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© 2002 American Society for Clinical Oncology T-Cell/Histiocyte–Rich Large B-Cell Lymphoma: A Distinct Clinicopathologic EntityByFrom the Departments of Morphology and Molecular Pathology, Hematology, and Oncology, University Hospitals K.U. Leuven, Leuven, Belgium. Address reprint requests to Ruth Achten, MD, Department of Morphology and Molecular Pathology, University Hospitals K.U. Leuven, Minderbroedersstraat 12, B-3000 Leuven, Belgium; email: Ruth.Achten{at}uz.kuleuven.ac.be
PURPOSE: Although it has proven difficult to delineate diagnostically reproducible and clinically relevant subgroups, the heterogeneity of diffuse large B-cell lymphomas (DLBCL) is widely acknowledged. In 1992, we reported on six cases that suggested that large B-cell lymphoma rich in stromal histiocytes and T cells may be identified as a distinct clinicopathologic entity within DLBCL. PATIENTS AND METHODS: An integrated clinicopathologic study of 40 cases of this DLBCL subtype is presented. RESULTS: Distinguishing a DLBCL rich in histiocytes and reactive T cells, designated T-cell/histiocyte–rich large B-cell lymphoma (THR-BCL), may be justified from a clinical point of view. The disease typically affects middle-aged male patients who usually present with advanced-stage disease that is not adequately managed with current therapeutic strategies. Whereas proliferation fraction and p53 overexpression, in addition to the clinical variables incorporated in the International Prognostic Index (IPI), significantly correlate with response to treatment and survival in a univariate analysis, only the IPI score identifies relevant prognostic THR-BCL subpopulations in a multivariate model. The morphologic and immunophenotypic profile of the neoplastic B cells in THR-BCL suggests that they may originate from a germinal center ancestor. CONCLUSION: THR-BCL constitutes a distinct clinicopathologic entity that is characterized by an aggressive behavior. Experimental therapeutic strategies may be indicated to obtain a more favorable response to treatment in this disease.
DIFFUSE LARGE B-CELL lymphoma (DLBCL) constitutes a heterogeneous lymphoma category, comprising all lymphoid tumors composed of large neoplastic B cells that do not satisfy the criteria of other more accurately delineated lymphoma entities.1,2 It is generally acknowledged that pronounced variability exists within DLBCL from a morphologic, an immunophenotypic, and a genetic point of view, suggesting that distinct disease entities may be recognized within this wastebasket subtype. Recent results obtained by studying the differential gene expression of numerous genes simultaneously have corroborated the notion that distinct disease entities are included within DLBCL.3 Moreover, considering that no more than approximately 40% of DLBCLs are ultimately cured,4 indicators identifying those DLBCL subtypes at greatest risk of treatment failure should be established.5 Given the doubtfulness of the reliability and the predictive value of histologic subclassification, clinicians are obliged to rely exclusively on pretreatment clinical variables incorporated in prognostic models to determine an individual patient’s prognosis. Among these predictive systems, the International Prognostic Index (IPI),6 proposed in 1994, has remained the gold standard in clinical practice and research. Nevertheless, it is clear that however accurate they may seem in predicting an individual patient’s outcome, clinical features represent surrogate variables that merely reflect the underlying biologic properties of the disease.5,7 To acquire insight into the basic disease mechanisms determining the behavior of DLBCL, numerous morphologic, immunophenotypic, and molecular features have been linked to treatment response and survival. Despite the fact that current attempts to determine reliable pathologic or biologic criteria have largely failed,5,7,8 there is agreement that straightforward guidelines for classification should be developed.2 Among the provisionally proposed DLBCL morphologic variants and subtypes,2,9 T-cell/histiocyte–rich large B-cell lymphoma (THR-BCL) merits special consideration. In 1992, our group described six cases of DLBCL characterized by peculiar pathologic features that mimic Hodgkin’s lymphoma. These peculiar morphologic features seemed to correlate with an advanced stage disease at presentation and a poor outcome.10 The consistent presence of numerous T cells in addition to a prominent histiocytic component indicates that this group of cases belongs to the spectrum of T-cell–rich B-cell lymphomas.11,12 Nevertheless, we chose to stress both the homogeneity within this series and the distinctiveness of these cases from other T-cell–rich B-cell lymphomas by coining the term "histiocyte-rich B-cell lymphoma." Because the relative importance of the T-cell component may be underestimated by overemphasizing the presence of histiocytes, THR-BCL, the term proposed in the World Health Organization classification of lymphoid neoplasms,2,9 may be a more appropriate designation. It remains to be emphasized, however, that because of their peculiar morphologic appearance, THR-BCLs constitute a particular subgroup of cases that should be distinguished within the spectrum of DLBCLs featuring an important reactive component. In this study we have analyzed 40 cases of THR-BCL to verify whether distinctive clinicopathologic features warrant recognition of THR-BCL as a separate clinicopathologic entity. In addition, the predictive value of several known clinical and biologic prognostic factors within the group of THR-BCL has been investigated.
THR-BCL Pathology Sixty cases of lymphoma with the features of THR-BCL were retrieved from the files of the University Hospitals of the K.U. Leuven. These cases were collected since we first reported on the distinctive features of histiocyte-rich B-cell lymphoma in 1992. The results of a detailed morphologic and immunophenotypic study of these 60 cases, including a more precise disease definition and reliable differential diagnostic criteria, are described in a separate article.13 This series comprised 33 local cases and 27 cases that had been referred to one of the authors (C.D.W.-P.). In 20 of these 60 cases, we were unable to collect clinical data. This clinicopathologic study has therefore been restricted to the 40 fully documented cases. Six cases that formed the basis of the initial report10 are also included in this study. Paraffin section immunohistochemistry stains were performed on deparaffinized tissue sections by using CD3, CD5, CD10, CD15, CD20, CD23, CD57, bcl-2, bcl-6, MIB-1, CD30, epithelial membrane antigen (EMA), and p53 and a streptavidin-biotin-peroxidase technique with the Ventana Immunostainer (Ventana Medical Systems, Tucson, AZ) according to the company’s protocol. For CD68 and CD138 (syndecan-1), a manual avidin-biotin complex method was used. Immunohistochemical stainings were assessed semiquantitatively. The percentage of tumor cells immunoreactive with the antibodies was estimated. For all antibodies of interest (CD10, bcl-2, bcl-6, p53, MIB-1, CD15, CD30, and EMA), a case was considered positive if immunoreactivity could be detected in more than 20% of the tumor cells. A case was called CD10 positive only if the tumor cells showed cytoplasmic staining. Reticular staining observed in several otherwise negative cases was considered aspecific. The staining of residual germinal center cells served as a positive control for CD10 as well as bcl-6. Staining of bcl-2–positive and CD5-positive small lymphocytes present in the biopsies provided an internal positive control for the bcl-2 and CD5 immunostaining. For MIB-1, mitotic figures present in the biopsy served as an internal control, whereas the quality of the CD138 immunostaining was evaluated by the presence of plasma cells.
Clinical Data Details with respect to the therapy given are listed in Table 1. Initial therapy generally included doxorubicin-containing chemotherapy. Because of an initial misdiagnosis of Hodgkin’s lymphoma, paragranuloma type, four patients (patient nos. 2, 4, 6, and 16) received chemotherapy for Hodgkin’s lymphoma. In one of these patients (patient no. 2), it became clear after two cycles of mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, and vinblastine (MOPP/ABV) that the disease required more aggressive treatment. Therefore, MOPP/ABV was discontinued and replaced by six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone. Patient no. 24, who presented with stage I disease in 1990, received radiation only, which was the standard type of treatment for limited-stage disease at that point in time. Two patients (patient nos. 12 and 40) were considered unable to support the toxicity associated with antitumor therapy. For that reason patient no. 12 received radiation only, whereas patient no. 40 was treated with chlorambucil. Patient no. 25 and patient no. 39 succumbed to their disease before treatment could be initiated. The evaluation of response was performed according to standard criteria.14
Survival analysis was performed to assess the relationships between the various clinical (age, IPI score, and the presence or absence of bone marrow involvement) and pathologic (bcl-2, bcl-6, MIB-1, p53, and CD30) variables of interest on the one hand and overall survival (OS) and treatment failure-free survival (FFS) on the other by using the product-limit method of Kaplan-Meier (SAS system; SAS Institute Inc, Cary, NC). The P values for these analyses are based on the log-rank test. OS and FFS were measured from the time of initial therapy to death or treatment failure, respectively. Treatment failures included patients who relapsed after complete remission (CR), who had treatment stopped because of toxicity, or who died from the lymphoma or treatment-related toxicity. Patients who did not achieve a CR were considered to have had treatment failures at time 0. Patients who died as a result of tumor-unrelated deaths and were without any sign of relapse of their disease, as well as patients who were lost to follow-up after the diagnosis, were censored at that time. CR rates were compared by use of Fisher’s exact test. The Cox proportional hazards model was used to assess the joint effects of the pathology variables found to be associated with OS or FFS in the Kaplan-Meier analyses (SAS system). In fact, the proportional hazards assumption seemed valid for all pathology variables, but it was an inappropriate model for the IPI score. Therefore, it was decided to fit the Cox proportional hazards model for each of the pathology variables, stratifying on the IPI score. As such, it was determined which of the pathologic variables significantly added to the prediction of OS and FFS after adjusting for the IPI score.
Pathology In 35 cases, the initial diagnosis was established on a lymph node biopsy. In the remaining patients, splenectomy (two cases), a wedge biopsy of the liver (three cases), or both were performed at diagnosis. Morphologic features were remarkably consistent, independent of the biopsy site. The diagnosis of THR-BCL was based on the following criteria:
Except for a slight increase in the number of neoplastic cells in one patient, the overall features of repeat biopsies performed in the absence of clinically apparent disease evolution more or less reproduced those observed in the diagnostic biopsy specimen. A substantial increase in the number of large atypical B cells, indicative of evolution toward a DLBCL, was observed in four follow-up bone marrow trephines and in one hepatic wedge biopsy. All five patients succumbed to their disease soon after it had evolved to a DLBCL without a prominent stromal component. In four patients in whom an autopsy was performed, generalized lymphoma lesions were revealed, with involvement of lymph nodes, bone marrow, spleen, liver, kidneys, adrenal glands, peripancreatic tissue, and lungs. In contrast to the diagnostic lymph node specimen, the neoplastic infiltrate consisted almost exclusively of large neoplastic B cells, with only scattered small T cells. The immunophenotypic characteristics as they were observed in the diagnostic biopsy are listed in Table 2.
Clinical Features Clinical features, type of treatment, and response to therapy are listed in Table 3. A summary of these features is listed in Table 4. Table 1 provides a detailed description of the treatment regimen used.
There was an obvious male preponderance (male to female ratio, 2.6:1). The median patient age was 49 years (range, 21 to 87), and 73% of patients were younger than 60 years. Splenomegaly was reported in 24 patients (60%), hepatomegaly in 16 patients (40%), and bone marrow involvement in 17 patients (43%). Thirteen patients (33%) had an Eastern Cooperative Oncology Group status of  2, 13 patients (33%) had two involved extranodal disease sites, and in 22 patients (55%), the LDH level was above the reference range. Ann Arbor stage at diagnosis was as follows: stage I, n = 1; stage II, n = 6; stage III, n = 9; and stage IV, n = 24. The IPI score had the following distribution: low risk, n = 9; low intermediate risk, n = 15; high intermediate risk, n = 9; and high risk, n = 7. Response to therapy. A CR to chemotherapy for aggressive non-Hodgkin’s lymphoma was observed in 12 patients. Remarkably few patients achieved a continuous CR after standard chemotherapy, despite the relatively young age of the population affected. Six of the patients who obtained a CR had a continuous CR, whereas two patients who relapsed were rescued with peripheral stem-cell transplantation. Two patients who had a partial response after standard chemotherapy achieved a continuous CR after peripheral stem-cell transplantation or autologous bone marrow transplantation. One patient who received radiation only and two patients who initially received chemotherapy directed at Hodgkin’s lymphoma achieved a CR. One of these patients relapsed but achieved a CR after peripheral stem-cell transplantation. The IPI score, Ann Arbor stage, LDH level, the presence of "B" symptoms, hepatomegaly and splenomegaly, bone marrow involvement, and proliferation rate seemed to be significantly associated with CR rate (Table 5).
FFS. Survival curves for FFS and OS are indicated in Fig 1. With a median follow-up of 22.5 months, the median FFS was 5 months, with a 44% survival at 3 years. The extremely steep slope of the Kaplan-Meier curve is remarkable: many patients do not achieve a CR, and those who relapse after a good initial response to treatment usually do so early in the disease course. Variables important to predict FFS in a univariate analysis included IPI score, Ann Arbor stage, LDH level, the presence of splenomegaly, bone marrow involvement, proliferation rate, and p53 overexpression (Table 5).
OS. With a median follow-up of 22.5 months, the median OS was 31 months, with a 50% survival at 3 years and a 45% survival at 5 years. On the analogy of the FFS curve, the steep slope of the Kaplan-Meier curve for OS is noteworthy. Patients who succumb to their lymphoma do so early in the disease course, whereas few patients are lost after 3 years. Variables important to predict OS in a univariate analysis included IPI score, Ann Arbor stage, the presence of B symptoms, LDH level, the presence of splenomegaly, bone marrow involvement, and p53 overexpression (Table 5). Multivariate analysis. In a Cox proportional hazards model, the joint effects of the IPI score and pathology variables that were significantly associated with survival were evaluated. After stratification on the IPI score, only p53 overexpression added to the ability of the model to predict FFS.
In this study, the clinicopathologic features of 40 cases of THR-BCL have been described. The presence of numerous T cells, in addition to a substantial histiocytic population, implies that THR-BCL should be considered part of the spectrum of large B-cell lymphomas rich in stromal T cells and histiocytes. It is possible, however, to distinguish THR-BCL from other cases of DLBCL in general and from T-cell–rich B-cell lymphoma in particular by strictly applying four immunomorphologic criteria.13 Moreover, such a distinction may be justified from a clinical point of view. Indeed, this study confirms our initial findings that THR-BCL predominantly affects middle-aged men who present with advanced-stage disease and an unusually high percentage of bone marrow involvement. This contrasts with DLBCL in general, which tends to involve older people and is characterized by no more than a slight male preponderance.2,15,16 Furthermore, bone marrow involvement and organomegaly are uncommon findings at presentation in DLBCL in general.2,15-17 The aggressiveness of THR-BCL at presentation is highlighted by the poor response to initial treatment. A CR was obtained in no more than 16 (40%) of 40 patients, seven of whom subsequently relapsed. Despite this obviously poor response to initial treatment, the expected 5-year OS seems to be comparable to that reported for DLBCL in general. However, patients who succumb to their disease usually do so earlier in their disease course. Indeed, at 3 years, approximately 55% of our patients have already died, but thereafter a plateau was reached, and few additional patients were lost. It is clear that in this relatively young patient population, aggressive therapeutic strategies, in particular stem-cell transplantation, are applied whenever conventional regimens seem to fail. Our data indicate that these approaches may yield a favorable response and may result in protracted disease-free survival. The feasibility of experimental therapies and their ability to rescue initially treatment-resistant patients largely explains the rather favorable overall response rate that does not differ substantially from survival figures reported for DLBCL patients in general. The latter patients are indeed markedly older and often do not tolerate the toxicity associated with these aggressive treatments, if they are considered eligible at all. Moreover, considering the age difference between these populations, one might expect the relative percentage of disease-specific deaths to be higher for THR-BCL than for DLBCL in general. A closer look at the clinical data reveals that there seems to be a striking homogeneity among those THR-BCL patients who do not respond favorably to therapy. Contrary to what one may expect, the 19 of 25 patients (15 of whom were men) who did not achieve a complete response were not preferentially elderly people, but were predominantly younger to middle-aged individuals. Because these patients obviously are at high risk of treatment failure, novel therapeutic strategies, such as high-dose chemotherapy followed by stem-cell rescue, may be indicated as initial treatment, especially because these younger patients may tolerate possible toxicity better. Previous studies evaluating the clinical relevance of recognizing DLBCL rich in stromal T cells have not demonstrated the distinctiveness of T-cell–rich BCL. However, considering the imprecise disease definition used to select cases in these series, the obvious clinical heterogeneity observed is not an unexpected finding.18-22 Hence, it does not come as a surprise that this variety of B-cell lymphomas that happened to attract an exuberant T-cell infiltrate shows no substantial differences with other DLBCLs with respect to disease presentation and response to treatment.18-22 However, the series reported by Skinnider et al,23 McBride et al,24 Camilleri-Broet et al,25 Khan et al,26 and Chittal et al27 should be distinguished among the studies on T-cell–rich B-cell lymphomas. From a morphologic perspective, these cases lacked the heterogeneity characterizing T-cell–rich B-cell lymphomas in general and bore a striking resemblance to THR-BCL as we have defined it. Moreover, these cases also constituted a more uniform group from a clinical point of view, because, similarly to THR-BCL, they were usually diagnosed in an advanced disease stage and exhibited an aggressive course. Overall, we believe that the distinctive clinical characteristics we have observed in our series of THR-BCL, supported by similar findings reported by others for cases with comparable morphologic features, strongly suggest that THR-BCL may constitute a separate clinicopathologic entity. On the analogy of DLBCL in general, it may be useful to identify prognostic factors that specifically apply to THR-BCL. It is not unlikely that, even in the THR-BCL patient population generally characterized by an aggressive disease course, a subpopulation of low-risk patients should be isolated who will in fact do well with standard therapy and will incur dangerous side effects if they are treated with experimental regimens. Recent studies have suggested that bcl-2 protein expression may constitute an adverse prognostic factor in DLBCL.28-30 Nevertheless, our study indicates that the level of bcl-2 protein expression has no substantial effect on OS or FFS (P = .2427 and .3976, respectively) in the THR-BCL subgroup. The prognostic effect of proliferative rate and of p53 overexpression in aggressive non-Hodgkin’s lymphoma has also been extensively investigated, although with conflicting results.7,8,31-37 Our analyses suggest a trend associating p53 overexpression with shortened survival, whereas we found high proliferative activity to be positively correlated with response to treatment and survival. However, when compared with IPI score in a prognostic model, only p53 overexpression was found to provide additional prognostic information. Whatever the underlying mechanism of p53 overexpression, we found the vast majority of the p53-positive cells to be actively proliferating (MIB-1 positive). This indicates that p53 in THR-BCL is unable to exert its function as guardian of the genome by imposing growth arrest. Therefore, it does not come as a surprise that we have found overexpression of functionally inactive p53 to be inversely correlated with response to treatment and survival. In view of the findings of Alizadeh et al,3 who separated two clinically relevant groups within DLBCL on the basis of their gene expression profile, we attempted to correlate the tumor cells in THR-BCL with either germinal center B cells or activated B cells. Therefore, we studied the expression of CD10 and bcl-6, both generally accepted markers of germinal center differentiation.38-40 A germinal center origin for the neoplastic B cells may indeed be assumed in more than half of the THR-BCL cases that were found to express bcl-6, which is generally considered a more reliable marker of germinal center B cells than CD10.36,37 Presumably, even the cases that do not express bcl-6 may have descended from a germinal center ancestor that has lost bcl-6 somewhere during the course of its malignant transformation. The apparent relationship of the tumor cells in THR-BCL to the germinal center is in disagreement with the findings of Alizadeh et al,3 who suggested that germinal center characteristics are associated with an indolent clinical course. However, some residual clinical heterogeneity remained in the categories defined by gene expression profiling that could not be explained by gene expression patterns. Most of the patients in the favorable prognosis group who died experienced an aggressive type of disease, because they succumbed within the first 2 years after diagnosis. This indicates that some indicators might escape detection by gene expression profiling and that early identification of these aberrantly behaving sub-subgroups may improve prognostic accuracy.41 As suggested by its distinctive behavior, THR-BCL may represent such a peculiar germinal center neoplasm, with important prognostic implications justifying its recognition as a distinct clinicopathologic entity.
Supported in part by F.W.O. Flanders grant no. G.0362.01. R.A. is a research fellow of F.W.O. Flanders. We are indebted to our colleagues who submitted cases of THR-BCL or provided us with clinical data. Special thanks are due to C. Van den Broeck for excellent technical assistance.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
