Lymphoma — Hodgkin vs Non-Hodgkin, Staging, and Treatment Overview

Lymphomas are malignant neoplasms arising from lymphocytes within the lymphatic system, broadly classified into Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). This fundamental distinction, first established by the presence or absence of Reed-Sternberg cells, remains the cornerstone of lymphoma classification.

[KEY_CONCEPT] The lymphatic system comprises lymph nodes, spleen, thymus, bone marrow, and extranodal lymphoid tissues (MALT), making lymphomas capable of arising at virtually any anatomic site.

Epidemiology

Hodgkin Lymphoma:

• Accounts for ~10% of all lymphomas
• Bimodal age distribution: peaks at 25-30 years and >55 years
• Male-to-female ratio 1.4:1
• Annual incidence: 2.7 per 100,000
• Associated with EBV infection (~40% of cases)

Non-Hodgkin Lymphoma:

• Accounts for ~90% of all lymphomas
• Incidence increases with age (median age 67 years)
• Male predominance (1.7:1 ratio)
• Annual incidence: 19.6 per 100,000
• More heterogeneous group with >60 distinct subtypes

[HIGH_YIELD] The most common NHL subtypes are diffuse large B-cell lymphoma (DLBCL) (30-35%) and follicular lymphoma (20-25%), while classical Hodgkin lymphoma represents 95% of HL cases.

Pathophysiology

Lymphomas result from oncogenic mutations affecting normal lymphocyte development, apoptosis, and cell cycle control. Key pathways include:

• B-cell receptor (BCR) signaling disruption
• p53 tumor suppressor inactivation
• Apoptosis evasion via BCL-2 overexpression
• Cell cycle dysregulation through cyclin/CDK alterations

[CLINICAL_PEARL] Unlike leukemias, lymphomas typically maintain tissue architecture initially, later causing mass effects and organ dysfunction through progressive enlargement rather than bone marrow failure.

Lymphoma presentations vary significantly between HL and NHL, with important diagnostic and prognostic implications.

Hodgkin Lymphoma

Nodal Disease Pattern:

• Contiguous spread from node to adjacent node groups
• Mediastinal involvement common (85% of nodular sclerosis subtype)
• Supradiaphragmatic predominance
• Less frequent extranodal involvement (<10%)

Systemic Symptoms (B-symptoms):

• Fever >38°C without obvious infection
• Night sweats requiring clothing/sheet changes
• Weight loss >10% body weight over 6 months
• Present in 25-30% of HL patients

[HIGH_YIELD] Pel-Ebstein fever (cyclical fever pattern) is pathognomonic for HL but occurs in <5% of cases.

Non-Hodgkin Lymphoma

Nodal Disease Pattern:

• Non-contiguous spread with random node group involvement
• Frequent extranodal involvement (>40% at presentation)
• Common sites: GI tract, bone marrow, liver, CNS
• More likely to present with advanced stage disease

Clinical Syndromes by Subtype:

[CLINICAL_PEARL] Superior vena cava syndrome from mediastinal masses occurs more frequently in aggressive NHL (especially T-lymphoblastic) than HL, requiring emergent treatment.

Physical Examination Findings

Common to Both:

• Lymphadenopathy: painless, firm, mobile initially
• Hepatosplenomegaly: more common in NHL
• Performance status decline in aggressive subtypes

Hodgkin-Specific:

• Alcohol-induced pain at involved nodes (rare but pathognomonic)
• More localized adenopathy patterns

NHL-Specific:

• Waldeyer's ring involvement (nasopharynx, tonsils)
• CNS involvement in aggressive subtypes
• Skin involvement in cutaneous T-cell lymphomas

Accurate diagnosis requires histopathologic confirmation, while staging determines prognosis and treatment approach.

Diagnostic Workup

Essential Studies:

1. Excisional lymph node biopsy (preferred over FNA)
2. Immunohistochemistry and flow cytometry
3. Cytogenetics and molecular studies
4. Complete blood count with differential
5. Comprehensive metabolic panel including LDH
6. PET-CT scan for staging

[HIGH_YIELD] Reed-Sternberg cells or Hodgkin cells are pathognomonic for HL and must be identified on biopsy. These are large, abnormal B-cells with characteristic "owl's eye" nuclei.

Staging: Ann Arbor Classification

Stage I: Single lymph node region OR single extranodal site Stage II: ≥2 lymph node regions, same side of diaphragm Stage III: Lymph node regions on both sides of diaphragm Stage IV: Disseminated involvement of extranodal organs

Modifiers: A = Absence of B-symptoms B = Presence of B-symptoms (fever, night sweats, weight loss) E = Extranodal extension from nodal site X = Bulky disease (>10 cm or mediastinal mass >1/3 chest diameter)

[KEY_CONCEPT] PET-CT imaging has revolutionized lymphoma staging, providing both anatomic and metabolic information crucial for treatment planning and response assessment.

Risk Stratification

Hodgkin Lymphoma - International Prognostic Score (IPS):

• Age ≥45 years
• Male sex
• Stage IV disease
• Albumin <4 g/dL
• Hemoglobin <10.5 g/dL
• WBC ≥15,000/μL
• Lymphocyte count <600/μL or <8% of WBC

Score interpretation:

• 0-1 factors: 5-year freedom from progression 88%
• ≥4 factors: 5-year freedom from progression 61%

NHL - International Prognostic Index (IPI):

• Age >60 years
• Performance status ≥2
• Stage III-IV disease
• Elevated LDH

• 1 extranodal site

[CLINICAL_PEARL] Bone marrow biopsy is no longer routinely recommended in HL staging due to PET-CT accuracy, but remains important in certain NHL subtypes, particularly indolent lymphomas.

Treatment strategies differ markedly between HL and NHL, with HL generally more curable but NHL requiring subtype-specific approaches.

Hodgkin Lymphoma Treatment Algorithm

Early-Stage HL (I-II, favorable risk): → ABVD × 2 cycles → PET-CT → Involved-site RT (20 Gy)

Early-Stage HL (I-II, unfavorable risk): → ABVD × 4 cycles → PET-CT → Involved-site RT (30 Gy)

Advanced-Stage HL (III-IV): → ABVD × 6 cycles OR escalated BEACOPP × 6 cycles → PET-CT after 2 cycles (interim assessment) → Continue if PET-negative, consider escalation if PET-positive

Relapsed/Refractory HL: → Salvage chemotherapy → High-dose chemotherapy + ASCT → Brentuximab vedotin for CD30+ disease → Anti-PD-1 therapy (nivolumab, pembrolizumab)

ABVD Regimen:

• Adriamycin (doxorubicin)
• Bleomycin
• Vinblastine
• Dacarbazine

[HIGH_YIELD] Pulmonary function tests should be obtained before bleomycin therapy, as pulmonary toxicity is the dose-limiting side effect.

Non-Hodgkin Lymphoma Treatment

Aggressive NHL (DLBCL)

Standard Treatment:

• R-CHOP (Rituximab + CHOP) every 21 days × 6-8 cycles
• CHOP: Cyclophosphamide, Hydroxydaunomycin (doxorubicin), Oncovin (vincristine), Prednisone

Treatment Modifications:

• Age >60 or cardiac disease: Consider R-miniCHOP or dose reduction
• CNS risk: Add intrathecal chemotherapy or high-dose methotrexate
• Bulky disease: Consider consolidative radiation therapy

Indolent NHL (Follicular Lymphoma)

Treatment Algorithm:

Asymptomatic, low tumor burden: → Watch and Wait strategy

Symptomatic or high tumor burden: → R-CHOP, R-CVP, or Bendamustine-Rituximab → Maintenance rituximab × 2 years

Relapsed/Refractory: → Alternative immunochemotherapy regimens → CAR-T therapy (axicabtagene ciloleucel, tisagenlecleucel) → Novel agents (PI3K inhibitors, BCL-2 inhibitors)

[CLINICAL_PEARL] Rituximab maintenance after initial treatment significantly improves progression-free survival in follicular lymphoma, as demonstrated in multiple randomized trials.

Novel Therapies

CAR-T Cell Therapy:

• Approved for relapsed/refractory DLBCL after ≥2 prior therapies
• Axicabtagene ciloleucel and tisagenlecleucel are FDA-approved
• Requires specialized centers due to cytokine release syndrome risk

Targeted Therapies:

• Ibrutinib (BTK inhibitor): Mantle cell lymphoma, marginal zone lymphoma
• Venetoclax (BCL-2 inhibitor): Chronic lymphocytic leukemia/small lymphocytic lymphoma
• Brentuximab vedotin (anti-CD30): Anaplastic large cell lymphoma

Modern lymphoma management relies on standardized response criteria and advanced imaging to guide treatment decisions and monitor outcomes.

Lugano Response Criteria (2014)

Complete Response (CR):

• PET-CT: Deauville score 1-3 with no residual mass >1.5 cm
• CT alone: Complete resolution of all measurable disease
• Bone marrow: Normal if previously involved
• Clinical: No B-symptoms

Partial Response (PR):

• PET-CT: Deauville score 4-5 with decreased uptake from baseline
• CT: ≥50% reduction in sum of product diameters (SPD)
• Interim PET: Deauville score 1-3 indicates excellent response

Progressive Disease (PD):

• PET-CT: New lesions or increased uptake
• CT: >50% increase in SPD or new lesions >1.5 cm
• Individual nodes: >50% increase in longest diameter

[KEY_CONCEPT] Deauville scoring standardizes PET interpretation:

• Score 1-2: No uptake above background
• Score 3: Uptake ≤ mediastinal blood pool
• Score 4: Uptake > mediastinal but ≤ liver
• Score 5: Uptake > liver or new lesions

Response-Adapted Therapy

Interim PET-CT Assessment:

After 2-4 cycles of chemotherapy: → Deauville Score 1-3: Continue planned treatment → Deauville Score 4-5: Consider treatment intensification → New lesions: Immediate restaging and treatment modification

[HIGH_YIELD] Early response assessment after 2 cycles of ABVD in HL allows for treatment de-escalation (omitting bleomycin) in PET-negative patients, reducing pulmonary toxicity risk.

Treatment-Related Complications

Acute Complications

Tumor Lysis Syndrome:

• Risk factors: High LDH, bulky disease, aggressive histology
• Prevention: Allopurinol/rasburicase, aggressive hydration
• Monitoring: Electrolytes, phosphorus, uric acid, creatinine

Febrile Neutropenia:

• High-risk regimens: R-CHOP, ABVD, escalated BEACOPP
• Prophylaxis: G-CSF support for age >65 or high-risk patients
• Management: Broad-spectrum antibiotics within 1 hour

Late Effects

Secondary Malignancies:

• Acute leukemia: Risk 0.5-2% at 10 years (alkylating agents)
• Solid tumors: Risk increases with radiation exposure
• Breast cancer: Particular concern in young women receiving mediastinal RT

Cardiovascular Toxicity:

• Anthracycline cardiomyopathy: Cumulative dose-dependent
• Radiation-induced CAD: Risk begins 5-10 years post-treatment
• Monitoring: Baseline ECHO, annual cardiology follow-up

[CLINICAL_PEARL] Fertility preservation counseling is essential for reproductive-age patients, as alkylating agents (cyclophosphamide, procarbazine) significantly impact gonadal function.

Survivorship Care

Long-term Monitoring:

• Physical examination every 3-6 months × 5 years
• Complete blood count and comprehensive metabolic panel
• Thyroid function (neck radiation exposure)
• Mammography (chest radiation in women)
• Cardiovascular risk assessment

Vaccination Guidelines:

• Live vaccines: Contraindicated during treatment and 3-6 months after
• Inactivated vaccines: May have reduced efficacy during treatment
• Annual influenza vaccine: Recommended for all patients
• Pneumococcal vaccine: Important due to functional asplenia risk

Prognosis in lymphoma depends on histologic subtype, stage at presentation, patient factors, and response to initial therapy. Long-term survivorship issues require ongoing attention.

Survival Outcomes

Hodgkin Lymphoma

• Overall 5-year survival: 85-90%
• Early-stage favorable: >95% cure rate
• Advanced-stage: 80-85% cure rate
• Relapsed/refractory: 50-60% salvageable with ASCT

Prognostic Factors:

• Favorable: Young age, early stage, absence of B-symptoms
• Unfavorable: Advanced stage, bulky disease, B-symptoms, elevated ESR

Non-Hodgkin Lymphoma

[HIGH_YIELD] Follicular lymphoma has an excellent overall survival despite being incurable, with many patients living normal lifespans through sequential treatments over decades.

Relapse Patterns

Hodgkin Lymphoma:

• Early relapse (<12 months): Poor prognosis, requires aggressive salvage
• Late relapse (>12 months): Better outcomes with salvage therapy
• Sites: Often occurs in previously involved areas
• Histologic transformation: Rare (<5%)

Non-Hodgkin Lymphoma:

• Aggressive NHL: Most relapses occur within 2 years
• Indolent NHL: Continuous risk of relapse over decades
• Histologic transformation: 2-3% per year for follicular lymphoma → DLBCL
• Sites: Can occur at any site, including CNS sanctuary sites

Surveillance Strategy

Years 1-2 Post-treatment: → History & Physical every 3 months → CBC, CMP, LDH every 3-6 months → Imaging only if clinically indicated

Years 2-5 Post-treatment: → History & Physical every 6 months → Laboratory studies every 6-12 months → Annual imaging not recommended unless high-risk

Years 5+ Post-treatment: → Annual visits focusing on late effects → Age-appropriate cancer screening → Cardiovascular and endocrine monitoring

[CLINICAL_PEARL] Routine surveillance imaging is no longer recommended in asymptomatic lymphoma patients in remission, as it rarely detects curable relapses and increases anxiety and healthcare costs.

Special Populations

Elderly Patients (>65 years):

• Modified treatment regimens (R-miniCHOP, reduced-dose ABVD)
• Higher risk of treatment-related mortality
• Comprehensive geriatric assessment recommended
• Attention to comorbidities and functional status

Pregnancy-Associated Lymphoma:

• First trimester: Treatment delay if possible
• Second/third trimester: ABVD or R-CHOP generally safe
• Radiation: Contraindicated during pregnancy
• Rituximab: Use with caution (crosses placenta)

HIV-Associated Lymphoma:

• Higher incidence of aggressive B-cell lymphomas
• HAART therapy should be continued during treatment
• Increased risk of opportunistic infections
• CNS lymphoma more common than in immunocompetent patients

Quality of Life Considerations

Common Long-term Issues:

• Fatigue: Most common complaint, may persist for years
• Cognitive dysfunction: "Chemo brain" affects 20-30% of survivors
• Neuropathy: Vincristine-induced peripheral neuropathy
• Sexual dysfunction: Impact on libido and fertility
• Psychological distress: Anxiety about recurrence, depression

Supportive Care Interventions:

• Exercise programs for fatigue management
• Cognitive rehabilitation for memory issues
• Fertility counseling and preservation options
• Psychological support and survivorship programs

[KEY_CONCEPT] Shared care models between hematologists and primary care providers optimize long-term survivorship care, ensuring both cancer-specific monitoring and general health maintenance.