanced stages
Splenic involvement indicates advanced disease.
Microscopic Description
Histological Features:
Reed-Sternberg cells and variants in inflammatory background
Classical RS cells: large multinucleated cells with prominent nucleoli
Hodgkin cells: mononuclear variants
Lacunar cells (nodular sclerosis)
L&H cells (NLPHL)
Mixed inflammatory background.
Cellular Characteristics:
Reed-Sternberg cells: >20 μm diameter, multinucleated, prominent nucleoli
Mirror-image nuclei characteristic
Abundant eosinophilic cytoplasm
Lacunar cells: retracted cytoplasm in formalin
L&H cells: multilobated nuclei, inconspicuous nucleoli.
Architectural Patterns:
Nodular sclerosis: broad collagen bands, lacunar cells
Mixed cellularity: scattered RS cells, mixed inflammation
Lymphocyte rich: abundant lymphocytes, rare RS cells
Lymphocyte depleted: paucity of lymphocytes
NLPHL: nodular pattern, L&H cells.
Grading Criteria:
No formal grading system for classical HL
Nodular sclerosis may be graded (Grade 1 vs Grade 2)
Grade 2: >25% reticular or >80% lacunar cells
Cellularity and fibrosis vary by subtype
Depletion score used in lymphocyte depleted.
Immunohistochemistry
Positive Markers:
Classical HL: CD15+ (85%), CD30+ (99%), PAX5 (weak)
NLPHL: CD20+, CD79a+, OCT2+, BOB1+
EBV-LMP1 (40% classical HL)
PD-L1 expression common
MUM1 often positive.
Negative Markers:
Classical HL: CD20- (usually), CD45-, CD3-
NLPHL: CD15-, CD30-
ALK negative (both types)
EMA negative (except rare cases)
TdT negative
BCL6 variable in NLPHL.
Diagnostic Utility:
CD15+/CD30+ profile diagnostic for classical HL
CD20+/CD15-/CD30- profile for NLPHL
PAX5 weak positivity confirms B-cell origin
EBV status has prognostic implications
PD-L1 predicts immunotherapy response.
Molecular Subtypes:
EBV-positive vs EBV-negative classical HL
EBV association higher in mixed cellularity and developing countries
PD-L1/PD-L2 alterations common in classical HL
Different prognosis by EBV status in some populations.
Molecular/Genetic
Genetic Mutations:
Complex cytogenetics with gains of 2p16, 9p24, 12q
REL amplification (2p16)
JAK2 mutations
B2M mutations (immune evasion)
SOCS1 mutations
NLPHL: BCL6 translocations, IGH rearrangements.
Molecular Markers:
Clonal immunoglobulin gene rearrangements present
NF-κB pathway activation
JAK-STAT pathway alterations
9p24.1 amplification (PD-L1/PD-L2)
CIITA inactivation
HLA class I/II loss (immune evasion).
Prognostic Significance:
International Prognostic Score uses clinical factors
EBV status affects prognosis in some populations
Bulk disease important prognostic factor
Stage most important factor
Age and gender influence outcome
Response to therapy excellent overall.
Therapeutic Targets:
CD30-targeted therapy (brentuximab vedotin)
PD-1 inhibitors (nivolumab, pembrolizumab)
JAK inhibitors under investigation
Immunomodulatory agents
CAR-T therapy for refractory cases
Radiation therapy highly effective.
Differential Diagnosis
Similar Entities:
Anaplastic large cell lymphoma (ALK+ or ALK-)
Primary mediastinal B-cell lymphoma
Diffuse large B-cell lymphoma
Classical HL vs NLPHL
Metastatic carcinoma
Reactive hyperplasia
T-cell/histiocyte-rich DLBCL.
Distinguishing Features:
Classical HL: CD15+/CD30+/CD20-
NLPHL: CD20+/CD15-/CD30-
ALCL: ALK+/CD30+/EMA+
PMBCL: CD20+/CD30+/CD15-
DLBCL: CD20+/CD30-/CD15-
Carcinoma: cytokeratin+
Reactive: polymorphous, no RS cells.
Diagnostic Challenges:
Distinction from ALCL (especially ALK-negative)
Recognition of RS cells in fibrotic background
Syncytial variant vs large cell lymphoma
Interfollicular NLPHL vs T-cell/histiocyte-rich DLBCL
Composite lymphomas
Transformation of NLPHL to DLBCL.
Rare Variants:
Lymphocyte depleted classical HL (rare)
Syncytial variant of nodular sclerosis
Interfollicular NLPHL
T-cell/histiocyte-rich NLPHL
Composite lymphomas
Hodgkin-like PTLD (post-transplant)
Gray zone lymphoma.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
[lymph node/tissue], measuring [size] cm in greatest dimension
Diagnosis
[Classical/Nodular lymphocyte predominant] Hodgkin Lymphoma
Subtype Classification
Subtype: [Nodular Sclerosis/Mixed Cellularity/Lymphocyte Rich/Lymphocyte Depleted/NLPHL]
Histological Features
Shows [Reed-Sternberg cells/L&H cells] in [inflammatory background pattern]
Neoplastic Cells
[Reed-Sternberg/Hodgkin/Lacunar/L&H] cells with [morphological features]
Immunohistochemistry
Neoplastic cells: CD15 [+/-], CD30 [+/-], CD20 [+/-], PAX5 [weak/strong/-]
EBV Status
EBV-LMP1: [positive/negative], EBER ISH: [positive/negative]
Staging and Prognostic Factors
Ann Arbor Stage: [if known], B-symptoms: [present/absent], Bulk disease: [present/absent]
Prognostic Assessment
IPS score: [if calculable], Risk factors: [age, stage, bulk, B-symptoms]
Final Diagnosis
[Classical/Nodular lymphocyte predominant] Hodgkin Lymphoma, [subtype], [stage if known]