What is Aggressive Hodgkin's Lymphoma?
"Aggressive" Hodgkin's lymphoma refers to advanced-stage disease (Ann Arbor stages III-IV) or intermediate-stage disease with unfavorable risk factors, characterized by a 20% risk of relapse or refractory disease despite standard therapy. 1, 2
Clinical Presentation
Typical Initial Symptoms
The majority of patients (>60%) present with painless, enlarged cervical or supraclavicular lymph nodes that are firm and rubbery on examination. 3, 4
- Mediastinal involvement is extremely common, particularly in young adults with nodular sclerosis subtype, and may cause cough, chest discomfort, or superior vena cava syndrome 3, 4
- The disease spreads in a contiguous, predictable pattern from one lymph node group to adjacent groups, rather than random distribution 3
- Isolated inguinal or sub-diaphragmatic presentations are atypical 3, 4
Constitutional "B Symptoms" (Present in ~35% of Cases)
- Unexplained fever >38°C 5, 4
- Drenching night sweats requiring clothing changes 5, 4
- Unintentional weight loss >10% of body weight in 6 months 5, 4
What Makes It "Aggressive"?
Advanced Stage Disease (Stages III-IV)
Advanced stage is defined as disease on both sides of the diaphragm (stage III) or disseminated involvement of extralymphatic organs (stage IV). 5
Unfavorable Risk Factors in Earlier Stages
Even stage I-II disease becomes "aggressive" when these risk factors are present: 5
- Bulky mediastinal mass (>1/3 of maximum horizontal chest diameter on X-ray, or >7.5 cm on CT) 5, 1
- Elevated ESR (>50 mm/h without B-symptoms, or >30 mm/h with B-symptoms) 5
- ≥3-4 involved nodal areas 5
- Extranodal disease 5
- Age >50-60 years (depending on classification system) 5
Physical Examination Findings
Look for firm, rubbery, non-tender lymphadenopathy in cervical, supraclavicular, and axillary chains that moves freely without skin fixation. 3, 4
- Hepatomegaly or splenomegaly (splenic involvement usually occurs with hepatic disease and systemic symptoms) 4
- Palpable abdominal masses in advanced disease 4
- Signs of superior vena cava syndrome if large mediastinal mass present 4
Histologic Appearance
Classical Hodgkin lymphoma (95% of cases) contains rare malignant Hodgkin-Reed-Sternberg (HRS) cells surrounded by abundant reactive inflammatory cells including lymphocytes, eosinophils, neutrophils, histiocytes, and plasma cells. 5, 4
Four Subtypes of Classical HL:
- Nodular sclerosis (most common in young adults, often with mediastinal involvement) 5, 4
- Mixed cellularity 5, 4
- Lymphocyte-rich 5, 4
- Lymphocyte-depleted 5, 4
The HRS cells are large, binucleated or multinucleated cells with prominent nucleoli ("owl's eye" appearance), but constitute only 1-2% of the tumor mass. 4, 6
Metabolic Characteristics of Aggressive Disease
Recent evidence shows that aggressive/relapsed Hodgkin's lymphoma exhibits high metabolic heterogeneity: HRS cells demonstrate high mitochondrial metabolism (high TOMM20 and MCT1 expression) while tumor-associated macrophages show high glycolysis (high MCT4 expression). 2
- This metabolic signature is associated with a hazard ratio of 5.87 for relapsed or refractory disease 2
- This pattern is absent in reactive lymph nodes 2
Clinical Presentation in Young Adults
Hodgkin's lymphoma has its highest incidence peak between ages 15-34 years, making it the most common lymphoma in adolescents and young adults. 1, 3, 7
- Incidence in ages 15-39 is 3.5 per 100,000 3, 7
- 5-year survival exceeds 90% with modern therapy, but young patients face decades of potential late treatment toxicity including secondary cancers and cardiovascular disease 1, 3
Treatment Implications for Aggressive Disease
Advanced-stage aggressive Hodgkin's lymphoma requires intensive chemotherapy: 5
- Eight cycles of ABVD (adriamycin/bleomycin/vinblastine/dacarbazine) is standard in many countries 5, 8
- Eight cycles of escalated BEACOPP (bleomycin/etoposide/adriamycin/cyclophosphamide/vincristine/procarbazine/prednisone) shows superior disease-free survival (88%) and overall survival (92%) at 5 years for patients <60 years, but with higher toxicity 5
- Additional 30 Gy radiotherapy to residual masses >1.5 cm after chemotherapy 5
For relapsed/refractory disease (the 20% with truly aggressive biology), high-dose chemotherapy with autologous stem cell transplantation is the treatment of choice. 5, 1, 4