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From www.bloodjournal.org by guest on August 9, 2017. For personal use only. REVIEW ARTICLE The Cellular Biology of the Reed-Sternberg Cell By Frank G. Haluska, Adam M. Brufsky, and George P. Canellos F OR STUDENTS OF the history of medicine, the evolution of our understanding of Hodgkin's disease (HD) has long proved a compelling subject. Traced in the chronology of this disorder, from its first descriptions, through the refinements in its classification, to its medical and radiotherapeutic cure, is a more general outline of the development of our knowledge of malignant lymphoma.'.' Yet, recently advances in cell and molecular biology have afforded a better comprehension of the pathogenesis of non-Hodgkin's lymphomas (NHLs)~than of HD itself. In fact, historically long-standing enigmas regarding the nature of HD continue to defy understanding. The most prominent of these enigmas concerns the origin of the Reed-Sternberg (RS) cell itself. It has been variously identified as a cell deriving from lineages related to macrophages or histio~ytes?~ interdigitating reticulum cells: dendritic reticulum cells,' or granulocytes.8 It has been postulated to result from fusions between lymphocytes: lymphocytes and reticulum cells," or virus-infected cells." However, the weight of recent evidence supports the thesis that the Reed-Stemberg cell originates with a B or T lympho~yte.''.'~ Advances in our understanding of the derivation of the RS cell have been driven by developments in five areas of cell biology. (1) Immunophenotyping of fixed tissues and cell lines has facilitated the characterization of the RS cell's surface, and allowed precise subclassification and identification of phenotypically distinct, but perhaps related, disorders (eg, nodular lymphocyte predominance HD, Ki-l anaplastic large-cell lymphoma, and lymphomatoid papulosis). (2) Genotyping, both by way of cytogenetic and molecular techniques, has provided some genetic correlates to immunophenotyping data. (3) The cultivation of cell lines derived from HD specimens has enabled the development of reliable and specific monoclonal antibodies (MoAbs) and has allowed detailed study in vitro of the putative malignant cells. (4) The finding of an association between HD and Epstein-Barr virus (EBV) infection has suggested a potential pathogenetic relationship between the two. ( 5 ) Descriptions of numerous cytokines produced in HD lesions have provided insight into the histogenesis and pathophysiology of the disorder. These lines of research have at last begun to coalesce into a uniform body of knowledge relating to the cellular biology of the RS cell. In the discussion that follows, we will review the recent developments in each of these areas in turn. IMMUNOPHENOTYPING The antigenic characteristics of RS and Hodgkin cells and variants (RS-H cells) have been investigated in numerous studies. The most useful reagents have been MoAbs with well-defined cell and tissue specificities. An additional useful class of MoAbs produced by immunization with an HD cell line are Ki-l and relatedL5antibodies. Various groups using these reagents have compiled a detailed description of the Blood, Vol84, No 4 (August 15). 1994 pp 1005-1019 RS-H cell surface. However, studies differ as to its precise features; no completely uniform phenotype has emerged. Moreover, no precursor cell or benign counterpart to the phenotype of the antigenically defined RS-H cell has yet been identified. Many studies have defined a set of epitopes common to most RS-H samples in pathologic specimens. A significant fraction of RS-H cells express surface markers consistent with a B- or T-lymphocyte lineage. Markers expressed on cells of myeloid or monocytic derivation are usuallynot identifiable on RS-H cells, with the prominent exception of Leu-M 1, which is found on a high proportion of HD samples. The cells usually express a number of activation antigens, including the interleukin-2 (L-2) receptor (CD25), Ki-l (CD30), the transferrin receptor (OKT 9, CD71), and HLA DR epitopes. Lymphocytic markers. T-cell marker expression by RSH cells is variable. Some studies report negative16 orequivocal results, but others demonstrate expression of various Tcell markers. Kadin et al'7.'8showed expression of CD2, CD3, or CD4 in up to 40% of examined cases; expression was limited to primarily nodular sclerosis (NS) or mixed cellularity (MC) subtypes. Several s t ~ d i e sfound ' ~ ~ ~frequent ~ expression of CD1, CD2, CD3, and CD4 in lymphocytedepleted (LD), NS, and MC histologies. Other workers, using plastic embedding, have confirmed a large proportion of T-cell marker positivity." Additional studies have found variable T-cell marker p~sitivity.'~~''~'~ The consensus is that a significant fraction of RS-H cells do in fact carry pan-Tcell antigens on their surface. The expression of B-cell markers has been similarly explored. As for the T-cell markers, some studies report negative findings, but most groups report that some pathologic samples exhibit staining with B-lymphocyte markers, albeit less commonly than with T-cell reagents. Ig heavy or light chains are usuallynot expressed by RS-H cells, although occasionally individual cases that stain positive are n~ted.'~.'~ In addition, although in one study in situ hybridization failed to detect Ig light chain mRNA synthesis in RS cells,27 a recent report using in situ techniques detected K or A light chain mRNAs in H-RS cells in 50% of nodular lymphocyte predominant (LP) HD cases." B-cell-restricted antigens CD19, CD20, and CD22 are expressed in a small fraction of cases18.21-Z326.29 of all histologies, although in some series From the Division of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA. Submitted December 7, 1992; accepted May 4, 1994. Supported by a Fellowship from the Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation. Address reprint requests to Frank G. Haluska, MD, PhD, Division of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115. 0 1994 by The American Society of Hematology. 0006-4971/94/8404-0040$3.00/0 1005 From www.bloodjournal.org by guest on August 9, 2017. For personal use only. 1006 HALUSKA, BRUFSKY, AND CANELLOS Table 1. Surface Phenotype of HD Subtypes and ALCL HD Antigen LeuM1 (CD15) K i - l (CD30) LCA (CD45) L26 (CD20) J Chain NS, MC, LD + + -* +l- Nodular LP ALCL + + + + + -t - Although most workers regardHD as LCA negative, data are conflicting; see text. t The majority of ALCL are T-cell malignancies, but B-cell cases comprise 20% i n some series. they are expressed in the majority of cases3' The B-cell antigen BLA.36 has been shown to be expressed on some RS cells.3' Expression of the B-cell-specific J chain has also been examined, and shown to occur exclusively in the nodular LP s~btype.~' This variant of HD also exhibits nearly uniform positivity for the CD20 antigen, although a small proportion of malignant cells in up to 50% of non-LP HD cases also stain for CD20.33Nodular lymphocyte predominance HD is now largely accepted as an immunophenotypically distinct B-cell subtype of this malignancy.34The immunophenotypic features of nodular LP HD are contrasted with other subtypes in Table 1. Myelomonocytic markers. HD specimens are usually negative for myeloid and monocytic antigenic markers. In an excellent review by Drexler et a1," a tabulation of various studies showed that, of 196 samples tested for CD1 lb (Mol) and CD14 ( M o ~ ) none , was positive. Other MoAbs, such as antimonocyte antibodies 20.2 and 20.3,6 antimacrophage marker EBMl1 and antily~ozyme,~~ fail to stain HD specimens. However, taken against the body of negative immunophenotyping data is the evidence from histochemical studies. Because of technical differences, these studies are often difficult to interpret. Yet, some groups find that HD samples stain weakly positive for two markers generally takento characterize histiocytes, nonspecific esterase and acid phosphata~e.'.~'To these investigators, the histochemical evidence suggests a shared lineage with interdigitating reticulum cells. The finding of exogenous polyclonal Ig in RS-H cells is felt to be consistent with a macrophage lineage.5 Stein et alx initially reported staining of RS-H cells by MoAbs including T9 and 3C4, which react with granulocytes. Hsu and Jaffe" later reported RS-H cells to be positive for Leu M1. These antibodies recognize CD1 5. Although initially itwashopedthatLeuM1might prove tobe a specific and sensitive HD reagent, this has not proven to be the case. A number of studies have shown CD15 positivity in NHLs, primarily of T-cell rigi in,^'.^' although some reports are negati~e.~' CD15 has also been shown to be expressed in nonhematopoietic malignan~ies.~~ Conversely, the nodular LP subtype is uniformly negative for CD15.32.33,38 The significance of the expression of CD15 and of the histochemical findings noted is not clear. Few investigators feelthat the RS-H cell is derived from myelomonocytic precursors. However, that fact that CD15 is expressed on bothRS-H cells and a small proportion of T-lymphocyte malignancies, when taken in the context of the pattern of lymphocyte marker expression on RS-H cells discussed earlier, may suggest common origins for these tumors. Recently, polymerase chain reaction analyses of reverse transcribed mRNA (RT-PCR) from single RS-H cells lends has provided some support to this hypothesis. mRNA coding for both the hck family of tyrosine kinases and other genes common to myelomonocytic cells, as well as mRNA coding for the lck family of tyrosine kinases and other genes common to T cells, have been shown in individual RS-H cells."*45 The CD30 antigen. The Ki-l antibody was produced in an attempt to isolate specific markers for HD. It was raised against the HD cell line L428,I5and initial studies on biopsy material suggested that it detected an antigen (later designated CD30) restricted to RS-H cells. Subsequently, the antigen was found to be expressed on both T and B cells4'when activated in vitro by a variety of stimuli. In addition, CD30 was detected in a significant proportion of peripheral T-cell lyrnphomas,4' in angioimmunoblastic lymphaden~pathy,~' in lymphomatoid p a p u l ~ s i s , ~and ~,~~,~~ in anaplastic large-cell lymphoma (ALCL)!6,50-52 The latter tumor, by virtue of its Ki-l positivity, has been regarded as a distinct entity with some pathologic features of carcinoma or histiocytosis, and usually derives from activated T cells.52 Table l contrasts the immunophenotype of ALCL with that of HD. Ki-l is one of several a n t i b ~ d i e s ~that ~ . ' ~recognize the CD30 antigen. This marker is expressed primarily on lymphocytes, although its expression on differentiated macrophages in culture has been reported.55The K - l reagent has been used to assay for soluble CD30 in sera of patients with HD, and levels have been demonstrated to reflect disease Other anti-CD30 antibodies have been linked to ricin for use as immunotoxins to image HD and treat refractory HD.54.57,58 Antibodies to CD30 linked toricin59can eradicate primary HD xenografts propagated in severe combined immunodeficient (scid) mice.60The CD30 transcript has been cloned.6' It codes for a protein that is homologous to members of the nerve growth factor receptor superfamily of proteins. In addition, CD30 was recently found to function as a signal transducing molecule in a specific subset of CD45RO' T cells." These findings suggest a potential role for CD30 in the genesis of HD via disturbances in its expression or function. Although a causal relationship between such CD30 alterations and RS-H transformation has yet to be proven, the exciting prospect of a molecular understanding of this aspect of the pathogenesis of HD now exists. Activation markers. Several other antigens, although not specific for HD, are commonly expressed on RS-H cells in biopsy specimens. These include the IL-2 receptor (CD25), HLA-DR (Ia), and OKT9 (CD71, the transferrin receptor~~16-18,21-23.26,46 Ki-67, a nuclear proliferation marker, is usually present.2'~22~'3 Findings with antibodies to leucocyte common antigen (CD45, T200), a hematopoietic and lymphoid antigen, are variable. Some studies report no expression of this marker,17,30.m,65 whereas others demonstrate From www.bloodjournal.org by guest on August 9, 2017. For personal use only. CELLULAR BIOLOGY OF THE REED-STERNBERG CELL 1007 patterns of chromosomal and immunogenetic abnormalities virtually uniform positivity.16,18321 The positive findings likely suggest, as do the immunophenotypic findings, that the RSreflect more sensitive immunocytochemical techniques” and H cell may derive from the lymphocyte lineage. support the lymphoid origin of the RS-H cell. Of note, all Cytogenetics. Chromosome abnormalities were initially HD cell lines express CD 45 (see below). shown to characterize human malignancies by Nowell and A recent report identified a novel B-cell activation antigen Hungerford7’ in 1960; shortly thereafter, RS-H cells were recognized by MoAb FUN-1 FUN-l recognizes a 75-kD examined for characteristic abn~rmalities.~’ However, the protein present on activated B cells, EBV-transformed B cytogenetics of HD presented particular problems. Malignant cells, large B-cell lymphomas, ALCL, and RS-H cells. Restlesions have few cells, low mitotic indices, exhibit a complex ing lymphocytes, activated T cells, acute lymphocytic leukekaryotype, and are difficult to band.80 Thus, in Rowley’s mia (ALL), and low-grade B-cell leukemias do not react series of 25 involved lymph nodes, 10 nodes showed abnorwith the antibody. This finding also lends support to a Bmal cells and only four of these yielded clones, none of lymphoid origin of some ALCL and RS-H cells. which could be completely karyotyped.” Yet, recent techniProliferation of the H-RS cell. Although H-RS cells excal improvements have afforded an improved description of press proliferative markers such as Ki-67, their proliferative RS-H cell cytogenetics. potential was, until recently, unclear. Initially, it was thought HD lymph nodes exhibit clonal karyotypic changes. that mononuclear H cells fused into terminally differentiated Teerenhovi et a18’ first showed that clonal chromosomal abmultinucleated RS cells in a process similar to multinuclenormalities are carried by cells expressing Leu-MI and ated giant cell formation by cells of monocyte/macrophage CD30, ie, RS-H cells. More extensive series confirmed the origin.67However, cultures of HD explants showed 3H-thypresence of clonal abnormalities and showed that numerical midine uptake in multinucleated RS cells, challenging this abnormalities of virtually all of the chromosomes characterview.68Recent results have confirmed this latter view. Using ize most HD Structural changes also occur, alimmunoperoxidase techniques, 50% to 95% of H-RS cells stain for proliferating cell nuclear antigen (PCNA), a marker though no single translocation or other abnormality predomiof cell di~ision.~’-~’ In addition, expression of PCNA in Hnates. Cabanillas et alsaE6 reported cytogenetic findings RS cells correlates with expression of another activation consistent with those of lymphoid malignancies; abnormaliantigen, Ki-67.7’ Finally, Drexler et a17’ showed that the ties of bands 8q22-24, llq23, and 14q32 were seen. They multinuclear RS cells form in culture from mononuclear HD also reported finding a t( 14;18) typical of follicular B-cell cell lines through nuclear division without cytokinesis, or lymphoma.83Tilly et a185also found abnormalities typical of lymphomas, but suggested that the findings inHDmore cell division. Thus, the RS cell is a truly neoplastic cell with closely resemble T-cell malignancy. More recently, Podefects in cytokinesis. pemma et a187showed abnormal metaphases in 23 of 28 HD Cytoskeletal markers. H-RS cells immunochemically cases. 14q32 abnormalities were found in 6 cases, but stain for vimentin, which may be a general indicator of neot( 1 4 s ) was infrequent. Another recent study also showed plastic growth73or may indicate EBV integration into the H-RS cell with latent membrane protein (LMP) e x p ~ e s s i o n . ~ ~a low frequency of t(14;18) in HD metaphases.88 More recently, a novel cytoskeletal protein, expressed only Immunogenetics. The same features that have made the in H-RS cells and ALCL, has been d e ~ c r i b e d Restin . ~ ~ is a analysis of cytogenetic changes in HD difficult have hin160-kD protein encoded by a cDNA isolated from in vitro dered molecular genetic study as well. The variable and cultured peripheral blood mononuclear cells (PBMs).~~ Reusually minor proportion of RS-H cells in biopsy specimens stin is associated with the intermediate filament cytoskeletal has impeded investigation of their molecular pathology. Furnetwork, and has an a-helical rod structure similar to interthermore, no uniform cytogenetic abnormality has provided mediate filament proteins.75Restin expression appears lima convenient clue to the location of a genetic lesion, as has ited to H-RS cells of primary HD tissues, HD cell lines, been the case for a number of other lymphomas.’ Asa result, and ALCL.75,76 The function of restin is unknown, but it is our understanding of the molecular genetics of HD is limited. tempting to speculate that abnormalities of restin expression Most molecular analyses have involved examination of may underlie the abnormalities in cell division and cytokineIg and T-cell receptor (TCR) Because these genes sis seen in the RS cell. The gene for restin has been mapped rearrange during lymphocyte ontogeny, they afford ready to chromosome 12~24.3by in situ h~bridization.~~ markers both for lineage and for clonality.” A number of studies have shown that a small proportion of HD cases GENOTYPING carry clonal rearrangements of one or more Ig or TCR loci. The demonstration of TCR-P rearrangement in the HD Investigations of both the cytogenetics and molecular genetics of HD have been productive. These studies have been cell line L428 first suggested that such an approach might be promising.” Subsequently, Weiss et a123,92 analyzed fresh particularly difficult to perform in fresh biopsy specimens, tissues for rearrangements. They initially found Ig heavy (H) largely because of the paucity of malignant RS-H cells in involved tissues; they generally constitute approximately 2% and light (L) chain rearrangement in one of 16 cases of HD; of cellular material in biopsied lymph nodes. Nonetheless, however, when cases were selected for larger proportions of genotypic studies have been central to establishing the clonRS-H cells, 6 of 7 cases showed IgH or IgL rearrangements. ality of the HD disease lesion. They have also shown that no Other investigators have found Ig rearrangements as well, uniform HD genotype is distinguishable. Instead, the general although the proportion of cases exhibiting clonal re- From www.bloodjournal.org by guest on August 9, 2017. For personal use only. 1008 arrangements varies widely, from about 10% of cases in some ~ e r i e s ~to ~ -approximately '~ 50% of cases in others.22.26 Rearrangements of IgH, IgL, or both have been found. Notably, several studies have found an IgL rearrangement carried with a germline IgH locus,23an unusual pattern ofIg rearrangement also seen in ALCL.y6Some studies are negative for Ig re arrangement^.'^-^' It has been suggested that negative studies reflect a low proportion of RS-H cells in samples, and one group reports that enrichment of RS-H cell populations using density gradient centrifugation yields identifiable clonal Ig rearrangements.'OO~loi However, the intensity of rearranged bands on Southern blots often does not correlate with the size of the population of RS-H and tissues with prominent RS-H cell populations are often without Ig rearrangements.'00It thus seems likely that the variable finding of Ig rearrangement in RS-H cells is biologic and not technical in nature. The situation is much the same with regard to TCR rearrangements. Griesser et aIy7first reported finding faint clonal TCR-P rearrangements in 4 of 8 cases of HD. No Ig rearrangements were seen. Later, the same group found that, in 22 cases of HD, 4 TCR-P and 15 TCRy rearrangements were pre~ent.'~ TCR-y rearrangement has been shown by other investigators as we11,26,'02 ashas TCR-p.26,98,Y9 The significance of these Ig and TCR rearrangements is unclear. Most investigators agree that these studies demonstrate clonal populations of cells, possibly corresponding to RS-H cells, in some biopsy specimens. Yet, these cells are not simply B or T lymphocytes. Although two studies have suggested that Ig rearrangements occur primarily in RS-H cells having B-cell immun~phenotypes,~~.'~ a third hasshown this not to be the case.26At best, it can be stated that the finding of antigen receptor rearrangements in a proportion of RS-H cells supports the hypothesis that these cells derive from a lymphocytic cell. In this light, the recent demonstration, using sensitive RTPCR, thatRS-H cells do not express the recombinase activating genes RAG-l and RAG-2'03 is of interest. This suggests that RS-H cells, if of lymphocytic origin, are derived from a more differentiated lymphocyte precursor that has already undergone Ig gene rearrangement. Oncogene alterations. Analyses looking for abnormalities in a number of oncogenes have been performed. StetlerStevenson et a1" first showed rearranged bcl-2 genes caused by t( 14;18) translocations in 17 of 32 cases of HD. Subsequently, several other workers replicated this finding. Gupta et allos found the translocation in 20% of cases; sequence analyses demonstrated the PCR products to represent bcl-UJ, fusion in all cases. Similarly, Reid et al" showed the translocation in 9% of cases. Recently, the translocation has beenfoundin a series of cases of HD occurring in combination with follicular lymphoma.ia7However, a number of groups have been unable to detect t( 14;18) translocations by Southern or PCR analysis.3"~'08-"' This discrepancy isnot understood, but is possibly the result of technical factors, including variables in the preparation of pathologic specimens and the relative underrepresentation of RS-H cells in tumors. One reports7 failed to show consistent bcl-2 ex- HALUSKA, BRUFSKY, AND CANELLOS pression is RS-H cells, and suggested that bcl-2 positivity of HD cases may simply reflect the presence of small bystander B lymphocytes carrying the bcl-2 rearrangement that are found in other reactive lymphoid tissues such as tonsils. Thus, the precise frequency of bcl-2 translocations in HD is at this timenot clear. Nonetheless, the association of the t( 14;18) with HD is apotentially significant finding. It further supports the lymphoid derivation of RS-H cells. It also has implications for the role of EBV infection in HD, as discussed below. Itspotentially important role in the pathogenesis of HD needs to be further elucidated. The expression of other oncogenes has also been examined. The c-myc and ras proteins have been detected immunohistochemically in RS-H and samples from two patients carried activated N-ras genes."' No mutations were detected in 25 biopsy samples in another s t ~ d y . "Although ~ a number of oncogene products have been found in HD cell lines,"' including c-myc, p53, c-jun, c-raJ N-ras, and others, no characteristic pattern of expression has emerged. Recent reports have investigated the tumor suppressor gene p53 in RS-H cells. High-level immunoreactivity for p53 protein using monoclonal antisera is found in RS-H cells of all HD subtypes, except nodular LP,"6 in approximately 30% to 40% of cases."7 p53 overexpression did notcorrelate with bcl-2 expression inRS-H cells in one study.'" Point mutations in exons 5 and 8 of the p53 gene have been demonstrated byDNA sequencing in 1 of 6 HD cell lines,II8 and mutation of p53 gene codon 246 has been demonstrated by single cell PCRin 5 of 7 RS-H cells examined from 4 patients with NS HD.45Interestingly, in a study of Ki- 1 positive ALCL, high-level p53 expression in most cases was not accompanied by mutations in p53 exons 5 through 9, suggesting alternate mechanism of increased p53 expression."' The significance of these findings is unclear, but they suggest that alterations of p53 protein expression, by several mechanisms, are common in HD and ALCL. CELL LINES DERIVED FROM HD The establishment of cell lines from pathologic specimens of HD has, for several reasons, been technically difficult. Again, the relative dearth of malignant RS-H cells in involved tissues makes their in vitro cultivation problematic. A number of methods have been devised to enrich or purify populations of RS-H cells.'1s,120"24 Still, in some cases, resulting cultivated lines fail to derive from RS-H cells, or fail to propogate.'25 Ten cell lines have been established thatlikely derive from RS-H cells.12,i%~25-~36 Their availability has facilitated the study of the molecular characteristics of putative RS-H cells. In particular they have been used in the generation of MoAbs specific for CD30" and in the cloning of the gene encoding this molecule!' These cell lines, and their salient features, are described in Table 2. General features. The various cell lines share several characteristics. Most of them are derived from advanced cases of HD in patients who were previously treated with radiation, chemotherapy, or both. Nine of the cases were of nodular sclerosing histology. The lines have largelybeen From www.bloodjournal.org by guest on August 9, 2017. For personal use only. 1009 CELLULARBIOLOGY OF THEREED-STERNBERGCELL Table 2. HD Cell Lines Reference Cell Line No. Origin Phenotype L428 125 NS, IV, PE L59 1 126 NS, IV, PE DEV 121 NS, 111, PE KM H2 129 MC, IV, PE 20 131 NS, II, PE SUP HD1 133 NS, 111, PE L540 126 NS, IV, BM CO 128 NS, 111, LN HD LM2 130 NS, IV, PE H0 132 NS, II, LN CD 19, 15, 30, 45 CD 19, 20, 15, 30, 45 CD 19, 20, 15, 30, 45 CD 19, 21, 15, 30,45 BIB, CD 15, 30; CD45slgK, CD 15, 45, 45; CD30CD 2, 4, 15, 30,45 CD 3, 5, 7, 15, 30, 45 CD 2, 4, 15, 30, 45 CD 3. 4, l , 30, 45; CD15- lmrnuncgenotype Cell lines are described in detail in the references noted. Stage at establishment of line is noted. Abbreviations: PE, cells obtained from malignant pleural effusion; PCE,cells obtained from a malignant pericardial effusion; LN, cells from lymph node biopsy; BIB, B-cell immunoblastic NHL antigen’”; slgK, surface K Ig. cultivated from malignant effusions containing enriched populations of H-RS cells. Thus, these cell lines may represent only a subset of HD cell types, and our ability to draw general conclusions from their features may be limited. For example, the cell lines of primarily B-cell phenotype and genotype all were cultivated from malignant effusions; in contrast, three of the four lines with T-cell features were derived from lymph nodes or bone marrow (Table 2). It is not clear whether this observation reflects an aspect of the biology of the disease at this time. Zmmunophenotypes. The immunophenotypes of the HRS cell lines generally reflect expression of activation markers, including CD15 (Leu Ml), CD25 (IL-2R), CD30 (Kil), CD45 (LCA), CD71 (transfemn receptor), and HLA-DR. All of the HD cell lines exhibit B- or T-cell surface markers. B-lymphoid markers include CD9, CD19, CD20, CD21, CD22, Igs, and an antigen expressed by B-immunoblastic NHL. T-cell markers include CD2, CD3, C M , CD5, and CD7. Genotypes. Gene rearrangement studies show that, in most cases, immunogenotype is consistent with the cell surface phenotype. The cell lines LA28 and Sup HD1 exhibit rearrangement of both Ig and TCR loci (although reports differ with regard to Ig light chain rearrangement in LA281”136). Other lines demonstrate B-lymphocyte surface phenotypes with Ig rearrangement or T-cell surface phenotypes with TCR rearrangements. Receptor gene expression is variable in B-lymphoid lines, but all of the T-lymphoid lines express TCR mRNA. Conclusions from cell lines. For a number of reasons conclusions must be drawn from the above data with caution. The cell lines, primarily nodular sclerosing variants, many from effusions, have been isolated from samples not fully representative of the clinical spectrum of HD. They vary one from another and, taken together, they fail to define a single cell type. However, in general, the cell line data are consonant with data derived from study of RS-H cells in pathologic specimens. The cell lines express activation antigens as do RS-H cells in situ. One of these, Ki-l, was identified first in the L428 line, and subsequently shown to be widely expressed in HD tissue. With regard to lymphoid markers, pathologic specimens express B-cell antigens in a small fraction (up to 15%) of cases, and T-cell antigens more often (in up to 67% of cases), whereas each cell line expresses B- or T-lymphoid markers. Moreover, study of fresh HD specimens shows Ig or TCR rearrangements in a fraction of cases. All the cell lines exhibit one or the other. The lymphoid characteristics of the putative HD cell lines are their most striking feature^.'^,'^ Although unequivocal proof that these lines do in fact represent cultured RS cells is unavailable, this is strongly suggested by the above comparisons. The HD cell lines thus further support the proposition that RS-H cells represent components of the lymphoid lineage. CYTOKINES IN HD Aside from the identity of the cell giving rise to the RSH cell, several other aspects of HD remain enigmatic. Its histogenesis is not understood. Involved tissues often consist of only 2% RS-H cells, with apredominant reactive lymphocyte population, eosinophils, and varying degrees of fibrosis or sclerosis. The commonly observed paraneoplastic phenomena including B symptoms of fever, sweats, and cachexia; generalized pnuitis; and immune abnormalities consisting in impaired T-cell immunity (reviewed in Hellman et all3’); and a proclivity for disorders of autoimmunity such as immune thr~mbocytopenia’~~ all remain to be explained. It is possible that many of these clinical features of HD are mediated through elaboration of cytokines by either the malignant H-RS cells or by the lymphocyte populations infiltrating the involved tissues. A number of cytokines have been shown to be present in H-RS cells in pathologic specimens or produced by HD cell lines. IL-l. L-l,first shown to be produced by monocytes and to facilitate lymphocyte proliferation, consists of IL-la and E-lp. These are produced by monocytes, lymphocytes, fibroblasts, epithelial, and endothelial cells. IL-1 is required for the induction of T-cell a ~ t i v a t i o n and ’ ~ ~plays a role in B-cell regulation.’” It may also regulate fibroblast proliferationI4’ and function as a pyrogen.’” IL-1 was detected by immunoperoxidase in 20 cases of HD, representing all four histologies: no expression in B- or T-cell lymphomas was detected.’43 Excised tumor nodules from spleens of HD patients produced IL-l when cultured From www.bloodjournal.org by guest on August 9, 2017. For personal use only. 1010 for periods of up to 2 months.'" Two of the HD cell lines, HDLM- l and K"H2, also produce IL- l .'4','46 Using in situ hybridization, IL-1 amRNA was detected in H-RS cells in 12 of 19 cases examined in one study.'47 Although IL-1 expression in HD has been taken as evidence of an interdigitating reticulum cell or macrophage origin for H-RS cells,'43 this cytokine is also produced by activated B cells'4aas well as other tissues. Thus its detection in HD tissues may not clarify the origin of the H-RS cell. IL-1 may, however, play a role in lymphocyte recruitment, in lymph node sclerosis, and in the production of fever in HD patients. However, in one study, immunohistochemical positivity of HD tissues for IL-1 did not correlate with symptom~.'~~ IL-2receptor (IL-2R). IL-2R has also been detected in HD. The receptor consists of two subunits: a low-affinity a subunit (CD25), a 55-kD glycoprotein expressed by activated T cells; and the intermediate affinity p subunit, consisting of two glycoproteins, 70 and 75 k D , that mediate membrane signal transduction and IL-2R internalization.'50.'5' Immunoperoxidase studies show IL-2R in the cytoplasm of H-RS cells and on a high fraction of surrounding lymphocytes in HD tissue se~tions.''~ Other investigators find similar IL-2R expres~ion.'~~''~~''~ Interestingly, in some HD cases, IL-2Ra (CD25), but not IL-2R@,positive cells formed clusters and aggregates in the primary tissue.Is5 Of note, the IL2R is also expressed in B- and T-cell lymphomas and on scattered histiocytes in HD lesi~ns.''~ The HD cell line L540 similarly expresses IL-2R,lS6as do HDLM-2 and KMH2." Increased serum levels of IL-2R have been found in a number of B- and T-cell malignancies, including NHL, acute lymphoblastic leukemia, chronic lymphocytic leukemia, hairy cell leukemia, adult T-cell leukemia, and Sezary syndrome. Soluble IL-2R is also elevated in HD."7.'S8The serum level in children has been shown to correlate with stage, B symptoms, and, independently, with treatment fai1~re.I'~ IL2 itself has not been found to be expressed in HD tissues160 or cell lines.'46 ZL-3. IL-3 is poorly studied, but in a single investigation was found to be rarely expressed by HD cell lines or RS cells.'@' IL-4. The cytokine L - 4 (BSF-1) is a T-cell-derived 68M) glycoprotein that acts on B and T cells, natural killer (NK) cells, and monocytes.'61 It is expressed on the HD cell line L428 and stimulates L428 cell proliferation.I6' However, it is not expressed bytwo other HD cell lines.'& InHD tissues, one study demonstrated expression in 2 of 13 samples.Im IL-5. Eosinophils are often a prominent component of the cellular infiltrate in tissues involved by HD. IL-5 is produced by activated T cells and may stimulate eosinophils in murine'63 andhuman" systems. In one study, in situ hybridization showed expression of IL-5 mRNA in the cytoplasm of H-RS cells in 16 of 16 cases of HD with eosinophil~.'~' HD cell lines also produce IL-5.'60These data suggest an explanation for the eosinophilia associated with HD, and also suggest a functional similarity between H-RS cells and activated IL-5-producing T lymphocytes. HALUSKA, BRUFSKY, AND CANELLOS IL-6. IL-6 is also T-cell-derived; identified originally as BSF-2, it is a 21-kD protein involved in maturation of B lymphocytes, in myeloma proliferation, and in T-cell activation, and is produced by B and T lymphocytes, monocytes, epithelial cells, and fibroblasts.'" IL-6 expression was found in 50% to 70% of HD tissues'@'.'67 and in 4 of 6 HD cell lines146.167 tested. Receptors for IL-6 were expressed in 5 of 6 HD cell lines t e ~ t e d . ' ~Recently, ~ . ' ~ ~ IL-6 mRNA was detected by in situ hybridization in H-RS cells in 19 of 23 primary HD specimens.I6* IL-9. Recently, IL-9 has been shown to be produced in HD cells and K1-l large cell anaplastic l y m p h ~ m a . ' ~ ~IL.'~' 9 is produced by activated CD4+ T cells'71and induces CD4' T-lymphocyte pr01iferation.l~' Merz et all6' analyzed 29 cases of B- and T-cell NHL without finding expression of IL-9; however, 6 of 13 cases of HD exhibited expression. Other cytokines. Additional cytokines have been studied in relation to HD, although their expression is generally less characterized. These include IL-8,'46E-rosette inhibiting macrophage colony-stimulating factor (M-CSF; CSF-1) and c - f m ~ , ' ~granulocyte-macrophage ,'~~ CSF (GMCSF),'75 i n t e r f e r ~ n - y , ' transforming ~~ growth factor P (~~~@),146.176-178 and tumor necrosis factor a (TNFa).'46.'7' Lymphotoxin and TNFa immunostaining'80.'8' as well as mRNA expression'68can be found in H-RS cells in primary HD tissues as well as in HD cell lines; however, only LT protein is found in HD cell line supernatants.'68.The significance of these findings is not yet well defined. The studies of cytokine expression in HD suggest several conclusions. The finding that lymphokines, including IL-2R, IL-4, IL-5, IL-6, and IL-9, are produced by HD tissues and cell lines supports the argument that RS-H cells derive from lymphocytes. Moreover, the expression of these molecules may explain several histologic peculiarities (IL-1 and fibrosis; IL5 and eosinophilia; IL-9 and CD4 T-cell infiltration) as well as systemic manifestations (IL-l, TNF, and B symptoms) of the disease. Ultimately, a clearer understanding of the cytokine interactions involved in HD may offer insight into the pathogenesis of this disease as well as potential strategies for therapeutic interventions. HD AND EBV The issue of the possible infectious etiology of HD is a long-standing one. Clinically, the disease may present with features of seemingly infectious origin, with fever, leukocytosis, eosinophilia, sweats, adenopathy, and hepatosplenomegaly. Thus, for many years after its description, clinicians and pathologists debated the view that HD is a response to an exogenous pathogen and not a truly neoplastic disorder. Most investigators now agree that HD indeed has neoplastic characteristics. Infectious and malignant etiologies are not mutually exclusive. A number of features of the epidemiology of HD suggest that the disease might result from infectious cofactors.'82Gutensohn and C ~ l e ' ~have ~ , argued '~ that the incidence patterns of HD reflect an uncommon consequence of a common infection. Features of the disease supporting this view include its bimodal age distribution, varia- From www.bloodjournal.org by guest on August 9, 2017. For personal use only. CELLULAR BIOLOGY OF THE REED-STERNBERG CELL 1011 Other hybridization methods enhance the sensitivity of EBV detection. PCR generally detects EBV in 60% to 80% of cases.186,2W,208-214 EBV also encodes small RNAs, transcribed at up to 10 copies per genome, called EBERs.'I6 These can be detected in 50% to 75% of HD cases.186*202-216 What is the significance of the detection of EBV in HD? It has already been pointed out that epidemiologic studies suggest a possible infectious etiology for HD; EBV infection could be responsible. Indeed, underscoring this point, in developing countries such as Peru, the incidence of HD associated with EBV is higher (95% in one study)Z26than in the United States. The possible transforming role of EBV LMP tients with HD exhibit elevated antibody titers against EBV has been underscored. But, EBV infection may also bear on capsid antigens (VCA)'s5,'94*'95; titers to early antigen, indicathe identity of the RS-H cell of origin. EBV has generally tive of viral activity, can also be dete~ted.'~'.'" A retrospecbeen taken to be a B-cell pathogen, infecting mature B lymtive study has shown that rising anti-EBV titers antedate phocytes via the C3d receptor.227But recently, EBV has been the development of HD.'97 These indirect data provided the shown to be present in T cells in Kawasaki disease?" in Trationale for attempting to detect evidence of EBV in tissues cell lymph~rna?'~and in T-cell lethal midline gran~lorna?~' involved byHD. Initial evidence for the presence of the as well as in epithelial cells in nasopharyngeal carcinoma virus in HD lesions consisted in demonstration of the EBV (NPC).225Thus the presence of EBV in itself does not necesnuclear antigen (EBNA) in a single case.198Subsequently, sarily imply that the infected cell is of B-cell, or even HD lesions were shown to express EBV antigens,199-202 to lymphoid, lineage. Of note, EBV in HD expresses LMP but carry EBV DNA demonstrable by conventional Southern or not EBNA-2.'W*2W In NPC, expression is ~imilar.'~'Howin situ hybridization technique^^^^‘^^^ as well as by ever, in vitro transformed B-cell lymphoblastoid cell lines p~~,lX6,203.208-214 and to contain EBV-encoded RNA.202~2'5*216 (EBNA-1 through -6 positive, LMP positive), Burkitt's A number of EBV-associated antigens have been demonlymphoma (EBNA-2 negative, LMP negative), and T-cell strated in HD lesions. Poppema et a l l 9 ' first demonstrated midline granuloma (EBNA-2 positive, LMP positive)230all EBNA in the nuclei of RS-H cells. Subsequently, several differ from NPC and HD.232Does this imply some aspect of groups showed that the EBV LMP is expressed in up to 49% differentiation shared by epithelial cells and H-RS cells, or of HD cases. LMP is a virally encoded 60-kD transmemdoes it reflect some component of the viral transforming or brane protein.'I7When transfected into rodent cells, it is latency strategy?232These are questions for active investigatransforming:" and when transfected into human B cells, it tion. protects them from apoptosis via augmented expression of bcl-2.219,220 The induction of bcl-2 by EBV may parallel its CONCLUSION induction by t(1 4 3 ) in NHLs, and mayexplain the presence Each of the lines of evidence we discussed above has of bcl-2 immunohistochemical expression in the absence of afforded a detailed description of the characteristics of the bcl-2 chromosomal rearrangement described in one reRS cell. In some cases it expresses antigens found onT port.88322' However, several studies fail to demonstrate a firm cells; less often those found on Bcells; and usually activation correlation between LMP expression, bcl-2 expression, and antigens. It can carry rearranged TCR genes, rearranged Ig EBV expression in H-RS cells and HD tissues.222-2xLMP loci, both, or neither. It exhibits chromosomal abnormalities, expression varies among subtypes, andis found in up to 96% of MC cases, 34% of NS cases, and 10% of LP cases.'99-20' but no unique and defining aberration, and may carry a rearranged bcl-2 gene. It can express a number of cytokines, EBNA-2 expression was not found,'99-20'nor was expression but, again, in no unique pattern. EBV appears to infect the of the VCA, early antigen (EA), or membrane antigen majority of cases. Cell lines, variously reflecting most of (MA)."' these features, have been established. Yet, despite the extent Using various methods to detect nucleic acids, up to 79% of these descriptive data, we lack a definitive understanding of HD specimens have been shown to carry EBV.'" Convenof the nature and origin of the RS-H cell. At best, these tional DNA hybridization techniques have demonstrated the characteristics describe a cell having lymphoid features. monoclonality of EBV-infected H-RS cells.z03-2w The EBV A final avenue of investigation that may offer further inencodes approximately 500-bp tandem repeats at each of its sight into the nature of the RS-H cell is the emerging relatermini, and viruses are heterogeneous in the number of tionship between HD and several closely related conditions. repeats they carry. Thus, probing for terminal fragments may The B-cell variant of HD is clearly represented by the nodushow monoclonal or polyclonal viral populations.225HD tislar lymphocyte predominant histology.34This malignancy, sues carry monoclonal EBV p o p ~ l a t i o n s . ~Furthermore, ~~-'~~ as described earlier, expresses the J-chain" and the B-lymin situ hybridization shows EBV in the nuclei of RS-H cells,Z04.205,207 proving the clonality of these cells as well. phocyte marker CD20.33The RS-H cells of nodular LP HD Taken together with the Ig and TCR rearrangement studies are clearly malignant B cells. cited earlier, these data provide strong evidence for the A corresponding T-cell variant of HD also likely exmonoclonality of RS-H cells. ists. Observations on the relationship betweenHD, lymtions in its geographic distribution, its relation to social class,'83 and its relation to childhood social en~ironment.''~ Several viruses have been proposed as the putative infectious cofactor for HD, including cytomegal~virus'~~ and herpesvirus-6 (HHV-6).'86.'87The most prominent candidate is EBV. EBV is clearly implicated in the pathogenesis of Burkitt's lymphoma and nasopharyngeal carcinoma. Several lines of evidence indirectly suggest a role in HD as well. First, several large cohort studies demonstrate that the risk of HD in patients with a history of infectious mononucleosis is increased up to fivefold in excess over control populations.188-193 Second, a larger than expected proportion of pa- From www.bloodjournal.org by guest on August 9, 2017. For personal use only. 1012 phomatoid papulosis, mycosis fungoides, and Ki- l ALCL48,51,52,233,234have suggested that these entities might share a common pathogenesis. Ki-l ALCL has been discussed earlier. It is usually a T-cell malignancy composed of large pleomorphic cells that express CD30 and activation antigens that frequently infiltrate the kin.^'^^' RS cells may be present in involved tissue^.^' Lymphomatoid papulosis is also a cutaneous infiltration, with atypical T-lymphoid cells having a resemblance to RS-H or Sezary cells.4xTCR rearrangements can be detected in some cases, and canbe polyclonalz3sor monoclona1.236 The atypical cells, like RSH cells, express Ki-l (CD 30).'37 Moreover, HD, lymphomatoid papulosis, and mycosis fungoides occur in association more frequently than expected.233For instance, a patient was described who developed lymphomatoid papulosis, HD, cutaneous T-cell lymphoma, and ALCL in successi0n.4~Examination of tissues from the patient's consecutive diagnoses showed that clonal TCR rearrangements and a t(8;9) translocation were consistently present in the successive lesions. An abnormal T-cell clone was therefore successively manifest as each of these disorders in this patient. Thus, Kadin and othe r have ~ suggested ~ ~ that ~ these disorders are closely related and represent a spectrum of T-lymphocyte malignancy. If HD disease is truly a unique lymphoid malignancy, it is tempting to draw analogies between its pathogenesis and that of the NHLs. In particular, immunosuppression, EBV, and bcl-2, each of which may playa role in the development of HD, together act as cofactors in the development of aggressive B-cell malignancies, including Burkitt's lymphoma (BL).239,24"BLoccurs endemically in equatorial Africa in the setting of hyperendemic malaria and near uniform EBV infe~tion.'~"EBV promotes the expansion of infected Blymphocyte populations, possibly through upregulation of bcl-2 expression by the viral latent membrane protein. Suppression of these infected B-cell populations is probably abrogated through the T-cell immunosuppressive effect of malaria.241The result is that the expanded B-lymphocyte pool is subject to genetic errors that may eventually result in the characteristic translocations seen in BL, and ensuing malignancy.242It is noteworthy that, in other types of NHL, parallel factors are probably operative. Other forms of immunosuppre~sion:~~including transplantation-related iatrogenic immunosuppression and HIV infection,'@ are associated with an increased incidence of aggressive NHL. Furthermore, bcl-2 activation obviously need notresult from viral infection; aggressive NHLs carry t(14;18) translocat i o n ~ : ~and ~ bcl-2 activation via translocation may precede the development of a second translocation that activates crn~c.'~~ It is intriguing that the same factors appear to operate in HD. The roles of EBV infection and of LMP and bcl-2 expression have been detailed already. In addition, it is well known that patients with HD exhibit abnormal T-cell immunity. It is possible that these factors recapitulate those described above for BL. That is, immunosuppression may precede the development of HD, and may set the stage for an abnormal response to EBV infection, bcl-2 activation, and subsequent malignancy. In this view, the abnormal T-cell HALUSKA, BRUFSKY, AND CANELLOS IMMUNOSUPPRESSION Iatrogenic, viral 1 EBV INFECTION or bcl-2 REARRANGEMENT in lymphoid precursor Other genetic alterations 1 CLONAL EXPANSION of lymphoid cells with morphologic features of RS-H cells HODGKIN'S DISEASE Clinical syndrome and histopathology determined by cellular biologic and cytokine characteristics of RS-H cells Fig 1. Schematic representationof one hypothesis for the pathogenesis of HD. The interrelationship between immunosuppression, EBV infection, bcl-2 activation or expression, and malignancy is diagrammed. function well-documented in HD is not a consequence, but a part of the cause, of the disease. The recent observation that HIV infection confers a fivefold elevated risk of HD on HIV ~ a r r i e r s ? ~that ~ , ~there ~ ' is a high frequency of EBVpositive H-RS cells in HIV-associated HD,z49and that HD occurs with increased frequency in other immunosuppressive states,243supports this hypothesis. Thus, in the setting of impaired immune surveillance, the expansion of a lymphoid precursor to the H-RS cell might occur. This might be facilitated by bcl-2 activation, whether by translocation or EBV infection, which in turnwould enlarge the pool orH-RS precursors subject to further genetic alterations and tumor progression. This hypothesis is represented in Fig 1. The RS cell is protean. Despite a century of research into the origin of this cell, this histopathologic designation continues to encompass what is likely to be a number of immunophenotypic and immunogenetic entities. Although a definitive understanding of HD is lacking, investigation into the nature of its histogenesis continues to provide insight into the origin and pathogenesis of this disorder. The present direction of research suggests that ultimately it will be scientifically correct to term HD a lymphoma. From www.bloodjournal.org by guest on August 9, 2017. For personal use only. CELLULAR BIOLOGY OF THE REED-STERNBERG CELL REFERENCES 1. Taylor C: A history of the Reed-Stemberg cell. Biomedicine 28:196, 1978 2. Aisenberg A A historical overview of malignant lymphoma, in Wiemik P, Canellos G, Kyle R, Schiffer C (eds): Neoplastic Diseases of the Blood. New York, NY, Churchill Livingstone, 1991, chapter 36, p 597 3. 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For personal use only. 1994 84: 1005-1019 The cellular biology of the Reed-Sternberg cell [see comments] FG Haluska, AM Brufsky and GP Canellos Updated information and services can be found at: http://www.bloodjournal.org/content/84/4/1005.citation.full.html Articles on similar topics can be found in the following Blood collections Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.