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NEOPLASIA
From the Institute of Pathology, Klinikum Benjamin
Franklin, Free University Berlin, Berlin, Germany; Senkenbergisches
Center for Pathology, University of Frankfurt, Frankfurt, Germany;
Department of Pathology, Helsinki University Central Hospital,
Helsinki, Finland; Department of Pathology, Christie Hospital,
Manchester, England; Department of Pathology, Massachusetts General
Hospital, Boston MA; National Cancer Institute, Bethesda, MD;
Department of Pathology, University Medical Center, Nijmegen, The
Netherlands; Department of Pathology Faculty of Medical Sciences,
University of Groningen, Groningen, The Netherlands; and the First
Clinic for Internal Medicine, University of Cologne, Cologne, Germany.
Paraffin blocks and clinical data from 521 patients with lymphocyte
predominance Hodgkin disease (LPHD) diagnosed between 1970 and 1994 were collected from 16 European and United States oncological
centers to establish the pathologic and clinical characteristics of a large patient cohort, to determine how frequent T-cell-rich large
B-cell lymphoma (TCRLBCL) is among LPHD, and to find
differential diagnostic criteria distinguishing between the 2 lymphoma
categories. For this purpose, conventionally and immunohistologically
stained sections were reviewed by a panel of hematopathologists. The
diagnosis of LPHD was confirmed in only 219 of the 388 assessable cases (56.5%). This low confirmation rate was due
mainly to the presence of a new variant of classical Hodgkin disease
(CHD), which resembled, in terms of nodular growth and
lymphocyte-richness, nodular LPHD and, in terms of the immunophenotype
of the tumor cells, CHD and was designated nodular
lymphocyte-rich CHD (NLRCHD). The nodules of LRCHD consisted The Rye classification scheme of Hodgkin disease
(HD)1 is based on the concept that the histologic subtypes
represent morphologic variations of a neoplasm in which Hodgkin and
Reed-Sternberg (HRS) cells are embedded in a reactive background,
showing a characteristic cellular composition for each histotype. This
concept remained unquestioned in the many years of its existence,
except for the issue of the relationship of lymphocyte predominance HD
(LPHD) to the other subtypes. LPHD, characterized by a lymphocyte-rich background with admixed histiocytes, was first described by Jackson in
1937 under the term "early HD."2 The observation of a
long, indolent disease course in most cases led Jackson and
Parker3 to designate it in 1944 as "paragranuloma" to
separate it from Hodgkin "granuloma." Rappaport4
distinguished in 1956 a nodular form of paragranuloma and
separated it from follicular lymphoma. In 1966 Lukes and
Butler5 renamed paragranuloma "lymphocytic and/or
histiocytic predominance HD," described a nodular and a diffuse type
and established the term of lymphocytic and histiocytic (L&H) RS-cell
variant for the predominant diagnostic cell.6 At the Rye
symposium, it was decided, for practical reasons, to combine the
nodular and diffuse types of the Lukes and Butler classification into
LPHD.1 In the last decade, a considerable body of evidence
has accumulated establishing that LPHD exhibits features of a B-cell
lymphoma, with a characteristic antigen profile and clinical
behavior.7-19 This was taken into account by the REAL
classification proposal: LPHD was separated as a distinct clinicopathologic entity from the other subtypes of HD, which were
subsumed under the term "classical HD"
(CHD).20,21
The merging of nodular and diffuse LPHD in the Rye classification was
not unanimously accepted by pathologists and oncologists. Unfortunately, the subsequently published studies did not clarify the
issue, as they led to discordant results. This was caused by both the
lack of precise immunophenotypical criteria and the fact that the
clinical studies analyzed cases without consideration of their
immunophenotypic features.22-25 The question of the
existence of diffuse LPHD became more complex when several authors
described a diffuse large B-cell lymphoma variant, the T-cell or
histiocyte-rich large B-cell lymphoma (TCRLBCL), which frequently
simulated the morphology of diffuse LPHD but exhibited a more
aggressive disease course and frequent bone marrow involvement at
presentation.26-35 Furthermore, more recently, 2 additional types of HD with an abundance of lymphocytes were
recognized: (1) a "lymphocyte-rich form of classical HD" included
in the REAL classification, which was thought to have a diffuse growth
pattern in most instances, and (2) "follicular HD," forming
B-cell-rich nodules, which was identified at the lymphoma workshop of
the European Association of Haematopathology in Toledo, Spain, in 1994 and subsequently published by Ashton-Key and colleagues.36
The need to establish widely accepted criteria for the diagnosis of
LPHD and its differentiation from TCRLBCL led H.S. and V.D. to initiate
a multinational study, under the auspices of the European Task Force on
Lymphoma (ETFL). Sixteen oncology centers from Europe and the United
States participated by submitting paraffin blocks and clinical data
from 521 patients who had initially been diagnosed as LPHD according to
the Rye criteria. All submitted samples were immunostained with a broad
array of antibodies and reviewed by a panel of expert
hematopathologists without prior knowledge of the initial diagnosis and
clinical features, and a consensus diagnosis was reached. This study
revealed that the diagnosis of LPHD can be correctly made by
morphologic criteria in only two thirds of the cases. Difficult and
borderline cases, however, require consideration of both the
morphologic features and the immunophenotypical findings. The most
unexpected finding of this combined approach was that the tumor cells
of a large proportion (21%) of the cases submitted under the diagnosis
LPHD had an antigen profile of classical HRS cells and thus represented cases of CHD rather than of LPHD. These cases exhibited a nodular growth pattern. The nodules consisting mainly of IgM+ and
IgD+ B cells frequently contained In this paper we present the morphologic and immunohistologic criteria
developed by the panel that proved the most useful for establishing the
diagnosis of LPHD, LRCHD, and other types of CHD. An extensive report
on clinical presentation, course, and prognostic factors has been
published elsewhere.37
Submitted cases
Histology and immunohistology
In-situ hybridization In-situ hybridization for detection of Epstein-Barr virus (EBV)-encoded small nuclear RNAs (EBERs) was performed as described elsewhere,39 using in vitro transcribed digoxigenin-labeled sense (negative controls) and antisense RNA probes on paraffin sections. Detection of the bound labeled probes was achieved by incubation with a monoclonal digoxigenin-specific antibody conjugated with alkaline phosphatase that was developed afterward using naphtol-as-biphosphate and new fuchsin.Evaluation of submitted cases Each case was evaluated by a panel of pathologists (H.S, M.-L.H, I.A., and T.M.) without knowledge of the submitting diagnosis or the clinical data. As a first step, H&E- and Giemsa-stained slides were assessed for the presence of atypical cells with morphologic features of L&H and RS cells. The number and distribution of these cells, the architecture of the infiltrate as well as the number of epithelioid cells, of eosinophils and neutrophils, and the presence of fibrosis were noted. The panel then proposed a diagnosis based solely on histomorphologic features. The immunostained and in-situ hybridization slides were then reviewed. The immunophenotype of the atypical cells was evaluated as well as the pattern of the meshwork of follicular dendritic cells, the number and distribution of CD3- and CD57-expressing cells within nodular tumor areas, the presence of T-cell rosettes around L&H or RS cells, and the number of small B lymphocytes within nodular structures. All these parameters were considered for establishing a final diagnosis. A large number of cases (approximately 300), comprising all unusual or difficult cases, were reviewed in the same manner in several sessions by an extended panel, including K.F., M.H., N.L.H., E.S.J., J.H.J.M.vK., and S.P.
Excluded cases Of the 521 cases submitted, 86 were initially excluded because of missing clinical data, or the patient's age being less than 15 years. From the remaining 435 cases, 47 were excluded after histologic evaluation, as they were found either to contain too little tissue in the submitted paraffin blocks, making immunophenotypical analysis impossible, or because they represented errors of the submitting centers (eg, the paraffin blocks contained unrelated tissues such as ovaries, skin, lung, or were devoid of any lymphoid infiltrates). The final study was based on 388 cases with complete clinical data and adequate histologic material.Morphology versus immunohistology After screening of the H&E- and Giemsa-stained sections alone, the 388 cases were classified as follows (Figure 1): 248 cases as LPHD, 40 cases as CHD of mixed cellularity (MC) or nodular sclerosis (NS) type, 12 cases as non-Hodgkin lymphomas (NHL), and 12 cases as reactive, usually corresponding to progressively transformed germinal centers. In the remaining 76 cases, no consensus diagnosis could be reached between the panel members. Within the LPHD group, approximately one third of the cases were regarded as not totally typical, as these cases frequently contained neoplastic cells resembling classic RS cells as well as L&H cells. In addition, occasional atrophic germinal centers were encountered within the lymphocyte-rich nodular background, whereas these proved to be absent in the "typical LPHD" cases.
Reevaluation of the cases after the review of immunohistologic slides confirmed the diagnosis of LPHD in 175 cases. The 12 NHL and the 12 reactive cases were also confirmed. Thirty-one cases classified as CHD remained in this category. However, immunophenotyping resulted in the reclassification of following cases: 1. Seventy-three of the cases initially classified as LPHD showed CD30+ and CD15+ neoplastic cells and were reclassified as CHD. Because of the presence of neutrophils and/or eosinophils, 6 of these cases were subtyped as CHD, either of MC type or because of the presence of nodular sclerosing collagen bundles as NS type. The remaining 67 cases exhibited a lymphocyte-rich background infiltrate with a nodular growth pattern. For the classification of these cases, a new term was created, which is "nodular lymphocyte-rich CHD" (NLRCHD). 2. Thirty-five of the 76 cases without morphologic consensus diagnosis
were reclassified after immunophenotyping as LPHD (CD20+,
CD30 3. Nine of 40 cases initially classified as CHD were reclassified as
LPHD after immunostaining (CD20+, CD30 In conclusion, the diagnoses established after morphologic and immunohistologic evaluation showed that 219 cases fulfilled the criteria of LPHD, whereas an additional 134 cases belonged to the category of CHD. The largest group within the CHD cases (115 of 134) was characterized by a lymphocyte-rich background, termed LRCHD. Fourteen additional cases were classified as reactive, 12 cases represented NHL, whereas 9 cases remained unclassified. Cases classified as LPHD Morphology of neoplastic cells.
In all 219 LPHD cases, at least some of the neoplastic cells exhibited
the characteristic morphology of L&H cells with folded and lobated
("popcorn") nuclei and inconspicuous nucleoli (Figure 2A). Mono- and binuleated cells with
large acidophilic nucleoli resembling RS cells of CHD were observed in
120 cases (55%) (Figure 2B). These cells represented only a small
proportion of the neoplastic cells in most (n = 108) cases. They were
frequent in 11 cases, and in one case, they made up the majority of the
neoplastic cell population.
Immunophenotype of the neoplastic cells (Table
3).
CD20 was expressed in 211 cases (Figure 2C, D). Tissue artifacts did
not allow CD20 detection in an additional 3 cases, whereas 5 cases were
negative. Only one of the CD20-negative cases showed a complete absence
of B-cell-related antigens (CD79a, J-chain).
Association with EBV infection. In-situ hybridization for detection of EBER-transcripts was assessable only in 174 cases, as inappropriate tissue fixation did not permit analysis of 45 cases. EBER transcripts were detectable only in 43 of the 174 assessable cases. The labeled cells corresponded to small lymphocytes. Composition of the reactive background.
The background infiltrate in all cases was rich in CD20+ B
cells (Figure 3B). There were rare cases
with a predominant T-cell population in some (Figure 3C) or in the
majority of the nodules. CD3+ cells showed prominent
rosetting around the neoplastic cells in 154 cases (70%).
CD57+ cells were found in all cases, being most prominent
within the nodular structures (Figure 3G). Rosettes composed of
CD57+ cells occurred in 40 cases (18%) (Figure 3H).
Epithelioid cells were present in almost all cases, and were very
prominent in 22 (10%), occasionally forming large aggregates with a
granuloma-like appearance. Neutrophils were completely absent from 165 cases (75%), being solely found within blood vessels. The remaining cases contained only scattered single neutrophils within the background infiltrate. Eosinophils were not observed in any case.
Growth patterns.
The most prominent architectural hallmark was the presence of nodular
structures within the reactive cellular background. By conventional
histology, the usually large nodules were composed of aggregates of
small lymphocytes with slightly irregular hyperchromatic nuclei, thus
simulating expanded primary follicles (Figure 3A). A variable number of
epithelioid cells was admixed with this lymphoid population. Germinal
center cells corresponding to centrocytes and centroblasts were usually
absent from these nodules. Fine and rarely coarse bands of hyalinized
connective tissue were observed in most cases, frequently surrounding
the nodular structures. The nodularity became more evident on
evaluation of the following immunostains (Table
4): (1) labeling for CD20 and CD79a
revealed aggregates of small B cells within the nodules (Figure
3B,C,D), (2) CD21 detection disclosed an extended meshwork of
follicular dendritic cells within the nodules (Figure 3E), which
engulfed the neoplastic cells and the surrounding T-cell rosettes
(Figure 3F), and (3) CD57 detection highlighted a T-cell population
concentrated within the nodular structures (Figure 3G).
Cases classified as lymphocyte-rich classical Hodgkin disease Morphology of the neoplastic cells. At least some mono-, bi-, or multinucleated cells with large, slightly irregularly shaped nuclei and prominent broad, round, or clublike nucleoli, corresponding to classic RS cells were present in 103 of 115 cases (89.5%). In 57 cases (49.5%), these cells were rare, being more prominent in the remaining cases. Mononuclear neoplastic cells with folded nuclei and small nucleoli closely resembling the L&H cells were found in almost all cases (113 of 115; 98%). Such L&H-like cells were rare in 43 cases (37%), whereas they constituted the majority of the neoplastic cell population in 5 cases (4%). Immunophenotype of the neoplastic cells. CD30 expression was found in 107 cases; 2 cases showed complete absence of expression, whereaas the immunostaining in the remaining 6 cases was unsatisfactory, mostly for technical reasons (improper fixation of specimen, section artifacts). Expression of CD15 was detectable in 85 of 115 cases. There was not a single case with absent expression either of CD30 or of CD15 antigen. Expression of CD20 was identified in 37 of 115 cases, CD79a was detected in 15 of 115 cases, and EMA in 7 of 115 cases. J-chain expression could not be found in any of the cases. Association with EBV infection.
EBER-transcripts were identified in 55 of the 98 assessable cases.
Inappropriate fixation of the specimens in the remaining 17 cases led
to deterioration of the morphology during the procedure of in-situ
hybridization, thus making any analysis impossible The labeled cells
corresponded to neoplastic cells in 46 of 98 cases, and in an
additional 9 cases, only to small non-neoplastic lymphocytes. In 15 cases, a mixture of labeled neoplastic and small bystander lymphocytes
was identified. The immunophenotypical and in-situ hybridization data
characteristic for LRCHD are summarized in Table 6.
Growth patterns and composition of the reactive background. Three growth patterns were encountered: a nodular pattern without prominent interfollicular zones (80 cases), a pattern with small nodules and expanded interfollicular zones (27 cases), and a diffuse growth pattern (8 cases). LRCHD, nodular. In 80 of 115 cases, a nodular growth pattern was discernible by conventional histology (Figure 5A). The nodules consisted of small lymphoid cells exhibiting morphologic features of follicular mantle zone cells, showing round nuclei with dense chromatin. In occasional nodules, small, atrophic germinal centers could be identified lying eccentrically to the expanded mantle zone (Figure 5B). The neoplastic cells were usually embedded within the expanded mantle zones in a dispersed pattern, only rarely forming aggregates (Figure 5B). In some cases, the neoplastic cells were found in the outer rim of the mantle zones, expanding into the adjacent interfollicular area. Within the expanded mantle zones, epithelioid cells occasionally occurred. This arrangement of nodular aggregates of small lymphocytes admixed with epithelioid cells was highly reminiscent of the nodules found in LPHD. Fine bands of frequently hyalinized, connective tissue were identified in all cases, often engulfing nodular structures. Neutrophils and eosinophils were absent or rare in all of these cases.
Immunohistologic analysis highlighted the nodular growth and revealed that the nodules corresponded to expanded mantle zones: the small cells expressed the B-cell antigens CD20 (Figure 5E) and CD79a and exhibited surface immunoglobulin heavy chains IgD (Figure 6A) and IgM. Immunostaining for CD21 highlighted the small, atrophic germinal centers located eccentrically within the mantle zones (Figure 6B). In addition, an expanded meshwork of follicular dendritic reticulum cells was identified within the mantle zones. The neoplastic cells within the mantle zones were easily identified by the CD3 immunostaining, which highlighted the rosettes of CD3+ lymphocytes around these cells (Figure 6D). Only a small number of CD57+ T cells was observed. These cells were encountered within the atrophic follicle centres (Figure 6C), whereas rosettes composed of CD57+ cells were not identified. The neoplastic cells expressed CD30 (74 of 80; Figure 5C) and CD15 (65 of 80; Figure 5D), whereas B-cell antigens were identified in a minority of the cases: CD20 expression was found in 26 of 80 (Figure 5F) and CD79a in 7 of 80 cases, respectively (Table 6). Expression of EMA was seen in 2 cases. The morphologic and immunophenotypical criteria useful for differentiating NLRCHD from NLPHD are summarized in Table 7.
The phenotype of the neoplastic cells (Table 6) showed a predominance of CD30 (32 of 35), and CD15 (25 of 35) expression, whereas B-cell antigens were less frequently encountered (CD20: 11 of 35; CD79a: 2 of 35). Weak expression of EMA was rare (4 of 35). Most of the lymphocytes present in the interfollicular zones, as well as in the diffuse cellular background, expressed the CD3 antigen and formed rosettes around the neoplastic cells in all cases. Only rare CD57+ T cells were observed in these cases, mostly located within the reactive follicles. Rosettes composed of such cells surrounding neoplastic cells were not detectable in any case. Clinical presentation of LPHD and LRCHD versus NS/MC CHD The characteristics of clinical presentation of the 219 LPHD and 115 LRCHD cases were compared with those from 599 NS and 174 MC CHD patients recruited in the multicenter trials of the German Hodgkin Study Group from 1988 to 1992.40LPHD and LRCHD showed great similarities in the presence of B symptoms
and the stage of the disease as well as in extension of organ
involvements (Table 8). The only
differences were the patient's age (more than 50 years: 18% in LPHD
vs 32% in LRCHD), presence of stage III disease (14% in LPHD vs 24%
in LRCHD), and the presence of mediastinal involvement (7% in LPHD vs
15% in LRCHD).
The principal differences between LRCHD and the other types of CHD were the mainly early stage (stage I: 46% in LRCHD vs 10% in NS and 21% in MC), infrequent B symptoms (11% in LRCHD vs 42% in NS and 35% in MC), infrequent bulky disease (11% in LRCHD vs 54% in NS and 40% in MC), and infrequent mediastinal involvement (15% in LRCHD vs 80% in NS and 40% in MC). Survival (SV) and failure-free survival (FFS) for LPHD and LRCHD
patients were analyzed (Figure
8A,B).37 Although survival appears to be slightly worse for LRCHD patients, no significant difference was observed between the 2 groups (P = .067 for
SV; P = .57 for FFS). Analysis of the data from disease
relapses showed that 21% of the LPHD patients experienced a first
relapse after achieving a complete remission, whereas the same was the
case in 17% of LRCHD patients. The LPHD patient group was also
characterized by the occurrence of multiple relapses in 12 of the
relapsing patients, whereas this was observed only in one of the 19 relapsing patients with LRCHD (data not shown).37 LRCHD
patients younger than 45 had a worse prognosis after relapse when
compared with the LPHD patient group. Patients older than 45 had an
equally bad prognosis in both disease groups (Figure 9)..37
We report the largest series of cases submitted with the diagnosis of LPHD. The cases were reviewed by a large panel of hematopathologists who achieved a consensus diagnosis in all cases after the evaluation of immunohistologic stains. The initial attempt by the panel to classify the cases according to the H&E stains alone led to the diagnosis of LPHD in 248 of the 388 assessable cases, of CHD in 40 cases, of reactive lesions in 12 cases, and of NHL in 12 cases, whereas in 76 cases no consensus could be reached. Most of the diagnostic problems in the cases without consensus could be solved after combined evaluation of histologic and immunohistologic findings, leaving only 9 cases unclassified. This combined approach led also to the reclassification of 73 cases diagnosed as LPHD, according to the H&E morphology as CHD. The final classification of the 388 assessable cases revealed that the submitting pathologists' diagnosis of LPHD could be confirmed only in 219 cases (56.5%), whereas the remaining cases were found to represent CHD (134 cases; 34.5%), reactive lesions (14 cases; 4%), and NHL (12 cases; 3%). This unexpected result appears to be due to the fact that most of the CHD cases (115 of 134) exhibited a lymphocyte-rich background. In particular, the majority of the lymphocyte-rich CHD cases (80 of 115) were characterized by a nodular background with admixed histiocytes and absent neutrophils and eosinophils closely resembling NLPHD, particularly at low power. Furthermore, a varying proportion of the neoplastic cells exhibited morphologic features of L&H cells. The finding that many of the neoplastic cells had the cytomorphologic features of classical RS cells was the first hint that these cases differed from typical NLPHD. In addition, the identification of small germinal centers at the periphery of the nodular structures distinguished these nodules from those of NLPHD, which do not contain germinal centers. Immunohistologic analysis revealed that the nodular structures corresponded to expanded mantle zones composed of B cells with surface IgD and IgM expression. CD21 immunostaining highlighted the presence of eccentrically placed small germinal centers with a dense, sharply defined meshwork of follicular dendritic cells (FDC) and of an expanded mantle zone with a loose, ill-defined FDC meshwork. The neoplastic cells were found to be engulfed by this meshwork and were often surrounded by CD3+ T-cell rosettes. The phenotype of the neoplastic cells was characteristic of CHD with expression of CD30 in 92.5% and of CD15 in 81% of the cases. Expression of B-cell antigen CD20 by the neoplastic cells was found in only 32.5% and of CD79a in 8.7% of the cases, a much lower frequency than that observed in LPHD (see below). A further difference from LPHD was the complete absence of J-chain in all cases and a weak expression of EMA in only 2.5% of the cases. Examples of this CHD variant had been first identified at the meeting of the European Society of Haematopathology in 1994 in Toledo, Spain, followed by a publication of 4 such cases under the term "follicular HD" by Ashton-Key et al.36 The finding that this CHD variant made up a significant proportion of the cases in the present series (80 of 388; 21%) indicates that it is not as rare as initially suspected. It seems also that this CHD-variant has remained unrecognized even in the recently published large study on LPHD from the German Hodgkin Study Group.41 In that study, 25 cases were described, which had been classified as LPHD according to morphology but became reclassified as CHD after immunophenotyping. Unfortunately, no details on the characteristics of these cases have been presented. During the review of these cases, some of the members of the panel proposed that some of these might represent a variant of "cellular phase of nodular sclerosis." However, the original description of cellular phase of NSHD was imprecise, and there appears to be no consensus as to what cases this term should cover.5,7,42,43 The additional observation of the low frequency of mediastinal involvement led to the conclusion that these cases are not related to NSHD. Therefore, the panel members decided unanimously to propose the term "nodular lymphocyte-rich classical HD (NLRCHD)" for these cases to emphasize (1) that they simulate NLPHD and might be mistaken for it and (2) that they are a variant of CHD. For these reasons, the term NLRCHD was also favored over "follicular HD." In addition to the 80 cases with a nodular pattern, 35 LRCHD cases with an interfollicular or a diffuse growth pattern were recognized. These cases corresponded to the provisional LRCHD entity established in the REAL classification.20 The background infiltrate was rich in CD3+ T cells with almost absent neutrophils and eosinophils, whereas the phenotype of the neoplastic cells was similar to that of the nodular variant. Analysis of the patient characteristics at presentation disclosed marked differences between the LRCHD patient group and the NS and MC types of CHD: LRCHD patients usually presented with early stage disease, infrequent B symptoms, infrequent bulky disease, and infrequent mediastinal involvement. These data further justify the separation of LRCHD as a distinct type of CHD. LRCHD cases showed many similarities to LPHD; however, they differed in having an older age (more than 50 years: 32% in LRCHD vs 18% in LPHD), more frequent involvement of mediastinum (15% in LRCHD vs 7% in LPHD), and a higher incidence of stage III disease (24% in LRCHD vs 14% in LPHD). Interestingly, both LPHD and LRCHD patients were found to have a good-to-excellent prognosis. Relapses were frequent in both groups, and patients continued to relapse within the observation period. Multiple relapses were more common and survival after relapse was slightly better in LPHD patients, which may in part reflect a more benign character of relapse. However, LRCHD patients were older than LPHD patients and this may have influenced the outcome of a relapse.37 LPHD was correctly recognized using H&E sections in 175 cases. Immunohistologic analysis, however, revealed that 73 cases classified as LPHD, according to conventional histology, exhibited the phenotypical criteria of CHD. Also, 9 cases initially classified as CHD were reclassified as LPHD after review of the immunostains. A particular finding posing diagnostic problems in conventional histology was the fact that neoplastic cells with morphologic features of classic RS cells were not as infrequent in LPHD, as previously reported in the literature.17,44 Such cells were observed in low numbers in most cases and were a frequent and often prominent finding in 5% of the cases. The immunophenotype of the neoplastic cells in LPHD, including those with classic RS morphology, was found to be characteristic: constant expression of CD20 in almost all cases, expression of CD79a in 80%, and expression of J-chain in 91.5% of the cases. These findings are largely in line with published data with one exception: the slightly lower frequency of CD79a expression compared with the 100% figure given in one study.45 In contrast to the published data on CD15 expression in LPHD,46 CD15 was never found to be expressed by the neoplastic cells in the current series. It has also been repeatedly reported that CD30 is expressed on L&H cells in a proportion of cases.17,15,47,48 However, careful review of the CD30 immunostains of the current study revealed that this antigen was not expressed by the neoplastic cell population, but rather by blasts that corresponded in morphology to normally occurring CD30+ extrafollicular blast cells in reactive lymphoid tissues. Only in rare cases was an extremely faint staining of isolated L&H cells observed. In-situ hybridization for detection of EBV-encoded small nuclear transcripts (EBER-1 and -2) was found to represent a valuable tool in differentiating LPHD from LRCHD. In all LPHD cases studied, the neoplastic cells were devoid of EBER-specific signals. The only cells found to be EBV-infected in LPHD were single, small non-neoplastic lymphocytes occurring in 25% of the cases. In contrast, 47% of the LRCHD cases harbored EBER-positive RS cells. Thus, the current data clarify the previously confusing picture of the association of LPHD with an EBV infection with some reports showing positive,39-52 and others negative53-55 cases. It seems plausible that errors in classification have been the reason for the discordant data published. The growth patterns of LPHD were highlighted with immunohistology. In particular, immunostaining for CD20 was helpful in identifying nodular aggregates of small B cells with an accompanying CD21+ meshwork of FDC. A useful adjunct was the demonstration of CD57+ T cells, which were preferentially found within nodular structures occasionally forming rosettes around the neoplastic cells. As precise definitions on the classification of a given LPHD case according to its growth pattern do not exist in the literature, a pragmatic approach to classification was chosen: The presence of nodular structures occupying more than 30% of the involved lymph node area led to the diagnosis of NLPHD, with or without diffuse areas, whereas the absence of any nodularity in up to 70% of the tumor area was classified as diffuse LPHD (DLPHD) with nodular areas. The evaluation of the LPHD cases according to this approach led to the finding that at least partial nodularity was present in 97% (212 of 219) of the cases. The problem of discrimination between DLPHD and TCRLBCL occurred only in 7 cases, a much lower number than initially expected. These cases contained neoplastic cells that mostly resembled L&H cells in morphology and immunophenotype. The neoplastic cells were frequently arranged in a vaguely nodular pattern, but the background consisted predominantly of T cells. A small number of accompanying small B lymphocytes and CD57+ cells was observed only in 3 of the cases. Although these findings would support the diagnosis of DLPHD, they have also been described in TCRLBCL. It has been reported that the morphology of the T cells in the background infiltrate can assist in differentiation between LPHD and TCRLBCL, as these cells can show nuclear atypia in latter entity.26,28 The panel members did not find that this phenomenon was of particular value, as it is rather subjective. In addition, atypical T cells were also encountered within nodular and diffuse structures of LPHD in a number of cases of the present series. The most important finding supporting the classification of these cases as DLPHD was that they did not show any significant differences in clinical presentation and follow-up to the NLPHD group of cases.37 Although the differential diagnosis of predominantly diffuse LPHD from TCRLBCL remains difficult and precise criteria were not established in this study, this differential diagnostic problem was extremely rare in this series of cases. In conclusion, this study has shown that HD with a nodular growth pattern and a lymphocyte-rich background encompasses 2 entities with distinct morphologic, phenotypical, and clinical features. Therefore, the precise classification of such cases requires a combination of conventional histology and immunohistology using a distinct panel of antibodies. LPHD may contain a broad morphologic spectrum of neoplastic cells, which nonetheless always exhibit a characteristic immunophenotype with expression of B-cell-specific antigens and/or J-chain and absent expression of CD30 and CD15. Furthermore, it could be shown by means of immunostains that the vast majority of LPHD cases contain areas with nodular growth pattern, whereas purely diffuse cases are extremely rare. LRCHD cases also exhibit, in the majority of cases, a nodular growth pattern as well as a broad morphologic spectrum of the neoplastic cells. The tumor cell phenotype, however, is always characteristic of CHD with expression of CD30 and CD15, infrequent expression of B-cell antigens, and absent expression of J-chain. In addition to immunophenotyping, in-situ hybridization for EBER detection can assist in the differential diagnosis between the 2 HD entities as the neoplastic cells in LPHD appear not to be permissive for an EBV infection.
We thank the following colleagues who contributed essentially to this study: Clinicians: A. Anselmo, U. Axdorf, M. Björkholm, G. Bonadonna, V. Bonfante, B. Coiffier, D. Crowther, H. Eghbali, A. M. Gianni, B. Glimelius, A. Gustavsson, T. Habermann, F. B. Hagemeister, T. Lister, F. Mandelli, E. Noordjik, S. Proctor, J. Radford, L. Specht, P. Taylor, and L. Teerenhovi. Pathologists: B. Angus, C. Baroni, F. Berger, M. Dictor, A. Georgii, K. Hou-Jensen, P. Kluin, P. Kurtin, A. MacDonald, J. A. McBride, J. Menarguez, A. Norton, A. Öst, S. Pilotti, W. Pugh, I. Soubeyran, and C. Sundström. We are also particularly indebted to C. Cieluch, H. Karg, H. Protz, P. Wendler, I. Winter, and C. Kreschel for their excellent technical assistance, and to L. Udvarhelyi for help with the text.
Submitted June 16, 1999; accepted April 26, 2000.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Harald Stein, Professor of Pathology, Klinikum Benjamin Franklin, Free University Berlin, Hindenburgdamm 30, D-12200 Berlin, Germany; e-mail: stein{at}ukbf.fu-berlin.de.
1. Lukes RJ, Craver LF, Hall TC, Rappaport H, Ruben P. Report of the nomenclature committee. Cancer Res. 1966;26:1311. 2. Jackson H. Classification and prognosis of Hodgkin's disease and allied disorders. Surg Gynecol Obstet. 1937;64:465. 3. Jackson H, Parker F. Hodgkin's disease. I. General considerations. N Engl J Med. 1944;230:1. 4. Rappaport H, Winter WJ, Hicks EB. Follicular lymphoma: a re-evaluation of its position in the scheme of malignant lymphoma, based on a survey of 253 cases. Cancer. 1956;4:792.
5.
Lukes RJ, Butler JJ.
The pathology and nomenclature of Hodgkin's disease.
Cancer Res.
1966;26:1063 6. Lukes RJ, Butler JJ, Hicks EB. Natural history of Hodgkin's disease as related to its pathologic picture. Cancer. 1966;19:317. 7. Hansmann M-L, Wacker HH, Radzun HJ. Paragranuloma is a variant of Hodgkin's disease with predominance of B cells. Virchows Arch (Pathol Anat). 1986;409:171. 8. Hansmann M-L, Zwingers T, Böske A, Löffler H, Lennert K. Clinical features of nodular paragranuloma (Hodgkin's disease, lymphocyte predominance type, nodular). J Cancer Res Clin Oncol. 1984;108:321[Medline] [Order article via Infotrieve].
9.
Pinkus GS, Said JW.
Hodgkin's disease, lymphocyte predominance type, nodular 10. Poppema S, Kaiserling E, Lennert K. Epidemiology of nodular paragranuloma (Hodgkin's disease with lymphocyte predominance, nodular). J Cancer Res Clin Oncol. 1979;95:57[Medline] [Order article via Infotrieve]. 11. Poppema S, Kaiserling E, Lennert K. Nodular paragranuloma and progressively transformed germinal centers: ultrastructural and immunohistological findings. Virchows Arch (Cell Pathol). 1979;31:211. 12. Stein H, Hansmann M-L, Lennert K, Brandtzaeg P, Gatter KC, Mason DY. Reed-Sternberg and Hodgkin cells in lymphocyte-predominant Hodgkin's disease of nodular subtype contain J chain. Am J Clin Pathol. 1986;86:292[Medline] [Order article via Infotrieve]. 13. Timens W, Visser L, Poppema S. Nodular lymphocyte predominance type of Hodgkin's disease is a germinal center lymphoma. Lab Invest. 1986;54:457[Medline] [Order article via Infotrieve]. 14. Coles FB, Cartun RW, Pastuszak WT. Hodgkin's disease, lymphocyte predominant type: immunoreactivity with B cell antibodies. Mod Pathol. 1988;1:274[Medline] [Order article via Infotrieve]. 15. Chittal SM, Caveriviere P, Schwarting R, et al. Monoclonal antibodies in the diagnosis of Hodgkin's disease: the search for a rational panel. Am J Surg Pathol. 1988;12:9[Medline] [Order article via Infotrieve]. 16. Pinkus GS, Said JW. Hodgkin's disease, lymphocyte predominance type, nodular-further evidence for a B cell derivation: L&H variants of Reed-Sternberg cells express L26, a pan B cell marker. Am J Pathol. 1988;133:211[Abstract].
17.
Nicholas DS, Harris S, Wright DH.
Lymphocyte predominance Hodgkin's disease 18. Chittal SM, Alard C, Rossi J-F, et al. Further phenotypic evidence that nodular, lymphocyte-predominant Hodgkin's disease is a large B-cell lymphoma in evolution. Am J Surg Pathol. 1990;14:1024[Medline] [Order article via Infotrieve]. 19. Pileri S, Sabattini E, Tazzari PL, et al. Hodgkin's disease: update of findings. Haematologica. 1991;76:175[Medline] [Order article via Infotrieve].
20.
Harris NL, Jaffe ES, Stein H, et al.
A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group.
Blood.
1994;84:1361 21. Mason DY, Banks PM, Chan J, et al. Nodular lymphocyte predominance Hodgkin's disease: a distinct clinicopathological entity. Am J Surg Pathol. 1994;18:526[Medline] [Order article via Infotrieve]. 22. Regula DP, Hoppe RT, Weiss LM. Nodular and diffuse types of lymphocyte predominance Hodgkin's disease. N Engl J Med. 1988;318:214[Abstract]. 23. Borg-Grech A, Radford JA, Crowther D, Swindell R, Harris M. A comparative study of the nodular and diffuse variants of lymphocyte-predominant Hodgkin's disease. J Clin Oncol. 1989;7:1303[Abstract]. 24. Tefferi A, Zellers RA, Banks PM, Therneau TM, Colgan JP. Clinical correlates of distinct immunophenotypic and histologic subcategories of lymphocyte-predominance Hodgkin's disease. J Clin Oncol. 1990;8:1959[Abstract]. 25. Hansmann M-L, Stein H, Dallenbach F, Fellbaum C. Diffuse lymphocyte-predominant Hodgkin's disease (diffuse paragranuloma): a variant of the B-cell derived nodular type. Am J Pathol. 1991;138:29[Abstract]. 26. Jaffe ES, Longo DL, Cossman J, Hsu S-M, Arnold A, Kosrmeyer SJ. Diffuse B-cell lymphomas with T-cell predominance in patients with follicular lymphoma or "pseudo T-cell lymphoma" [abstract]. Lab Invest. 1984;50:27a. 27. Chittal SM, Brousset P, Voigt JJ, Delsol G. Large B-cell lymphoma rich in T-cells and simulating Hodgkin's disease. Histopathology. 1991;19:211[Medline] [Order article via Infotrieve]. 28. Macon WR, Williams NE, Greer JP, Stein RS, Collins RD, Cousar JB. T-cell rich B-cell lymphomas: a clinicopathologic study of 19 cases. Am J Surg Pathol. 1992;16:351[Medline] [Order article via Infotrieve]. 29. Ng CS, Chan JKC, Hui PK, Lau WH. Large B-cell lymphomas with high content of reactive T cells. Hum Pathol. 1989;20:1145[Medline] [Order article via Infotrieve]. 30. Osborne BM, Butler JJ, Pugh WC. The value of immunophenotyping on paraffin sections in the identification of T-cell rich B-cell large-cell lymphomas: lineage confirmed by JH rearrangement. Am J Surg Pathol. 1990;14:933[Medline] [Order article via Infotrieve]. 31. Ramsay AD, Smith WJ, Isaacson PG. T-cell rich B-cell lymphoma. Am J Surg Pathol. 1988;12:433[Medline] [Order article via Infotrieve]. 32. Krishnan J, Wallberg K, Frizzera G. T-cell rich large B-cell lymphoma. Am J Surg Pathol. 1994;18:455[Medline] [Order article via Infotrieve].
33.
Rodriguez J, Pugh WC, Cabanillas F.
T-cell rich B-cell lymphoma.
Blood.
1993;82:1586 34. de Wolf Peeters C, Pittaluga S. T-cell rich B-cell lymphoma: a morphological variant of non Hodgkin's lymphomas or a clinico-pathological entity? Histopathology. 1995;26:383[Medline] [Order article via Infotrieve]. 35. de Jong D, van Gorp J, Sie-Go D, van Heerde P. T-cell rich B-cell non Hodgkin's lymphoma: a progressed form of follicle centre cell lymphoma and lymphocyte predominance Hodgkin's disease. Histopathology. 1996;28:15[Medline] [Order article via Infotrieve]. 36. Ashton-Key M, Thorpe PA, Allen JP, Isaacson PG. Follicular Hodgkin's disease. Am J Surg Pathol. 1995;19:1294[Medline] [Order article via Infotrieve]. 37. Diehl V, Sextro M, Franklin J, et al. Clinical presentation, course and prognostic factors in lymphocyte predominant Hodgkin's disease and lymphocyte-rich classical Hodgkin's disease: report from the European Task Force on Lymphoma Project on lymphocyte-predominant Hodgkin's disease. J Clin Oncol. 1999;117:776. 38. Norton AJ, Jordan S, Yeomans P. Brief, high-temperature heat denaturation (pressure cooking): a simple and effective method of antigen retrieval for routinely processed tissues. J Pathol. 1994;173:371[Medline] [Order article via Infotrieve]. 39. Hummel M, Anagnostopoulos I, Dallenbach F, Korbjuhn P, Dimmler C, Stein H. EBV infection patterns in Hodgkin's disease and normal lymphoid tissue: expression and cellular localization of EBV gene products. Br J Haematol. 1992;83:689. 40. Georgii A, Fischer R, Hübner K, Schwarze EW, Bernhards J. Classification of Hodgkin's disease biopsies by a panel of four histopathologists: report of 1140 patients from the German national trial. Leuk Lymphoma. 1993;9:365[Medline] [Order article via Infotrieve]. 41. von Wasielewski R, Werner M, Fischer R, et al. Lymphocyte-predominant Hodgkin's disease: an immunohistochemical analysis of 208 reviewed Hodgkin's disease cases from the German Hodgkin Study Group. Am J Pathol. 1997;150:793[Abstract]. 42. Kadin ME, Glatstein E, Dorfman RF. Clinicopathological studies of 117 untreated patients subjected to laparotomy for the staging of Hodgkin's disease. Cancer. 1971;27:1277[Medline] [Order article via Infotrieve].
43.
Lukes RJ.
Criteria for involvement of lymph node, bone marrow, spleen and liver in Hodgkin's disease.
Cancer Res.
1971;31:1755 44. Poppema S, Kaiserling E, Lennert K. Hodgkin's disease with lymphocytic predominance, nodular type (nodular paragranuloma) and progressively transformed germinal centers: a cytohistological study. Histopathology. 1979;3:295[Medline] [Order article via Infotrieve]. 45. Korkolopoulou P, Cordell J, Jones M, et al. The expression of the B-cell marker mb-1 (CD79a) in Hodgkin's disease. Histopathology. 1994;24:511[Medline] [Order article via Infotrieve].
46.
Hall PA, D' Ardenne AJ.
Value of CD15 immunostaining in diagnosing Hodgkin's disease: a review of published literature.
J Clin Pathol.
1987;40:1298 47. Angel CA, Warford A, Campbell AC, Pringle JH, Lauder I. The immunohistology of Hodgkin's disease: Reed-Sternberg cells and their variants. J Pathol. 1987;153:21[Medline] [Order article via Infotrieve]. 48. Algara P, Martinez P, Sachez L, et al. Lymphocyte predominance Hodgkin's disease (nodular paragranuloma)-a bcl-2 negative germinal centre lymphoma. Histopathology. 1991;19:69[Medline] [Order article via Infotrieve]. 49. Fellbaum C, Hansmann M-L, Niedermeyer H, et al. Influence of Epstein-Barr virus genomes on patient survival in Hodgkin's disease. Am J Clin Pathol. 1992;98:319[Medline] [Order article via Infotrieve]. 50. Pallesen G, Hamilton-Dutoit SJ, Rowe M, Young LS. Expression of Epstein-Barr virus latent gene products in tumor cells of Hodgkin's disease. Lancet. 1991;337:320[Medline] [Order article via Infotrieve]. 51. Delsol G, Brousset P, Chittal S, Rigal Huguet F. Correlation of the expression of Epstein-Barr virus latent membrane protein and in situ hybridization with biotinylated BamHI-W probes in Hodgkin's disease. Am J Pathol. 1992;140:247[Abstract]. 52. Murray PG, Young LS, Rowe M, Crocker J. Immunohistochemical demonstration of the Epstein-Barr virus encoded latent membrane protein in paraffin sections of Hodgkin's disease. J Pathol. 1992;166:1[Medline] [Order article via Infotrieve]. 53. Weiss LM, Chen YY, Liu XF, Shibata D. Epstein-Barr virus and Hodgkin's disease: a correlation in situ hybridization and polymerase chain reaction study. Am J Pathol. 1991;139:1259[Abstract]. 54. Coates PJ, Slavin G, d'Ardenne AJ. Persistence of Epstein-Barr virus in Reed-Sternberg cells throughout the course of Hodgkin's disease. J Pathol. 1991;164:291[Medline] [Order article via Infotrieve]. 55. Alkan S, Ross CW, Hanson CA, Schnitzer B. Epstein-Barr virus and bcl-2 protein overexpression are not detected in neoplastic cells of nodular lymphocyte predominance Hodgkin's disease. Mod Pathol. 1995;8:544[Medline] [Order article via Infotrieve].
© 2000 by The American Society of Hematology.
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  M. Al-Mansour, J. M. Connors, R. D. Gascoyne, B. Skinnider, and K. J. Savage Transformation to Aggressive Lymphoma in Nodular Lymphocyte-Predominant Hodgkin's Lymphoma J. Clin. Oncol., February 10, 2010; 28(5): 793 - 799. [Abstract] [Full Text] [PDF]
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 A. I. Lee and A. S. LaCasce Nodular Lymphocyte Predominant Hodgkin Lymphoma Oncologist, July 1, 2009; 14(7): 739 - 751. [Abstract] [Full Text] [PDF]
|
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 B. Chetaille, F. Bertucci, P. Finetti, B. Esterni, A. Stamatoullas, J. M. Picquenot, M. C. Copin, F. Morschhauser, O. Casasnovas, T. Petrella, et al. Molecular profiling of classical Hodgkin lymphoma tissues uncovers variations in the tumor microenvironment and correlations with EBV infection and outcome Blood, March 19, 2009; 113(12): 2765 - 3775. [Abstract] [Full Text] [PDF]
|
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L. Nogova, T. Reineke, C. Brillant, M. Sieniawski, T. Rudiger, A. Josting, H. Bredenfeld, R. Skripnitchenko, R.-P. Muller, H.-K. Muller-Hermelink, et al. Lymphocyte-Predominant and Classical Hodgkin's Lymphoma: A Comprehensive Analysis From the German Hodgkin Study Group J. Clin. Oncol., January 20, 2008; 26(3): 434 - 439. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Schulz, U. Rehwald, F. Morschhauser, T. Elter, C. Driessen, T. Rudiger, P. Borchmann, R. Schnell, V. Diehl, A. Engert, et al. Rituximab in relapsed lymphocyte-predominant Hodgkin lymphoma: long-term results of a phase 2 trial by the German Hodgkin Lymphoma Study Group (GHSG) Blood, January 1, 2008; 111(1): 109 - 111. [Abstract] [Full Text] [PDF]
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E. Oflazoglu, I. J. Stone, K. A. Gordon, I. S. Grewal, N. van Rooijen, C.-L. Law, and H.-P. Gerber Macrophages contribute to the antitumor activity of the anti-CD30 antibody SGN-30 Blood, December 15, 2007; 110(13): 4370 - 4372. [Abstract] [Full Text] [PDF]
|
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 |
|
 D. de Jong, J. Bosq, K. A. MacLennan, J. Diebold, J. Audouin, J. Chasle, A.-M. Mandard, J. Marnay, M. Henry-Amar, and On behalf of the European Organization for Researc Lymphocyte-rich classical Hodgkin lymphoma (LRCHL): clinico-pathological characteristics and outcome of a rare entity Ann. Onc., January 1, 2006; 17(1): 141 - 145. [Abstract] [Full Text] [PDF]
|
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|
|
 |
|
 L. Nogova, T. Rudiger, and A. Engert Biology, Clinical Course and Management of Nodular Lymphocyte-Predominant Hodgkin Lymphoma Hematology, January 1, 2006; 2006(1): 266 - 272. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Nogova, T. Reineke, H. T. Eich, A. Josting, H. K. Muller-Hermelink, K. Wingbermuhle, C. Brillant, A. Gossmann, J. Oertel, M. V. Bollen, et al. Extended field radiotherapy, combined modality treatment or involved field radiotherapy for patients with stage IA lymphocyte-predominant Hodgkin's lymphoma: a retrospective analysis from the German Hodgkin Study Group (GHSG) Ann. Onc., October 1, 2005; 16(10): 1683 - 1687. [Abstract] [Full Text] [PDF]
|
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A. Shimabukuro-Vornhagen, H. Haverkamp, A. Engert, L. Balleisen, P. Majunke, G. Heil, H. T. Eich, H. Stein, V. Diehl, and A. Josting Lymphocyte-Rich Classical Hodgkin's Lymphoma: Clinical Presentation and Treatment Outcome in 100 Patients Treated Within German Hodgkin's Study Group Trials J. Clin. Oncol., August 20, 2005; 23(24): 5739 - 5745. [Abstract] [Full Text] [PDF]
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L. Boudova, E. Torlakovic, J. Delabie, P. Reimer, B. Pfistner, S. Wiedenmann, V. Diehl, H.-K. Muller-Hermelink, and T. Rudiger Nodular lymphocyte-predominant Hodgkin lymphoma with nodules resembling T-cell/histiocyte-rich B-cell lymphoma: differential diagnosis between nodular lymphocyte-predominant Hodgkin lymphoma and T-cell/histiocyte-rich B-cell lymphoma Blood, November 15, 2003; 102(10): 3753 - 3758. [Abstract] [Full Text] [PDF]
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 R F Jarrett, A S Krajewski, B Angus, J Freeland, P R Taylor, G M Taylor, and F E Alexander The Scotland and Newcastle epidemiological study of Hodgkin's disease: impact of histopathological review and EBV status on incidence estimates J. Clin. Pathol., November 1, 2003; 56(11): 811 - 816. [Abstract] [Full Text] [PDF]
|
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B. C. Ekstrand, J. B. Lucas, S. M. Horwitz, Z. Fan, S. Breslin, R. T. Hoppe, Y. Natkunam, N. L. Bartlett, and S. J. Horning Rituximab in lymphocyte-predominant Hodgkin disease: results of a phase 2 trial Blood, June 1, 2003; 101(11): 4285 - 4289. [Abstract] [Full Text] [PDF]
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 A. Brauninger, H.-H. Wacker, K. Rajewsky, R. Kuppers, and M.-L. Hansmann Typing the Histogenetic Origin of the Tumor Cells of Lymphocyte-rich Classical Hodgkin's Lymphoma in Relation to Tumor Cells of Classical and Lymphocyte-predominance Hodgkin's Lymphoma Cancer Res., April 1, 2003; 63(7): 1644 - 1651. [Abstract] [Full Text] [PDF]
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R. Bouabdallah, N. Mounier, C. Guettier, T. Molina, V. Ribrag, C. Thieblemont, A. Sonet, A. Delmer, K. Belhadj, P. Gaulard, et al. T-Cell/Histiocyte-Rich Large B-Cell Lymphomas and Classical Diffuse Large B-Cell Lymphomas Have Similar Outcome After Chemotherapy: A Matched-Control Analysis J. Clin. Oncol., April 1, 2003; 21(7): 1271 - 1277. [Abstract] [Full Text] [PDF]
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A. F. Wahl, K. Klussman, J. D. Thompson, J. H. Chen, L. V. Francisco, G. Risdon, D. F. Chace, C. B. Siegall, and J. A. Francisco The Anti-CD30 Monoclonal Antibody SGN-30 Promotes Growth Arrest and DNA Fragmentation in Vitro and Affects Antitumor Activity in Models of Hodgkin's Disease Cancer Res., July 1, 2002; 62(13): 3736 - 3742. [Abstract] [Full Text] [PDF]
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G. Z. Rassidakis, L. J. Medeiros, S. Viviani, V. Bonfante, G.-P. Nadali, T. P. Vassilakopoulos, O. Mesina, M. Herling, M. K. Angelopoulou, R. Giardini, et al. CD20 Expression in Hodgkin and Reed-Sternberg Cells of Classical Hodgkin's Disease: Associations With Presenting Features and Clinical Outcome J. Clin. Oncol., March 1, 2002; 20(5): 1278 - 1287. [Abstract] [Full Text] [PDF]
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S A Pileri, S Ascani, L Leoncini, E Sabattini, P L Zinzani, P P Piccaluga, A Pileri Jr, M Giunti, B Falini, G B Bolis, et al. Hodgkin's lymphoma: the pathologist's viewpoint J. Clin. Pathol., March 1, 2002; 55(3): 162 - 176. [Abstract] [Full Text] [PDF]
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H. Stein, T. Marafioti, H.-D. Foss, H. Laumen, M. Hummel, I. Anagnostopoulos, T. Wirth, G. Demel, and B. Falini Down-regulation of BOB.1/OBF.1 and Oct2 in classical Hodgkin disease but not in lymphocyte predominant Hodgkin disease correlates with immunoglobulin transcription Blood, January 15, 2001; 97(2): 496 - 501. [Abstract] [Full Text] [PDF]
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J. M. Connors, E. M. Noordijk, and S. J. Horning Hodgkin's Lymphoma: Basing the Treatment on the Evidence Hematology, January 1, 2001; 2001(1): 178 - 193. [Abstract] [Full Text] [PDF]
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N. L. Harris, H. Stein, S. E. Coupland, M. Hummel, R. D. Favera, L. Pasqualucci, and W. C. Chan New Approaches to Lymphoma Diagnosis Hematology, January 1, 2001; 2001(1): 194 - 220. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
as
in nodular LPHD
, CD15
