Morphological variability of tumour cells in T-cell-rich B-cell lymphoma

T-cell-rich B-cell lymphoma (TCRBCL) is an unusual lymphoma which is difficult to diagnose. A majority of reactive T-cells and numerous histiocytes mask the few large neoplastic B-cells. Fourteen cases of TCRBCL were studied in order to identify the main histological and cytological features useful for this diagnosis. Neoplastic cells are atypical and sometimes difficult to classify. Several types are seen; they are mostly centroblasts, which represent more than 50% of the tumour cells but are sometimes multilobated, immunoblasts- or Reed-Sternberg-like cells. Interestingly, at least two, and often three, types of tumour cell are present in all the cases. Epithelioid cells and histiocytes are always found and are often numerous. Hypervascularization and fibrosis are present in the majority of cases, but without annular bands. Necrosis is absent. All tumour cells express CD20 but EMA is expressed in less than half the cases. In two cases, the association of a diffuse large B-cell lymphoma in one site and a TCRBCL in another suggests that TCRBCL may be considered as a peculiar pattern of a diffuse large B-cell lymphoma with a strong stroma reaction. TCRBCL may not represent a clinicopathological entity.     

Non-Hodgkin's lymphoma, multilobated B-cell type: report of nine cases with immunohistochemical and immunoultrastructural evidence for a follicular center cell derivation

The clinical, pathologic, and immunologic features in nine cases of non-Hodgkin's lymphoma of the multilobated B-cell type are described. Clinical and phenotypic heterogeneity was observed in these B-cell neoplasms. A probable follicular center cell derivation for these cytologically unusual B-cell lymphomas is supported by antecedent histories of follicular center cell neoplasms in three cases; a focal nodular pattern in one case; the demonstration of peanut lectin (PNA) receptors, a marker for follicular center cells, on neoplastic multilobated B cells; and immunoultrastructural studies of nonneoplastic tonsillar cells that identified and characterized rare multilobated cells, immunoreactive for B1, B2, and Ia membrane antigens, a phenotype consistent with follicular center-type cells. Comparison of B- and T-cell multilobated lymphomas revealed that only immunologic studies accurately discriminated between these neoplasms.     

High-grade non-Hodgkin''s lymphoma of B-cell type. I. Histopathology

One hundred and twenty-eight cases of high-grade malignant B-cell lymphoma were studied with a plastic re-embedding technique and classified according to the Kiel classification. The cytological details could be better recognized than in the original paraffin sections, thus permitting a more precise definition of the various lymphoma types. The entities centroblastic and immunoblastic lymphoma are more precisely defined and supplemented by the addition of several new variants. In contrast to the present Kiel classification we separate Burkitt's from lymphoblastic lymphoma. In all cases investigated, the B-cell nature of the tumour cells was proven by immunohistochemistry using monoclonal antibodies. The four entities of high-grade malignant B-cell lymphoma described in this paper are: (1) centroblastic lymphoma with four morphological variants (monomorphic, polymorphic, multilobated and centrocytoid); (2) immunoblastic lymphoma with three morphological variants (with or without plasmacytic differentiation, with many lymphocytes); (3) Burkitt's lymphoma and the closely related Burkitt's lymphoma-like lymphoma with plasmablastic differentiation; and (4) lymphoblastic lymphoma. Only the centroblastic lymphomas (in 17%) showed occasional follicular growth pattern, which further confirms the view that they are derived from germinal centre cells.     

Relative distribution of tumour cells and reactive cells in follicular lymphoma

Follicular lymphoma is the most common low-grade B-cell lymphoma. It is characterized by at least a partial follicular growth pattern in the majority of cases, by the morphological resemblance of the tumour cells to follicle centre centroblasts and centrocytes, and by the distinctive expression of Bcl-2 protein as a consequence of a translocation between chromosomes 14 and 18, resulting in the juxtaposition of Bcl-2 and the immunoglobulin heavy chain locus. It is not known whether the follicular growth pattern of follicular lymphoma is a consequence of properties of the tumour cells, or whether the tumour cells invade and gradually occupy a niche generated by a normal T-cell-dependent B-cell response. This study has identified cases of follicular lymphoma in which the tumour cells are apparent within a normal reactive germinal centre background. The reactive background has been investigated in these cases and also in cases showing a more characteristic appearance, in which entire malignant follicles appear to be Bcl-2-positive, as assessed by microdissection and analysis of clonality by the polymerase chain reaction (PCR). A reactive oligoclonal background was observed in all cases studied, characteristic of a normal follicle centre response. These data suggest that the progression of follicular lymphoma is dependent on the normal germinal centre microenvironment. Disruption of this dependence might be considered as a novel therapeutic strategy.     

Utility of SKP2 and MIB-1 in grading follicular lymphoma using quantitative imaging analysis

Follicular lymphoma is classified into grades (G)1, 2, and 3 based on the number of centroblasts in neoplastic follicles. However, the accuracy of manually counting these centroblasts is limited by certain cells (large centrocytes, follicular dendritic cells, and histiocytes) that could mimic centroblast morphology. The reproducibility of follicular lymphoma grading is dependent upon observer experience; therefore, significant variations occur. This study is to explore a more objective, reliable way of grading follicular lymphoma using a quantitative imaging system in conjunction with immunostains with antibodies to proliferation markers MIB-1 and S-phase kinase-associated protein 2 (SKP2). Fifty-eight follicular lymphomas (G1, n = 23; G2, n = 18; and G3, n = 17) were studied on formalin-fixed, paraffin-embedded sections. Positive nuclear staining of both Ki-67 and SKP2 was recorded using the quantitative Clarient ACIS II system (Aliso Viejo, CA, USA). Ten high-power fields (x400) from randomly selected neoplastic follicles were counted by a pathologist blinded to the previously assigned morphologic grade. The results show that the percentages of Ki-67+ and SKP2+ cells significantly differ among the different grades of follicular lymphoma. A higher grade of follicular lymphoma is associated with a higher percentage of Ki-67+ and SKP2+ cells. The overall SKP2+% cells are substantially lower than Ki-67+% cells in the same grade of follicular lymphoma. Statistical significance is observed in Ki-67+ cells between follicular lymphoma G1 and follicular lymphoma G3 and between G1 and G2. In contrast, statistical significance is noted in SKP2+% cells between follicular lymphoma G1 and follicular lymphoma G3 and between follicular lymphoma G2 and follicular lymphoma G3. The findings suggest that the SKP2 expression has better discrimination with grades of follicular lymphoma than Ki-67 expression. Compared with traditional methods, quantitation of SKP2 expression using a quantitative image analysis system might be a useful and objective approach in grading follicular lymphoma.     

Immunohistological characterization of malignant lymphomas of the Waldeyer''s ring other than the nasopharynx

Among extranodal lymphomas, the Waldeyer's ring is the second most frequently involved site after the gastrointestinal tract. Fresh tissue from 23 consecutive cases of malignant lymphoma of the faucial tonsil, palate and base of tongue were studied histologically and with a panel of 25 monoclonal antibodies. Twenty cases were primary Waldeyer's ring lymphoma, and all were found to express B-cell phenotype. Most cases were classified as diffuse centroblastic lymphoma, polymorphic subtype, in which there were immunoblast-like, centrocyte-like and/or multilobated centroblasts. All except one case expressed all three B-cell lineage antigens CD19, CD20 and CD22, but they showed inconsistent expression of the B-cell antigens CD9 and CD24. Four cases lacked surface immunoglobulin. Six cases expressed interleukin-2 receptor, suggesting that they were composed of highly activated B-cells. Three cases represented relapse in the tonsil or tongue in patients with known malignant lymphoma in other sites; one case expressed T-cell and two cases B-cell phenotype (both of which also expressed interleukin-2 receptor). The clinical features and immunohistological findings suggest that Waldeyer's ring lymphomas, other than those of the nasopharynx, share some of the characteristics of 'mucosa-associated lymphoid tissue' lymphomas. In contrast, nasopharyngeal lymphomas are more related to nasal lymphomas, and are almost exclusively peripheral T-cell neoplasms.     

Expression of p63 in anaplastic large cell lymphoma but not in classical Hodgkin's lymphoma

Immunohistochemical determination of p63 protein is frequently used in the pathologic diagnosis of nonhematological solid tumors. In malignant hematological disease, p63 expression has been reported in 22% of follicular lymphoma, about 35% of diffuse large B-cell lymphoma, 23% of chronic lymphocytic leukemia, and in some cases of blast crisis of chronic myelogenous leukemia. Anaplastic large cell lymphoma is a rare disease that accounts for less than 5% of all cases of non-Hodgkin's lymphoma. There is little information concerning p63 expression in this specific type of lymphoma. In some cases, the morphological and phenotypic features between anaplastic large cell lymphoma and classical Hodgkin's lymphoma are similar, making this differential diagnosis challenging. We studied p63 expression using a tissue microarray approach in 154 cases of anaplastic large cell lymphoma, including 38% anaplastic large cell kinase positive and 62% anaplastic large cell kinase negative, and 58 Hodgkin's lymphoma cases. Sixty-eight cases of anaplastic large cell lymphoma (44%) showed p63 nuclear positivity (41% of anaplastic large cell kinase positive and 47% of anaplastic large cell kinase negative). Of 130 cases of systemic-anaplastic large cell lymphoma, 42% showed p63 positivity. The neoplastic cells expressed p63 in 38% of the cases of CD45-negative/anaplastic large cell kinase-negative null cell-type anaplastic large cell lymphoma, a subgroup that offers the most difficulties in the differential diagnosis with classical Hodgkin's lymphoma. In contrast, none of the cases of classical Hodgkin's lymphoma demonstrated any p63 expression. These results demonstrate that p63 protein expression is frequently expressed in a subset of anaplastic large cell lymphoma cases and may be used as a potential tool in the differential diagnosis between anaplastic large cell lymphoma and classical Hodgkin's lymphoma.     

CD20-negative follicular lymphoma

Follicular lymphoma is one of the commoner diagnosed Non-Hodgkin Lymphomas (NHL) of adults in the North America and Europe. It is a B-cell lymphoma, composed of neoplastic centrocytes and centroblasts that express the pan-B cell antigens CD20 and CD79a and the follicle centre markers CD10 and bcl-6.     

Monocytoid/marginal zone B-cell differentiation in follicle centre cell lymphoma

We report on two cases of low grade follicle centre cell lymphoma with a pronounced parafollicular monocytoid/marginal zone B-cell component. One patient had a history of preceeding follicular high grade B-cell lymphoma of centroblastic type showing the same light chain restriction and identical immunoglobulin heavy chain gene rearrangement as the low grade lymphoma diagnosed 15 months later. Morphologically, in both cases the two constituents of the low grade tumours were clearly distinguishable. Immunohistochemically, the follicular component strongly expressed bcl-2 protein in contrast to a weak staining of the marginal zone B-cell component. Performing PCR, a rearrangement of the major breakpoint region of bcl-2 was not found. Identical light chain restriction of the follicular and the monocytoid B-cell/marginal zone components strongly indicates a clonal relationship between them. A monocytoid/marginal zone B-cell component in follicular lymphoma probably results from differentiation of the follicle centre cells and does not indicate a composite lymphoma.     

Ultrastructural characteristics of malignant non-Hodgkin's lymphoma in baboons

The ultrastructure of 29 malignant non-Hodgkin's lymphomas of baboons including prolymphocytic lymphoplasmacytic, lymphoblastic, and immunoblastic malignant lymphomas is described. The ultrastructure of the cells of B-cell malignant lymphomas is characterized by a more developed strands system of rough endoplasmic reticulum in the tumor cell cytoplasm and the presence of structural abnormalities in the protein synthesis in some B-cell malignant lymphoma cells in the form of Russell's and Dutcher bodies. Analogous baboon and human tumors were shown to have a high degree of cell ultrastructure similarity. Rare forms of baboon malignant non-Hodgkin's lymphomas including a large-cell variant of T-cell lymphoblastic lymphoma with large multilobated nuclei and a variety of B-cell lymphoma with an intermediate degree of cell differentiation have been found. Malignant lymphoma of large multilobated T-cell type and lymphoma of the intermediate lymphocytic type occur rarely in human pathology too.     

A malignant lymphoma with histological features and immunophenotypic profile intermediate between EBV-positive diffuse large B-cell lymphoma and EBV-positive classical Hodgkin lymphoma in a 67-year-old female: a "gray zone" lymphoma associated with Epstein-Barr virus in the elderly

Epstein-Barr virus (EBV) can be associated with both classical Hodgkin lymphoma (cHL) and non-Hodgkin lymphoma of the B-cell type, particularly in immunodeficient patients or elderly individuals. While polymorphic variants of EBV-positive large B-cell lymphoma (EBV+ DLBCL) frequently resemble cHL in morphology, and thereby may cause diagnostic difficulty, a true gray zone lymphoma with overlapping morphological and immunophenotypical features of EBV+ DLBCL and EBV+ cHL has not been reported in the literature. We describe a unique case of an EBV+ malignant lymphoma of B-cell origin with hybrid features of EBV+ DLBCL and EBV+ cHL in a 67-year-old female without an identifiable etiology for immunodeficiency. The biopsy of an enlarged lymph node showed a polymorphic infiltrate containing Reed-Sternberg-like pleomorphic large cells, which were positive for CD30 and CD15. Although CD20 was negative and PAX5 and CD45 were down-regulated, the pleomorphic large cells expressed multiple other B-cell antigens which are characteristically absent in cHL. EBV-encoded RNA hybridization (EBER) studies demonstrated nuclear reactivity in the large cells as well as in the smaller bystander cells. A clonal rearrangement of the immunoglobulin heavy chain gene was also detected by PCR. Although the results of the EBV and genotypic studies suggest this case may be an example of EBV+ DLBCL of the elderly instead of EBV+ cHL, the immunophenotype is strikingly ambiguous. Thus, this case may represent an interface between EBV+ DLBCL and EBV+ cHL.     

The morphological spectrum of monocytoid B-cell lymphoma and its relationship to lymphomas of mucosa-associated lymphoid tissue

We report 10 cases of monocytoid B-cell lymphoma, five of which had extranodal lymphomas of mucosa-associated lymphoid tissue (MALT) type. In one patient the MALT lymphoma in the salivary gland was microscopic. In another, the small bowel lymphoma, which preceded the monocytoid B-cell lymphoma by 11 years, showed different clonal immunoglobulin gene rearrangements. Attention is drawn to the extreme degree of plasmacytic differentiation and epithelioid cell infiltration that may occur in monocytoid B-cell lymphoma. In addition to the cytological and immunophenotypic likeness of monocytoid B-cells and centrocyte-like cells, monocytoid B-cell and MALT lymphomas share a number of micro-anatomical and behavioural characteristics. These include the sharp separation of the monocytoid B-cells and plasma cells, follicular colonization and progression to high-grade lymphoma. It is suggested that the frequent association of monocytoid B-cell lymphoma with Sjögren's syndrome may be due to the fact that the salivary glands drain to cervical lymph nodes that are part of the systemic, rather than the mucosal, lymphocyte circulation pathway.     

Expression of FoxO3a in clinical cases of malignant lymphoma

Cancer-initiating cells (CICs) are a limited number of cells with tumorigenic activity. Few studies have been performed on CICs in malignant lymphoma. We recently demonstrated that a small number of FoxO3a-expressing cells possessed CIC-like potential in Hodgkin's lymphoma (HL) cell lines. In the present study, FoxO3a expression was examined immunohistochemically in 137 patients with malignant lymphoma. Among patients with HL, FoxO3a-positive tumor cells were detected in 11 of 11 with nodular sclerosis classical HL, 8 of 15 with mixed cellularity classical HL, 0 of 1 with lymphocyte-rich classical HL, and 2 of 3 with nodular lymphocyte-predominant HL. Only limited numbers of patients with non-HL expressed FoxO3a: 4 of 66 with diffuse large B-cell lymphoma, 1 of 20 with follicular lymphoma, and 1 of 5 with peripheral T-cell lymphoma, not otherwise specified. No FoxO3a expression was detected in patients with mantle cell lymphoma (n = 3), extranodal marginal zone B-cell lymphoma (n = 3), mediastinal large B-cell lymphoma (n = 1), NK/T cell lymphoma (n = 5), anaplastic large cell lymphoma (n = 2), or T-lymphoblastic lymphoma/leukemia (n = 2). These results suggest that FoxO3a is expressed mostly in patients with HL, but not in patients with non-HL. FoxO3a expression was limited to a small number of Hodgkin cells in a quiescent state. FoxO3a may be a CIC marker of HL, but not of non-HL.     

Follicular lymphoma of the skin and superficial soft tissues associated with a prominent follicular dendritic cell proliferation: an unusual pattern which may represent a diagnostic pitfall

We describe two elderly patients with follicular lymphoma (FL) involving the skin and superficial soft tissues, with a striking proliferation of follicular dendritic cells (FDC). In addition, one patient had bone marrow involvement by FL. Histopathologically, the most remarkable feature in both cases seen at low magnification was a striking pallor of the constituent cells, which were arranged in fascicles, whorls, and round islands. The majority of the cells had the typical cytologic features of FDCs. They were intimately intermingled with centroblasts and centrocytes. A large amount of the clear cytoplasm and the pale nuclei of FDCs, which predominated in the tumors, caused the striking overall pallor of the lesions. Small reactive lymphocytes were scattered between the fascicles. A vague follicular growth pattern was seen only focally. The mantle zones were markedly reduced or absent so that the follicles were seen lying unseparated. The close intermixture of the FDCs and the germinal center cells was responsible for the FDCs appearing to be decorated with B-associated marker, and the germinal center cells seemed to be stained to some degree with FDC-markers. The tumor bulk demonstrated a diffuse and strong reaction with CD10, CD20, CD21, CD35, and stained weakly with CD79a. Fascin and CD23 showed only a weak and focal staining pattern. Bcl-2 decorated large centroblasts and small reactive T-cells. The tumor bulk was negative for actin, EMA, cytokeratins, vimentin, desmin, and factor XIIIa. The proliferative index was rather low; MIB-1 mainly decorated large centroblasts. No monoclonal rearrangement of IgH genes was detected. Epstein-Barr virus was not identified. Electron microscopy revealed typical features of FDCs intermingled with germinal center cells. Such cases may represent a diagnostic pitfall, as FDC overgrowth can mask FL and give the neoplasm the appearance of FDC sarcoma/tumor. We believe that, in both cases, the FDC proliferation had a reactive character.     

Malignant lymphoma with myxoid stroma: a new pattern in need of recognition

We report a case of malignant lymphoma in the soft tissues exhibiting prominent myxoid stromal changes and cord-like cellular arrangement, mimicking the architectural as well as cytological features of myxoid chondrosarcoma, except for the absence of tumour lobulation. The only clue to the possible lymphomatous nature of the lesion was the past history of lymphoma. Immunohistochemical studies showed that this represented a B-cell lymphoma, staining positively for leucocyte common antigen and five B-lineage markers L26, MB2, B1 (CD20), B4 (CD19) and To15 (CD22). We conclude that malignant lymphoma should not be excluded from consideration when one encounters a myxoid tumour.     

原发性胃肠非MALT型淋巴瘤的临床与病理分析

目的：研究胃肠原发性非ＭＡＬＴ型淋巴瘤形态特征、诊断要点和鉴别、为临床治疗和预后提供依据,方法：胃肠淋巴瘤标本常规制片,免疫组化ＡＢＣ法标记光镜观察。结果：３１例非ＭＡＬＴ型淋巴瘤中,（１）肠病相关／不相关Ｔ细胞淋巴瘤２１例,其中肠病盯关１６例;（２）ＭＭＣＬ３例在肠道呈息肉样,套细胞增生或浸润反应性滤泡内。（３）ＭＦＬ２料呈息肉样或形成肿块,由中心细胞和中心母细胞组成;（４）大多叶核淋巴瘤２例;     

Expression of Grb2 distinguishes classical Hodgkin lymphomas from primary mediastinal B-cell lymphomas and other diffuse large B-cell lymphomas

Growth factor receptor-bound protein 2 is an adaptor molecule that mediates B-cell receptor (BCR) signaling pathways, but the expression of growth factor receptor-bound protein 2 in lymphoma tissues has not been reported. We sought to characterize growth factor receptor-bound protein 2 protein expression in reactive tonsillar tissues and lymphoma tissues obtained from diagnostic biopsies of classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, diffuse large B-cell lymphoma, nodular lymphocyte predominant Hodgkin lymphoma, and 20 low-grade B-cell lymphomas. Growth factor receptor-bound protein 2 expression was assessed in tissues by immunohistochemistry and in lymphoma cell lines by immunoblotting. In reactive lymphoid tissues, growth factor receptor-bound protein 2 was expressed in the cytoplasm of B-cells and histiocytes but not T-cells. Strong, cytoplasmic growth factor receptor-bound protein 2 expression was seen in the neoplastic cells of follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, splenic marginal zone lymphoma, primary mediastinal large B-cell lymphoma, diffuse large B-cell lymphoma, and nodular lymphocyte predominant Hodgkin lymphoma. In contrast, only 10% of the classical Hodgkin lymphomas showed growth factor receptor-bound protein 2 expression in the neoplastic cells. Growth factor receptor-bound protein 2 protein expression was detected by Western blotting in all lymphoma cell lines tested with higher levels in primary mediastinal large B-cell lymphoma compared with classical Hodgkin lymphoma cell lines. These findings support a role for growth factor receptor-bound protein 2 in the diagnostically challenging workup of classical Hodgkin lymphoma versus primary mediastinal large B-cell lymphoma and warrant further studies to evaluate the biologic significance of growth factor receptor-bound protein 2 in the pathogenesis of classical Hodgkin lymphoma.     

Diffuse large B-cell lymphoma arising in a composite lymphoma with biclonality by flow cytometry and one monoclonal band by PCR

Composite lymphoma (CL) refers to the presence of two or more distinct types of lymphomas in a single organ or tissue. CL is an infrequent finding and may be due to the existence of two genetically related neoplasms, i.e. transformation of a single lymphoma into another lymphoma, or be due to the presence of two clonally unrelated lymphomas. CL composed of more than two lymphomas is even rare. Herein we describe a case of diffuse large B-cell lymphoma (DLBCL) arising in a CL of follicular lymphoma (FL) and small lymphocytic lymphoma (SLL) in an inguinal lymph node of an 85 year old woman. The three lymphomas were morphologically and immunophenotypically distinct while flow cytometry detected two monoclonal B-cell populations. Karyotyping and Polymerase Chain Reaction (PCR) for B-cell clonality each detected a single monoclonal B-cell population. The morphology findings may suggest DLBCL being transformed from FL while Richter transformation from SLL appears to be less likely in our case. Due to the single clone by chromosome study and PCR study, the precise relationships of the three lymphomas are unknown.     

Composite lymphoma: the interface between Hodgkin's and non-Hodgkin's lymphoma

Hodgkin's lymphoma is a rare neoplasm mainly affecting young people. Within the last decade, nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL) has been separated from all other cases of the so-called classical type. Moreover, the derivation of Hodgkin's lymphoma from germinal centre B-cells has been established, giving rise to a possible clonal relationship between Hodgkin's lymphoma and the non-Hodgkin's lymphomas (NHLs). The interface between them therefore has both diagnostic and biological aspects. Diagnostic difficulties arise, due to overlapping definitions, between biologically unrelated entities, e.g. classical Hodgkin's lymphoma and NLPHL or anaplastic large cell lymphoma, respectively. On the other hand, there is a biological grey zone regarding composite lymphomas consisting of Hodgkin's lymphoma and any NHL. This simultaneous or subsequent occurrence of Hodgkin's lymphoma and non-Hodgkin's lymphomas may, or may not, be clonally related. For management purposes lymphomas, e.g. NLPHL and T cell-rich B-cell lymphoma, must be distinguished along a continuous spectrum of progression.     

An unusual morphological variant of follicular lymphoma. Report of two cases

Most follicular lymphomas can be readily diagnosed on morphological grounds by finding closely packed pale-staining follicles partitioned by scanty dark-staining interfollicular tissue. We describe two cases of an unusual 'reverse' variant of follicular lymphoma in which the nodules have dark-staining centres and pale-staining cuffs due to concentration of centroblasts at the periphery of the neoplastic follicles. Recognition of this unusual pattern of follicular lymphoma is important, to avoid confusion with progressive transformation of germinal centres or nodular lymphocyte predominance Hodgkin's disease.