A. Introduction [1,2]

1. Incidence ~2.4 per 100,000 per year
2. Excellent prognosis with >90% 10 year survival; most are cured
3. Diagnosis requires presence of abnormal B cells called Reed Sternberg (RS) cells
   1. RS cells express antigens found mainly on B lymphocytes
   2. Believed to be the pathologic cell in Hodgkin's Disease
   3. Specific phenotype depends on histological type of disease
4. RS Cells [3]
   1. RS cells are probably derived from germinal center B cells
   2. These cells appear to be crippled germinal B cells which do not undergo apoptosis
   3. Most RS cells have undergone aberrant immunoglobulin (Ig) gene rearrangements
   4. Classic RS cells contain Ig genes with germline (non-mutated) sequences
   5. RS cells express CD30, CD25 (IL2R), CD71 (Transferrin-R) and HLA
   6. CD15+ (with other granulocyte markers +) is found on many HL cells
   7. RS cells produce more than 10 cytokines including Interleukin (IL)-6, IL-1, others
   8. Monoclonal or polyclonal populations of RS cells are found
   9. RS cells from nodular lymphocyte predominant HL are post-germinal and CD20+
5. Four Classical Variants of HL
   1. Nodular Sclerosis
   2. Mixed Cellularity
   3. Lymphocyte Predominant
   4. Lymphocyte Depleted
   5. Fifth type: Nodular Lymphocyte Predominant HL

B. Risk Factors

1. Genetic - increased in twins, certain MHC genes (see below)
2. Epstein Barr Virus infection
3. AIDS
4. Concordance in Identical Twins [8]
   1. Nearly 100X increased risk in monozygotic twin of an affected patient [15]
   2. No apparent increased risk in dizygotic twin
   3. Histologic subtype is often the same in the twins; NS predominates
   4. Indicates strong genetic susceptibility to this disease
5. Major Histocompatibility Complex (MHC) and HL Risk [13]
   1. Genes within the HLA Classes I and III regions are associated with HL risk
   2. Genes only within HLA Class I are associated with EBV+ HL
   3. Genes within HLA Class III are associated with EBV- HL
6. Epstein Barr Virus (EBV) Infections [5,6]
   1. Overall, ~50% of HL are positive for EBV DNA
   2. EBV viral Proteins EBNA-1, EBER, LMP-1 and -2 implicated in certain (MC and LD) HL
   3. Patients often have high levels of anti-EBV antibodies
   4. Infectious mononucleosis associated with 4X increased risk of EBV+ HL [6]
   5. No increase in EBV negative HL following infectious mononucleosis
   6. EBV+ HL is associated with polymorphisms in HLA Class I (but not class III) which may be associated with presentation of EBV antigens to cytotoxic T lymphocytes [13]
7. AIDS and HL [7]
   1. Incidence of HL is increased in patients with AIDS, risk ~7X
   2. Majority of HIV+ HL tumors are EBV RNA positive

C. Subtypes of Hodgkin's Lymphoma

1. Nodular Sclerosing (NS): 65% [4]
   1. Occurs primarily in young women; best prognosis
   2. Presents with mediastinal lymphadenopathy, often insidious symptoms
   3. Pruritus not uncommon
   4. Uncommonly, primary breast involvement can occur [9]
   5. Marked elevation of erythrocyte sedimentation rate
   6. Infrequently, can progress to high grade large cell Non-Hodgkin's lymphoma [10]
   7. Aggressive but curable disease
2. Mixed Cellularity (MC): 25%
   1. Occurs primarily in men
   2. Peripheral presentations common
   3. Para-aortic nodes and spleen commonly involved
   4. Most are associated with EBV proteins EBNA-1, LMP-1 and -2
3. Lymphocyte Predominant (LP): 5%
   1. Least common overall
   2. Obliterated lymph node structure, large histiocytic cells, small lymphocytes
   3. The histiocytic cells express B cell markers and are clonal [11,12]
   4. These B cells have undergone somatic mutation (likely T cell induced) [2]
   5. CD45+ (leukocyte common Ag), CD15-
   6. Excellent long term prognosis
4. Lymphocyte Depleted (LD): <5%
   1. Very uncommon in modern series
   2. Now usually diagnosed as nodular sclerosis or anaplastic large cell lymphoma
5. Nodular Lymphocyte Predominant: ~5%
   1. Newer classification most closely related to LP
   2. These are mainly post-germinal center B cell derived with CD20+ marker
   3. ~70% in males
   4. Usually presents with limited nodal disease in neck without constitutional symptoms
   5. Mediastinal lymphadenopathy is uncommon
   6. Indolent disease with late relapses

D. Staging (Ann Arbor System)

1. Stage I
   1. Involvement of single LN region or lymphoid organ
   2. Lymphoid organ includes spleen, thymus, Waldeyer's ring
2. Stage II
   1. Involvement of more than one LN region on same side of diaphragm
   2. Number of anatomical sites involved indicated by a subscript
3. Stage III
   1. Involvement of LN regions or structures on both sides of the diaphragm
   2. III-1 - Involvement of splenic, hilar, portal or celiac nodes
   3. III-2 - Involvement of para-aortic, iliac or mesenteric nodes
4. Stage IV: at least 1 extranodal site involved in addition to site in which designation E is used
5. Additional Designations
   1. A = no symptoms
   2. B = symptoms (fever >38°C), drenching night sweats, weight loss >10% within six months
   3. X = bulky disease (widened mediastinum or LN > 10cm)
   4. E = involvement of single extranodal site contiguous with known site
   5. Note: fever may be cyclical over weeks and is called "Pel-Ebstein Fever"
6. Elevated serum Interleukin 6 correlates with adverse prognostic features

E. Diagnostic and Staging Strategy

1. History and Examination (especially for B symptoms, lymphadenopathy)
2. Radiologic Tests
   1. Chest Radiograph
   2. CT Scan of Chest, Abdomen and Pelvis
   3. Gallium Scan
   4. Positron Emission Tomography with fluoro-deoxyglucose is most sensitive
   5. Bipedal lymphography is obsolete)
3. Laboratory
   1. Complete Blood Count (CBC), Sedimentation Rate (ESR)
   2. Electrolytes and Renal Function
   3. Liver Function Tests
   4. Lactate Dehydrogenase
4. Bone marrow aspiration and biopsy
5. Laparotomy is indicated only where radiation alone is therapeutic consideration
6. Ann Arbor Stage is primary driver for therapy and prognosis [1]
   1. EORTC risk factors for favorable and unfavorable prognoses in localized disease
   2. Seven component Hasenclever index for prognosis in advanced disease (see below) [16]
7. Response assessment mainly with CT and PET-FDG scanning

F. Initial Treatment [1]

1. Both localized and advanced HL can be cured
2. Nodular lymphocyte-predominant HL
   1. Usually localized disease
   2. Surgical excision and local radiation therapy is usually used
   3. Advanced disease treated with chemotherapy combinations as below
   4. For CD20+ disease, rituxumab (Rituxan®) anti-CD20 monoclonal antibody has been useful
3. Combination Chemotherapy for All Types of Classical HL [14]
   1. ABVD (preferred) or MOPP/ABVD for stage III or IV (see below)
   2. MOP-BAP - mustard, vincristine, prednisone, bleomycin, adriamycin, procarbazine
   3. BEACOPP=bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone
   4. BEACOPP regimens have better complete response rates than MOPP/ABVD [20]
   5. BEACOPP have better survival than MOPP/ABVD or COPP/ABVD in advanced HL [20]
   6. Often combined with radiation therapy (but benefit probably only in partial responders [21]
4. Radiation Therapy
   1. Combined with chemotherapy for later stage disease
   2. May be effective as single agent for early stage disease
   3. Local versus multiple windows
   4. Depends on staging and symptoms
   5. Low dose involved field in Stage III/IV improves survival in NS HL
   6. No added benefit in advanced stage HL with complete remission to chemotherapy [21]
   7. Radiation doses 20-30 Gy in childhood HL associated with ~10X increased thyroid cancer risk [24]
5. Side Effects of Radiotherapy
   1. Pulmonary fibrosis and increased long term cardiovascular disease
   2. Recurrent Pulmonary Infection
   3. Esophageal Radiation Damage - stricture, esophagitis, odynophagia, dysmotility
   4. Overall ~18 fold increased risk of second neoplasm after HL
   5. Breast cancer was the most common of these second neoplasms (>10 fold risk increase)
   6. Older age at radiation and higher dose for HL were risk factors
   7. Pelvic radiation (and chemotherapy) associated with high risk of infertily in women
6. Infection Prophylaxis
   1. Vaccination is critical because patients are at increased risk of serious infection
   2. HIB-conjugate, 23-valent pneumococcal, and 4-valent meningococcal vaccines are given
   3. Responses to these vaccines are similar to those in normal hosts [9]
   4. The 7-valent pneumococcal vaccine was not as effective as 23-valent
   5. Antibiotic prophylaxis is recommended with splenectomy
7. Pamidronate, a bisphosphonate, reduces vertebral fractions in Hodgkin's patients receiving chemotherapy [23]

G. ABVD Chemotherapy

1. Regimen
   1. Doxorubicin (adriamycin)
   2. Bleomycin (alkylating agent)
   3. Vinblastine (Velban®)
   4. Dacarbazine
   5. Given for 6-8 months
2. Side Effects (major)
   1. Bleomycin induced pulmonary fibrosis and eosinophilic pneumonitis
   2. Adriamycin induced cardiomyopathy
   3. Vinblastine much better tolerated than vincristine
   4. Very low incidence of acute leukemias ten years out
   5. Overall, this therapy is fairly well tolerated
3. Efficacy
   1. As effective, possible more so, than MOPP
   2. Stage II
   3. Stages III and IV: ~80% overall 5 year survival
4. Often alternated with MOPP or ABV combined with MOPP

H. MOPP Chemotherapy

1. Regimen
   1. Mechlorethamine (alkylating agent)
   2. Vincristine (Oncovin®)
   3. Procarbazine
   4. Prednisone
   5. Given for 3-8 cycles (3-8 months) depending on favorable or unfavorable prognosis
   6. MOPP-ABV (MOPP-doxorubicin, bleomycin, vinblastine) now standard of care Stage I/II [26]
2. Side Effects (major)
   1. Bone marrow toxicity: primarily from mechlorethamine
   2. Vincristine induced peripheral neuropathy
   3. Acute Leukemias develop within 5-10 years in >20% of patients treated with MOPP
   4. Increased risk of breast cancer if received radiation therapy with chemotherapy
3. Variations
   1. COPP: Cyclophosphamide substituted for mechlorethamine
   2. MVPP: Vinblastine substituted for Vincristine
   3. ChlVPP: Chlorambucil substituted for mechlorethamine / Vinblastine for Vincristine
   4. MOPP/ABVD alternating. Given for 6 months; reduced toxicity, equal efficacy
4. Efficacy
   1. Overall: >50% 20 year survival
   2. Stages III and IV: 5 year survival ~65% with MOPP alone
   3. COPP / ABVD alternating Stage III and IV: 5 year survival ~80%
   4. Increased dose BEACOPP for Stage III and IV: 5 year survival 90% [20]
   5. MOPP-ABV 3 cycles + involved-field radiotherapy for Stage I/II faborable prognosis supradiphragmatic HD: event-free survival 98% at 5 years [26]
   6. MOPP-ABV 4 cycles+involved field radiotherapy for STage I/II unfavorable prognosis supradiaphragmatic HD: event-free survival 88% [26]

I. Salvage Therapy

1. Other Chemotherapies
   1. Dexamethasone + BEAM used for salvage chemotherapy in Europe
   2. BEAM is BCNU (carmustine), etoposide, cytarabine, melphalan
   3. G-CSF is given to support neutrophil counts during BEAM
2. Stem cell transplantation following ablative high dose therapy [17]
   1. Comparison of Dexa-BEAM versus BEAM with transplantation in first relapse HL
   2. Only patients with partial or complete remission after BEAM randomized
   3. High dose BEAM was used for ablation therapy
   4. BEAM-transplant had better relapse-free but similar overall survival to Dexa-BEAM
3. Reduced Intensity Allogeneic Transplantation [18]
   1. Studied in multiply relapsed HL
   2. Recipient is given reduced intensity chemotherapy and T cell ablation
   3. Donor leukocytes are treated with anti-T cell agents to reduce graft-versus-host disease
   4. Durable responses were observed with relatively low treatment related mortality
   5. In patients with relapse after transplant, donor leukocyte infusions were given
4. Gemcitabine is also active in HL
5. Monoclonal antibodies specific to CD30 or other HL markers being developed
6. Cryopreserved ovarian cortical strips have been used to restore ovulation after high dose chemotherapy for HL [19]

J. Prognosis [1,11]

1. Stage I or II: >90% Ten Year survival
2. Stage III: ~50% Ten Year survival
3. Stage IV: ~30% Ten Year survival
4. Side Effects of Hodgkin's Chemotherapy
   1. Sterility (only with MOPP or variant therapy)
   2. Myelodysplasia (MOPP)
   3. Acute non-lymphocytic leukemia (MOPP)
5. Prognosis in Advanced Hodgkin's Disease [15]
   1. Seven components for increased risk (1 point each)
   2. Serum albumin <4gm/dL
   3. Hemoglobin <10.5gm/dL
   4. Male sex
   5. Stage IV disease
   6. Age >44 years
   7. White cell count >15,000/µL
   8. Lymphocyte count <600/µL or <8% of white blood cell count
   9. Score 0 has ~85% survival at 7 years
   10. Score 1 has ~80% survival at 7 years
   11. Score 2 has ~70% survival at 7 years
   12. Score 3 has ~60% survival at 7 years
   13. Score 4 has ~50% survival at 7 years
   14. Score >4 has ~40% survival at 7 years
6. First Relapse
   1. Significantly reduced survival overall
   2. Depends also on timing of relapse (short versus long relapse)
   3. Short interval relapse has ~10% 20 year survival
   4. Long interval relapse has ~20% 20 year survival
7. Second Cancers
   1. Leading cause of death in long-term survivors of HL
   2. Alkylating agents associated with myelodysplastic syndromes
   3. Radiation associated with local fibrosis and breast cancer
   4. Breast cancer increased 3-8X in young women with HL receiving only radiation therapy [22]
   5. Alkylating agengs and hormonal ablation reduce risk of radiation induced breast cancer [22]
8. Vanishing Bile-Duct Syndrome [25]
   1. Rare entity with progressive loss of small intrahepatic bile ducts
   2. Cholestasis with marked progressive hyperbilirubinemia, modest enzyme increases
   3. Progressive disease and often death
   4. Clear association with Hodgkin's lymphoma, likely paraneoplastic (tumor mass not found)
   5. May resolve followeing effective chemotherapy for Hodgkin's

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