Download The Cellular Biology of the Reed-Sternberg Cell

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. Haluska F, Tsujimoto Y, Croce C: The molecular genetics of
non-Hodgkin’s lymphomas, in Magrath I (ed): The Non-Hodgkin’s
Lymphomas. London, UK, Edward Arnold, 1990, chapter 6, p 96
4. Kaplan H, Gartner S: “Stemberg-Reed” giant cells of Hodgkin’s disease: Cultivation in vitro, heterotransplantation, and characterization as neoplastic macrophages. Int J Cancer 19511, 1977
5. Kadin M, Stites D, Levy R, Wamke R Exogenous immunoglobulin and the macrophage origin of the Reed-Stemberg cells in
Hodgkin’s disease. N Engl J Med 299:1208, 1978
6. Kadin M: Possible origin of the Reed Sternberg cell from an
interdigitating reticulum cell. Cancer Treat Rep 60:601, 1982
7. Curran R, Jones E: Hodgkin’s disease: An immunohistochemical and histological study. J Pathol 125:39, 1978
8. Stein H, Uchanska-Zeigler B, Gerdes J, Ziegler A, Wernet P:
Hodgkin and Stemberg-Reed cells contain antigens specific to late
granulopoesis. Int J Cancer 29:283, 1982
9. Sinkovics J, Schullenberger C: Hodgkin’s disease. Lancet
2:960, 1975
10. Warner T: Origin of the Reed-Sternberg cell. Lancet 25111,
1973
11. Bucsky P: Hodgkin’s disease: The Reed-Sternberg cell. Blut
55:413, 1987
12. Drexler H, Jones D, Diehl V, Minowada J: Is the Hodgkin
cell a T- or B-lymphocyte? Recent evidence from geno- and immunophenotypic analysis and in vitro cell lines. Hematol Oncol 7:95,
1989
13. Diehl V, von Kalle C, Fonatsch C, Tesch H, Juecker M,
Schadt M: The cell of origin in Hodgkin’s disease. Semin Oncol
17:660, 1990
14. Jaffe E: The elusive Reed-Sternberg cell. N Engl J Med
320529, 1989
15. Schwab U, Stein H, Gerdes J, Lemke H, Kirchner H, Schaadt
M, Diehl V: Production of a monoclonal antibody specific for Hodgkin and Sternberg-Reed cells of Hodgkin’s disease and a subset of
normal lymphoid cells. Nature 299:185, 1982
16. Hsu S, Yang K, Jaffe E: Phenotypic expression of Hodgkin’s
and Reed-Sternberg cells in Hodgkin’s disease. Am J Pathol
118:209, 1985
17. Kadin M, Muramoto L, Said J: Expression of T-cell antigens
by Reed-Sternberg cells in Hodgkin’s disease. Am J Pathol 130:345,
1988
18. Agnarsson B,Kadin M: The immunophenotype of ReedSternberg cells: A study of 50 cases of Hodgkm’s disease using
fixed frozen tissues. Cancer 63:2083, 1989
19. Falini B, Stein R, Pileri S, Canino S, Farabbi R, Martelli M,
Grignani F, Fagoli M, Minelli 0, Ciani C, Flenghi L: Expression of
lymphoid-associated antigens on Hodgkin’s and Reed-Stemberg
cells in Hodgkin’s disease. An immunocytochemical study on lymph
node cytospins using monoclonal antibodies. Histopathology
11:1229, 1987
20. Dallenbach F, Stein H: Expression of T-cell receptor beta
chain in Reed-Stemberg cells. Lancet 2:828, 1989
2 1. Casey T, Olson S, Cousar J, Collins R Immunophenotypes
of Reed-Sternberg cells: A study of 19 cases of Hodgkin’s disease
in plastic embedded sections. Blood 74:2624, 1989
22. Brinker M, Poppema S, Buys C, Timens W, Osinga J, Visser
1013
L: Clonal immunoglobulin gene rearrangements in tissues involved
by Hodgkm’s disease. Blood 70:186, 1987
23. Weiss L, Strickler J, Hu E, Wamke R, Sklar J: Immunoglobulin gene rearrangements in Hodgkin’s disease. Hum Path01 17:1009,
1986
24. Abdulaziz Z, Mason D, Stein H, Gatter K, Nash J: An immunohistological study of the cellular constituents of Hodgkin’s disease
using a monoclonal antibody panel. Histopathology 8: 1, 1984
25. Angel C, Warford A, Campbell A, Pringle J, Lauder I: The
immunohistology of Hodgkin’s disease-Reed-Stemberg cells and
their variants. J Pathol 153:21, 1987
26. Herbst H, Tippelmann G, Anagnostopoulos I, Gertes J,
Schwarting R, Boehm T, Pileri S, Jones D, Stein H: Immunoglobulin
and T-cell receptor gene rearrangements in Hodgkin’s disease and
Ki-l positive anaplastic large cell lymphoma: Dissociation between
genotype and phenotype. Leuk Res 13:103, 1989
27. Ruprai A, Pringle J, Angel C, Kind C, Lauder I: Localization
of immunoglobulin light chain mRNA expression in Hodgkin’s disease by in situ hybridization. J Path01 164:37, 1991
28. Hell K, Pringle JH, Hansmann ML, Lorenzen J, Colloby P,
Lauder I, Fischer R: Demonstration of light chain messenger RNA
in Hodgkin’s disease. J Path01 171:137, 1993
29. Stuart A, Volssen S, Zola H: The reactivity of Reed-Stemberg
cells with monoclonal antisera at thin section and ultrastructural
levels. J Pathol 141:71, 1983
30. Schmid C, Pan L, Diss T, Issacson P: Expression of B-cell
antigens by Hodgkin’s and Reed-stemberg cells. Am J Pathol
139:701, 1991
31. Della Croce D, Imam A, Brynes R, Nathwani B, Taylor C:
Anti BLA.36 monoclonal antibody shows reactivity with Hodgkin’s
cells and B lymphocytes in frozen and paraffin-embedded tissues.
Hematol Oncol 9:103, 1991
32. Stein H, Hansmann M, Lennert K, Brandtzaeg P, Gatter K,
Mason D: Reed-Stemberg and Hodgkin cells in lymphocyte-predominant Hodgkin’s disease of nodular subtype contain J-chain. Am J
Clin Pathol 96:292, 1986
33. Pinkus G, Said J: Hodgkin’s disease, lymphocyte predominance type, nodular-further evidence for a B cell derivation. Am J
Pathol 133:211, 1988
34. Timens W, Visser L, Poppema S: Nodular subtype predominance type of Hodgkin’s disease is a germinal center lymphoma.
Lab Invest 54:457, 1986
35. Carbone A, Manconi R, Poletti A, Sulfaro S, Menin A, Tirelli
U, Betta P, Volpe R: Reed-Sternberg cells and their cell microenvironment in Hodgkin’s disease with reference to macrophage-histiocytes and interdigitating reticulum cells. Cancer 60:2662, 1987
36. Beckstead J, Warnke R, Bainton D: Histochemistry of Hodgkin’s disease. Cancer Treat Rep 66:609, 1982
37. Hsu S, Jaffe E: Leu M1 and peanut agglutinin stain the neoplastic cells of Hodgkin’s disease. Am J Clin Pathol 82:29, 1984
38. Pinkus G, Thomas P, Said J: Leu MI-A marker for ReedStemberg cells in Hodgkin’s disease. Am J Clin Pathol 119:242,
1985
39. Strauchen J, Breakstone B: LeuM1 antigen: Comparitive
expression in Hodgkm’s disease and T-cell lymphoma. Hematol
Oncol 5x107, 1987
40. Wieczorek R, Burke J, Knowles D 111: Leu-M1 antigen expression in T-cell neoplasia. Am J Pathol 121:374, 1985
41. Sheibani K, Battifora H, Burke J, Rappaport H: Leu-M1 antigen in human neoplasms: An immunohistologic study of 400 cases.
Am J Surg Path01 10:227, 1986
42. Ree H, Neiman R, Martin A, Dallenbach F, Stein H: Paraffin
section markers for Reed-Sternberg cells. A comparative study of
peanut agglutinin, Leu M1, LN-2 and Ber-H2. Cancer 63:2030, 1989
From www.bloodjournal.org by guest on August 9, 2017. For personal use only.
1014
43. Pinkus G, Said J: Leu M1 immunoreactivity in nonhematopoetic neoplasms and myeolproliferative disorders. Am J Clin Pathol
85:278, 1986
44. Trumper LH, Brady G, Vicini S, Cossman J, Mak T W : Gene
expression in single Reed Sternberg cells of Hodgkin’s disease:
Results from PCR generated single cell cDNA libraries. Ann Oncol
4:25, 1992
45. Trumper LH, Brady G, Bagg A, Gray D, Loke SL, Griesser
H, Wagman R, Braziel R, Gascoyne RD, Vicini S , Iscove NN,
Cossman J, Mak TW: Single-cell analysis of Hodgkin and ReedSternberg cells: Molecular heterogeneity of gene expression and p53
mutations. Blood 81:3097, 1993
46. Stein H, Mason D, Gerdes J, O’Connor N. Wainscoat J, Pallesen G, Gatter K, Falini B, Delsol G, Lemke H, Schwarting R,
Lennert K: The expression of the Hodgkm’s disease associated antigen Ki-l in reactive and neoplastic lymphoid tissue: Evidence that
Reed-sternberg cells and histiocytic malignancies are derived from
activated lymphoid cells. Blood 665348, 1985
47. Andreesen R, Osterholz J, Lohr G, Bross K: A Hodgkin cellspecific antigen is expressed on a subset of auto- and alloactivated
T (helper) lymphoblasts. Blood 63:1299, 1984
48.Kadin M: Histogenesis of Hodgkin’s disease: Possible insights from a comparison with lymphomatoid papulosis. Hum Pathol
118:1085, 1987
49. Davis TH, Morton CC, Miller-Cassman R, Balk SP, Kadin
ME: Hodgkin’s disease, lymphomatoid papulosis, and cutaneous Tcell lymphoma derived from a common T-cell clone. N Engl J Med
326:1115, 1992
50. Kadin M, Sako D, Berliner N, Franklin W, Woda B, Borowitz
M, Ireland K, Schweid A, Herzog P, Lange B, Dorfman R: Childhood Ki-l lymphoma presenting with skin lesions and peripheral
adenopathy. Blood 68:848, 1986
51. Kadin M: Ki-l positive anaplastic large cell lymphoma: A
clinicopathological entity? J Clin Oncol 9:533, 1991
52. Greer J, Kinney M, Collins R, Salhany K, Wolff S , Hainsworth J, Flexner J, Stein R: Clinical features of 31 patients with KJ1 anaplastic large cell lymphoma. J Clin Oncol 9:539, 1991
53. Schwarting R, Gerdes J, Durkop H, Falini B, Pileri S, Stein
H: Ber-HZ A new anti-Ki-l (CD30) monoclonal antibody directed
at a formol-resistant epitope. Blood 74:1678, 1989
54. Engert A, Burrows F, Jung W, Tazzari P, Stein H,
Pfreundschuh N, Diehl V, Thorpe P: Evaluation of ricin A chaincontaining imunotoxins directed against the CD30 antigen as potential reagents for the treatment of Hodgkin’s disease. Cancer Res
50:84, 1990
55. Andreesen R, Brugger W, Lohr G, Bross K: Human macrophages can express the Hodgkin’s cell associated antigen Ki-l
(CD30). Am J Pathol 134:187, 1989
56. Gause A, Pohl C, Tschiersch A, Da Costa L, Jung W, Diehl
V, Hasenclever D Clinical significance of soluble CD30 antigen in
the sera of patients with untreated Hodgkin’s disease. Blood 77: 1983,
1991
57. Falini B, Bolognesi A, Fleghini L, Tazzari P, Broe M, Stein
H, Durkop H, Aversa F, Corneli P, Pizzolo G, Barbabietola G,
Sabattini E, Pileri S , Martelli M, Stirpe F: Response of refractory
Hodgkin’s disease to monoclonal anti-CD30 immunotoxin. Lancet
339:1195, 1992
58. Falini B, Flenghi L, Fedeli L, Broe MK, Bonino C, Stein H,
Durkop H, Bigema B, Barbabietola G, Venturi S, Aversa F, Pizzolo
G, Bartoli A, Pileri S, Sabatini E: In vivo targeting of Hodgkin
and Reed-Stemberg cells of Hodgkin’s disease with monoclonal
antibody Ber-H2 (CD30): Immunohistological evidence. Br J
Haematol 82:38, 1992
59. Winkler U, Gottstein C, Schon G, Kapp U, Wolf J, Hansmann
HALUSKA, BRUFSKY. AND CANELLOS
ML, Bohlen H, Thorpe P, Diehl V, Engert A: Successful treatment
of disseminated human Hodgkins disease in SCID mice with deglycosylated ricin a-chain immunotoxins. Blood 83:466, 1994
60. Kapp U, Wolf J, Hummel M, Pawlita M, Vonkalle C, Dallenbach F, Schwonzen M, Krueger G, Mullerlantzsch N, Fonatsch C,
Stein H, Diehl V: Hodgkins lymphoma-derived tissue serially transplanted into severe combined immunodeficientmice. Blood 82: 1247,
1993
61. Durkop H, Latza U, Hummel M, Eitelbach F, Seed B, Stein
H: Molecular cloning and expression of a new member of the nerve
growth receptor family that is characteristic for Hodgkin’s disease.
Cell 68:421, 1992
62. Ellis TM, Simms PE, Slivnick DJ, Jack HM, Fisher RI: Cd30
is a signal-transducing molecule that defines a subset of human
activated cd45ro+ T-cells. J Immunol 151:2380, 1993
63. Gerdes J, Van Baarlen J, Pileri S, Schwarting R, Van Unnik
J, Stein H: Tumor cell growth fraction in Hodgkin’s disease. Am J
Pathol 129:390, 1987
64. Strauchen J: Leukocyte common antigen inthe differential
diagnosis of Hodgkin’s disease. Hematol Oncol 7:149, 1989
65. Werner M, Georgii A, Bernhards J, Hubner K, Schwarze E,
Fischer R: Characterization of giant cells in Hodgkin’s lymphoma
by immunohistochemistry applied to randomly collected biopsies
from the German Hodgkin Trial. Hematol Oncol 8:241, 1990
66. Nozawa Y, Wachi E, Tominaga K, Abe M, Wakasa H: A
novel monoclonal antibody (FUN-1) identifies an activation antigen
in cells ofthe B-cell lineage and Reed-Stemberg cells. J Pathol
169:309, 1993
67. Peckham M, Cooper E: Proliferation characteristics ofthe
various classes of cells in Hodgkin’s disease. Cancer 24:135, 1969
68. Kadin M, Astbury A: Long-term cultures of Hodgkin’s tissue.
A morphologic and radio-autographic study. Lab Invest 28: 181, 1973
69. Schmid C, Sweeney E, Isaacson PG: Proliferating cell nuclear
antigen (PCNA) expression inHodgkin’s disease. J Pathol168:1,
1992
70. Hell K, Lorenzen J, Hansmann ML, Fellbaum C, Busch R,
Fischer R: Expression of the proliferating cell nuclear antigen in the
different types of hodgkins disease. Am J Clin Pathol 99:598, 1993
71. Sabattini E, Gerdes J, Gherlinzoni F, Poggi S, Zucchini L,
Melilli G, Grigioni F, Delvecchio MT, Leoncini L, Falini B, Pileri
SA: Comparison between the monoclonal antibodies Ki-67 and pc10
in 125 malignant lymphomas. J Pathol 169:397, 1993
72. Drexler H, Gignac S , Hoffbrand A, Minowada J: Formation
of multinuccleated cells in a Hodgkin’s-disease-derived cell line. Int
J Cancer 43:1083, 1989
73. Angel CA, Cullen RA, Pringle JH, Lauder I: Vimentin expression by Reed-Sternberg cells in Hodgkin’s disease. Virchows Arch
A Pathol Anat Histopathol 421:9, 1992
74. Carbone A, Gloghini A, Zanette I, Canal B, Rizzo A, Volpe
R:CO-expression of Epstein-Barr vims latent membrane protein
and vimentin in “aggressive” histological subtypes of Hodgkin’s
disease. Virchows Arch A Pathol Anat Histopathol 422:39, 1993
75. Bilbe G, Delabie J, Bruggen J, Richener H, Asselbergs FA,
Cerletti N, Sorg C, Odink K, Tarcsay L, Wiesendanger W, DeWolfPeeters C, Shipman R: Restin: A novel intermediate filament-associated protein highly expressed in the Reed-Sternberg cells of Hodgkin’s disease. EMBO J 11:2103, 1992
76. Delabie J, Shipman R, Bruggen J, De Strooper B, van Leuven
F, Tarcsay L, Cerletti N, Odink K, Diehl V, Bilbe G, De WolfPeeters C: Expression of the novel intermediate filament-associated
protein restin in Hodgkin’s disease and anaplastic large-cell
lymphoma. Blood 80:2891, 1992
77. Hilliker C, Delabie J, Speleman F, Bilbe G, Bruggen J, Vanleuven F, Vandenberghe H: Localization of the gene (rsn) coding
From www.bloodjournal.org by guest on August 9, 2017. For personal use only.
CELLULAR BIOLOGY OF THE REED-STERNBERG CELL
for restin, a marker for Reed-Stemberg cells in hodgkins disease, to
human chromosome band 12q24.3 and YAC cloning of the locus.
Cytogenet Cell Genet 65:172, 1994
78. Nowell P, Hungerford D: A minute human chromosome in
human chronic granulocytic leukemia. Science 132:1497, 1960
79. Spriggs A, Boddington M: Chromosomes of Stemberg-Reed
cells. Lancet 2:153, 1962
80. Rowley J: Chromosomes in Hodgkin’s disease. Cancer Treat
Rep 66:639, 1982
81. Teerenhovi L, Lindholm C, Pakkala A, Franssila K, Stein H,
Knuutila S : Unique display of a pathologic karyotype in Hodgkin’s
disease by Reed-Stemberg cells. Cancer Genet Cytogenet 34:305,
1988
82. Reeves B, Pickup V: The chromosome changes in non-Burkitt’s lymphomas. Hum Genet 53:349, 1980
83. Cabanillas F, Pathak S , Trujillo J, Grant G , Cork A, Hagemeister F, Velasquez W, McLaughlin P, Redman J, Katz R, Butler
J, Freireich E: Cytogenetic features of Hodgkin’s disease suggest a
possible origin from a lymphocyte. Blood 71:1615, 1988
84. Schouten H, Sanger W, Duggan M, Weisenberger D, MacLennan K, Armitage 1: Chromosomal abnormalities inHodgkin’s
disease. Blood 73:2149, 1989
85. Tilly H, Bastard C, Delastre T, Duval C, Bizet M, Lenormand
B, Dauce J-P, Monconduit M, Piguet H: Cytogenetic studies in
untreated Hodgkin’s disease. Blood 77:1298, 1991
86. Cabanillas F: A review and interpretation of cytogenetic abnormalities identified in Hodgkin’s disease. Hematol Oncol 6:271,
1988
87. Poppema S , Kaleta J, Hepperle B: Chromosomal abnormalities in patients with Hodgkin’s disease: Evidence for frequent
involvement of the 14q chromosomal region but infrequent bcl-2
gene rearrangement in Reed-Stemberg cells. J Natl Cancer Inst
84:1789, 1992
88. Lorenzen J, Hansmann ML, Pezzella F, Hesse C, Kneba M,
Gatter KC, Fischer R: Expression of the bcl-2 oncogene product
and chromosomal translocation t(14; 18) in Hodgkin’s disease. Hum
Pathol 23: 1205, 1992
89. Tonegawa S : Somatic generation of antibody diversity. Nature 302:57, 1983
90. Minden M, Mak T The structure of the T-cell antigen receptor genes in normal and malignant T cells. Blood 68:327, 1986
91. Rabbitts T, Stinson A, Forster A, Eoroni L, Luzzato L, Catovsky D, Hammarstrom L, Smith C, Jones D, Karpas A, Minowada J,
Taylor A: Heterogeneity of T-cell B-chain gene rearrangements in
human leukemias and lymphomas. EMBO J 4:2217, 1985
92. Weiss L, Warnke R, Sklar J: Clonal antigen receptor gene
rearrangements and Epstein-Barr viral DNA in tissues of Hodgkin’s
disease. Hematol Oncol 6:233, 1988
93. O’Connor N, Crick J, Gatter K, Mason D, Falini B, Stein H:
Cell lineage in Hodgkin’s disease. Lancet 1:158, 1987
94. Griesser H, Feller A, Lennert K, Minden M, Mak T: Clonal
rearrangements of T-cell receptor and immunoglobulin antigen expression in different subclasses of Hodgkin’s disease. Int J Cancer
40157, 1987
95. Raghavachar A, Blinder T, Bartram C: Immunoglobulin and
T-cell receptor gene rearrangements in Hodgkin’s disease. Cancer
Res 48:3591, 1988
96. Griesser H, Mak T: Immunogenotyping in Hodgkin’s disease.
Hematol Oncol 6:239, 1988
97. Griesser H, Feller A, Lennert K, Minden M, Mak T: Rearrangement of the B chain of the T cell antigen receptor and immunoglobulin genes in lymphoproliferative disorders. J Clin Invest
78: 1 179, 1986
98. Knowles DMI, Neri A, Pelicii PG, Burke JS, Wu A, Winberg
1015
CD, Sheibani K, Dalla-Favera R: Immunoglobulin and T-cell receptor B-chain rearrangement analysis of Hodgkin’s disease: fmplications for lineage determination and differential diagnosis. Proc Natl
Acad Sci USA 83:7942, 1986
99. Roth MS, Schnitzer B, Bingham EL, Hamden CE, Hyder
DM, Ginsburg D Rearrangement of immunoglobulin and T-cell
receptor genes in Hodgkin’s disease. Am J Clin Path01 131:331,
1988
100. Sundeen J, Lipford E, Uppenkamp M, Sussman E, Wahl L,
Raffeld M, Cossman J: Rearranged antigen receptor genes in Hodgkin’s disease. Blood 70:96, 1987
101. Cossman J, Sundeen J, Uppenkamp M, Sussman E, Wahl
L, Coupland R, Lipford E, Raffeld M: Rearranging antigen-receptor
genes in enriched Reed-Stemberg cell fractions of Hodgkin’s disease. Hematol Oncol 6:205, 1988
102. Fenoglio-Prieser CM, Willman CL: Molecular biology and
the pathologist. General principles and applications. Arch PatholLab
Med 3:601, 1987
103. Knecht H, Joske DJ, Emery GA, Bachmann E, Bachmann F,
Odermatt BF: Expression of human recombination activating genes
(RAG-l and RAG-2) in Hodgkin’s disease. Blood 80:2867, 1992
104. Stetler-Stevenson M, Crush-Stanton S , Cossman J: Involvement of the bcl-2 gene in Hodgkin’s disease. J Natl Cancer Inst
82:855, 1990
105. Gupta RK, Whelan JS, Lister TA, Young BD, Bodmer JG:
Direct sequence analysis of the t(14; 18) chromosomal translocation
in Hodgkin’s disease. Blood 79:2084, 1992
106. Reid AH, Cunningham RE, Frizzera G, OLeary TJ: bcl-2
rearrangement in Hodgkin’s disease. Results of polymerase chain
reaction, flow cytometry, and sequencing on formalin-fixed, paraffinembedded tissue. Am J Pathol 142:395, 1993
107.Lebrun DP, Ngan BY, Weiss LM, Huie P, Warnke RA,
Cleary ML: The bcl-2 oncogene in Hodgkin’s disease arising in the
setting of follicular non-Hodgkins lymphoma. Blood 83:223, 1994
108. Shibata D, Hu E, Weiss LM, Brynes RK, Nathwani BN:
Detection of specific t(14; 18) chromosomal translocations in fixed
tissues. Hum Pathol 21:199, 1990
109. Said H, Sassoon A, Shintaku I, Kurtin PJ, Pinkus GS: Absence of bcl-2 major breakpoint region and JH gene rearrangement
in lymphocyte predominance Hodgkin’s disease: Results of Southern
blot analysis and polymerase chain reaction. Am J Pathol 138:261,
1991
110. Louie DC, Kant JA, Brooks JJ, ReedJC: Absence of
t(14; 18) major and minor breakpoints and of bcl-2 protein overproduction in Reed-Stemberg cells of Hodgkin’s disease. Am J Pathol
139:1231, 1991
11l. Athan E, Chadbum A, Knowles DM: The bcl-2 gene translocation is undetectable in Hodgkin’s disease by Southern blot hybridization and polymerase chain reaction. Am J Pathol 141:193, 1992
112. Mitani S , Sugawara I, Shiku H, Mori S : Expression of cmyc oncogene product and ras family oncogene products in various
human malignant lymphomas defined by immunohistochemicaltechniques. Cancer 62:2085, 1988
113. Sklar M, Kitchingman G: Isolation of activated ras transforming genes from two patients with Hodgkin’s disease. Int J Radiat
Oncol Biol Phys 11:49, 1985
114. Steenvorden A, Janssen J, Drexler H, Lyons J, Tesch H,
Binder T, Jones D, Bartram C: Ras mutations in Hodgkin’s disease.
Leukemia 2:325, 1988
115. Jucker M, Schaadt M, Diehl V, Poppema S , Jones D, Tesch
H: Heterogeneous expression of proto-oncogenes in Hodgkin’s disease derived cell lines. Hematol Oncol 8:191, 1990
116. Gupta RK, Norton A J , Thompson W ,Lister TA, Bodmer
From www.bloodjournal.org by guest on August 9, 2017. For personal use only.
1016
JG: p53 expression in Reed-Stemberg cells of Hodgkin’s disease.
Br J Cancer 66549, 1992
117. Doussis IA, Pezzella F, Lane DP, Gatter KC, Phil D, Mason
DY: An immunocytochemical study of p53 and bcl-2 protein expression in Hodgkin’s disease. Am J Clin Pathol 99:663, 1993
118. Gupta RK, Patel K, Bodmer WF, Bodmer JG: Mutation of
p53 in primary biopsy material and cell lines from Hodgkin disease.
Proc Natl Acad Sci USA 90:2817, 1993
119. Cesarman E, Inghirami G, Chadbum A, Knowles DM: High
levels of p53 protein expression do not correlate with p53 gene
mutations in anaplastic large cell lymphoma. Am J Pathol 143~845,
1993
120. Sitar G, Brusamolino E, Bemasconi C, Ascari E: Isolation
of Reed-Stemberg cells from lymph nodes of Hodgkin’s disease
patients. Blood 73:222, 1989
121. Pretlow T, Luberoff D, Hamilton L, Weinberger P, Maddox
W, Durant J: Pathogenesis of Hodgkin’s disease: Separation and
culture of different kinds of cells from Hodgkin’s disease in a sterile
isokinetic gradient of Ficoll in tissue culture medium. Cancer
31:1120, 1973
122. Wilson J, Zaremba J, Pretlow T: Functional characterization
of cells separated from suspensions of Hodgkin’s disease tumor cells
in an isokinetic gradient. Blood 50:783, 1977
123. McGuire R, Pretlow T 11, Waering T, Bradley JEL: Hodgkin’s cells and attached lymphocytes. A possible prognostic indicator
in splenic tumor. Cancer 44:183, 1979
124. Sitar G, Brusamolino E, Scivetti P, Borroni R: The disaggregation of Hodgkin’s lymph node: A preparative technique using a
new dissociation chamber. Haematologica 72:23, 1987
125. Schaadt N. Diehl V, Stein H, Fonatsch C, Kmhner H: Two
neoplastic cell lines with unique features derived from Hodgkin’s
disease. Int J Cancer 26:723, 1980
126. Diehl V, Kirchner H, Burrichte RH, Stein H, Fonatsch C,
Gerdes J, Schaadt M, Heit W, Uchanska-Ziegler B, Ziegler A, Heintz
F, Sueno K: Characteristics of Hodgkin’s disease-derived cell lines.
Cancer Treat Rep 66:615, 1982
127. Poppema S, De Jong B, Atmosoerodjo J, Idenburg V, Visser
L,DeLeyL:
Morphologic, immunologic, enzyme, histochemical,
and chromosomal analysis of a cell line derived from Hodgkin’s
disease. Cancer 55:683, 1985
128. Jones D, Scott C, Wright D, Stein H, Beverly P, Payne S,
Crawford D: Phenotypic analysis of an established cell line derived
from a patient with Hodgkin’s disease. Hematol Oncol 3:133, 1985
129. Kamesaki H, Fukuhara S, Tatsumi E, Uchino H, Yamabe
H, Shirakawa S, Hatanaka N, Honjo T: Cytochemical, immunologic,
chromosomal and molecular genetic analysis of a novel cell line
derived from Hodgkin’s disease. Blood 68:285, 1986
130. Drexler H, Gaedicke G, Lok M, Diehl V, Minowada J:
Hodgkin’s disease derived cell lines HDLM-2 and L-428: Comparison of morphology, immunological and isoenzyme profiles. Leuk
Res 10:487, 1986
I3 1. Poppema S, Visser L, De Jong B, Brinker M, Atmosoerodjo
J, Timens W: The typical Reed-Stemberg phenotype and Ig gene
rearrangement of Hodgkin’s disease derived cell line ZO indicates
a B-cell origin. Recent Results Cancer Res 117:67, 1989
132. Jones D, Furley A, Gerdes J, Greaves M, Stein H, Wright
D: Phenotypic and genotypic analysis of two cell lines derived from
Hodgkin’s disease tissue biopsies. Recent Results Cancer Res
117:62, 1989
133. Naumovski L, Utz P, Bergstrom S, Morgan R, Molina A,
Toole J, Glader B, McFall P, Weiss L, Wamke R, Smith S: SUPHDI: A new Hodgkin’s disease-derived cell line with lymphoid
features produces interferon-y. Blood 74:2733, 1989
134. Drexler H, Leber B, Norton J, Yaxley J, Tatsumi E, Hoff-
HALUSKA, BRUFSKY, AND CANELLOS
brand A, Minowada J: Genotypes and immunophenotypes of Hodgkin’s disease-derived cell lines. Leukemia 2:371, 1988
135. Athan E, Paietta E, Papenhausen P, Augenlicht L, Wiernik
P, Gallagher R: Stability of multiple antigen receptor gene rearrangements and immunophenotype in Hodgkin’s disease-derived
cell line L428 and variant subline L428KSA. Leukemia 3:505, 1989
136. Falk M, Tesch H, Stein H, Diehl V, Jones D, Fonatsch C,
Bomkamm G: Phenotype versus immunoglobulin and T-cell receptor genotype of Hodgkin-derived cell lines: Activation of immature
lymphoid cells in Hodgkin’s disease. Int J Cancer 40:262, 1987
137. Hellman S, Jaffe E, DeVita JVT: Hodgkin’s disease, in DeVita JVT, Hellman S, Rosenberg S (eds): Cancer: Principles and
Practice of Oncology. Philadelphia, Lippincott, 1989, chapter 49, p
1696
138.Waddell C, Cimo P: Idiopathic thrombocytopenic purpura
occurring in Hodgkin’s disease after splenectomy: A report of two
cases and review of the literature. Am J Hematol 7:381, 1979
139. Mizel S: Interleukin 1 and T cell activation. Immunol Rev
6 3 5 1, 1982
140. Falkoff R, Maraguchi A, Hong J-X, Butler J, Dinarello C,
Fauci A: The effects of interleukin 1 on human B cell activation
and proliferation. J Immunol 13l:801, 1983
141. Schmidt J, Mizel S, Cohen D, Green I: Interleukin 1, a
potential regulator of fibroblast proliferation. J Immunol 128:2177,
1982
142. Murphy P, Simon P, Willoughby W: Endogenous pyrogens
made by rabbit peritoneal exudate cells are identical with lymphocyte
activation factors made by rabbit alveolar macrophages. J Immunol
124:2498, 1980
143.Hsu S-M, Zhao X: Expression of interleukin-] in ReedStemberg cells and neoplastic cells from true histiocytic malignancies. Am J Pathol 125:221, 1986
144. Ford R, Mehta S, Davis F, Maize1A: Growth factors in
Hodgkin’s disease. Cancer Treat Rep 66:633, 1982
145. Hsu S-M,Krupen K, Lachman L: Heterogeneity of interleukin 1 production in cultured Reed-Stemberg cell lines HDLM-l,
HDLM-Id, and K”H2. Am J Pathol 135:33, 1989
146. Gruss H-J, Brach M, Drexler H-G, Bonifer R, Mertelsmann
R, Herrmann F: Expression of cytokine genes, cytokine receptor
genes, and transcription factors in cultured Hodgkin and Reed-Sternberg cells. Cancer Res 52:3353, 1992
147. Xerri L, Birg F, Guigou V, Bouabdallah R, Poizot MI, Hassoun J: In situ expression of the IL-l-alpha and TNF-alpha genes
by Reed-Stemberg cells in Hodgkin’s disease. Int J Cancer 50:689.
1992
148. Matsushuma K, Procopio A, Abe H, Scala G , Ortaldo J,
Oppenheim J: Production of interleulun 1 activity by normal human
peripheral B lymphocytes. J Immunol 135:1132, 1985
149. Ree H, Crowley J, Dinarello C: Anti-interleukin-l reactive
cells in Hodgkin’s disease. Cancer 59:1717, 1987
150. Leonard W, Depper J, Crabtree G, Rudikoff S, Pumphrey
J, Robb R, Kronke M, Svetlik P, Peffer N. Waidmann T, Greene
W: Molecular cloning and expression of cDNAs for the human
interleukin-2 receptor. Nature 3 11 :626, 1984
151. Robb R, Rusk C, Yodoi J, Greene W: Interleukin 2 binding
molecule distinct from the tac protein: Analysis of its role in formation of high affinity receptors. Proc Natl Acad Sci USA 84:2002,
1987
152. Pizzolo G , Chilosi M, Semenzato G, Caligaris-Cappio F,
Fiore-Donati L, Peron G, Janossy G: Immunohistological analysis
of Tac antigen expression in tissues involved by Hodgkin’s disease.
Br J Cancer 50:415, 1984
153. Strauchen J, Breakstone B: IL-2 receptor expression in hu-
From www.bloodjournal.org by guest on August 9, 2017. For personal use only.
CELLULAR BIOLOGY OF THE REED-STERNBERGCELL
man lymphoid lesions: Immunohistochemical study of 166 cases.
Am J Pathol 126506, 1987
154. Sheibani K, Winberg C, Van de Velde S , Blayney D: Distribution of lymphocytes with interleukin-2 receptors (TAC antigens)
in reactive lymphoproliferative processes, Hodgkin’s disease., and
non-Hodgkin’s lymphomas: An immunohistologic study of 300
cases. Am J Path01 127:27, 1987
155. Tesch H, Gunther A, Abts H, Jucker M, Klein S , Krueger
GR, Diehl V: Expression of interleukin-2R alpha and interleukin2R beta in Hodgkin’s disease. Am J Path01 142:1714, 1993
156. Tesch H, Herrmann T, Abts H, Diamantstein T, Diehl V:
High affinity L - 2 receptors on a Hodgkin’s derived cell line. Leuk
Res 14:953, 1990
157. Pizzolo G, Chilosi M, Semanzato G: The soluble interleukin2 receptor in haematological disorders. Br J Haematol67:377, 1987
158. Pizzolo G, Chilosi M, Vinante F, Pazzo F, Lestani M, Perona
G, Benedetti F, Todeschini G, Vincenzi C, Trentin L, Semenzato
G: Soluble interleukin-2 receptors in the serum of patients with
Hodgkin’s disease. Br J Cancer 55:427, 1987
159. Pui C-H, Ip S, Thompson E, Williams J, Brown M, Dodge
R, De Hoyos R, Berard C, Crist W: High serum interleukin-2 receptor levels correlate with a poor prognosis in children with Hodgkm’s
disease. Leukemia 3:481, 1989
160. M e n H, Fliedner A, Orscheschek K, Binder T, Sebald W,
Muller-Hermelink H, Feller A: Cytokine expression in T-cell
lymphomas and Hodgkin’s disease. Am J Pathol 139:1173, 1991
161. Paul W, Ohara J: B-cell stimulatory factor-l/interleukin-4.
AMU Rev Immunol 5:429, 1987
162. Newcom S , Ansari A, Gu L Interleukin-4 is an autocrine
growth factor secreted by the L-428 Reed-Stemberg cell. Blood
79:191, 1992
163. Sanderson C, Campbell H, Young I: Molecular and cellular
biology of eosinophil differentiation factor (interleukin-5) and its
effects on human and mouse B cells. Immunol Rev 102:29, 1988
164. Clutterbuck E, Hirst E, Sanderson C: Human interleukin-S
regulates the production of eosinophils in human bone marrow cultures. Blood 73:1504, 1989
165. Samoszuk M, Nansen L: Detection of interleukin-5 messenger RNA in Reed-Sternberg cells of Hodgkin’s disease with eosinophilia. Blood 75:13, 1990
166. Kishimoto T The biology of interleukin-6. Blood 74: 1, 1989
167. Jucker M, Abts H, Ki W, Schindler R, Merz H, Gunther A,
Von Kalle C, Schaadt M, Diamantstein T, Feller A, Krueger G,
Diehl V,Blankenstein T, Tesch H: Expression of interleukin-6 and
interleukin-6 receptor in Hodgkin’s disease. Blood 77:2413, 1991
168. Foss HD, Herbst H, Oelmann E, Sam01 J, Grebe M, Blankenstein T, Matthes J, Qin ZH, Falini B, Pileri S , Diamantstein T,
Stein H: Lymphotoxin, tumour 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
169. Merz H, Houssiau F, Orscheschek K, Renauld J, Fliedner
A, Herin M, Noel H, Kadin M, Mueller-Hermelink H, Van Snick J,
Feller A: Interleukin-9 expression in human malignant lymphomas:
Unique association with Hodgkin’s disease and large cell anaplastic
lymphoma. Blood 78:1311, 1991
170. Gruss H-J, Brach M, Drexler H-G, Bross K, Hemnann F
Interleukin 9 is expressed by primary and cultured Hodglun and
Reed-Sternberg cells. Cancer Res 52:1026, 1992
171. Schmitt E, Van Brandwijk R, Van Snick J, Siebold B, Rude
E: TCGF III/P@ is produced by naive murine CD4+ T cells but is
not a general T cell growth factor. Eur J Immunol 19:2167, 1989
172. Cottenhove C, Simpson R, Van Snick J: Functional and
structural characterization of p40 a mouse glycoprotein with T-cell
growth factor activity. Proc Natl Acad Sci USA 85:8934, 1988
1017
173. Katay I, Wimitzer U, Burrichter H, Von Kalle C, SchellFrederick E, Diehl V, Schaadt M L428 cells derived from Hodgkin’s
disease produce E-rosette-inhibiting factor. Blood 76:791, 1990
174. Paietta E, Racevskis J, Stanley E, Andreef M, Papenhausen
P, Wiernik P: Expression of the macrophage growth factor, CSF-l
and its receptor c-fms by a Hodgkm’s disease-derived cell line and
its variants. Cancer Res 50:2049, 1990
175. Byme P, Heit W, March C: Human granulocyte-macrophage
colony-stimulating factor purified from a Hodgkin’s tumor cell line.
Biochim Biophys Acta 874:266, 1986
176. Newcom S , Muth L, Parker E: Production of monoclonal
antibodies that detect Hodgkin’s high molecular weight transforming
growth factor-B. Blood 75:2434, 1990
177. Hsu SM, Lin J, Xie S S , Hsu PL, Rich S : Abundant expression of transforming growth factor-beta 1 and -beta 2 by Hodgkin’s
Reed-Stemberg cells and by reactive T lymphocytes in Hodgkin’s
disease. Hum Path01 24:249, 1993
178. Kadin M, Agnarrson B, Ellingsworth L, Newcom S R Immunohistochemical evidence of arole for transforming growth factor
beta in the pathogenesis of nodular sclerosing Hodgkin’s disease.
Am J Pathol 1361209, 1990
179. Ruco L, Pomponi D, Pigott R, Stoppacciaro A, Monardo F,
Uccini S , Boraschi D, Tagliabue A, Santoni A, Dejana E, Mantovani
A, Baroni CD: Cytokine production ( L - l alpha, L-l beta, and TNF
alpha) and endothelial cell activation (ELAM-l and HLA-DR) in
reactive lymphadenitis, Hodgkin’s disease, and in non-Hodgkin’s
lymphomas. Am J Pathol 137:1163, 1990
180. Kretschmer C, Jones D, Morrison K, Schluter C, Feist W,
Ulmer AJ, Arnold J, Matthes J, Diamantstein T, Flad H-D, Gerdes
J: Tumor necrosis factor alpha and lymphotoxin production in Hodgkin’s disease. Am J Path01 137:341, 1990
181. Sappino A, Seelentag W, Peke M, Albert0 P, Vassalli P:
Tumor necrosis factodcachectin and lymphotoxin gene expression
in lymph nodes from lymphoma patients. Blood 75:958, 1990
182. MacMahon B: Epidemiology of Hodgkin’s disease. Cancer
Res 26:1189, 1966
183. Gutensohn N, Cole P Epidemiology of Hodgkin’s disease.
Semin Oncol 7:92, 1980
184. Gutensohn N, Cole P Childhood social environment and
Hodgkin’s disease. N Engl J Med 304:155, 1981
185. Evans A, Gutensohn N:A population-based case-control
study of EBV and other viral antibodies among persons with Hodgkin’s disease and their siblings. Int J Cancer 34:149, 1984
186. Gledhill S , Gallagher A, Jones D, Krajewski A, Alexander
F, Klee E, Wright D, O’Brien C, Onions D, Jarrett R: Viral involvement in Hodgkin’s disease: Detection of clonal type A Epstein-Barr
virus genomes in tumour samples. Br J Cancer 64:227, 1991
187. Torelli G, Marasca R, Luppi M, Selleri L, Ferrari S , Nami
F, Mariano M, Federico M, Ceccherini-Nelli L, Bendinelli G, Montorsi M, Artusi T: Human herpesvirus-6 in human lymphomas: Identification of specific sequences in Hodgkin’s lymphomas by polymerase chain reaction. Blood 77:2251, 1991
188. Miller R, Beebe G: Infectious mononucleosis and the empirical risk of cancer. J Nat Cancer Inst 50:315, 1973
189. Connelly R, Christine B: A cohort study of cancer following
infectious mononucleosis. Cancer Res 34:1172, 1974
190. Rosdahl N, Larsen S, Clemmensen J: Hodgkin’s disease in
patients with infectious mononucleosis: 30 years’ experience. Br
Med J 2:253, 1974
191. Carter C, Brown T, Herbert J, Heath C: Cancer incidence
following infectious mononucleosis. Am J Epidemiol 105:30, 1977
192. Munoz N, Davidson R, Witthoff B, Ericsson J, De The G:
Infectious mononucleosis and Hodgkin’s disease. Int J Cancer 22:10,
1978
From www.bloodjournal.org by guest on August 9, 2017. For personal use only.
1018
193. Kvaale G, Hoiby E, Pederson E Hodgkin’s disease in patients with previous infectious mononucleosis. Int J Cancer 23:593,
1979
194. Johansson B, Klein G, Henle W, Henle G: Epstein-Barr
virus (EBV) associated antibody patterns in malignant lymphoma
and leukemia. I. Hodgkin’s disease. Int J Cancer 6:450, 1970
195. Levine P, Ablashi D, Berard C, Carbone P, Waggoner D,
Malam L: Elevated antibody titers to Epstein-Barr virus in Hodgkin’s
disease. Cancer 27:416, 1971
196. DeSchryver A, Klein G, Henle G, Henle W, Cameron H,
Santesson L, Clifford P EB-virus associated serology in malignant
disease: Antibody levels to viral capsid antigens (VCA), membrane
antigens (MA), and early antigens (EA) in patients with various
neoplastic conditions. lnt J Cancer 9:353, 1972
197. Mueller N, Evans A, Hanis N, Comstock G, Jellum E, Magnus K, Orentreich N, Folk B, Vogelman J: Hodgkin’s disease and
Epstein-Barr virus: Altered antibody patterns before diagnosis. N
Engl J Med 320:689, 1989
198. Poppema S , van Imhoff G, Torensma R, Smit J: Lymphadenopathy morphologically consistent with Hodgkin’s disease associated with Epstein-Barr virus infection. Am J Clin Pathol 84:385,
1985
199. Pallesen G , Hamilton-Dutoit S, Rowe M, Youn L: Expression of Epstein-Barr virus latent gene products in tumour cells of
Hodgkin’s disease. Lancet 1:337, 1991
200. Herbst H, Dallenbach F, Hummel M, Niedobitek G, Pileri
S, Muller-Lantzsch N, Stein H: Epstein-Barr virus latent membrane
protein expression in Hodgkin and Reed-Stemberg cells. Proc Natl
Acad Sci USA 88:4766, 1991
201. Pallesen G, Sandvej K, Hamilton-Dutoit S, Rowe M, Young
L: Activation of Epstein-Barr virus replication in Hodgkin and ReedSternberg cells. Blood 78:1162, 1991
202. Herbst H, Steinbrecher E, Niedobitek G, Young L, Brooks
L, Muller-Lantzsch N, Stein H Distribution and phenotype of Epstein-Barr virus-harboring cells in Hodgkin’s disease. Blood 80:484,
1992
203. Weiss L, Strickler J, Wamke R, Purtillo D, SMar J: EpsteinBarr viral DNA in tissues of Hodgkin’s disease. Am J Pathol 129:86,
1987
204. Weiss L, Movahed L, Warnke R, Sklar I: Detection of Epstein-Barr viral genomes in Reed-Stemberg cells of Hodgkin’s disease. N Engl J Med 320502, 1989
205. Anagnostopoulos l, Herbst H, Niedobitek G, Stein H: Demonstration of monoclonal EBV genomes in Hodgkin’s disease and
Ki-l positive anaplastic large cell lymphoma by combined Southern
blot and in situ hybridization. Blood 74:810, 1989
206. Staal S, Ambinder R, Beschomer W, Hayward G, Mann R:
A survey of Epstein-Barr virus DNA in lymphoid tissue. Am J Clin
Pathol 91:1, 1989
207. Uccini S , Monardo F, Stoppacciaro A, Gradilone A, Agliano
A, Faggioni A, Manzari V, Vag0 L, Costanzi G, Rugo L, Baroni C:
High frequency of Epstein-Barr virus genome detection in Hodgkin’s
disease of HIV-positive patients. Int J Cancer 46581, 1990
208. Bignon Y-J, Bernard D, Cure H, Fonck Y, Pauchard J, Travade P, Legros M, Dastugue B, Plagne R: Detection of Epstein-Barr
viral genomes in lymph nodes of Hodgkin’s disease patients. Mol
Carcinog 3:9, 1990
209. Herbst H, Niedobitek G, KnebaM, Hummel M,Finn T,
Anagnostopoulos I, Bergholz M, Krieger G, Stein H: High incidence
of Epstein-Barr virus genomes in Hodgkin’s disease. Am J Pathol
137:13, 1990
210. Knecht H, Odermatt B, Bachmann E, Texeira S, Sahli R,
Hayoz D, Heitz P, Bachmann F Frequent detection of Epstein-Barr
virus DNA by thepolymerase chain reaction in lymph node biopsies
HALUSKA, BRUFSKY, AND CANELLOS
from patients with Hodgkin’s disease without genomic evidence of
B- of T-cell clonality. Blood 78:760, 1991
21 1. Brocksmith D, Angel C, Pnngle I, Lauder I: Epstein-Barr
viral DNA in Hodgkin’s disease: Amplification and detection using
polymerase chain reaction. J Pathol 1651 I , 1991
212. Stein H, Herbst H, Anagnostopoulos I, Niedobitek G, Dallenbach F, Kratzsch H-C: The nature of Hodgkin and Reed-Stemberg
cells, their association with EBV, and their relationship to anaplastic
large cell lymphoma. Ann Oncol 2:33, 1991 (suppl 2)
213. Wright C, Reid A, Tsai M, Venter K, Murari P, Frizzera G,
O’Leary T: Detection of Epstein-Barr virus sequences in Hodgkin’s
disease by the polymerase chain reaction. Am J Pathol 139:393,
1991
214. Weiss L, Chen Y, Liu X, Shibata D: Epstein-Barr virus and
Hodgkin’s disease. A correlative in situ hybridization and polymerase chain reaction study. Am J Pathol 139:1259, 1991
215. Brousset P, Chittal S, Schlaifer D, kart J, Payen C, RigalHuguet F, Voigt J-J, Delsol G: Detection of Epstein-Barr virus messenger RNA in Reed-Stemberg cells of Hodgkin’s disease by in
situ hybridization with biotinylated probes on specially processed
modified acetone methyl benzoate xylene (ModAMeX) sections.
Blood 77:1781, 1991
216. Wu T-C, Mann R, Charache P, Hayward D, Staal S, Lambe
B, Ambinder R Detection of EBV gene expression in Reed-Stemberg cells of Hodgkin’s disease. lnt J Cancer 462301, 1990
217. Hennessy K, Fennewald S, Hummel M, Cole T, Kieff E: A
membrane protein encoded by Epstein-Barr virus in latent growth
transforming infection. Proc Natl Acad Sci USA 81:7207, 1984
2 18. Wang D, Liebowitz D, Kieff E: An EBV membrane protein
expressed in immortalized lymphocytes transforms established rodent cells. Cell 43:831, 1985
219. Henderson S, Rowe M, Gregory C, Croom-Carter D, Wang
F, Longnecker R, Kieff E, Bickinson A: Induction of bcl-2 expression by Epstein-Barr virus latent membrane protein 1 protects infected B cells from programmed cell death. Cell 65: 1107, 1991
220. Fincke J, Fritzen R, Temes P, Trivedi P, Bross K, Lange
W, Mertelsmann R, Dolken G: Expression of bcl-2 in Burkitt’s
lymphoma cell lines: Induction by latent Epstein-Barr virus genes.
Blood 80:459, 1992
221. Bhagat SK, Medeiros LJ, Weiss LM, Wang J, Raffeld M,
Stetler-Stevenson M: bcl-2 expression in Hodgkin’s disease. Correlation with the t(14; 18) translocation and Epstein-Barr virus. Am J
Clin Pathol 99:604, 1993
222. Khan G, Gupta RK, Coates PJ, Slavin G: Epstein-barr virus
infection and bcl-2 proto-oncogene expression-Separate events in
the pathogenesis of Hodgkin’s disease. Am J Path01 143:1270, 1993
223. Amstrong AA, Gallagher A, Krajewski AS, Jones DB, Wilkins BS, Onions DE, Jarrett RF. The expression of the EBV latent
membrane protein (LMP-l) is independent of CD23 and bcl-2 in
Reed-Stemberg cells in Hodgkin’s disease. Histopathology 21:72,
1992
224. Jiwa NM, Kanavaros P, van der Valk P, Walboomers JM,
Horstman A, Vos W, Mullink H, Meijer CJ: Expression of c-myc
and bcl-2 oncogene products in Reed-Stemberg cells independent
of presence of Epstein-Barr virus. J Clin Pathol 46:211, 1993
225. Raab-Traub N, Flynn K The structure of the termini of the
Epstein-Barr virus as a marker of clonal cellular proliferation. Cell
47383, 1986
226. Chang KL, Albujar PF, Chen YY, Johnson R M , Weiss LM:
High prevalence of Epstein-Barr virus in the Reed-Stemberg cells
of Hodgkin’s disease occurring in Peru. Blood 81:496, 1993
227. Fingeroth J, Weis J, Tedder T, Strominger J, Biro P, Fearon
D: Epstein-Barr virus receptor of human B lymphocytes is the C3d
receptor CR2. Proc Natl Acad Sci USA 81:4510, 1984
From www.bloodjournal.org by guest on August 9, 2017. For personal use only.
CELLULAR BIOLOGY OF THE REED-STERNBERG CELL
228. Kikuta H, Taguchi Y, Tomizawa K, Kojima K, Kawamura
N, Ishikaza A, Sakiyama Y, Matsumoto S, Imai S , Kinoshita T:
Epstein-Barr virus genome-positive T lymphocytes in a boy with
chronic active EBV infection associated with Kawasaki-like disease.
Nature 333:455, 1988
229. Jones J, Shurim S , Abramowsky C, Tubbs R, Sciotto C,
Wahl R, Sands J, Gottman D, Katz B, Sklar T T cell lymphomas
containing Epstein-Barr viral DNA in patients with chronic EpsteinBarr virus infections. N Engl J Med 318:733, 1988
230. Harabuchi Y, Yamanaka N, Kataura A, Imai S , Knoshita T,
Mizuno F, Osato T: Epstein-Barr virus in nasal T-cell lymphomas
in patients with lethal midline granuloma. Lancet 335:128, 1990
231. Klein G: Viral latency and transformation: The strategy of
Epstein-Barr virus. Cell 5 8 5 , 1989
232. Klein G: The Epstein-Barr virus-canying cells in Hodgkin’s
disease. Blood 80:299, 1992
233. Willemze R, Scheffer E, Van Vloten W, Meijer C Lymphomatoid papulosis and Hodgkin’s disease: Are they related? Arch
Dermatol Res 275:159, 1983
234. Kadin M: Common activated helper-T cell origin for lymphomatoid papulosis, mycosis fungoides, and some types of Hodgkin’s disease. Lancet 2:864, 1985
235. Weiss L, Wood G, Trela M, Wamke R, Sklar J: Clonal Tcell populations in lymphomatoid papulosis: Evidence of a lymphoproliferative origin for a clinically benign disease. N Engl J Med
315:475, 1986
236. Kadin M, Vonderheid E, Sako D, Clayton L, Olbricht S :
Clonal composition ofT cells in lymphomatoid papulosis. Am J
Path01 126:13, 1987
237. Kadin M, Nasu K, Sako D, Said J, Vonderheid E: Lymphomatoid papulosis: A cutaneous proliferation of activated helper T
cells expressing Hodgkin’s disease-associated antigens. Am J Path01
119:315, 1985
238. Slater D: Epstein-Barr virus: An aetiological factor in cutaneous lymphoproliferative disorders? J Path01 165:1, 1991
239. Haluska F, Tsujimoto Y, Croce C: Oncogene activation by
1019
chromosome translocation in human malignancy. Annu Rev Genet
21:321, 1987
240. Klein G, Klein E: Evolution of tumors and the impact of
molecular oncology. Nature 315:190, 1985
241. Whittle H, Brown J, Marsh K, Greenwood B, Seidelin P,
Tighe H, Wedderburn L T-cell control of Epstein-Barr virus-infected B cells is lost during P. fakipancm malaria. Nature 312449,
1984
242. Haluska F, Finver S , Tsujimoto Y, Croce C: The t(8;14)
chromosomal translocation occurring in B-cell malignancies results
from mistakes in V-D-J joining. Nature 324:158, 1986
243. Robison L, Mertene A, Frizzera G: Lymphoproliferative disorders associated with immunodeficiency, in Magrath I (ed): The
Non-Hodgkin’s Lymphomas. London, UK, Edward Arnold, 1990,
chapter 9, p 135
244. Ziegler J, Beckstead J, Volberding P,Abrams D, Levine A,
Lukes R, Burkes R, Meyer P, Metrola C, Mouradian J, Moore A,
Riggs S, Butler J, Cabanillas F, Hersh E, Newel1 G, Laubenstein L,
Knowles D, Odajnyk C, Raphael B, Koziner B, Urmacher C,
Clarkson B: Non-Hodglun’s lymphoma in 90 homosexual men. Relation to generalized lymphadenopathy and the acquired immunodeficiency syndrome. N Engl J Med 311:565, 1984
245. Aisenberg AC, Wilkes BM, Jacobson JO: The bcl-2 gene is
rearranged in many diffuse B-cell lymphomas. Blood 71:969, 1988
246. Gauwerky C, Haluska F, Tsujimoto Y, Nowell P, Croce C:
Evolution of B-cell malignancy: Pre-B-cell leukemia resulting from
MYC activation in a B-cell neoplasm with a rearranged BCL2 gene.
Proc Natl Acad Sci USA 85:8548, 1988
247. Hessol N, Katz M, Kiu J, Buchbinder S , Rubino C, Holmberg S : Increased incidence of Hodgkin disease in homosexual men
with HIV infection. Ann Intern Med 117:309, 1992
248. Gamier G, Michiels J: HIV associated Hodgkin disease. Ann
Intern Med 115:233, 1991
249. Herndier BG, Sanchez HC, Chang KL, Chen YY, Weiss
LM: High prevalence of Epstein-Barr virus in the Reed-Stemberg
cells of HIV-associated Hodgkin’s disease. Am J Path01 142:1073,
1993
From www.bloodjournal.org by guest on August 9, 2017. 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.