Hodgkin Disease

Aka: Hodgkin Disease, Hodgkin's Lymphoma, Hodgkin Lymphoma, Hodgkin's Disease

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II. Epidemiology

  1. Second most common solid Hematologic Malignancy
    1. Most common is Non-Hodgkin's Lymphoma
    2. Accounts for one seventh of all Lymphomas
  2. Incidence: 2.8 cases per 100,000, or in 2008, was 8200 new cases per year in United States
  3. Age at diagnosis
    1. Bimodal peaks: Age 20 to 34 years old and over age 60 years
    2. Rare under age 5 years

III. Risk Factors

  1. See Lymphoma (for risk factors common to all Lymphomas)
  2. Epstein-Barr Virus Related Infectious Mononucleosis history (1 case per 1000 persons)
  3. Family History of Hodgkin Lymphoma
    1. Any first degree relative: 3.1 fold increased risk
    2. Same-sex sibling confers 10 fold risk
    3. Higher risk in monozygotic twins
  4. Immunocompromised conditions
    1. Human Immunodeficiency Virus infection (10 fold increased risk)

IV. Symptoms

  1. Painless Lymph Node enlargement
    1. Lymph Node pain provoked by Alcohol is reported, but uncommon
  2. Dermatologic symptoms
    1. Pruritus
    2. Erythema Nodosum
    3. New-onset Eczema
    4. Mycosis Fungoides
  3. Miscellaneous symptoms
    1. Fatigue
    2. Abdominal Pain
  4. B Symptoms
    1. Periodic low grade fever and Night Sweats
    2. Cachexia

V. Signs

  1. Lymphadenopathy
    1. Firm to Rubbery, discrete, nontender nodes
    2. Nonsuppurative
  2. Hepatomegaly
  3. Splenomegaly

VI. Staging: Ann Arbor classification

  1. See Lymphoma for Lugano Classification which expands on Ann Arbor to include PET/CT data
  2. Stage I
    1. I: Single Lymph Node region (I) or
    2. IE: One extranodal site
  3. Stage II
    1. II: Two or more Lymph Nodes on same side of diaphragm or
    2. IIE: Local extralymphatic extension and one or more Lymph Nodes on same side diaphragm
  4. Stage III
    1. III: Lymph Nodes involve both sides diaphragm or
    2. IIIE: Lymph Nodes on both sides of diaphragm and localized Spleen or extralymphatic involved
  5. Stage IV
    1. Diffuse or disseminated disease
    2. Liver or Bone Marrow involvement
  6. Modifier
    1. A: Asymptomatic
    2. B: Fever (>100 F), Night sweat, or weight loss (>10% in 6 months)

VII. Labs: Secondary (for staging)

  1. Complete Blood Count
    1. Normocytic normochromic Anemia
    2. Leukocytosis with lymphopenia
  2. Bone Marrow Aspiration and biopsy
  3. Liver Function Tests
    1. Alkaline Phosphatase
    2. 5' Nucleotidase
  4. Erythrocyte Sedimentation Rate (ESR)

VIII. Imaging (for staging)

  1. Chest XRay
    1. Anterior mediastinal or hilar Lymphadenopathy
    2. Osteosclerotic or osteoporotic lesions
  2. Ultrasound Liver and Spleen
  3. CT scan of Abdomen
  4. Bipedal lower extremity lymphangiography

IX. Diagnosis: Lymph Node excisional or needle biopsy

  1. See Reed-Sternberg Cells
  2. Avoid biopsy of inguinal or axillary nodes due to super-imposed inflammation

X. Classification: Pathology (Histologic Types)

  1. Nodular Sclerosis (60-80% of classical Hodgkin Disease cases)
    1. More common in young adults and teens
    2. Overall good prognosis since it tends to present as localized disease (early stage)
  2. Mixed cellularity (15-30% of classical Hodgkin Disease cases)
    1. More frequent in third world countries and associated with HIV Infection
    2. Bimodal distribution: More common in children and in the elderly
    3. Worse prognosis due to its presentation at later stages
  3. Lymphocytic predominance (2-7% of classical Hodgkin Disease cases)
    1. Abundance of Reed-Sternberg Cells
    2. Overall good prognosis since it tends to present as localized disease (early stage)
  4. Lymphocyte depletion (1-6% of classical Hodgkin Disease cases)
    1. Paucity of cellular elements
    2. More common in the elderly
    3. Worse prognosis as presents at later stage
    4. Associated with retroperitoneal nodes and extranodal involvement, as well as symptoms
  5. Nodular Lymphocyte-predominant (3-8% of all Hodgkin Disease cases)
    1. Non-Classical Hodgkin's that lacks Reed-Sternberg Cells
    2. Characterized by atypical lymphocytic and histiocytic cells
    3. Overall good prognosis with localized disease with indolent course

XI. Management: Chemotherapy Regimens

  1. Protocol
    1. Given in 2 to 8 cycles as determined by staging listed below
  2. ABVD Regimen (standard regimen)
    1. Adriamycin (Doxorubicin)
    2. Bleomycin
    3. Vinblastine
    4. Dacarbazine
  3. Stanford V (experimental)
    1. Adriamycin (Doxorubicin)
    2. Bleomycin
    3. Vinblastine
    4. Mechlorethamine
    5. Vincristine
    6. Etoposide
    7. Prednisone
  4. BEACOPP regimen (experimental)
    1. Adriamycin (Doxorubicin)
    2. Bleomycin
    3. Vincristine
    4. Procarbazine
    5. Gemcitabine
    6. Prednisone
  5. MOPP regimen (no longer used, listed for historical purposes)
    1. Mechlorethamine
    2. Vincristine
    3. Procarbazine
    4. Prednisone
  6. Monoclonal Antibodies (experimental)
    1. Anti-CD30 antibodies (SGN-30, MDX-060)
    2. Anti-CD20 antibodies (Rituximab)

XII. Management: Approach

  1. Stage IA and Nodular Lymphocyte Predominant (non-classical)
    1. Involved Region Radiation Therapy (35 Gy)
  2. Classical Hodgkin (and non-classical above Stage IA)
    1. Involved Region Radiation Therapy (30-35 Gy)
      1. In stage III-IV, radiation directed at sites of bulky disease up to 10 cm diameter
    2. Combination Chemotherapy of ABVD Regimen (see above)
      1. Stage I-II Favorable: 2-3 cycles at 28 day intervals
      2. Stage I-II Unfavorable: 4-6 cycles at 28 day intervals
      3. Stage III-IV: 6-8 cycles as 28 day intervals

XIII. Management: Monitoring following treatment

  1. See Lymphoma for general surveillance protocols
  2. Clinic visits
    1. Year 1-2: Every 3 months
    2. Year 3: Every 4 months
    3. Year 4-5: Every 6 months
    4. After year 5: Annually
  3. Labs: Follow local protocols (controversial due to low yield)
    1. Consider at each visit
      1. Complete Blood Count
      2. Erythrocyte Sedimentation Rate
      3. Chemistry panel (e.g. chem8)
    2. Consider annually in first 5 years (if neck Radiation Therapy)
      1. Thyroid Stimulating Hormone (TSH)
  4. Imaging: Follow local protocols (controversial due to low yield)
    1. Chest XRay or Chest CT every 6-12 months for 2 years
    2. Abdomen and Pelvis CT every 6-12 months for 2 years
  5. Cardiovascular screening
    1. Lipid panel annually
    2. Consider Stress Imaging and Echocardiogram every 10 years

XIV. Prevention: Secondary

  1. Routine Health Maintenance and monitoring as described above
  2. Tobacco Cessation
  3. Vaccination
    1. See Lymphoma for common Vaccinations for both Hodgkin Lymphoma and Non-Hodgkin Lymphoma

XV. Prognosis: General

  1. Prior to Chemotherapy had been uniformly fatal
  2. Large majority are now cured with Chemotherapy
  3. Overall survival rates after treatment
    1. Post-treatment by 1 year: 94% survival rate
    2. Post-treatment by 5 years: 85% survival rate
    3. Post-treatment by 10 years: 82% survival rate
    4. Post-treatment by 15 years: 74% survival rate
    5. Post-treatment by 20 years: 63% survival rate
  4. Five years survival rates based on staging (see above)
    1. Stage I: 90-95%
    2. Stage 2: 90-95%
    3. Stage 3: 85-90%
    4. Stage 4: 80%

XVI. Prognosis: Localized Hodgkin Lymphoma

  1. Adverse Factors
    1. Mediastinal Mass ratio >0.33 (N) or >0.35 (E/G)
    2. Nodal mass >10 cm (N)
    3. Age >50 years (E)
    4. Nodal regions >2 (G) or >3 (E)
    5. Increased Erythrocyte Sedimentation Rate (E/G)
    6. B Symptoms of fever, Night Sweats and weight loss present (N)
  2. Legend
    1. North America study group including United States and Canada (N)
    2. European Organization for Research and Treatment of Cancer (E)
    3. German Hodgkin Study Group (G)

XVII. Prognosis: International Prognostic Score for Advanced Hodgkin Lymphoma

  1. Risk Factors
    1. Ann Arbor Stage IV Disease
    2. Male gender
    3. Age 45 years or older
    4. Hemoglobin <10.5 g/dl
    5. White Blood Cell Count >15,000/ul
    6. Lymphocyte Count <600/ul (or <8% of total White Blood Cell Count)
    7. Albumin <4.0 g/dl
  2. Interpretation: 5 year survival based on number of risk factors present
    1. No risk factors: 89%
    2. 1 risk factors: 90%
    3. 2 risk factors: 81%
    4. 3 risk factors: 78%
    5. 4 risk factors: 61%
    6. 5-7 risk factors: 56%
  3. References
    1. Hassenclever (1998) N Engl J Med 339(21): 1506-14 [PubMed]

XVIII. Complications

  1. See Lymphoma for complications shared by all Lymphomas
  2. Relapse
    1. Early-Stage Hodgkin Lymphoma: 10-15% relapse rate
    2. Late-Stage Hodgkin Lymphoma: 40% relapse rate
  3. Secondary malignancy (related to Chemotherapy and radiation)
    1. See Cancer Survivor Care
    2. Breast Cancer in women
      1. Follows latency of at least 10-15 years
      2. Higher risk with high dose radiation and age of treatment under 35
      3. Risk approaches 20% by age 45 years old
      4. Start annual Breast MRI and Mammogram 8-10 years after chest or axillary radiation (or by age 40 years)
    3. Lung Cancer
      1. Higher risk with Alkylating Agent exposure (old MOPP Chemotherapy protocols)
      2. Tobacco use compounds risk
    4. Leukemia (1-3% risk)
      1. Types: Acute Myeloid Leukemia, Large cell lympoma, Myelodysplastic Syndromes
      2. Higher risk with Alkylating Agent exposure (old MOPP Chemotherapy protocols)
        1. Lower risk with ABVD regimen used currently
    5. Thyroid Cancer
      1. Associated with prior neck irradiation
  4. Other adverse effects
    1. Cardiovascular disease
      1. Coronary Artery Disease (most common cardiovascular adverse effect)
        1. Associated with mediastinal radiation and Adriamycin exposure
      2. Cardiomyopathy
        1. Associated with Adriamycin exposure
        2. Increased risk in younger women and with higher Adriamycin doses
    2. Pulmonary disease
      1. Pulmonary fibrosis associated with Bleomycin use
    3. Hypothyroidism
      1. Typically occurs in first 5 years after treatment (can occur up to 20 years later)
    4. Premature Ovarian Failure
    5. Male Infertility
      1. Due to decreased spermatogenesis following Chemotherapy
      2. Lower risk with ABVD regimen
    6. Osteoporosis
    7. Paraneoplastic Syndromes (rare)
      1. Paraneoplastic Cerebellar Degeneration
      2. Dermatomyositis
      3. Polymyositis

XIX. References

  1. Ansell (2006) Mayo Clin Proc 81(3):419-26 [PubMed]
  2. Connors (2005) J Clin Oncol 23:6400-8 [PubMed]
  3. Glass (2008) Am Fam Physician 78(5): 615-22 [PubMed]
  4. Horning in Lichtman (2006) Williams Hematology, 7 ed, McGraw Hill, p. 1461-82 [PubMed]
  5. Lewis (2020) Am Fam Physician 101(1):34-41 [PubMed]
  6. Tsang (2006) Curr Probl Cancer 30(3):107-58 [PubMed]
  7. Wilbur (2014) Am Fam Physician 91(1):29-36 [PubMed]

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