New drugs for aggressive B-cell and T-cell lymphomas

Over the past decade an unprecedented number of new drugs for lymphomas have been developed. Most of these new drugs target molecules or pathways that are important for the growth and proliferation of lymphomas. The introduction of the B-lymphoma specific monoclonal anti-CD20 antibody, rituximab, has improved the prognosis of patients with B-cell lymphomas more than any other drug in the past 50 years; today less than half of the patients with aggressive B-cell lymphomas die of their disease than in the pre-rituximab era. Many new drugs are now available for clinical testing in addition to new CD20 antibodies and antibodies directed against other surface molecules specifically or preferentially expressed on the lymphoma-cell surface. A prerequisite for the development of these drugs was the recognition of aberrant cell-signal transduction involved in lymphoma pathogenesis and progression. New therapeutic targets include receptor tyrosine and cyclin-dependent kinases, histone deacetylases, and molecules involved in the regulation of apoptosis. The definition of the role of these new drugs alone or in combination with established chemotherapy regimens in adequately designed prospective trials represents one of the major challenges in clinical lymphoma research.     

Skin involvement of malignant B-cell lymphomas

In 1186 patients with systemic malignant B-cell lymphomas, the skin was involved in 6.17% of low-grade malignant, 9.7% of medium-grade malignant, and 7.4% of high-grade malignant lymphomas. Skin involvement is associated with an impaired prognosis in malignant B-cell lymphomas, with the exception of medium-grade malignant lymphomas.     

Primary gastrointestinal malignant lymphomas. A morphologic and immunohistochemical study

Thirty-nine primary gastric and 22 intestinal malignant lymphomas collected from 1969 to 1980 have been studied morphologically and immunohistochemically. Eighteen of the 61 gastrointestinal lymphomas were of low-grade malignancy (9 lymphoplasmacytoid/cytic, 3 centrocytic, 6 centroblastic/centrocytic) and 43 were of high-grade malignancy (14 centroblastic, 7 lymphoblastic, 22 immunoblastic malignant lymphomas) according to the Kiel classification. The peroxidase-antiperoxidase (PAP) method was used in 53 of the 61 cases. Twenty-seven of them revealed a monoclonal positivity for intracytoplasmic IgS: kappa light chains in 18 and lambda light chains in 7 cases. Two cases represented alpha chain disease, revealing only a heavy chain positivity. The most frequent staining pattern of the lymphoma cells was that of kappa/mu. Cells with a mixed centrocytic and plasma cell configuration (centrocytoid plasma cells) proved to be positive for intracytoplasmic IgS. Lymphoma cells of all tested cases proved to be negative for all histiocytic markers. Histologically and immunohistochemically, the Greek cases of primary gastrointestinal malignant lymphomas seem to resemble "western" type lymphomas.     

Histomorphologic and immunophenotypic spectrum of primary gastro-intestinal B-cell lymphomas.

In order to compare primary gastro-intestinal (GI) B-cell lymphomas histomorphologically and immunophenotypically with orthologous steps of B-cell differentiation within the mucosa-associated lymphoid tissue (MALT) of the GI tract, a comprehensive panel of well characterized leucocyte differentiation antigens was composed. It comprised immunoglobulin constituents CD5, CD10, CD11c, CD20, CD23, CD24, CD30, CDw32, CD38, CD39, CDw75, CD76, and vimentin. These antigens yield characteristic immunoprofiles for the following B-cell compartments of the MALT, per se closely linked to cytologically distinct B-cell phenotypes: mantle zone (MZ), extrafollicular compartment (EF), follicle center (FC), and plasma-cell compartment (PC). An unselected series of 31 MALT B lymphomas (13 of low and 18 of high grade malignancy) was classified histologically in routine preparations and subsequently characterized immunohistochemically using fresh frozen tissue, monoclonal antibodies (MAbs) against the antigen panel listed above, and an indirect immunoperoxidase method. The final classification considered both morphology and immunoprofile of tumor cells. Ten tumors were "typical" in both respects: 2 closely corresponded to MZ, 5 to EF, 2 to FC and 1 to PC. The remaining 21 cases were characterized as "atypical" because of anaplastic cytology and/or abnormal co-expression and/or loss of antigens. A hybrid EF/FC phenotype was most frequently observed together with centrocyte-like or centrocytic anaplastic cytology of tumor cells. We conclude that MALT B-cell neoplasia comprises a broad spectrum of histo- and immunophenotypes ranging from well differentiated forms closely mimicking normal B-cell development to highly abnormal tumors which cannot be subclassified.     

Fine-needle aspiration biopsy of peripheral T-cell lymphomas. A cytologic and immunophenotypic study of 33 cases

INTRODUCTION: Peripheral T-cell lymphoma (PTCL) accounts for 10-20% of all non-Hodgkin lymphomas in the United States. In this study, the authors reviewed the cytologic and immunophenotypic findings of 33 fine-needle aspirations (FNAs) of PTCL. METHODS: Thirty-three FNAs from 26 patients (12 females and 14 males) with PTCL were identified during 1991-1999. The patients' age ranged from 19 to 96 years. Immunophenotyping was performed in 24 cases by using either flow cytometry (FC; 21 cases) or immunocytochemistry (IC; 3 cases). Follow-up included review of prior or current histology and clinical records. RESULTS: Nine cases were associated with mycosis fungoides, three cases were classified as T-cell chronic lymphocytic leukemia, and two were angioimmunoblastic adenopathy (AILD)-like T-cell lymphoma. The remaining 19 were classified as PTCL, not otherwise specified. The latter consisted of eight mixed cell variant, eight large cell variant, and three anaplastic variant. One of the mixed cell variant and one of the large cell variants contained numerous epithelioid histiocytes (Lennert lymphoma). Thirty (91%) cases had a definitive diagnosis of malignant lymphoma. Twenty-two cases (2 IC and 20 FC) showed a predominant population of T lymphocytes without a monoclonal B-cell population. In addition, FC revealed an aberrant expression of T-cell markers in 13 cases. Two cases were interpreted as "atypical lymphoid population"; one case was an AILD-like T-cell lymphoma, and the other case was PTCL, large cell type. One case initially was interpreted as granulomatous lymphadenitis; subsequent biopsy revealed PTCL, Lennert type. CONCLUSIONS: Peripheral T-cell lymphoma is a heterogeneous group of lesions with diverse cytomorphology. Cytologic analysis and immunophenotyping is an accurate method of diagnosing peripheral T-cell lymphoma.     

Neoplastic and reactive follicles within B-cell malignant lymphomas. A morphological and immunological study of 30 cases

Thirty cases originally diagnosed as B-cell lymphomas, either LP immunocytoma, centrocytic (Cc), or centroblastic-centrocytic (Cb/Cc), containing follicular structures of an uncertain nature were critically reviewed using both morphological criteria and immunological techniques. In particular, they were tested by conventional antisera for detection of immunoglobulins in paraffin sections and also, in the 5 cases in which frozen material was available, by a panel of monoclonal antibodies. At the first histological evaluation the cases were divided into two groups. Group A consisted of 12 examples which showed homogeneous features and, because of the neoplastic nature of the follicular structures, could be classified as follicular centroblastic-centrocytic lymphomas with marked plasmacellular differentiation. Group B comprised 18 cases which at onset of disease revealed a mantle-fashion growth around reactive-appearing follicles formed by polytypic germinal centre cells. On closer examination, however, this group appeared heterogeneous: 13 cases displayed cytological and immunological findings consistent with the diagnosis of Cc and usually contained polytypic plasma cells; 5 cases were examples of LP immunocytoma consisting of monotypic elements only. Therefore, the so-called mantle-zone lymphoma does not appear to be an entity.     

Classification and treatment of rare and aggressive types of peripheral T-cell/natural killer-cell lymphomas of the skin.

BACKGROUND: The classification of cutaneous lymphomas has been contentious. Two major competing classifications were the World Health Organization (WHO) and the European Organization for Research and Treatment of Cancer (EORTC). The principal authors met for a consensus meeting resulted in a combined classification called WHO-EORTC Classification of Cutaneous Lymphoma. METHODS: We review the classification of "mature" or peripheral T-cell lymphoma (PTCL) with high predilection to the skin as published by the WHO-EORTC. We also highlight new information and changes from the previous classifications of cutaneous PTCL according to the WHO classification or the EORTC classification. Finally, the salient findings are compared with similar-looking nodal PTCLs with a high frequency of skin involvement. RESULTS: This review focuses on a rare group of cutaneous PTCLs other than mycosis fungoides or its variants. Changes from the previous classifications are discussed, and the rare group of nodal PTCLs with high predilection to the skin are presented. The salient findings, diagnostic features, and treatments are included, along with summary tables and clinical-histopathologic images. CONCLUSIONS: This review may serve as a guide for hematologists, oncologists and dermatologists in the diagnosis and management of these rare, aggressive, and often difficult to diagnose lymphomas. Although cutaneous lymphomas are morphologically identical to systemic lymphomas, the former behave differently, require divergent management, and should be recognized as separate entities. The consensus WHO-EORTC classification presents unified terminology and definitions to promote conformity in diagnosing and treating these cases, to foster a multidisciplinary approach to these often-obscure diseases, and to lead to more advances in identifying molecular targets specific to these entities.     

Molecular predictors of response in aggressive T-cell lymphomas

Aggressive T-cell lymphomas are a heterogeneous group of malignancies of mature T and natural killer cells, many of which have recently been identified as distinct entities in the classification of non-Hodgkin lymphomas according to the World Health Organization. Owing in part to a limited understanding of the molecular features and pathogenesis of many of these disorders, treatment strategies using conventional lymphoma regimens have been used, with generally inferior outcomes. Recent data are now emerging from gene expression profiling and molecular analysis of tumors, which has led to development of novel, targeted therapeutic strategies and has provided a basis for more accurate diagnosis and prognostic characterization.     

Primary malignant lymphomas of the spleen. A morphologic and immunohistochemical analysis of 17 cases

Seventeen cases of primary malignant lymphoma of the spleen (PMLS) were identified among 500 splenectomy specimens showing involvement by Hodgkin's disease or non-Hodgkin's lymphoma. All PMLS represented non-Hodgkin's lymphoma and most of them were of B-cell origin. In two cases PMLS were associated with hamartomas of the spleen (splenomas). Histologic and immunohistochemical studies did not reveal any differences between PMLS and disseminated malignant lymphomas with splenic involvement with regard to morphologic features, immunophenotype, host cell infiltrates, or proliferation activity. The reasons for the infrequent occurrence of primary lymphomas in the spleen may not be sought in a special immunophenotype of PMLS, a vigorous host response in the spleen, or in a lower proliferation activity of splenic lymphomas.     

Comparison of peripheral T-cell lymphomas and diffuse large B-cell lymphoma

BACKGROUND: Peripheral T-cell lymphomas (PTCLs) are a biologically heterogeneous subgroup of lymphomas with poor prognosis. In this study, the authors analyzed the clinical behaviors of PTCLs and diffuse large B-cell lymphoma (DLBCL). METHODS: The authors compared the characteristics and outcomes of 59 patients with PTCLs, including 33 angioimmunoblastic T-cell lymphomas and 26 unspecified peripheral T-cell lymphomas, with the characteristics and outcomes of 193 patients with DLBCLs who were treated in the era before rituximab. RESULTS: Based on the clinical characteristics, elevated lactate dehydrogenase (LDH), poor PS, advanced stage, higher International Prognostic Index score, and B symptoms were more common in patients with PTCLs, and bulky mass was more common in patients with DLBCL. The rates of complete response (CR) or an unconfirmed CR (CRu) were higher in patients with DLBCL (72%) than in patients with PTCLs (56%; P = .03). The 5-year overall survival (OS), progression-free survival (PFS), and disease-free survival (DFS) rates were 31%, 26%, and 47%, respectively, in patients with PTCLs and 59%, 55%, and 73%, respectively, in patients with DLBCL (P = .001, P < .001, and P = .003, respectively). Although multivariate analysis identified several risk factors that were significant in PTCLs, but not in DLBCLs, for the CR/CRu, OS, PFS, and DFS rates, the immunophenotype was not identified as a risk factor. CONCLUSIONS: The poor response and survival of patients who had PTCLs, compared with patients who had DLBCL, was caused by numerous initial risk factors. T-cell phenotype itself did not appear to have a significant impact on either response or survival.     

T-cell/histiocyte-rich large B-cell lymphomas and classical diffuse large B-cell lymphomas have similar outcome after chemotherapy: a matched-control analysis.

PURPOSE: Because it is unclear whether T-cell/histiocyte-rich large B-cell lymphomas (H/TCRBCL) should be considered as a true clinicopathologic entity, we conducted a matched-control analysis comparing patients with H/TCRBCL and patients with diffuse large-B cell lymphoma (B-DLCL). PATIENTS AND METHODS: More than 4,500 patients were enrolled onto non-Hodgkin's lymphoma trials conducted by the Groupe d'Etude des Lymphomes de l'Adulte. After histologic review, 50 patients were subclassified as H/TCRBCL. They were matched to 150 patients with B-DLCL for each of the factors of the International Prognostic Index (IPI). RESULTS: Clinical characteristics of H/TCRBCL patients showed a male predominance and a median age of 47 years. Performance status was normal in 89% of patients, whereas lactate dehydrogenase level was increased in 60% of patients. The disease was disseminated in 81% of patients, and 48% had two or more involved extranodal sites. The IPI score was >or= 2 in 53% of patients. The complete response rate to chemotherapy was 63%, and 5-year overall survival (OS) and event-free survival (EFS) rates (mean +/- SD) were 58% +/- 18% and 53% +/- 16%, respectively. The matched-control analysis showed a trend toward a better response to chemotherapy for patients with B-DLCL (P =.06), whereas no difference was observed in OS (P =.9) and EFS (P =.8). CONCLUSION: H/TCRBCL is an aggressive disease that often presents with adverse prognostic factors. However, when treatment is adapted to the disease risk, outcome is equivalent to that observed in patients with B-DLCL. Thus H/TCRBCL should be considered a pathologic variant that belongs to the B-DLCL category.     

Leukemogenesis and bone marrow hematopoietic disorders in baboons with immunoblastic malignant lymphomas of B- and T-cell types

Leukemization in baboon B- and T-cell immunoblastomas was investigated. Immunologic identification of tumor was carried out using standard immunological and cytochemical tests, e. g. identification of several types of E-rosette forming lymphocytes, surface and cytoplasmic immunoglobulin-carrying lymphocytes and assay of such acid hydrolases as acid phosphatase, acid alpha-naphthyl acetate esterase and beta-glucuronidase in lymphoid cells. Leukemization of immunoblastomas with bone marrow infiltration by tumor immunoblasts and the appearance of the latter in peripheral blood were observed rather frequently--in 7 of 10 cases of B-cell and in all 4 cases of T-cell immunoblastoma. Immunoblastoma progression was accompanied by a rise in lymphoid element level in peripheral blood and a lesser increase in bone marrow. At terminal stage, both patterns of immunoblastoma sometimes involved the development of leukemoid reactions of a myeloid type and disturbances in bone marrow hematopoiesis which manifested themselves by mild anemia and a slightly pronounced failure to produce platelets.     

儿童侵袭性成熟B细胞淋巴瘤的临床病理学及分子遗传学特点

 目的　分析总结中国儿童各类型侵袭性成熟B细胞淋巴瘤的临床病理学及分子遗传学特点,为其诊断的标准化提供依据。方法　收集97例儿童侵袭性成熟B细胞淋巴瘤石蜡包埋组织标本,包括伯基特淋巴瘤（BL）81例、弥漫大B 细胞淋巴瘤（DLBCL）8例、介于BL和DLBCL间的不能分类的B细胞淋巴瘤（BL／DLBCL）8例,利用免疫组织化学技术和间期荧光原位杂交（FISH）技术检测其免疫表型和分子遗传学特征。结果　BL的bcl-2和MUM1的阳性率分别为3 %（2／66）和17 %（12／71）,DLBCL分别为50 %（4／8）和63 %（5／8）,BL／DLBCL分别为 50 %（4／8）和63 %（5／8）。BL、DLBCL 和BL／DLBCL 的Ki-67平均值分别为（93±4.4）%、（83±14.3）%和（80±11.5）%。BL、DLBCL 和BL／DLBCL 的c-myc 基因易位的比例分别为98 %（79／81）、38 %（3／8）和50 %（4／8）。38 %（3／8）的DLBCL和25 %（2／8）的BL／DLBCL 存在bcl-6基因的多拷贝,BL与DLBCL 之间、BL与BL／DLBCL之间bcl-2、MUM1和 Ki-67平均值的差异及c-myc基因易位和bcl-6基因多拷贝的差异均有统计学意义（均P＜0.05）。结论　儿童侵袭性成熟B细胞淋巴瘤的诊断和分型需要综合分析形态学、免疫表型和分子遗传学特征。儿童BL／DLBCL 可能是DLBCL 的一个亚型。CD+10、bcl-6+、bcl-2-、Ki-67＞90 %、伴有IGH／c-myc重排、不伴有bcl-2和bcl-6重排时,支持BL的诊断;bcl-2+、Ki-67 为50 %～90 %,同时伴有bcl-6基因的多拷贝时,支持 DLBCL或BL／DLBCL 的诊断。     

Proliferation and apoptosis in malignant and normal cells in B-cell non-Hodgkin's lymphomas.

We have examined apoptosis and proliferation in lymph node cell suspensions from patients with B-cell non-Hodgkin''s lymphoma using flow cytometry. A method was developed which allowed estimation of the fractions of apoptotic cells and cells in the S-phase of the cell cycle simultaneously with tumour-characteristic light chain expression. Analysis of the tumour S-phase fraction and the tumour apoptotic fraction in lymph node cell suspensions from 95 B-cell non-Hodgkin''s lymphoma (NHL) patients revealed a non-normal distribution for both parameters. The median fraction of apoptotic tumour cells was 1.1% (25 percentiles 0.5%, 2.7%). In the same samples, the median fraction of apoptotic normal cells was higher than for the tumour cells (1.9%; 25 percentiles 0.7%, 4.0%; P = 0.03). The median fraction of tumour cells in S-phase was 1.4% (25 percentiles 0.8%, 4.8%), the median fraction of normal cells in S-phase was significantly lower than for the tumour cells (1.0%; 25 percentiles 0.6%, 1.9%; P = 0.004). When the number of cases was plotted against the logarithm of the S-phase fraction of the tumour cells, a distribution with two Gaussian peaks was needed to fit the data. One peak was centred around an S-phase fraction of 0.9%; the other was centred around 7%. These peaks were separated by a valley at approximately 3%, indicating that the S-phase fraction in NHL can be classified as ''low'' (< 3%) or ''high'' (> 3%), independent of the median S-phase fraction. The apoptotic fractions were log-normally distributed. The median apoptotic fraction was higher (1.5%) in the ''high'' S-phase group than in the ''low'' S-phase group (0.8%; P = 0.02). However, there was no significant correlation between the two parameters (P > 0.05).     

Differentiation between malignant B-cell lymphomas and pseudolymphomas of the skin

Among cutaneous pseudolymphomas (PL) in a strict sense, in which the etiology is largely unknown, B-cell types, simulating malignant B-cell lymphoma, and T-cell types, simulating malignant T-cell lymphoma of the skin, can be differentiated. Criteria favoring a pseudolymphomatous rather than a malignant lymphoid infiltrate of B-cell type may be clinical (solitary lesion on the head), histologic (wedge-shaped infiltrate with follicle formation and sharply demarcated germinal centers), or cytomorphologic (polymorphous infiltrate showing an admixture of great numbers of macrophages, plasma cells, and eosinophils). Additional information can be provided by enzymophenotyping of the cells, showing the typical starry-sky pattern of the macrophages in pseudolymphomatous infiltrates, and by the demonstration of the polyclonality of the lymphoid cells in pseudolymphomas with respect to surface markers and intracytoplasmatic Ig production, as shown by immunophenotyping techniques.     

Phenotypic overlaps between pleomorphic malignant T-cell lymphomas and mixed-cellularity Hodgkin's disease.

Histologically diagnosed, or in part questionable, malignant pleomorphic peripheral T-cell lymphomas (pPTCLs, n = 16) and mixed-cellularity Hodgkin's disease (MCHD, n = 12) were objectively compared by the use of combined immunohistochemistry on paraffin sections, test-point analysis of tissue components, and semi-automated nuclear morphometry on semi-thin resin sections. Classical, qualitative histomorphological distinction of these sub-types of lymphomas proved to be valid and is probably still the best method. Quantitative discriminant features, in order of decreasing significance, were: (i) expression by large atypical cells (LACs) of CD45R0, CD43 and CD45 in pPTCLs, and of CD30 and CD15 in MCHD; (ii) means and standard deviations (SDs) of LAC nuclear-profile areas (greater in MCHD than in pPTCLs); (iii) expression of CD3 by LACs in pPTCLs; (iv) prominence of small lymphoid cells in MCHD; (v) higher percentage of medium-sized lymphoid cells in pPTCLs; and (vi) higher SDs of nuclear-profile circularity factor of small lymphoid cells in MCHD. The medians of the largest nucleolar profile areas in LACs per field did not differ in pPTCLs and MCHD, but dispersion of individual values towards higher levels was significantly greater in the latter. Stepwise discriminant analysis of test point and nucleometric variables that best distinguished pPTCLs from MCHD revealed considerable overlaps, and questionable cases tended to be intermediate between the two. In conclusion, our results confirm and expand the notion of intra-group heterogeneity, with indistinct borders and the existence of intermediate phenotypes between these two taxonomic categories of malignant lymphomas.     

Quantitative study of KI-67 antibody staining in 46 T-cell malignant lymphomas using image analysis.

Image analysis with a SAMBA 2005 (ALCATEL-TITN, Co) was used to quantify the Ki-67 stained area percentage in 46 T-cell malignant lymphomas (T-ML), classified according to the updated Kiel classification. This parameter demonstrated correlation with the number of Ki-67-positive cellular profiles (r = 0.88, P less than 0.001) and was more reproducible than cell counting. A significant difference was found between low and high grade T-ML (mean values +/- SEM respectively of 10.20 +/- 1.82 per cent and 25.63 +/- 3.15 per cent). The most interesting findings were that: (1) AILD-type T-ML showed an intermediate proliferation rate (15.55 +/- 2.72 per cent) between pleomorphic T-ML with medium and with large cells (respectively 12.53 +/- 3.64 per cent and 22.43 +/- 3.46 per cent), both of which belong to the high grade malignancy group. This finding is in accordance with the poor prognosis of this subtype despite its classification in the low grade malignancy group. (2) Subclassification of the pleomorphic MLs according to the predominance of small, medium or large cells, demonstrated significant differences between these three subtypes. However, the great overlap of values between pleomorphic T-ML with medium and with large cells, seems to indicate that the subclassification of these two subtypes is less valid. (3) A wide range of values with overlap was observed in AILD-type ML, in pleomorphic with medium or large cells and in lymphoblastic T-ML: for these T-ML with variable survival courses, the Ki-67 area percentage, one parameter of proliferative activity, appears worth studying as a prognostic factor.     

Similar outcome of treatment of B-cell and T-cell diffuse large-cell lymphomas: the Stanford experience.

Although previous studies have suggested a relatively poor prognosis for some patients with peripheral T-cell lymphoma, the clinical significance of immunologic phenotype in diffuse large-cell lymphoma (DLCL) remains controversial. One hundred one patients with a uniform morphologic diagnosis of DLCL treated at Stanford between 1975 and 1986 with cyclophosphamide, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), vincristine, and prednisone (CHOP), methotrexate, bleomycin, Adriamycin, cyclophosphamide, vincristine, and dexamethasone ([M]BACOD), or methotrexate, Adriamycin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) chemotherapy were studied with regard to immunologic phenotype. Immunologic analysis, performed on frozen or paraffin-embedded tissue, identified 77 cases of B-cell origin, 21 cases of T-cell origin, and three cases that lacked B-cell or T-cell markers. Analysis of complete remission (CR) rates (84% v 95%), 5-year actuarial freedom from disease progression (38% v 53%), and 5-year actuarial overall survival (52% v 79%) showed no statistically significant differences in prognosis between B- and T-cell patients, respectively. The 5-year actuarial survival of patients with stage IV T-cell DLCL (56%) also did not differ in a statistically significant way from stage IV B-cell patients (36%). We conclude that treatment selection for DLCL should not be based on immunologic phenotype alone.