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Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, Vol. 94 No. 9 (November 1), 1999: pp. 3108-3113 Frequent Expression of the B-Cell-Specific Activator Protein in Reed-Sternberg Cells of Classical Hodgkin's Disease Provides Further Evidence for Its B-Cell Origin By Hans-Dieter Foss, Regina Reusch, Gudrun Demel, Georg Lenz, Ioannis Anagnostopoulos, Michael Hummel, and Harald Stein From Konsultations-und Referenzzentrum für Lymphknoten und Hämatopathologie, the Institute of Pathology, Klinikum Benjamin Franklin, Free University of Berlin, Berlin, Germany.     ABSTRACT TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES The neoplastic cells of classical Hodgkin's disease (cHD), ie, Hodgkin and Reed-Sternberg cells (HRS cells), contain clonally rearranged Ig genes, but are dissimilar to normal B cells in that they mostly do not display B-cell antigens such as CD20 or CD19. The transcription factor B-cell-specific activator protein (BSAP) influences numerous B-cell functions such as B-cell antigen expression, Ig expression, and class switch. We analyzed the expression of BSAP in cHD and control tissues by isotopic in situ hybridization and immunohistochemistry to determine whether BSAP is expressed in HRS cells and, if so, whether it may be involved in the genesis of the abnormal phenotype of these cells. Both in normal lymphoid tissue and non-Hodgkin lymphomas, BSAP transcripts and protein were almost exclusively found in B cells and B-cell lymphomas (40 cases), but were absent from the tumor cells of T-cell neoplasms (41 cases), including 19 cases of anaplastic large cell lymphoma of T- and null-cell type. Among cHD, variable numbers of HRS cells exhibited BSAP transcripts (22 of 25 cases) and protein (28 of 31 cases). Our findings show that BSAP is sufficiently specific to serve as B-cell marker. BSAP expression in HRS cells provides further strong evidence for a frequent B-cell origin of cHD and helps distinguish this disease from anaplastic large cell lymphoma of T- and null-cell type. Because BSAP is much more frequently expressed in HRS cells than the conventional B-cell antigens, the abnormal immunophenotype of HRS cells with frequent absence of B-cell antigens does not appear to be due to absent BSAP expression.     INTRODUCTION TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES CLASSICAL HODGKIN'S DISEASE (cHD) is one of the most frequent malignant lymphomas.1 Despite intensive research, its cellular origin was a very controversial issue up to the middle of this decade. Phenotypic analysis of HD-derived cell lines or tumor cells in HD tissues was variously interpreted to suggest a derivation from lymphoid cells,2,3 T cells,4,5 B cells,6,7 interdigitating reticulum cells,8,9 follicular dendritic cells,10 or macrophages11 comprising most of the normal constituents of the lymph node. Although not completely specific, the consistent expression of the lymphoid activation antigen CD30,2,3 the presence of the Epstein-Barr virus (EBV) in a substantial proportion of cHD cases,12,13 and the cytokine profile with expression of lymphotoxin ,14,15 however, indicated a derivation from lymphoid cells. More recently, two groups showed the presence of clonally rearranged Ig genes in single tumor cells isolated from cHD tissues, which is strong evidence for a B-cell derivation of this disease.16,17 For a B-cell derivation, the immunophenotype of the Hodgkin and Reed-Sternberg cells (HRS cells), however, is highly unusual: unlike most peripheral B-cell neoplasms, expression of B-cell antigens is only found in a minority of cHD cases and usually only in a small number of HRS cells.7,18 An origin of HRS cells from T cells, in some cases, has been repeatedly suggested, and this hypothesis has more recently gained support from the demonstration that HRS cells of 10% to 20% of cHD cases express cytotoxic molecules that are considered to be specific for cytotoxic lymphocytes.19,20 However, the final proof for a T-cell derivation of some cHD cases, ie, the demonstration of rearranged T-cell receptor genes in HRS cells, is still to be provided. B-cell-specific activator protein (BSAP) has recently been found to be specific for B-cell lineage,21 and its expression in HRS cells has been reported in a proportion of cHD cases in a small series.22 This molecule is a transcription factor encoded by the Pax-5 gene and is expressed in all B cells except terminally differentiated plasma cells.21 BSAP has been shown to be essential for the development of murine B cells, because mice with disrupted Pax-5 genes do not possess any peripheral B cells.23 It exerts many functions in B cells, including enhancement of B-cell antigen expression and of proliferation.24,25 Expression of BSAP in late B cells is sufficient to inhibit plasmacellular differentiation, indicating that alteration of BSAP levels is associated with plasmacellular differentiation.26 Some cases of lymphoplasmacytic lymphoma (immunocytoma) and marginal zone B-cell lymphoma harbor translocations, which result in upregulated BSAP expression.27,28 These genetic lesions are considered to contribute to lymphomagenesis in these cases.27,28 In this study we investigated the expression of BSAP transcripts and protein in cHD cases by isotopic in situ hybridization and immunohistochemistry with a monoclonal antibody. We were interested in the expression of this factor in HRS cells for several reasons: (1) The expression of BSAP would provide further evidence for a B-cell derivation of this disease; (2) it could help distinguish this disease from anaplastic large cell lymphoma (ALCL), which can pose differential diagnostic problems with cHD; and (3) given the numerous functions of BSAP in B-cell physiology, deregulated BSAP expression in HRS cells could explain some of the unusual phenotypic features of these neoplastic B cells. B-cell lymphoma and T-cell lymphoma cases, as well as reactive lymphoid tissues, were also examined to confirm the specificity of BSAP expression for the B-cell lineage.     MATERIALS AND METHODS TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES Tissues Formol-fixed/paraffin-embedded biopsy specimens of the following diseases were taken from the archives of the Institute of Pathology, Klinikum Benjamin Franklin: slightly hyperplastic tonsils (2 cases), ulcerating tonsillitis (1 case, human immunodeficiency virus [HIV]+ patient), hyperplastic adenoids (1 case, HIV+ patient), Piringer's lymphadenitis (3 cases), different types of B-cell lymphomas (Table 1) and peripheral T-cell lymphomas (Table 1), 10 cases of nodular lymphocyte predominance HD, and 33 cases of cHD (Table 2). The plasmacytoma cases were all from extramedullary sites. All the diagnosis were established according to the Revised European-American Classification of Lymphoid Neoplasms.29 Because the existence and classification of anaplastic large cell lymphoma Hodgkin's-like is controversial, such cases were excluded from the study.                                View this table: [in this window] [in a new window]   Table 1. Expression of BSAP in B- and T-Cell Lymphomas                                View this table: [in this window] [in a new window]   Table 2. Expression of BSAP in cHD Immunohistology Four-micrometer sections of paraffin-embedded tissue blocks were stained applying the immunoalkaline phosphatase (APAAP) method.30 The primary antibodies used in this study were L26 (CD20), BER-H2 (CD30), and Cs1-4, a cocktail of 4 antibodies specific for the EBV-encoded latent membrane protein 1 (DAKO, Glostrup, Denmark). For the detection of CD3, a polyclonal antibody was used. All antibodies were used after high-pressure cooking to optimally visualize the antigens in paraffin sections. The monoclonal anti-BSAP antibody was purchased from Transduction Laboratories (Lexington, KY) and used after high-pressure cooking in citrate buffer (10 mmol, pH 6.0, 2 minutes) in a dilution of 1:10. For the detection of the bound anti-BSAP antibody, the APAAP method was applied. This resulted in nuclear positivity, which in a few cells was accompanied by very weak cytoplasmic staining. Simultaneous detection of 2 antigens was performed using the peroxidase technique for membraneous/cytoplasmic antigens (CD3, CD20, CD30) and the APAAP method for BSAP. Plasmids The Pax-5 probe was prepared from cDNA that was generated by reverse-transcriptase polymerase chain reaction (RT-PCR) from a B-cell line. The nucleic acid sequence of this probe was determined on the DNA sequencer 377 (Applied Biosystems, Foster City, CA) and proved to conform to published data.21 The EBER-1 and -2 probes were kindly provided by Dr G. Niedobitek (Erlangen, Germany). After linearization of the plasmid construct with appropriate restriction enzymes, anti-sense and sense (control) RNA probes were generated by run-off transcription as described,31 but with incorporation of 2 [35S]-labeled nucleotides. In Situ Hybridization (ISH) ISH was performed as previously described,31 but with microwave irradiation (5 minutes in citrate buffer) before the prehybridization steps. The slides were exposed for 3 and 6 weeks. Simultaneous double labeling for EBV-encoded small nuclear transcripts (EBER) and BSAP was performed as reported,32 also with the inclusion of microwave irradiation. Sections hybridized with sense probes showed only weak nonspecific background (not shown). Evaluation In cHD cases the whole slide was screened for BSAP-positive tumor cells, and only unequivocally labeled neoplastic cells containing huge nuclei with inclusion-like nucleoli were accepted as positive. Cases showing labeling of only 1 or 2 presumably neoplastic cells were considered negative. The slides of both the ISH experiments and of immunohistology were evaluated by 2 independent investigators (H.-D.F. and R.R. or H.-D.F. and I.A.). Cases with discrepant evaluations were discussed at the microscope.     RESULTS TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES Reactive Lymphoid Tissues ISH.   In the lymphoid tissue of tonsils, strong BSAP-specific signals were observed in lymphoid cells within germinal centers and in the mantle zone, as well as in intraepithelial lymphocytes (Fig 1A). In contrast, only rare lymphoid cells were labeled in the interfollicular zone. Signals were not observed in mesenchymal cells; however, focal weak labeling was found in the basal and parabasal parts of the squamous epithelium. View larger version (130K): [in this window] [in a new window]   Fig 1. BSAP expression in reactive lymphoid tissues and lymphomas. (A) BSAP transcripts are strongly expressed in lymphoid cells of the germinal center and the mantle zone but are largely absent from interfollicular cells (tonsil, in situ hybridization). (B) BSAP is not found in CD3+ lymphocytes but present in mantle zone and germinal center cells (tonsil, immunohistological detection of CD3 [peroxidase, brown color] and BSAP [APAAP, red color]). (C through E) BSAP expression in Piringer's lymphadenitis. (C) In addition to a secondary follicle, monocytoid B cells (arrow) and some interfollicular blasts are labeled whereas most interfollicular lymphoid cells are negative (APAAP-staining). (D and E) Higher magnifications of (C); these show labeled germinal center and mantle zone cells (D) and monocytoid B cells (E). (F) The neoplastic cells of an intestinal Burkitt lymphoma express BSAP protein (APAAP-staining). (G) The CD30+ tumor cells of a systemic anaplastic large cell of T-cell type do not express BSAP (immunohistological detection of CD30 [peroxidase, brown color] and BSAP [APAAP, red color]). (H) BSAP expression in this case is restricted to CD20+ reactive cells whereas the neoplastic cells are not labeled (immunohistological detection of CD20 [peroxidase, brown color] and BSAP [APAAP, red color]). HRS cells of cHD display BSAP transcripts (I; in situ hybridization) and BSAP protein (J, APAAP staining).(K) Allocation of the BSAP expression to HRS cells is confirmed by the coexpression of CD30 (immunohistological detection of CD30 [peroxidase, brown color] and BSAP [APAAP, red color]). Immunohistochemistry (IH).   In tonsils, analysis of BSAP protein expression yielded almost identical results as ISH. However, the squamous epithelium did not display any labeling. The simultaneous demonstration of CD3 or CD20 and BSAP showed expression of BSAP in CD20+ cells and absence of BSAP in CD3+ T cells (Fig 1B). In addition to the findings described in tonsils, Piringer's lymphadenitis cases demonstrated labeling of monocytoid B cells and some interfollicular blasts (Fig 1C through E). Non-Hodgkin Lymphomas ISH.   All the B-cell lymphomas investigated, except plasmacytoma cases, consistently expressed BSAP transcripts (Table 1). In most cases, the majority of the neoplastic cells proved to contain BSAP transcripts; however, in immunocytoma cases, the number of labeled neoplastic cells was more variable than in the other B-cell neoplasms. Two of five plamocytoma cases focally expressed BSAP transcripts (<25% of tumor cells labeled), whereas the other cases were negative. In 10 of 11 cases of peripheral T-cell lymphoma, the tumor cells did not contain BSAP transcripts (Table 1); in 1 case of anaplastic large cell lymphoma (null cell type), there was a slight focal increase in silver grains over the neoplastic cells which, however, was not sufficient to meet the criteria for definitive positivity. IH.   Again IH provided similar results as ISH with almost all B-cell neoplasms expressing BSAP protein (Table 1A and B, Fig 1F). A notable exception were plasmacytomas, which were consistently negative, including the 2 cases that were focally positive by ISH. Similarly, the neoplastic cells of all peripheral T-cell lymphomas did not contain BSAP protein, including the case of ALCL with equivocal labeling in ISH. Combined immunohistology for BSAP and CD20 or CD30 was performed in 2 ALCL cases containing some BSAP-positive medium-sized lymphoid cells. These experiments confirmed that BSAP expression is absent from the CD30+ neoplastic cells and is restricted to CD20+ reactive B cells (Fig 1G and H). Classical Hodgkin's Disease ISH.   BSAP transcripts were found in the tumor cells of 22 of 25 cases (Table 2, Fig 1I). This was also true for EBV-infected HRS cells as evidenced by simultaneous detection of EBER and BSAP. The number of labeled cells varied considerably from case to case. In 7 cases, more than 75% of the tumor cells expressed BSAP whereas in 4 cases less than 10% of the neoplastic cells were labeled. In all cases, scattered small- or medium-sized reactive cells and nodular accumulations of mantle zone cells expressed BSAP transcripts. Surprisingly, BSAP protein expression was detected in some of the cases in more neoplastic cells compared with BSAP transcript expression (see below and Table 2). This difference may be due to the fact that weak BSAP transcript expression may be difficult to distinguish from background signal and that rather short exposure times were used in the ISH experiments. IH.   BSAP protein was detectable in HRS cells of 28 of 31 cHD cases (Fig 1J and K). In contrast to most of the B-cell lymphomas, the staining intensity was often very variable ranging from week to moderate to rarely strong (compared with small reactive lymphocytes). There was no obvious association between BSAP protein positivity and histological subtype (nodular sclerosis versus mixed cellularity), the expression of CD20, or the presence of EBV in the neoplastic cells. Two cases expressed cytotoxic molecules in the neoplastic cells; one of these (case 18) also displayed BSAP in HRS cells, whereas the other (case 33) did not. LPHD.   The neoplastic cells of all 10 cases of nodular LPHD expressed BSAP protein (not shown). This occurred in more than 75% of the tumor cells in 8 cases and in 50% to 75% of the cells in an additional case. In 1 of the cases, the percentage of labeled tumor cells could not be determined because of staining inhomogeneity. The staining intensity, while being variable, appeared to be stronger than in cHD cases, with 6 of 10 LPHD cases containing at least some neoplastic cells displaying the same staining intensity as that seen in small lymphocytes.     DISCUSSION TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES In this study we investigated the expression of a B-cell-specific transcription factor, BSAP, in cHD and controls. In agreement with an earlier study using 2 polyclonal antibodies,22 analysis of the control tissues confirmed that BSAP protein detection with a monoclonal antibody is sufficiently specific for B cells: expression of this molecule was found in B-cell regions of nonneoplastic lymphoid tissues but was mostly absent from interfollicular areas and not found in CD3+ lymphocytes. Similarly, among non-Hodgkin lymphomas BSAP expression was observed in all B-cell lymphomas (with the exception of plasmacytoma cases confirming earlier findings33) but not detected in the tumor cells of any peripheral T-cell neoplasm. ISH yielded very similar results as did IH, with minor exceptions: Weak/questionable signals were observed in 1 case of anaplastic large cell lymphoma of null-cell type, in the tonsillar squamous epithelium, and in a minority of cells of 2 of 5 plasmacytoma cases. The lack of protein expression in these instances may indicate that BSAP transcripts are not always translated into a protein product. In cHD, BSAP was found in a variable number of HRS cells in more than 80% of the cases both by IH and ISH. These findings strongly support a frequent B-cell derivation of cHD, which is in line with the molecular characteristics of this disease, ie, the presence of clonally rearranged Ig receptor genes in most cases.16,17 Similarly, detection of BSAP in all LPHD cases further confirms the well-established B-cell nature of this neoplasm. Our findings for cHD are only in partial agreement with another study22 describing BSAP expression in 5 of 14 cHD cases. The polyclonal antibodies used in the quoted study produced in our hands a markedly weaker staining than the monoclonal antibody applied in this study, suggesting that this discrepancy may be caused by different sensitivities of the immunohistochemical procedures. Our results differ from those obtained by Hsu et al,34 who did not find functional BSAP in HD-derived cell lines. Our preliminary investigations indicate that BSAP protein expression is less frequently found in these lines than in primary tissues. In addition to the confirmation of the B-cell nature of cHD, our results may have important diagnostic implications. In particular, BSAP protein expression may help to delineate ALCL of T-/null cell type from cHD. Both of these tumors contain large CD30-positive tumor cells that are usually numerous in ALCL and scarce in cHD.4 However, tumor-cell-rich cases of cHD may be difficult to differentiate from ALCL and vice versa, and these cases may actually be differently diagnosed by different pathologists.35 In addition to the detection of the ALK-protein or EBV-encoded molecules, BSAP protein expression may be of value in this setting because it has not been observed in any ALCL case investigated so far, but is frequently detectable in HRS cells. In this regard, the detection of BSAP expression is particularly satisfying because it bases the differential diagnosis on lineage derivation. BSAP is known to influence many different B-cell functions, including the enhancement of the expression of B-cell antigens such as CD19 and, possibly, CD20.24,25 Therefore, it is conceivable that deregulated BSAP expression may be involved in the generation of the abnormal phenotype of HRS cells. Our results, however, show that BSAP expression in these cells is much more frequent than the detection of B-cell antigens.7,18 For these reasons, the complete absence of BSAP expression cannot account for the frequent absence of B-cell antigens in this disease. In contrast to most B-cell lymphomas, however, BSAP expression in cHD was only of weak to moderate intensity in the majority of cHD cases. Whether these low levels of BSAP expression in HRS cells do not suffice to induce B-cell antigens in HRS cells remains a matter of speculation. In summary, our results and those of Krenacs et al22 show that BSAP is a reliable B-cell marker that may be useful for diagnostic immunohistology. BSAP is frequently expressed in the neoplastic cells of cHD, and this expression both confirms the B-cell nature of this neoplasm and helps to separate cHD from ALCL of T/null-cell type. Whether weak expression of BSAP contributes to the frequent absence of B-cell antigens in cHD remains to be determined.     ACKNOWLEDGMENT This work contains part of the doctoral theses of R.R. and G.L. We are indebted to E. Berg and L. Öhring for excellent technical assistance.     FOOTNOTES Submitted March 23, 1999; accepted June 11, 1999. Supported by the Deutsche Forschungsgemeinschaft (Grant No. Ste 318/5-1/2) and by the Deutsche Krebshilfe (Grant No. M25/89/St1). The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. section 1734 solely to indicate this fact. 0006-4971/99/9409$3.00/0 Address reprint requests to Hans-Dieter Foss, MD, Institut für Pathologie, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, Berlin 12200, Germany.     REFERENCES TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES 1. 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Delsol G, Meggetto F, Brousset P, Cohen-Knafo E, al Saati T, Rochaix P, Gorguet B, Rubin B, Voigt JJ, Chittal S: Relation of follicular dendritic reticulum cells to Reed-Sternberg cells of Hodgkin's disease with emphasis on the expression of CD21 antigen. Am J Pathol 142:1729, 1993[Abstract] 11. Hsu SM, Xie SS, Hsu PL: Cultured Reed-Sternberg cells HDLM-1 and KM-H2 can be induced to become histiocyte-like cells. H-RS cells are not derived from lymphocytes. Am J Pathol 137:353, 1990[Abstract] 12. Weiss LM, Movahed AM, Warnke RA, Sklar J: Detection of Epstein-Barr viral genomes in Reed-Sternberg cells of Hodgkin's disease. N Engl J Med 320:502, 1989[Abstract] 13. Hummel M, Anagnostopoulos I, Dallenbach F, Korbjuhn P, Dimmler C, Stein H: EBV infection patterns in Hodgkin's disease and normal lymphoid tissue: Expression and cellular localization of EBV gene products. Br J Haematol 82:689, 1992[Medline] [Order article via Infotrieve] 14. Foss HD, Herbst H, Oelmann E, Samol J, Grebe M, Blankenstein T, Matthes J, Qin ZH, Falini B, Pileri S, Diamantstein T, Stein H: Lymphotoxin, tumor necrosis factor and interleukin-6 gene transcripts are present in Hodgkin and Reed-Sternberg cells of most Hodgkin's disease cases. Br J Haematol 84:627, 1993[Medline] [Order article via Infotrieve] 15. Hsu PL, Hsu SM: Production of tumor necrosis factor- and lymphotoxin by cells of Hodgkin's neoplastic cell lines HDLM-1 and KMH-2. Am J Pathol 135:735, 1989[Abstract] 16. Küppers R, Rajewsky K, Zhao M, Simons G, Laumann R, Fischer R, Hansmann ML: Hodgkin's disease: Hodgkin and Reed-Sternbeg cells picked from histological sections show clonal immunoglobulin gene rearrangements and appear to be derived from B cells at various stages of development. Proc Natl Acad Sci USA 91:10962, 1994[Abstract/Free Full Text] 17. 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Harris NL, Jaffe ES, Stein H, Banks PM, Chan JKC, Cleary ML, Delsol G, De Wolf-Peeters C, Falini B, Gatter KC, Grogan TM, Isaacson PG, Knowles DM, Mason DY, Muller-Hermelink H-K, Pileri SA, Piris MA, Ralfkier E, Warnke RA: A revised European-American classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group. Blood 84:1361, 1994[Free Full Text] 30. Cordell J, Falini B, Erber ON, Ghosh AK, Abdulaziz Z, MacDonald S, Pulford KA, Stein H, Mason DY: Immunoenzymatic labelling of monoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP complex). J Histochem Cytochem 32:219, 1984[Abstract] 31. Milani S, Herbst H, Schuppan D, Hahn EG, Stein H: In situ hybridization for collagen types I, III and IV mRNA in normal and fibrotic rat liver. Evidence for predominant expression in non-parenchymal liver cells. Hepatology 10:84, 1989[Medline] [Order article via Infotrieve] 32. Foss HD, Herbst H, Hummel M, Araujo I, Latza U, Rancsò C, Dallenbach F, Stein H: Patterns of cytokine expression in infectious mononucleosis. Blood 83:707, 1994[Abstract/Free Full Text] 33. Mahmoud MS, Huang N, Nobuyoshi M, Lisukov IA, Tanaka H, Kawano MM: Altered expression of Pax-5 gene in human myeloma cells. Blood 87:4311, 1996[Abstract/Free Full Text] 34. Hsu PL, Xie SS, Hsu SM: Absence of T-cell- and B-cell-specific transcription factors TCF-1, GATA-3 and BSAP in Hodgkin's and Reed-Sternberg cells. Lab Invest 74:395, 1996[Medline] [Order article via Infotrieve] 35. Rudiger T, Jaffe ES, Delsol G, deWolf-Peeters C, Gascoyne RD, Georgii A, Harris NL, Kadin ME, MacLennan KA, Poppema S, Stein H, Weiss LE, Muller-Hermelink HK: Workshop report on Hodgkin's disease and related diseases. Ann Oncol 9:S31, 1998 (suppl 5) 36. Delecluse HJ, Marafioti T, Hummel M, Dallenbach F, Anagnostopoulos I, Stein H: Disappearance of the Epstein-Barr virus in a relapse of Hodgkin's disease. 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