Childhood Hodgkin Lymphoma Treatment (PDQ®)–Health Professional Version - National Cancer Institute

Childhood Hodgkin Lymphoma Treatment (PDQ®)–Health Professional Version

Cellular Classification and Biologic Correlates of Childhood Hodgkin Lymphoma

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.[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 and cell signaling within the tumor microenvironment.[3-5]

The hallmark of Hodgkin lymphoma is the Reed-Sternberg cell and its variants,[6] which have 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.[6]
The malignant Reed-Sternberg cell comprises only about 1% of the abundant reactive cellular infiltrate of lymphocytes, macrophages, granulocytes, and eosinophils in involved specimens.[6]
Reed-Sternberg cells almost always express CD30, approximately 70% of patients express CD15, and 6% to 10% of patients express CD20. Generally Reed-Sternberg cells do not express B-cell antigens such as CD45, CD19, and CD79A.[7-9]
In nodular lymphocyte-predominant Hodgkin lymphoma, the Reed-Sternberg cells are usually mononuclear with a markedly convoluted and lobated nucleus (popcorn cells). Also known as lymphocytic and histiocytic cells, this Reed-Sternberg–cell variant does not express CD30, but does express CD20, suggesting that it is biologically distinct from other subtypes of Hodgkin lymphoma.
Most cases of classical Hodgkin lymphoma are characterized by expression of TNF-R and their ligands, as well as an unbalanced production of T helper lymphocytes type 2 (Th2) cytokines and chemokines. Activation of TNF-R results in constitutive activation of nuclear factor kappa B in Reed-Sternberg cells, which may prevent apoptosis and provide a survival advantage.[10]
Chromosomal rearrangements of CIITA result in downregulation of major histocompatibility complex class II expression,[11] and amplification of 9p24.1 leads to overexpression of programmed cell death-1 (PD-1) ligands and their induction by JAK2.[12]

Hodgkin lymphoma can be divided into the following two broad pathologic classes:[13,14]

Classical Hodgkin Lymphoma

Classical Hodgkin lymphoma is divided into four subtypes. 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 four histological subtypes of classical Hodgkin lymphoma include the following:

Lymphocyte-rich Hodgkin lymphoma. 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.[15] Lymphocyte-rich classical Hodgkin lymphoma cells express CD15 and CD30.
Nodular-sclerosing Hodgkin lymphoma. Nodular-sclerosing 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.[16]
This subtype is distinguished by the presence of collagenous bands that divide the lymph node into nodules, which often contain a Reed-Sternberg cell variant called the lacunar cell. Transforming growth factor-beta may be responsible for the fibrosis in the nodular-sclerosing Hodgkin lymphoma subtype.
A study of over 600 patients with nodular-sclerosing Hodgkin lymphoma from three different university hospitals in the United States showed that two haplotypes in the HLA class II region correlated with a 70% increased risk of developing nodular-sclerosing Hodgkin lymphoma.[17] Another haplotype was associated with a 60% decreased risk of developing Hodgkin lymphoma. It is hypothesized that these haplotypes are associated with atypical immune responses that predispose to Hodgkin lymphoma.
Mixed-cellularity 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.[16]
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 difficult to distinguish from non-Hodgkin lymphoma.
Lymphocyte-depleted Hodgkin lymphoma. Lymphocyte-depleted Hodgkin lymphoma is rare in children. It is common in adult patients with HIV.
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-sclerosing classical Hodgkin lymphoma with lymphocyte depletion.[18]

Nodular Lymphocyte-Predominant Hodgkin Lymphoma

The frequency of nodular lymphocyte-predominant Hodgkin lymphoma in the pediatric population ranges from 5% to 10% in different studies, with a higher frequency in children younger than 10 years than in children aged 10 to 19 years.[16] Nodular lymphocyte-predominant Hodgkin lymphoma is most common in males younger than 18 years.[19,20]

Characteristics of nodular lymphocyte-predominant Hodgkin lymphoma include the following:

Patients with nodular lymphocyte-predominant Hodgkin lymphoma generally present with localized, nonbulky, peripheral lymphadenopathy that rarely involves the mediastinum.[19,20] 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.[21]
- The OCT2 and BOB1 oncogenes are both expressed in nodular lymphocyte-predominant Hodgkin lymphoma; they are not expressed in the cells of patients with classical Hodgkin lymphoma.[22]
- 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.[23]
- Nodular lymphocyte-predominant Hodgkin lymphoma can be difficult to distinguish from progressive transformation of germinal centers and/or T-cell–rich B-cell lymphoma.[24]
- Histologic and immunophenotypic variants (including CD30 and immunoglobulin D expression) may impact event-free survival.[25]
Pediatric patients (aged <20 years) have better outcomes than do adult patients, even when controlled for other prognostic factors.[20] Chemotherapy and/or radiation therapy produce excellent long-term progression-free survival and overall survival in patients with nodular lymphocyte-predominant Hodgkin lymphoma; however, radiation therapy alone should not be considered for prepubescent patients because the evidence-based doses necessary for tumor control are associated with musculoskeletal impairment. When radiation is administered with chemotherapy, lower radiation doses are effective. Late recurrences have been reported up to 10 years after initial therapy.[26,27]; [28][Level of evidence: 2A]
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) than in refractory disease, underscoring the importance of judicious use of chemotherapy and radiation therapy at initial presentation and after recurrent disease.[26,27]

References

Bräuninger 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]
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]
Re D, Küppers R, Diehl V: Molecular pathogenesis of Hodgkin's lymphoma. J Clin Oncol 23 (26): 6379-86, 2005. [PUBMED Abstract]
Steidl C, Connors JM, Gascoyne RD: Molecular pathogenesis of Hodgkin's lymphoma: increasing evidence of the importance of the microenvironment. J Clin Oncol 29 (14): 1812-26, 2011. [PUBMED Abstract]
Diefenbach C, Steidl C: New strategies in Hodgkin lymphoma: better risk profiling and novel treatments. Clin Cancer Res 19 (11): 2797-803, 2013. [PUBMED Abstract]
Küppers R, Schwering I, Bräuninger A, et al.: Biology of Hodgkin's lymphoma. Ann Oncol 13 (Suppl 1): 11-8, 2002. [PUBMED Abstract]
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]
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]
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]
Skinnider BF, Mak TW: The role of cytokines in classical Hodgkin lymphoma. Blood 99 (12): 4283-97, 2002. [PUBMED Abstract]
Steidl C, Shah SP, Woolcock BW, et al.: MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature 471 (7338): 377-81, 2011. [PUBMED Abstract]
Green MR, Monti S, Rodig SJ, et al.: Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood 116 (17): 3268-77, 2010. [PUBMED Abstract]
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]
Harris NL: Hodgkin's lymphomas: classification, diagnosis, and grading. Semin Hematol 36 (3): 220-32, 1999. [PUBMED Abstract]
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]
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]
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]
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]
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]
Gerber NK, Atoria CL, Elkin EB, et al.: Characteristics and outcomes of patients with nodular lymphocyte-predominant Hodgkin lymphoma versus those with classical Hodgkin lymphoma: a population-based analysis. Int J Radiat Oncol Biol Phys 92 (1): 76-83, 2015. [PUBMED Abstract]
Shankar A, Daw S: Nodular lymphocyte predominant Hodgkin lymphoma in children and adolescents--a comprehensive review of biology, clinical course and treatment options. Br J Haematol 159 (3): 288-98, 2012. [PUBMED Abstract]
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]
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]
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]
Untanu RV, Back J, Appel B, et al.: Variant histology, IgD and CD30 expression in low-risk pediatric nodular lymphocyte predominant Hodgkin lymphoma: A report from the Children's Oncology Group. Pediatr Blood Cancer 65 (1): , 2018. [PUBMED Abstract]
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]
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]
Appel BE, Chen L, Buxton AB, et al.: Minimal Treatment of Low-Risk, Pediatric Lymphocyte-Predominant Hodgkin Lymphoma: A Report From the Children's Oncology Group. J Clin Oncol 34 (20): 2372-9, 2016. [PUBMED Abstract]