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NCI/PDQ^® Health professionals: Childhood Hodgkin Lymphoma Treatment (PDQ®)

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National Cancer Institute
Last Modified: October 25, 2012

TABLE OF CONTENTS

• General Information
  • Overview of Childhood Hodgkin Lymphoma
  • Epidemiology
    • Epstein-Barr virus and Hodgkin lymphoma
    • Immunodeficiency and Hodgkin lymphoma
  • Clinical Presentation
  • Prognostic Factors

• Cellular Classification and Biologic Correlates
  • Classical Hodgkin Lymphoma
  • Nodular Lymphocyte-Predominant Hodgkin Lymphoma

• Diagnosis and Staging
  • Pretreatment Staging
    • Systemic symptoms
    • Physical examination
    • Laboratory studies
    • Anatomic imaging
      • Definition of bulky disease
      • Criteria for lymphomatous involvement by CT
    • Functional imaging
  • Establishing the Diagnosis of Hodgkin Lymphoma
  • Ann Arbor Staging Classification for Hodgkin Lymphoma
  • Risk Stratification
  • Response Assessment
    • Interim response assessment
      • Results of selected trials using interim response to titrate therapy
    • End of chemotherapy response assessment

• Treatment for Newly Diagnosed Children and Adolescents with Hodgkin Lymphoma
  • Historical Overview of Treatment for Hodgkin Lymphoma
  • Treatment Approaches
    • Risk designation
    • Risk-adapted treatment paradigms
    • Histology-based therapy (stage I nodular lymphocyte-predominant Hodgkin lymphoma)
  • Radiation Therapy
    • Volume considerations
      • Considerations in IFRT Treatment Planning
    • Radiation dose
    • Technical considerations
    • Role of LD-IFRT in childhood and adolescent Hodgkin lymphoma
  • Chemotherapy
  • Results from Selected Clinical Trials
    • North American cooperative and consortium trials
    • German multicenter trials
  • Accepted Risk-Adapted Treatment Strategies for Newly Diagnosed Children and Adolescents with Hodgkin Lymphoma
  • Treatment of Adolescents and Young Adults with Hodgkin Lymphoma
  • Current Clinical Trials

• Treatment of Primary Refractory/Recurrent Hodgkin Lymphoma in Children and Adolescents
  • Response Rates for Primary Refractory Hodgkin Lymphoma
  • Current Clinical Trials

• Late Effects from Childhood/Adolescent Hodgkin Lymphoma Therapy
  • Male Gonadal Toxicity
  • Female Gonadal Toxicity
  • Thyroid Abnormalities
  • Cardiac Toxicity
    • Radiation-associated cardiovascular toxicity
    • Selected studies evaluating cardiovascular toxicity associated with radiation
    • Anthracycline-related cardiotoxicity
  • Subsequent Neoplasms

• Changes to This Summary (10/25/2012)

• About This PDQ® Summary
  • Purpose of This Summary
  • Reviewers and Updates
  • Levels of Evidence
  • Permission to Use This Summary
  • Disclaimer
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General Information

Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. 1 Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ® Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. 2 At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. 1 Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%. For Hodgkin lymphoma, the 5-year survival rate has increased over the same time from 81% to more than 94% for children and adolescents. 1 Childhood and adolescent cancer survivors require close follow-up since cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ® summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Overview of Childhood Hodgkin Lymphoma

Childhood Hodgkin lymphoma is one of the few pediatric malignancies that shares aspects of its biology and natural history with an adult cancer. When treatment approaches for children were modeled after those used for adults, substantial morbidities (primarily musculoskeletal growth inhibition) resulted from the unacceptably high radiation doses. Thus, new strategies utilizing chemotherapy and lower-dose radiation were developed. Approximately 90% to 95% of children with Hodgkin lymphoma can be cured, prompting increased attention to devising therapy that produces less long-term morbidity for these patients. Contemporary treatment programs use a risk-adapted approach in which patients receive multiagent chemotherapy with or without low-dose involved-field radiation therapy. Prognostic factors used in determining chemotherapy intensity include stage, presence or absence of B symptoms (fever, weight loss, and night sweats), and/or bulky disease.

Epidemiology

Hodgkin lymphoma comprises 6% of childhood cancers. In the United States, the incidence of Hodgkin lymphoma is age-related and is highest among adolescents aged 15 to 19 years (29 cases per million per year), with children ages 10 to 14 years, 5 to 9 years, and 0 to 4 years having approximately threefold, eightfold, and 30-fold lower rates, respectively. 3 In non-European Union countries, there is a similar rate in young adults but a much higher incidence in childhood. 4

Hodgkin lymphoma has the following unique epidemiological features:

• Hodgkin lymphoma has a bimodal age distribution that differs geographically and ethnically in industrialized countries; the early peak occurs in the middle to late 20s and the second peak after age 50 years. In developing countries, the early peak occurs before adolescence. 5
• The male-to-female ratio varies markedly by age. Children younger than 5 years show a strong male predominance (M:F = 5.3) and children aged 15 to 19 years show a slight female predominance (M:F = 0.8). 6 7
• There are three distinct forms of Hodgkin lymphoma:
  • Childhood formoccurs in individuals aged 14 years and younger. The childhood form of Hodgkin lymphoma increases in prevalence in association with larger family size and lower socioeconomic status. 5 Early exposure to common infections in preschool appears to decrease the risk of Hodgkin lymphoma, most likely by maturation of cellular immunity. 8
  • Young adult formeffects individuals aged 15 to 34 years. The young adult form is associated with a higher socioeconomic status in industrialized countries, increased sibship size, and earlier birth order. 9 The lower risk of Hodgkin lymphoma observed in young adults with multiple older, but not younger, siblings, is consistent with the hypothesis that early exposure to viral infection (which the siblings bring home from school, for example) may play a role in the pathogenesis of the disease. 8
  • Older adult formmost commonly presents in individuals aged 55 to 74 years.

• Rarely, clustering of cases of Hodgkin lymphoma within families has been reported, suggesting a genetic predisposition to the disease or a common exposure to an etiologic agent.

Epstein-Barr virus and Hodgkin lymphoma

Epstein-Barr virus (EBV) has been implicated in the causation of Hodgkin lymphoma. A large proportion of patients with Hodgkin lymphoma have high EBV titers, suggesting that an enhanced activation of EBV may precede the development of Hodgkin lymphoma in some patients. EBV genetic material can be detected in Reed-Sternberg cells from some patients with Hodgkin lymphoma.

The incidence of EBV-associated Hodgkin lymphoma also shows the following distinct epidemiological features:

• EBV positivity is most commonly observed in tumors with mixed-cellularity histology and is almost never seen in patients with lymphocyte-predominant histology. 10 11 12 13 14
• EBV positivity is more common in children younger than 10 years 10 14 compared with adolescents and young adults. 11 12
• The incidence of EBV tumor cell positivity for Hodgkin lymphoma in developed countries is 15% to 25% in adolescents and young adults. 13 14 15 There is a high incidence of mixed-cellularity histology in childhood Hodgkin lymphoma seen in developing countries, and these cases are generally EBV-positive (approximately 80%). 16

EBV serologic status is not a prognostic factor for failure-free survival in pediatric and young adult Hodgkin lymphoma patients. 10 13 14 15 17 Patients with a prior history of serologically confirmed infectious mononucleosis have a fourfold increased risk of developing EBV-positive Hodgkin lymphoma; these patients are not at increased risk for EBV-negative Hodgkin lymphoma. 18

Immunodeficiency and Hodgkin lymphoma

Among individuals with immunodeficiency, the risk of Hodgkin lymphoma is increased, although not as high as the risk of non-Hodgkin lymphoma.

Characteristics of Hodgkin lymphoma presenting in the context of immunodeficiency are as follows:

• Hodgkin lymphoma usually occurs at a younger age and with histologies other than nodular sclerosing in patients with primary immunodeficiencies. 19
• The risk of Hodgkin lymphoma increases as much as 50-fold over the general population in patients with autoimmune lymphoproliferative syndrome. 20
• Although it is not an AIDS-defining malignancy, the incidence of Hodgkin lymphoma appears to be increased in HIV-infected individuals, including children. 21 22

Clinical Presentation

The following presenting features of Hodgkin lymphoma result from direct or indirect effects of nodal or extranodal involvement and/or constitutional symptoms related to cytokine release from Reed-Sternberg cells.

• Approximately 80% of patients present with painless adenopathy, most commonly involving the supraclavicular or cervical area.
• Mediastinal disease is present in about 75% of adolescents and young adults and may be asymptomatic. In contrast, only about 35% of young children with Hodgkin lymphoma have mediastinal presentation, in part, reflecting the tendency of these patients to have either mixed cellularity or lymphocyte-predominant histology.
• Approximately 20% of patients will have bulky adenopathy (maximum mediastinal diameter one-third of the chest diameter or greater and/or a node or nodal aggregate larger than 10 cm).
• Based on data from large cooperative group cohorts, 80% to 85% of children and adolescents with Hodgkin lymphoma have involvement of lymph nodes and/or the spleen only (stages IIII).
• The remaining 15% to 20% of patients will have noncontiguous extranodal involvement (stage IV). The most common sites of extranodal involvement are the lung, liver, bones, and bone marrow. 23 24
• Nonspecific constitutional symptoms including fatigue, anorexia, weight loss, pruritus, night sweats, and fever occur in approximately 25% of patients. 23 24
• Only three specific constitutional (B) symptoms have been correlated with prognosisunexplained fever (temperature above 38.0C orally), unexplained weight loss (10% of body weight within the 6 months preceding diagnosis), and drenching night sweats. 25

Prognostic Factors

As the treatment of Hodgkin lymphoma has improved, factors that are associated with outcome have become more difficult to identify. Several factors, however, continue to influence the success and choice of therapy. These factors are interrelated in the sense that disease stage, bulk, and biologic aggressiveness are frequently codependent. Further complicating the identification of prognostic factors is their use in determining the aggressiveness of therapy. For example, in a report from the German-Austrian Pediatric multicenter trial DAL-HD-90, bulky disease was not a prognostic factor for outcome on multivariate analysis. However, in this study, boost irradiation doses were given to patients who had postchemotherapy residual disease, which could have obfuscated the relevance of bulky disease at presentation. 26 This underscores the complexity in determining prognostic factors.

Pretreatment factors associated with an adverse outcome in one or more studies include the following:

• Advanced stage of disease. 27
• Presence of B symptoms. 23 24
• Presence of bulky disease. 23
• Extranodal extension.
• Elevated erythrocyte sedimentation rate.
• Leukocytosis (white blood cell count 11,500/mm³ or higher). 27
• Anemia (hemoglobin lower than 11.0 g/dL).
• Male gender. 24 27
• Response to initial treatment with chemotherapy. 21 28 29

Prognostic factors identified in selected multi-institutional studies include the following:

• In the Society for Paediatric Oncology and Haematology (Gesellschaft fí¼r Pídiatrische Onkologie und Hímatologie [GPOH]) GPOH-95 study, B symptoms, histology, and male gender were adverse prognostic factors for event-free survival on multivariate analysis. 24
• In 320 children with clinically staged Hodgkin lymphoma treated in the Stanford-St. Jude-Dana Farber Cancer Institute consortium, male gender; stage IIB, IIIB, or IV disease; white blood cell count of 11,500/mm³ or higher; and hemoglobin lower than 11.0 g/dL were significant prognostic factors for inferior disease-free survival and overall survival (OS). Prognosis was also associated with the number of adverse factors. 27
• In the CCG-5942 study, the combination of B symptoms and bulky disease was associated with an inferior outcome. 23
• One single-institutional study showed that African American patients had a higher relapse rate than Caucasian patients, but OS was similar. 30

The rapidity of response to initial cycles of chemotherapy also appears to be prognostically important and is being used in the research setting to determine subsequent therapy. 28 29 31 Positron emission tomography (PET) scanning is being evaluated as a method to assess early response in pediatric Hodgkin lymphoma. Fluorodeoxyglucose-PET avidity after two cycles of chemotherapy for Hodgkin lymphoma in adults has been shown to predict treatment failure and progression-free survival. 32 33 34 Further studies in children are required to assess the role of early response based on PET. The value of PET avidity to predict outcome and whether improved outcome can be achieved by altering the therapeutic strategy based on early PET response is to be determined.

Although prognostic factors will continue to change because of risk stratification and choice of therapy, parameters such as disease stage, bulk, systemic symptomatology, and early response to chemotherapy are likely to remain relevant to outcome.

References:

1. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010. [PUBMED Abstract]
2. Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997. [PUBMED Abstract]
3. Ries LAG, Harkins D, Krapcho M, et al.: SEER Cancer Statistics Review, 1975-2003. Bethesda, Md: National Cancer Institute, 2006. Also available online [PUBMED Abstract]
4. Macfarlane GJ, Evstifeeva T, Boyle P, et al.: International patterns in the occurrence of Hodgkin's disease in children and young adult males. Int J Cancer 61 (2): 165-9, 1995. [PUBMED Abstract]
5. Grufferman S, Delzell E: Epidemiology of Hodgkin's disease. Epidemiol Rev 6: 76-106, 1984. [PUBMED Abstract]
6. Ries LA, Kosary CL, Hankey BF, et al., eds.: SEER Cancer Statistics Review 1973-1995. Bethesda, Md: National Cancer Institute, 1998. Also available online [PUBMED Abstract]
7. Percy CL, Smith MA, Linet M, et al.: Lymphomas and reticuloendothelial neoplasms. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649., pp 35-50. Also available online [PUBMED Abstract]
8. Chang ET, Montgomery SM, Richiardi L, et al.: Number of siblings and risk of Hodgkin's lymphoma. Cancer Epidemiol Biomarkers Prev 13 (7): 1236-43, 2004. [PUBMED Abstract]
9. Westergaard T, Melbye M, Pedersen JB, et al.: Birth order, sibship size and risk of Hodgkin's disease in children and young adults: a population-based study of 31 million person-years. Int J Cancer 72 (6): 977-81, 1997. [PUBMED Abstract]
10. Armstrong AA, Alexander FE, Cartwright R, et al.: Epstein-Barr virus and Hodgkin's disease: further evidence for the three disease hypothesis. Leukemia 12 (8): 1272-6, 1998. [PUBMED Abstract]
11. Araujo I, Bittencourt AL, Barbosa HS, et al.: The high frequency of EBV infection in pediatric Hodgkin lymphoma is related to the classical type in Bahia, Brazil. Virchows Arch 449 (3): 315-9, 2006. [PUBMED Abstract]
12. Makar RR, Saji T, Junaid TA: Epstein-Barr virus expression in Hodgkin's lymphoma in Kuwait. Pathol Oncol Res 9 (3): 159-65, 2003. [PUBMED Abstract]
13. Herling M, Rassidakis GZ, Medeiros LJ, et al.: Expression of Epstein-Barr virus latent membrane protein-1 in Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma: associations with presenting features, serum interleukin 10 levels, and clinical outcome. Clin Cancer Res 9 (6): 2114-20, 2003. [PUBMED Abstract]
14. Claviez A, Tiemann M, Lí¼ders H, et al.: Impact of latent Epstein-Barr virus infection on outcome in children and adolescents with Hodgkin's lymphoma. J Clin Oncol 23 (18): 4048-56, 2005. [PUBMED Abstract]
15. Jarrett RF, Stark GL, White J, et al.: Impact of tumor Epstein-Barr virus status on presenting features and outcome in age-defined subgroups of patients with classic Hodgkin lymphoma: a population-based study. Blood 106 (7): 2444-51, 2005. [PUBMED Abstract]
16. Chabay PA, Barros MH, Hassan R, et al.: Pediatric Hodgkin lymphoma in 2 South American series: a distinctive epidemiologic pattern and lack of association of Epstein-Barr virus with clinical outcome. J Pediatr Hematol Oncol 30 (4): 285-91, 2008. [PUBMED Abstract]
17. Herling M, Rassidakis GZ, Vassilakopoulos TP, et al.: Impact of LMP-1 expression on clinical outcome in age-defined subgroups of patients with classical Hodgkin lymphoma. Blood 107 (3): 1240; author reply 1241, 2006. [PUBMED Abstract]
18. Hjalgrim H, Askling J, Rostgaard K, et al.: Characteristics of Hodgkin's lymphoma after infectious mononucleosis. N Engl J Med 349 (14): 1324-32, 2003. [PUBMED Abstract]
19. Robison LL, Stoker V, Frizzera G, et al.: Hodgkin's disease in pediatric patients with naturally occurring immunodeficiency. Am J Pediatr Hematol Oncol 9 (2): 189-92, 1987. [PUBMED Abstract]
20. Straus SE, Jaffe ES, Puck JM, et al.: The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis. Blood 98 (1): 194-200, 2001. [PUBMED Abstract]
21. Biggar RJ, Jaffe ES, Goedert JJ, et al.: Hodgkin lymphoma and immunodeficiency in persons with HIV/AIDS. Blood 108 (12): 3786-91, 2006. [PUBMED Abstract]
22. Biggar RJ, Frisch M, Goedert JJ: Risk of cancer in children with AIDS. AIDS-Cancer Match Registry Study Group. JAMA 284 (2): 205-9, 2000. [PUBMED Abstract]
23. Nachman JB, Sposto R, Herzog P, et al.: Randomized comparison of low-dose involved-field radiotherapy and no radiotherapy for children with Hodgkin's disease who achieve a complete response to chemotherapy. J Clin Oncol 20 (18): 3765-71, 2002. [PUBMED Abstract]
24. Rí¼hl U, Albrecht M, Dieckmann K, et al.: Response-adapted radiotherapy in the treatment of pediatric Hodgkin's disease: an interim report at 5 years of the German GPOH-HD 95 trial. Int J Radiat Oncol Biol Phys 51 (5): 1209-18, 2001. [PUBMED Abstract]
25. Gobbi PG, Cavalli C, Gendarini A, et al.: Reevaluation of prognostic significance of symptoms in Hodgkin's disease. Cancer 56 (12): 2874-80, 1985. [PUBMED Abstract]
26. Dieckmann K, Pítter R, Hofmann J, et al.: Does bulky disease at diagnosis influence outcome in childhood Hodgkin's disease and require higher radiation doses? Results from the German-Austrian Pediatric Multicenter Trial DAL-HD-90. Int J Radiat Oncol Biol Phys 56 (3): 644-52, 2003. [PUBMED Abstract]
27. Smith RS, Chen Q, Hudson M, et al.: Prognostic factors in pediatric Hodgkin's disease. [Abstract] Int J Radiat Oncol Biol Phys 51 (3 Suppl 1): 119, 2001. [PUBMED Abstract]
28. Carde P, Koscielny S, Franklin J, et al.: Early response to chemotherapy: a surrogate for final outcome of Hodgkin's disease patients that should influence initial treatment length and intensity? Ann Oncol 13 (Suppl 1): 86-91, 2002. [PUBMED Abstract]
29. Landman-Parker J, Pacquement H, Leblanc T, et al.: Localized childhood Hodgkin's disease: response-adapted chemotherapy with etoposide, bleomycin, vinblastine, and prednisone before low-dose radiation therapy-results of the French Society of Pediatric Oncology Study MDH90. J Clin Oncol 18 (7): 1500-7, 2000. [PUBMED Abstract]
30. Metzger ML, Castellino SM, Hudson MM, et al.: Effect of race on the outcome of pediatric patients with Hodgkin's lymphoma. J Clin Oncol 26 (8): 1282-8, 2008. [PUBMED Abstract]
31. Weiner MA, Leventhal B, Brecher ML, et al.: Randomized study of intensive MOPP-ABVD with or without low-dose total-nodal radiation therapy in the treatment of stages IIB, IIIA2, IIIB, and IV Hodgkin's disease in pediatric patients: a Pediatric Oncology Group study. J Clin Oncol 15 (8): 2769-79, 1997. [PUBMED Abstract]
32. Hutchings M, Loft A, Hansen M, et al.: FDG-PET after two cycles of chemotherapy predicts treatment failure and progression-free survival in Hodgkin lymphoma. Blood 107 (1): 52-9, 2006. [PUBMED Abstract]
33. Gallamini A, Hutchings M, Rigacci L, et al.: Early interim 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography is prognostically superior to international prognostic score in advanced-stage Hodgkin's lymphoma: a report from a joint Italian-Danish study. J Clin Oncol 25 (24): 3746-52, 2007. [PUBMED Abstract]
34. Dann EJ, Bar-Shalom R, Tamir A, et al.: Risk-adapted BEACOPP regimen can reduce the cumulative dose of chemotherapy for standard and high-risk Hodgkin lymphoma with no impairment of outcome. Blood 109 (3): 905-9, 2007. [PUBMED Abstract]

Cellular Classification and Biologic Correlates

Hodgkin lymphoma is characterized by a variable number of characteristic multinucleated giant cells (Reed-Sternberg cells) or large mononuclear cell variants (lymphocytic and histiocytic cells) in a background of inflammatory cells consisting of small lymphocytes, histiocytes, epithelioid histiocytes, neutrophils, eosinophils, plasma cells, and fibroblasts. The inflammatory cells are present in different proportions depending on the histologic subtype. It has been conclusively shown that Reed-Sternberg cells and/or lymphocytic and histiocytic cells represent a clonal population. Almost all cases of Hodgkin lymphoma arise from germinal center B cells that cannot synthesize immunoglobulin. 1 2 The histologic features and clinical symptoms of Hodgkin lymphoma have been attributed to the numerous cytokines, chemokines, and products of the tumor necrosis factor receptors (TNF-R) family secreted by the Reed-Sternberg cells. 3

The hallmark of classic Hodgkin lymphoma is the Reed-Sternberg cell, 4 which has the following features:

• The Reed-Sternberg cell is a binucleated or multinucleated giant cell with a bilobed nucleus and two large nucleoli that give a characteristic owl's eye appearance. 4
• The malignant Reed-Sternberg cell comprises only about 1% of the abundant reactive cellular infiltrate of lymphocytes, macrophages, granulocytes, and eosinophils in involved specimens. 4
• Reed-Sternberg cells almost always express CD30, and approximately 70% of patients express CD15. CD20 is expressed in approximately 6% to 10% of cases, and generally Reed-Sternberg cells do not express B-cell antigens such as CD45, CD19, and CD79A. 5 6 7
• Most cases of classic Hodgkin lymphoma are characterized by expression of TNF-Rs and their ligands, as well as an unbalanced production of Th2 cytokines and chemokines. Activation of TNF-R results in constitutive activation of nuclear factor kappa B. 8
• Reed-Sternberg cells show constitutive activation of the nuclear factor kappa B pathway, which may prevent apoptosis and provide a survival advantage. 8

Hodgkin lymphoma can be divided into the following two broad pathologic classes: 9 10

• Classical Hodgkin lymphoma.
• Nodular lymphocyte-predominant Hodgkin lymphoma.

Classical Hodgkin Lymphoma

Classical Hodgkin lymphoma is divided into the following four subtypes:

• Lymphocyte-rich classical Hodgkin lymphoma.
• Nodular sclerosis Hodgkin lymphoma.
• Mixed-cellularity Hodgkin lymphoma.
• Lymphocyte-depleted Hodgkin lymphoma.

These subtypes are defined according to the number of Reed-Sternberg cells, characteristics of the inflammatory milieu, and the presence or absence of fibrosis.

Characteristics of the histological subtypes of classical Hodgkin lymphoma include the following:

• Lymphocyte-rich classical Hodgkin lymphoma may have a nodular appearance, but immunophenotypic analysis allows distinction between this form of Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma. 11 Lymphocyte-rich classical Hodgkin lymphoma cells express CD15 and CD30, while nodular lymphocyte-predominant Hodgkin lymphoma almost never expresses CD15.
• Nodular sclerosis Hodgkin lymphoma histology accounts for approximately 80% of Hodgkin lymphoma cases in older children and adolescents but only 55% of cases in younger children in the United States. 12 This subtype is distinguished by the presence of collagenous bands that divide the lymph node into nodules, which often contain an Reed-Sternberg cell variant called the lacunar cell. Some pathologists subdivide nodular sclerosis into two subgroups (NS-1 and NS-2) on the basis of the number of Reed-Sternberg cells present. Transforming growth factor-beta may be responsible for the fibrosis in the nodular sclerosis Hodgkin lymphoma subtype.

  A study of over 600 patients with nodular sclerosis Hodgkin lymphoma from three different university hospitals in the United States showed that two haplotypes in the HLA class II region were identified, which correlated with 70% increased risk of developing nodular sclerosis Hodgkin lymphoma. 13 Another haplotype was associated with a 60% decreased risk. It is hypothesized that these haplotypes result in atypical immune responses that lead to Hodgkin lymphoma. Another haplotype was associated with a 60% decreased risk. It is hypothesized that these haplotypes result in atypical immune responses that lead to Hodgkin lymphoma.

• Mixed-cellularity Hodgkin lymphoma is more common in young children than in adolescents and adults, with mixed-cellularity Hodgkin lymphoma accounting for approximately 20% of cases in children younger than 10 years, but only approximately 9% of older children and adolescents aged 10 to 19 years in the United States. 12 Reed-Sternberg cells are frequent in a background of abundant normal reactive cells (lymphocytes, plasma cells, eosinophils, and histiocytes). Interleukin-5 may be responsible for the eosinophilia in mixed-cellularity Hodgkin lymphoma. This subtype can be confused with non-Hodgkin lymphoma.
• Lymphocyte-depleted Hodgkin lymphoma is rare in children. It is common in adult patients with human immunodeficiency virus. This subtype is characterized by the presence of numerous large, bizarre malignant cells, many Reed-Sternberg cells, and few lymphocytes. Diffuse fibrosis and necrosis are common. Many cases previously diagnosed as lymphocyte-depleted Hodgkin lymphoma are now recognized as diffuse large B-cell lymphoma, anaplastic large-cell lymphoma, or nodular sclerosis classical Hodgkin lymphoma with lymphocyte depletion. 14

Nodular Lymphocyte-Predominant Hodgkin Lymphoma

• There are variable estimates for the relative frequency of nodular lymphocyte-predominant Hodgkin lymphoma in the pediatric population, ranging from 5% to 10%. The relative frequency is higher for children younger than 10 years compared with children aged 10 to 19 years. 12 Nodular lymphocyte-predominant Hodgkin lymphoma is most common in males younger than 18 years. 15
• Patients with nodular lymphocyte-predominant Hodgkin lymphoma generally present with localized, nonbulky disease that infrequently involves the mediastinum. 15 Almost all patients are asymptomatic.
• Nodular lymphocyte-predominant Hodgkin lymphoma is characterized by molecular and immunophenotypic evidence of B-lineage differentiation with the following distinctive features:
  • Nodular lymphocyte-predominant Hodgkin lymphoma is characterized by large cells with multilobed nuclei, referred to as popcorn cells. These cells express B-cell antigens, such as CD19, CD20, CD22, and CD79A, and are negative for CD15 and may or may not express CD30.
  • The OCT-2 and BOB.1 oncogenes are both expressed in nodular lymphocyte-predominant Hodgkin lymphoma; they are not expressed in the cells of patients with classical Hodgkin lymphoma. 16
  • Reliable discrimination from non-Hodgkin lymphoma is problematic in diffuse subtypes with lymphocytic and histiocytic cells set against a diffuse background of reactive T-cells. 17
  • Nodular lymphocyte-predominant Hodgkin lymphoma can be difficult to distinguish from progressive transformation of germinal centers and/or T-cell-rich B-cell lymphoma. 18

• Chemotherapy and/or radiation therapy produce excellent long-term progression-free survival and overall survival in patients with nodular lymphocyte-predominant Hodgkin lymphoma; however, late recurrences have been reported up to 10 years after initial therapy. 19 20
• Deaths observed among individuals with nodular lymphocyte-predominant Hodgkin lymphoma are more frequently related to treatment complications and/or the development of subsequent neoplasms (including non-Hodgkin lymphoma), underscoring the importance of judicious use of chemotherapy and radiation therapy at initial presentation and after recurrent disease. 19 20

References:

1. Bríuninger A, Schmitz R, Bechtel D, et al.: Molecular biology of Hodgkin's and Reed/Sternberg cells in Hodgkin's lymphoma. Int J Cancer 118 (8): 1853-61, 2006. [PUBMED Abstract]
2. Mathas S: The pathogenesis of classical Hodgkin's lymphoma: a model for B-cell plasticity. Hematol Oncol Clin North Am 21 (5): 787-804, 2007. [PUBMED Abstract]
3. Re D, Kí¼ppers R, Diehl V: Molecular pathogenesis of Hodgkin's lymphoma. J Clin Oncol 23 (26): 6379-86, 2005. [PUBMED Abstract]
4. Kí¼ppers R, Schwering I, Bríuninger A, et al.: Biology of Hodgkin's lymphoma. Ann Oncol 13 (Suppl 1): 11-8, 2002. [PUBMED Abstract]
5. Portlock CS, Donnelly GB, Qin J, et al.: Adverse prognostic significance of CD20 positive Reed-Sternberg cells in classical Hodgkin's disease. Br J Haematol 125 (6): 701-8, 2004. [PUBMED Abstract]
6. von Wasielewski R, Mengel M, Fischer R, et al.: Classical Hodgkin's disease. Clinical impact of the immunophenotype. Am J Pathol 151 (4): 1123-30, 1997. [PUBMED Abstract]
7. Tzankov A, Zimpfer A, Pehrs AC, et al.: Expression of B-cell markers in classical Hodgkin lymphoma: a tissue microarray analysis of 330 cases. Mod Pathol 16 (11): 1141-7, 2003. [PUBMED Abstract]
8. Skinnider BF, Mak TW: The role of cytokines in classical Hodgkin lymphoma. Blood 99 (12): 4283-97, 2002. [PUBMED Abstract]
9. Pileri SA, Ascani S, Leoncini L, et al.: Hodgkin's lymphoma: the pathologist's viewpoint. J Clin Pathol 55 (3): 162-76, 2002. [PUBMED Abstract]
10. Harris NL: Hodgkin's lymphomas: classification, diagnosis, and grading. Semin Hematol 36 (3): 220-32, 1999. [PUBMED Abstract]
11. Anagnostopoulos I, Hansmann ML, Franssila K, et al.: European Task Force on Lymphoma project on lymphocyte predominance Hodgkin disease: histologic and immunohistologic analysis of submitted cases reveals 2 types of Hodgkin disease with a nodular growth pattern and abundant lymphocytes. Blood 96 (5): 1889-99, 2000. [PUBMED Abstract]
12. Bazzeh F, Rihani R, Howard S, et al.: Comparing adult and pediatric Hodgkin lymphoma in the Surveillance, Epidemiology and End Results Program, 1988-2005: an analysis of 21 734 cases. Leuk Lymphoma 51 (12): 2198-207, 2010. [PUBMED Abstract]
13. Cozen W, Li D, Best T, et al.: A genome-wide meta-analysis of nodular sclerosing Hodgkin lymphoma identifies risk loci at 6p21.32. Blood 119 (2): 469-75, 2012. [PUBMED Abstract]
14. Slack GW, Ferry JA, Hasserjian RP, et al.: Lymphocyte depleted Hodgkin lymphoma: an evaluation with immunophenotyping and genetic analysis. Leuk Lymphoma 50 (6): 937-43, 2009. [PUBMED Abstract]
15. Hall GW, Katzilakis N, Pinkerton CR, et al.: Outcome of children with nodular lymphocyte predominant Hodgkin lymphoma - a Children's Cancer and Leukaemia Group report. Br J Haematol 138 (6): 761-8, 2007. [PUBMED Abstract]
16. Stein H, Marafioti T, Foss HD, et al.: Down-regulation of BOB.1/OBF.1 and Oct2 in classical Hodgkin disease but not in lymphocyte predominant Hodgkin disease correlates with immunoglobulin transcription. Blood 97 (2): 496-501, 2001. [PUBMED Abstract]
17. Boudová L, Torlakovic E, Delabie J, et al.: Nodular lymphocyte-predominant Hodgkin lymphoma with nodules resembling T-cell/histiocyte-rich B-cell lymphoma: differential diagnosis between nodular lymphocyte-predominant Hodgkin lymphoma and T-cell/histiocyte-rich B-cell lymphoma. Blood 102 (10): 3753-8, 2003. [PUBMED Abstract]
18. Kraus MD, Haley J: Lymphocyte predominance Hodgkin's disease: the use of bcl-6 and CD57 in diagnosis and differential diagnosis. Am J Surg Pathol 24 (8): 1068-78, 2000. [PUBMED Abstract]
19. Chen RC, Chin MS, Ng AK, et al.: Early-stage, lymphocyte-predominant Hodgkin's lymphoma: patient outcomes from a large, single-institution series with long follow-up. J Clin Oncol 28 (1): 136-41, 2010. [PUBMED Abstract]
20. Jackson C, Sirohi B, Cunningham D, et al.: Lymphocyte-predominant Hodgkin lymphoma--clinical features and treatment outcomes from a 30-year experience. Ann Oncol 21 (10): 2061-8, 2010. [PUBMED Abstract]

Diagnosis and Staging

Staging and evaluation of disease status is undertaken at diagnosis and performed again early in the course of chemotherapy and at the end of chemotherapy.

Pretreatment Staging

The diagnostic and staging evaluation is a critical determinant in the selection of treatment. Initial evaluation of the child with Hodgkin lymphoma includes the following: 1 2

• Detailed history of systemic symptoms.
• Physical examination.
• Laboratory studies.
• Anatomic imaging including chest x-ray and computed tomography (CT) scan of the neck, chest, abdomen, and pelvis.
• Functional imaging including positron emission tomography (PET) scan.

Systemic symptoms

The following three specific constitutional symptoms (B symptoms) correlate with prognosis and are considered in assignment of stage:

• Unexplained fever with temperatures above 38.0C orally.
• Unexplained weight loss of 10% within the 6 months preceding diagnosis.
• Drenching night sweats.

Additional Hodgkin-associated constitutional symptoms without prognostic significance include the following:

• Pruritus.
• Alcohol-induced nodal pain.

Physical examination

• All node-bearing areas, including the Waldeyer ring, should be assessed by careful physical examination.
• Enlarged nodes should be measured to establish a baseline for evaluation of therapy response.

Laboratory studies

• Hematological and chemical blood parameters show nonspecific changes that may correlate with disease extent.
• Abnormalities of peripheral blood counts may include neutrophilic leukocytosis, lymphopenia, eosinophilia, and monocytosis.
• Acute-phase reactants such as the erythrocyte sedimentation rate and C-reactive protein, if abnormal at diagnosis, may be useful in follow-up evaluation.

Anatomic imaging

Anatomic information from CT is complemented by PET functional imaging, which is sensitive in determining initial sites of involvement, particularly sites too small to be considered abnormal by CT criteria.

Definition of bulky disease

The postero-anterior chest radiograph remains important since the criterion for bulky mediastinal lymphadenopathy used in North American protocols is defined by the ratio of the diameter of the mediastinal lymph node mass to the maximal diameter of the rib cage on an upright chest radiograph; a ratio of 33% or higher is considered bulky. This definition is no longer used in some European protocols because it does not influence risk classification.

The criteria for bulky peripheral (nonmediastinal) lymphadenopathy has varied per cooperative group study protocols from aggregate nodal masses exceeding 4 to 6 cm. This disease characteristic has not been consistently used among all groups for risk stratification.

Criteria for lymphomatous involvement by CT

Defining strict CT size criteria for the establishment of lymphomatous nodal involvement is complicated by a number of factors, such as overlap between benign reactive hyperplasia and malignant lymphadenopathy and obliquity of node orientation to the scan plane. Additional difficulties more specific to children include greater variability of normal nodal size with body region and age and the frequent occurrence of reactive hyperplasia.

General concepts to consider in regard to defining lymphomatous involvement by CT include the following:

• Contiguous nodal clustering or matting is highly suggestive of lymphomatous involvement.
• Any focal mass lesion large enough to characterize in a visceral organ is considered lymphomatous involvement unless the imaging characteristics indicate an alternative etiology.
• North American protocols have used a consistent size criteria: A measurable lesion by CT is defined as one that can be accurately measured in two orthogonal dimensions, which typically requires a lesion at least 1 cm in diameter for extranodal sites; lymph nodes are considered abnormal if the long axis is 1.5 cm or greater or between 1.1 cm and 1.5 cm with a short axis of at least 1.0 cm.
• Criteria for nodal involvement may vary by cooperative group or protocol. For example, in the Society for Paediatric Oncology and Haematology (Gesellschaft fí¼r Pídiatrische Onkologie und Hímatologie [GPOH]) completed study (GPOH-HD-2002), nodal involvement was defined if the node was greater than 2 cm in largest diameter. The node was not involved if it was less than 1 cm and was considered questionably involved if it was between 1 cm and 2 cm. Involvement decision was then based on all further clinical evidence available. 3

Functional imaging

The recommended functional imaging procedure for initial staging is now PET. 4 5 In PET scanning, uptake of the radioactive glucose analog, 18-fluoro-2-deoxyglucose (FDG) correlates with proliferative activity in tumors undergoing anaerobic glycolysis. PET-CT, which integrates functional and anatomic tumor characteristics, is often used for staging and monitoring of pediatric patients with Hodgkin lymphoma. Residual or persistent FDG avidity has been correlated with prognosis and the need for additional therapy in posttreatment evaluation. 6 7 8 9

General concepts to consider in regard to defining lymphomatous involvement by FDG-PET include the following:

• Concordance between PET and CT data is generally high for nodal regions, but may be significantly lower for extranodal sites. In one study specifically analyzing pediatric Hodgkin lymphoma patients, assessment of initial staging comparing PET and CT data demonstrated concordance of approximately 86% overall. Concordance rates were significantly lower for the spleen, lung nodules, bone/bone marrow, and pleural and pericardial effusions. 10
• Integration of data acquired from PET scans can lead to significant changes in staging. In the previously mentioned study, PET findings resulted in a change in staging in 50% of patients (with a nearly equal number of patients up- and down-staged), and subsequent adjustments in involved-field radiation therapy treatment volumes in 70% of patients (more likely an addition rather than exclusion).
• Staging criteria using PET and CT scan information is protocol dependent, but generally areas of PET positivity that do not correspond to an anatomic lesion by clinical examination or CT scan size criteria should be disregarded in staging.
• A suspected anatomic lesion which is PET-negative should not be considered involved unless proven by biopsy.

FDG-PET has limitations in the pediatric setting. Tracer avidity may be seen in a variety of nonmalignant conditions including thymic rebound commonly observed after completion of lymphoma therapy. FDG-avidity in normal tissues, for example, brown fat of cervical musculature, may confound interpretation of the presence of nodal involvement by lymphoma. 4

Establishing the Diagnosis of Hodgkin Lymphoma

After a careful physiologic and radiographic evaluation of the patient, the least invasive procedure should be used to establish the diagnosis of lymphoma.

Key issues to consider in choosing the diagnostic approach include the following:

• If possible, the diagnosis should be established by biopsy of one or more peripheral lymph nodes. Aspiration cytology alone is not recommended because of the lack of stromal tissue, the small number of cells present in the specimen, and the difficulty of classifying Hodgkin lymphoma into one of the subtypes.
• An image-guided biopsy may be used to obtain diagnostic tissue from intra-thoracic or intra-abdominal lymph nodes. Based on the involved sites of disease, alternative noninvasive procedures that may be considered include thoracoscopy, mediastinoscopy, and laparoscopy. Thoracotomy or laparotomy is rarely needed to access diagnostic tissue.
• Patients with large mediastinal masses are at risk of cardiac or respiratory arrest during general anesthesia or heavy sedation. 11 After careful planning with anesthesia, peripheral lymph node biopsy or image-guided core needle biopsy of mediastinal lymph nodes may be feasible using light sedation and local anesthesia before proceeding to more invasive procedures. Care should be taken to keep patients out of a supine position. Most procedures, including CT scans, can be done with the patient on his or her side or prone.
• If airway compromise precludes the performance of a diagnostic operative procedure, preoperative treatment with steroids or localized radiation therapy should be considered. Since preoperative treatment may affect the ability to obtain an accurate tissue diagnosis, a diagnostic biopsy should be obtained as soon as the risks associated with general anesthesia or heavy sedation are alleviated.
• Because bone marrow involvement is relatively rare in pediatric Hodgkin lymphoma patients, bilateral bone marrow biopsy should be performed only in patients with advanced disease (stage III or stage IV) and/or B symptoms. 12

Ann Arbor Staging Classification for Hodgkin Lymphoma

Stage is determined by anatomic evidence of disease using CT scanning in conjunction with functional imaging. The staging classification used for Hodgkin lymphoma was adopted at the Ann Arbor Conference held in 1971 13 and revised in 1989. 14 Staging is independent of the imaging modality used.