—  SYMPOSIUM #20  —

Hodgkin Lymphoma: Diagnostic and Biological Insights
Moderators: Dr. Philippe Gaulard and Dr. Nancy Lee Harris

Section 2 - Nodular Lymphocyte Predominant Hodgkin's Lymphoma and T-cell rich/ Histiocyte-rich Large B-cell Lymphoma

Chris De Wolf-Peeters
Leuven, Belgium


Nodular lymphocyte predominance Hodgkin's lymphoma (NLPHL), is a particular subtype of Hodgkin's lymphoma (HL) characterized by distinct morphologic, phenotypic and clinical features. It has been recognized for almost 70 years. In 1944 it was designated as "paragranuloma" by Jackson and Parker. Later on a nodular and a diffuse type were described, which were grouped together as lymphocyte predominance Hodgkin's disease (LPHD) at the Rye conference. In Europe the term "paragranuloma" has remained in use to indicate the nodular form of LPHD. In the REAL classification LPHD was listed as a distinct clinico-pathological entity, separately from all other subtypes of Hodgkin's disease (HD) that were termed "classic HD" (cHD). [13] In the World Health Organization (WHO) Classification, the term Hodgkin's disease was changed to Hodgkin's lymphoma (HL), in recognition of the fact that this is now known to be a lymphoid neoplasm. [18]

NLPHL affects the B follicle resulting in its nodular growth pattern, in contrast to cHL, which localizes in the extra-follicular compartment. The aberrant, enlarged follicles show fragmentation of their germinal centre. These centers are supported by a disrupted follicular dendritic network that can be visualized by CD21 staining. The atypical cells of NLPHL display a particular morphology by which they are referred to as "popcorn" cells; these atypical cells are rather distinct from the Reed Sternberg cells in cHL. Moreover these popcorn cells express B cell antigens (e.g. CD20), which are either not expressed or expressed weakly and variably on classic Reed Sternberg cells. Furthermore, popcorn cells lack expression of CD15 and CD30, two markers characteristically expressed by classic Reed Sternberg cells.

Besides these features of the atypical cells, the stromal component is of equal interest in NLPHL. It is quite distinct from that found in cHL as the majority of the small lymphocytes are B cells. As in cHL the atypical cells are surrounded by T cells. Together with some small clusters of T cells within the expanded nodules, they express CD57, a finding that can be of diagnostic help. Further studies on the stromal T cells in NLPHL demonstrated that these CD4+ T cells, in particular those rosetting around the popcorn cells, express nuclear BCL6 while they lack CD40L expression. T cells surrounding classic Reed Sternberg cells, on the other hand, lack expression of BCL6 whereas they do express CD40L. [6] There is some variability within the morphological features of NLPHL, which largely results from the occasional presence of small clusters of epitheloid cells and from the number of T cells within the affected B follicles. As such the picture may resemble T cell rich/histiocyte rich large B cell lymphoma (THRLBCL) as discussed below.

Despite these distinctive features, the disease has several mimics and/or morphological variants. In a European task force study on LPHL, supposed to include a large number NLPHL cases, collected from different centers in Europe and the United States, the diagnosis could be confirmed on review in only 56% of the cases. [3] One of the main mimics/variants shares with NLPHL a nodular growth pattern and a stromal reaction, predominantly composed of B cells. The atypical cells however express a classical phenotype, showing CD15 and CD30 positivity without CD20 staining. This mimic/variant has been designated as nodular lymphocyte-rich classic HL (NLRCHL) and has formerly been described as follicular HL. In NLRCHL, atypical cells occur within an expanded mantle of the B follicle sparing out a residual atrophic germinal centre. In addition a diffuse variant of NLPHL sharing all features with NLPHL, except for the nodular growth pattern, was recognized.

NLPHL and NLRCHL have several clinical and behavioral features in common, distinguishing them from other subytpes of cHL. [9] Both predominantly affect male patients leading to early-stage disease with low risk factors at presentation. They infrequently have B symptoms, a bulky disease or a mediastinal mass. Overall survival and disease free survival are similar and mainly stage-dependent. Complete remission is obtained in 95% of both types. Relapses, based on clinical parameters and radiological imaging, are reported to occur in almost one third of the patients suffering from NLPHL. Nevertheless lymphadenopathy occurring in these patients may result from the presence of progressively transformed follicles without proven disease recurrence.

Whether NLPHL is a monoclonal or a polyclonal proliferation has been debated for a long time. Indeed only few studies could demonstrate a monoclonal immunoglobulin gene rearrangement most probably due to the admixture of numerous stromal, reactive, polyclonal B cells associated with the atypical cells. Molecular genetic studies on single, microdissected Reed Sternberg cells have demonstrated that these cells are clonally related, transformed B cells with somatically mutated immunoglobulin genes. [5, 15, 17] The latter feature is very characteristic for germinal centre B cells and their descendants. The expression of BCL6 by popcorn cells is in line with this concept. [11] This nuclear protein is considered to be rather specific for germinal centre cells.

The differential diagnosis of NLPHL and NLRCHL from THRLBCL is the most problematic. The recognition of THRLBCL as a clinico-pathological entity is still a matter of debate. The presence of high numbers of T cells within follicular centre lymphomas has been indicated as a caveat for pathologists [14] and has resulted in the introduction of the name "T cell rich B cell lymphoma".

In 1992 Delabie et al. [8] described a particular B cell lymphoma rich in histiocytes as well as T cells and mimicking NLPHL by morphology; the term, T-cell-rich/histiocyte-rich large B-cell lymphoma (THRLBCL) has been applied to this tumor. This lymphoma is characterized by a diffuse or vaguely nodular growth pattern, a background of non-epitheloid histiocytes and reactive T cells, and a limited number of scattered large atypical B cells. The atypical B cells display some features of popcorn cells though being somewhat smaller in size. They express B cell markers but are negative for CD15 and CD30. Small B cells or remnants of B follicles are nearly absent and no underlying follicular dendritic cell meshwork is found to support the neoplastic proliferation. This lymphoma does not occur within the B follicle but affects the extra-follicular compartment while T cells around the atypical B cells are CD57 negative. [1] The disease affects mainly elderly male patients. They frequently present with stage III and IV disease, splenomegaly, hepatomegaly and bone marrow involvement. It is a very aggressive behavior with virtually no response to therapy. [2] In some of these patients splenomegaly is the main symptom. In these cases, splenectomy will reveal a unique morphologic image referred to as "micro-nodular" THRLBCL. [10] A particular subtype of large B cell lymphoma characterized by a "host inflammatory response" has been identified recently. Some cases of this particular subtype featured characteristics of THRLBCL by morphology and by clinical parameters. [16]

THRLBCL should be recognized from B cell lymphomas rich in stromal T cells on the one hand, and from NLPHL on the other. In the former situation the T cell rich stroma might suggest the presence of peripheral T cell lymphoma. Such pseudo-T cell lymphomas should be correctly diagnosed as B cell lymphoma. In most cases the precise subtype of B cell lymphoma can be given.

The differentiation of THRLBCL from NLPHL can be more problematic. Several authors have speculated that THRLBCL evolves from NLPHL. [4, 7] In one of these studies [4] both disorders were compared by evaluating a series of 218 cases: in that series 17 cases were considered to belong to a gray zone between both lymphomas. These cases were characterized by neoplastic nodules comprising the atypical B cells and as such simulating THRLBCL. These nodules were however supported by a dendritic cell network and almost depleted of small B cells. Of interest, cases with this "gray zone" morphology show a high stage disease and B symptoms at presentation but behave like NLPHL. These findings illustrate the existence of a morphological continuum between both disorders. It can be questioned if this reflects a biological continuum as high numbers of T cells within the neoplastic nodules of NLPHL can occur.

The molecular genetic background of NLPHL and THRLBCL is difficult to explore, as the number of atypical B cells in both conditions is very low. Karyotyping was successful in a limited number of cases only and no recurrent abnormalities have been described. Comparative genomic hybridization performed on DNA obtained from microdissected tumor cells demonstrated that chromosomal imbalances are more numerous in NLPHL as compared to those found in THRLBCL. This finding argues against the hypothesis that THRLBCL develops from NLPHL, as tumor progression mostly goes together with an increased number of chromosomal abnormalities. Of interest the atypical B cells in NLPHL and in THRLBCL share imbalances on chromosome 4q and 19 suggesting a similar precursor for both disorders. [12] Both disorders may develop into more typical large B cell lymphoma; in NLPHL this large B cell lymphoma will be less aggressive than de novo large B cell lymphomas. Large B cell lymphomas developing from THRLBCL, on the contrary, herald a short term adverse outcome. [2]

Given the bad prognosis of THRLBCL further characterization of its inflammatory host response will be helpful to identify new and more appropriate therapeutic approaches.

References
  1. Achten R, Verhoef G, Vanuytsel L, De Wolf-Peeters C. Histiocyte-rich, T-cell-rich B-cell lymphoma: a distinct diffuse large B-cell lymphoma subtype showing characteristic morphologic and immunophenotypic features. Histopathology 2002; 40: 31-45.

  2. Achten R, Verhoef G, Vanuytsel L, De Wolf-Peeters C. T-cell/histiocyte-rich large B-cell lymphoma: a distinct clinicopathologic entity. J Clin Oncol 2002; 20: 1269-1277.

  3. Anagnostopoulos I, Hansmann ML, Franssila K, Harris M, Harris NL, Jaffe ES, Han J, van Krieken JM, Poppema S, Marafioti T, Franklin J, Sextro M, Diehl V, Stein H. 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 2000; 96: 1889-1899.

  4. Boudova L, Torlakovic E, Delabie J, Reimer P, Pfistner B, Wiedenmann S, Diehl V, Muller-Hermelink HK, Rudiger T. 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 2003; 102: 3753-3758.

  5. Braeuninger A, Kuppers R, Strickler JG, Wacker HH, Rajewsky K, Hansmann ML. Hodgkin and Reed-Sternberg cells in lymphocyte predominant Hodgkin disease represent clonal populations of germinal center-derived tumor B cells. Proc Natl Acad Sci U S A 1997; 94: 9337-9342.

  6. Atayar C., Poppema S., Visser L., van den Berg A. Cytokine gene expression profile distinguishes CD4+/CD57+ T cells of the nodular lymphocyte predominance type of Hodgkin's lymphoma from their tonsillar counterparts. J Pathol 2006; 208:423-430

  7. De Jong D, Van Gorp J, Sie-Go D, Van Heerde P. T-cell rich B-cell non-hodgkin's lymphoma: a progressed form of follicle centre cell lymphoma and lymphocyte predominance Hodgkin's disease. Histopathology 1996; 28: 15-24.

  8. Delabie J, Vandenberghe E, Kennes C, Verhoef G, Foschini MP, Stul M, Cassiman JJ, De Wolf-Peeters C. Histiocyte-rich B-cell lymphoma. A distinct clinicopathologic entity possibly related to lymphocyte predominant Hodgkin's disease, paragranuloma subtype. Am J Surg Pathol 1992; 16: 37-48.

  9. Diehl V, Sextro M, Franklin J, Hansmann ML, Harris N, Jaffe E, Poppema S, Harris M, Franssila K, van Krieken J, Marafioti T, Anagnostopoulos I, Stein H. Clinical presentation, course, and prognostic factors in lymphocyte-predominant Hodgkin's disease and lymphocyte-rich classical Hodgkin's disease: report from the European Task Force on Lymphoma Project on Lymphocyte-Predominant Hodgkin's Disease. J Clin Oncol 1999; 17: 776-783.

  10. Dogan A, Burke JS, Goteri G, Stitson RN, Wotherspoon AC, Isaacson PG. Micronodular T-cell/histiocyte-rich large B-cell lymphoma of the spleen: histology, immunophenotype, and differential diagnosis. Am J Surg Pathol 2003; 27: 903-911.

  11. Falini B, Bigerna B, Pasqualucci L, Fizzotti M, Martelli MF, Pileri S, Pinto A, Carbone A, Venturi S, Pacini R, Cattoretti G, Pescarmona E, Lo Coco F, Pelicci PG, Anagnastopoulos I, Dalla-Favera R, Flenghi L. Distinctive expression pattern of the BCL-6 protein in nodular lymphocyte predominance Hodgkin's disease. Blood 1996; 87: 465-471.

  12. Franke S, Wlodarska I, Maes B, Vandenberghe P, Achten R, Hagemeijer A, De Wolf-Peeters C. Comparative genomic hybridization pattern distinguishes T-cell/histiocyte-rich B-cell lymphoma from nodular lymphocyte predominance Hodgkin's lymphoma. Am J Pathol 2002; 161: 1861-1867.

  13. Harris N.S. Hodgkin's disease: classification and differential diagnosis. Mod Pathol 1999; 12(2): 159-176.

  14. Jaffe ES, Longo DL, Cossman J, Hsu SM, Arnold A, Krosmeyer SJ. Diffuse B-cell lymphomas with T-cell predominance in patients with follicular lymphoma or "pseudo T-cell lymphoma". Lab Invest 1984; 50: 27A-28A.

  15. Marafioti T, Hummel M, Anagnostopoulos I, Foss HD, Falini B, Delsol G, Isaacson PG, Pileri S, Stein H. Origin of nodular lymphocyte-predominant Hodgkin's disease from a clonal expansion of highly mutated germinal-center B cells. N Engl J Med 1997; 337: 453-458.

  16. Monti S, Savage KJ, Kutok JL, Feuerhake F, Kurtin P, Mihm M, Wu B, Pasqualucci L, Neuberg D, Aguiar RC, Dal Cin P, Ladd C, Pinkus GS, Salles G, Harris NL, Dalla-Favera R, Habermann TM, Aster JC, Golub TR, Shipp MA. Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response. Blood 2005; 105: 1851-1861.

  17. Ohno T, Stribley JA, Wu G, Hinrichs SH, Weisenburger DD, Chan WC. Clonality in nodular lymphocyte-predominant Hodgkin's disease. N Engl J Med 1997; 337: 459-465.

  18. Stein H. Hodgkin lymphomas: Introduction. In: Pathology and Genetics of tumours of haematopoietic and lymphoid tissues. Ed. Jaffe ES, Harris NL, Stein H, Vardiman JW, IARC Press, Lyon 2001; 239.