MD2B - Hodgkin's Disease

Introduction

Hodgkin's disease (HD) is a primary malignancy of lymphoid tissues, and represents approximately 11% of the malignant lymphomas but less than 1% of all cancers. It is distinguished histologically from other lymphomas by the presence of the characteristic Reed-Sternberg cell. This pathognomonic cell type is thought to be a clonal derivative of activated lymphoid cells. Unlike other lymphomas, the tumor bulk in Hodgkin's disease is primarily comprised of normal reactive lymphocytes with or without fibrosis, with a relatively small fraction of malignant Reed-Sternberg and mononuclear neoplastic cells.

Epidemiology and Etiology

• 8,190 new cases in the US in 2007 [1]
• Bimodal age distribution, with peaks at 15-34 years and again after 50 years.
• More common in Caucasians than in African-Americans (ratio of 2.9:1.6)
• Etiology remains unknown.
• Pathogenesis of classical HD linked to constitutive activation of nuclear transcription factor kappa beta (NF-κβ), which is critical for cell survival and is a target of novel therapies [2]
• Hereditary links are suggested by reports of familial clustering.
• Possible risk factors include: HIV, Epstein Barr virus (EBV), genetic predisposition, environmental exposures [3]

Microscopic Pathology

• Hodgkin’s disease is broadly classified as classical HD (with subtypes described later) and nodular lymphocyte predominant HD (NLPHD)
• Classical HD – Hodgkin/Reed-Sternberg (HRS) cell
• • large and bilobed
  • characteristic "owl-eye" appearance
  • CD30+ and CD15+
• NLPHD - "Lymphocytic and histiocitic" cell (L&H cell)
• • polypoid nuclear contours
  • "popcorn" appearance
  • CD30- and CD15 –, CD20+
• The malignant cells of both classical HD and NLPHD are derived from Germinal Center B cells, with a small percentage of classical HD that is T cell derived [2]
• Chromosomal abnormalities are present in 35-45% of cases.
• EBV genomes are found in 20% of tissues, with Southern Blot confirmation of monoclonality. EBV mRNA is detected in 30% of cases.

Clinical Presentation

• Palpable lymphadenopathy (cervical, supraclavicular, and/or axillary regions) in a contiguous pattern
• Cough, pulmonary symptoms, asymptomatic mediastinal mass on x-ray (suggestive of mediastinal involvement)
• Systemic "B" symptoms: fever, night sweats, weight loss in 25-40% of cases
• Pruritis, possibly secondary to cytokine secretion from affected lymphocytes

Staging Evaluation

• Dual system of both clinical stage and pathologic staging known as the Ann Arbor-Cotswolds classification schema [4]
• "A" designates absence of systemic symptoms, "B" one or more

For the purpose of both clinical trials and tailoring individual therapy, current practice is to divide patients into early favorable, early unfavorable, and advanced groups [5]

• Early favorable – Stage I or Stage II without adverse risk factors
• Early unfavorable – Stage I or Stage II with one or more adverse risk factors:
• • large mediastinal mass ("bulky" disease >10cm or >1/3 thoracic diameter)
  • extranodal involvement
  • increased ESR (>50 mm/hr for stage A)
  • B symptoms
  • 3 or more LN areas involved
  • >50 years old (sometimes included)
• Advanced – Stage III or Stage IV, International Prognostic Score developed based on presence of: [6]
• • Albumin <4.0
  • Hemoglobin <10.5
  • Male
  • Stage IV
  • WBC ≥15,000
  • Absolute lymphocyte count of <600 or <8% or WBC

Clinical Staging

• History and Physical exam
• • Attention to systemic symptoms; lymph nodes, pulmonary function, liver and spleen sizes, bony tenderness, neurologic exam
• Laboratory studies
• • CBC with differential, platelets, ESR
  • Serum alkaline phosphatase, LDH
  • Renal indices, including uric acid (usually normal level)
  • Liver function tests
• Radiologic studies
• • Chest x-ray (upright PA and lateral)
  • Bipedal lympangiogram (used to be performed routinely, now only performed in rare, selected cases)
  • CT of chest, abdomen and pelvis
  • PET/CT of whole body is sensitive and specific for disease staging [7]
  • Gallium scan (rarely used now in era of PET)
  • Bone scan/ bone x-rays when bony tenderness is present
• Special circumstances
• • MRI/US
  • Spirometry in patients with large mediastinal masses causing airway compression, where GA may be administered for biopsy.

Pathologic Staging

• Biopsy studies
• • Excisional biopsy of lymph node (needle biopsy is usually insufficient)
  • Bone marrow biopsy/aspirate especially in patients with "B" symptoms
  • Biopsy of suspicious disseminated extranodal sites (lung, liver) if clinically indicated
• Histopathologic classification –
• • Classical HD – characteristic HRS cells described above, with the following subtypes:
  • • Nodular Sclerosis (NS): Most common (50-65% of cases), younger ages, females, often present with incidental mediastinal mass
    • Mixed Cellularity (MC): Second most common (25-35% of cases), older patients, more commonly present with systemic symptoms and advanced-stage disease
    • Lymphocyte Depletion (LD): Rare, worst prognosis with systemic symptoms, often present with more advanced-stage disease and marrow involvement
  • Nodular lymphocyte-predominant HD (NLPHD) – distinguished clinically and pathologically from Classical HD
  • • Generally presents in earlier stages than CHD and without B symptoms (most common is asymptomatic peripheral lymphadenopathy)
    • Rare (5% of HD cases), more likely to be men, improved response to treatment in terms of achieving remission, progressive disease, and mortality [8]
• Staging Laparotomy
• • Risk of abdominal involvement is related to age, gender, clinical stage (I/II vs. III/IV), symptoms (A vs. B), number of sites (1 vs. >2)
  • Staging laparotomy is now rarely performed due to use of systemic chemotherapy (laparotomy not indicated) and unlikeliness to alter management or change outcome in early stage disease [9]

Treatment (Adults only)

• General Principles of Therapy
• • overall 5 year survival of Hodgkin’s disease in the US is 84% [1]
  • Systemic Chemotherapy consists mainly of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine).
  • • ABVD was found to be superior to MOPP (mecholrethamine, vincristine, procarbazine, prednisone) based on improved outcomes and decreased toxicity, particularly infertility and secondary malignancies [10]
    • Regimens under investigation include BEACOPP and Stanford V [11]
  • Radation therapy - fields are disease location specific and described below

• Recommendations [11]
• • Early Favorable (CHD) – Stage IA or Stage IIA disease
  • • Systemic chemotherapy +/- radiation therapy
    • Majority receive ABVD + involved field radiation therapy
    • >90% achieve longterm disease free state[10]
    • The focus of current trials is to reduce long-term complications while maintaining high cure rates [10]
  • Early Stage (Stage IA or IIA) Nodular Lymphocyte Predominant HD (NLPHD)
  • • Radiation therapy alone, also very responsive to chemotherapy
    • >90% cure, relapses also curable
    • Very favorable prognosis
  • Early Unfavorable (CHD) - Stage I or Stage II plus B symptoms or risk factors
  • • Systemic chemotherapy +/- radiation therapy
    • Majority receive ABVD + involved field radiation therapy
    • Trials comparing differing combinations (ABVD or BEACOPP, 20 Gy or 30 Gy, 4 or 6 cycles of ABVD) show no differences in overall survival or event-free survival
  • Advanced Disease – Stage III or Stage IV
  • • Systemic chemotherapy
    • Majority in the US receive ABVD regimens
    • Cure rates of >85% possible with high-dose regimens but with high toxicity (acute and long-term)
    • Consolidative radiation offers no benefit, although is sometimes used in select cases
    • High Dose Intensity: High dose BEACOPP offers improved rates of freedom from treatment failure and overall survival but with high hematologic toxicity
    • Current research aims to identify patients for high dose therapy using PET response and International Prognostic Score (described above), thereby reducing unnecessary toxicity
  • Relapsed Disease
  • • Combination chemotherapy if after radiation therapy alone
    • High dose combination chemotherapy with transplant (autologous bone marrow, allogeneic bone marrow, or peripheral stem cell)
    • Benefit of transplant is a graft vs host effect
    • Probability of relapse following blood or bone marrow transplant in recurrent disease was 53% after 10 years in a Hopkins study [12]

Long-Term Potential Complications of Treatment

• Radiation Therapy [13]
• • Hypothyroidism (25-50%)
  • Arrested bone growth (children who have not attained adult stature)
  • Pulmonary fibrosis/ pneumonitis (uncommon)
  • Pericarditis/ pericardial fibrosis (rare)
  • Increased risk of second malignant neoplasms (e.g. breast, lung) [14]

• Chemotherapy [13]
• • Sterility (MOPP > ABVD)
  • Immunosuppression and myelosuppression
  • Pulmonary fibrosis (Bleomycin)
  • Increased incidence of secondary malignancies, especially leukemias, especially with MOPP [14]