Classical Hodgkin Lymphoma
Nodular Lymphocyte-Predominant Hodgkin Lymphoma

Hodgkin lymphoma can be divided into two broad pathologic classes:[1,2]

• Classical Hodgkin lymphoma.
• Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL).

Classical Hodgkin lymphoma is divided into four subtypes:

• Lymphocyte-rich classical Hodgkin lymphoma (LRCHL).
• Nodular sclerosis Hodgkin lymphoma (NSHL).
• Mixed-cellularity Hodgkin lymphoma (MCHL).
• Lymphocyte-depleted Hodgkin lymphoma (LDHL).

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

The hallmark of classic Hodgkin lymphoma is the R-S cell.[3] This is a binucleated or multinucleated giant cell that is often characterized by a bilobed nucleus, with two large nucleoli, giving an owl’s eye appearance to the cells. A striking characteristic is the rarity (about 1%) of the malignant R-S cell in specimens and the abundant reactive cellular infiltrate of lymphocytes, macrophages, granulocytes, and eosinophils. R-S cells generally do not express B-cell antigens such as CD45, CD19, and CD79A. Almost all patients express CD30, and approximately 70% of patients express CD15. CD20 is expressed in approximately 5% to 10% of cases.[4-6] R-S cells show constitutive activation of the nuclear factor kappa B pathway, which may prevent apoptosis and provide a survival advantage. Most cases of classic Hodgkin lymphoma are characterized by expression of tumor necrosis factor receptors (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.[7]

The histologic features and clinical symptoms of Hodgkin lymphoma have been attributed to the numerous cytokines, chemokines, and products of the TNF-R family [8] secreted by the R-S cells. Interleukin-5 could be responsible for the eosinophilia in MCHL, and transforming growth factor-beta for the fibrosis in the NSHL subtype.

• In the United States, NSHL histology accounts for approximately 85% of Hodgkin lymphoma cases in older children and adolescents but only 50% of cases in younger children. This subtype is distinguished by the presence of collagenous bands that divide the lymph node into nodules, which often contain an R-S 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 R-S cells present.
• In the United States, MCHL histology is more common in younger children than in adolescents or adults. In a Children's Cancer Group (CCG) study, MCHL accounted for 30% of cases in children younger than 10 years. R-S cells are frequent in a background of abundant normal reactive cells (lymphocytes, plasma cells, eosinophils, and histiocytes). This subtype can be confused with non-Hodgkin lymphoma.
• LRCHL may have a nodular appearance, but immunophenotypic analysis allows distinction between this form of Hodgkin lymphoma and nodular lymphocyte-predominant disease.[9] LRCHL cells express CD15 and CD30 while NLPHL almost never expresses CD15.

This pathologic class of 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. These cells may or may not express CD30. The OCT-2 and BOB.1 oncogenes are both expressed in NLPHL; they are not expressed in the cells of patients with classical Hodgkin lymphoma.[10] While diffuse subtypes may exist with lymphocytic and histiocytic cells set against a diffuse background consisting of reactive T-cells, reliable discrimination from non-Hodgkin lymphoma is problematic.[11] In addition, a purely diffuse subtype would be classified as diffuse large B-cell lymphoma or T-cell-rich B-cell lymphoma. Even NLPHL can be difficult to distinguish from progressive transformation of germinal centers and/or T-cell-rich B-cell lymphoma.[12] NLPHL is most common in males younger than 18 years.[13] In the CCG-5942 study, NLPHL accounted for approximately 18% of cases in children younger than 10 years and 8% of cases in children 10 years or older. Approximately 80% of these patients were male.[14] Patients with NLPHL generally present with localized, nonbulky disease that infrequently involves the mediastinum.[13] Almost all patients are asymptomatic.

References

1. 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]
   
   
2. Harris NL: Hodgkin's lymphomas: classification, diagnosis, and grading. Semin Hematol 36 (3): 220-32, 1999.  [PUBMED Abstract]
   
   
3. Küppers R, Schwering I, Bräuninger A, et al.: Biology of Hodgkin's lymphoma. Ann Oncol 13 (Suppl 1): 11-8, 2002.  [PUBMED Abstract]
   
   
4. 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]
   
   
5. 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]
   
   
6. 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]
   
   
7. Skinnider BF, Mak TW: The role of cytokines in classical Hodgkin lymphoma. Blood 99 (12): 4283-97, 2002.  [PUBMED Abstract]
   
   
8. Re D, Küppers R, Diehl V: Molecular pathogenesis of Hodgkin's lymphoma. J Clin Oncol 23 (26): 6379-86, 2005.  [PUBMED Abstract]
   
   
9. 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]
   
   
10. 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]
    
    
11. 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]
    
    
12. 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]
    
    
13. 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]
    
    
14. Mauz-Körholz C, Gorde-Grosjean S, Hasenclever D, et al.: Resection alone in 58 children with limited stage, lymphocyte-predominant Hodgkin lymphoma-experience from the European network group on pediatric Hodgkin lymphoma. Cancer 110 (1): 179-85, 2007.  [PUBMED Abstract]
    
    

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