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MD2B - Hodgkin's Disease

Paul Aridgides MSIV, Upstate Medical University and Neha Vapiwala, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 9, 2007

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

Stage I

1 lymph node (LN) region or single extralymphatic site (IE)

Stage II

≥2 LN regions on same side of diaphragm, or 1 extralymphatic site (IIE) and LNs on same side of diaphragm

Stage III

LN regions on both sides of diaphragm, +/- involvement of contiguous extralyphmatic site(IIIE), spleen (IIIS), or both (IIIES)

Stage IV

Disseminated, multifocal disease of extralymphatic organ(s), +/- LN involvement

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]

References

  1. American Cancer Society. Cancer Facts and Figures 2007. Atlanta: American cancer society; 2007
  2. Re D, Thomas RK, Behringer K, et al: From Hodgkin disease to Hodgkin lymphoma: biologic insights and therapeutic potential. Blood 105:4553-4560, 2005
  3. Grufferman S, Delzell E: Epidemiology of Hodgkin's disease. Epidemiol Rev 6:76-106, 1984
  4. Lister TA, Crowther D, Sutcliffe SB, et al: Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting. J Clin Oncol 7:1630-1636, 1989
  5. Diehl V, Thomas RK, Re D: PartII: Hodgkin’s Lymphoma – diagnosis and treatment. Lancet Oncol 5:19-26, 2004
  6. Hasenclever D, Diehl V: A prognostic score for advanced Hodgkin’s disease. International Prognostic Factors Project on Advanced Hodgkin’s Disease. N Engl J Med 339:1506-1514, 1998
  7. Naumann R, Beuthien-Baumann B, ReiB A, et al: Substantial impact of FDG-PET imaging on the therapy decision in patients with early-stage Hodgkin’s lymphoma. Br J Cancer 90:620-625, 2004
  8. Nogova L, Reineke T, Josting A, et al: Lymphocyte-predominant and classical Hodgkin’s lymphoma – comparison of outcomes. Eur J Haematol 75:106-110, 2005
  9. Advani RH and Horning SJ: Treatment of early-stage Hodgkin’s disease. Semin Hematol 36:270-281, 1999
  10. Meyer RM, Gospodarowicz MK, Connors JM, et al: Randomized comparison of ABVD chemotherapy with a strategy that includes radiation therapy in patients with limited-stage Hodgkin’s lymphoma: National Cancer Institute of Canada Clinical Trials Group and the Eastern Cooperative Oncology Group. J Clin Oncol 23:4634-4642, 2005.
  11. Diehl V, Fuchs M: Early, intermediate and advanced Hodgkin’s lymphoma: modern treatment strategies. Ann Oncol 18 (supp9):71-79, 2007
  12. Akpek G, Cuttica A, Vitolo U, et al: Long-term results of blood and marrow transplantation for Hodgkin’s Lymphoma. J Clin Oncol 19:4314-4321, 2001
  13. Ruccione K, Weinberg K: Late effects in multiple body systems. Semin Oncol Nurs 5:4-13, 1989
  14. Fraser MG, Tucker MA: Second malignancies following cancer therapy. Semin Oncol Nurs 14:262-272, 1998