Identification of common germinal-center B-cell precursors in two patients with both Hodgkin's disease and non-Hodgkin's lymphoma

BACKGROUND: Hodgkin's disease and non-Hodgkin's B-cell lymphoma occasionally occur in the same patient. The identification of a common precursor of the two types of lymphoma would show definitively that Reed-Sternberg cells originate from B cells. METHODS: We studied lymphomas from two patients, one with a composite lymphoma (classic Hodgkin's disease and a follicular lymphoma in the same lymph node) and the other with a T-cell-rich B-cell lymphoma that was followed by classic Hodgkin's disease. Single Reed-Sternberg cells and non-Hodgkin's lymphoma cells from frozen sections were micromanipulated. The rearranged immunoglobulin variable-region genes (V genes) of the heavy and light chains were amplified by the polymerase chain reaction from genomic DNA and sequenced. RESULTS: In both patients, the Reed-Sternberg cells were related clonally to the non-Hodgkin's lymphoma B cells. The V genes carried somatic mutations (a hallmark of germinal-center B cells and their descendants). In both patients, some somatic mutations were shared by the Reed-Sternberg and non-Hodgkin's lymphoma cells, whereas other somatic mutations were found exclusively in one or the other cell type. CONCLUSIONS: In two patients with classic Hodgkin's disease and non-Hodgkin's B-cell lymphoma, we identified a common B-cell precursor, probably a germinal-center B-cell, for both lymphomas. This finding suggests that the two types of lymphoma underwent both shared and distinct transforming events and provides proof of the B-cell derivation of Reed-Sternberg cells in classic Hodgkin's disease.     

Clusterin expression in malignant lymphomas: a survey of 266 cases.

Clusterin expression has been reported to be characteristic of systemic anaplastic large cell lymphoma and usually negative in cutaneous anaplastic large cell lymphoma as well as other lymphoma types. We surveyed clusterin expression using immunohistochemical methods in 266 cases of non-Hodgkin's lymphoma and Hodgkin's disease to further assess the diagnostic utility of this marker. Clusterin immunostaining was observed in 40 of 49 (82%) systemic anaplastic large cell lymphomas and 12 of 29 (41%) cutaneous anaplastic large cell lymphomas. Clusterin also was expressed in 5 of 43 (12%) diffuse large B-cell lymphomas (4 of 5 CD30+), 1 of 14 (7%) peripheral T-cell lymphomas, 1 of 32 (3%) cases of nodular sclerosis Hodgkin's disease, and 1 case of mycosis fungoides in large cell transformation. Clusterin was negative in all other neoplasms assessed including follicular lymphoma of all grades (n = 24), mantle cell lymphoma (n = 13), marginal zone B-cell lymphoma (n = 12), precursor T-cell or B-cell lymphoblastic leukemia/lymphoma (n = 10), mixed cellularity Hodgkin's disease (n = 8), chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 7), Burkitt lymphoma (n = 7), mycosis fungoides (n = 4), nodular lymphocyte predominant Hodgkin's disease (n = 3), lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (n = 2), and plasmacytoma (n = 2). We conclude that clusterin is a marker of anaplastic large cell lymphoma and that addition of clusterin to antibody panels designed to distinguish systemic anaplastic large cell lymphoma from classical Hodgkin's disease is useful. However, clusterin is also positive in a substantial subset of cutaneous anaplastic large cell lymphomas, a smaller subset of diffuse large B-cell lymphomas, and rarely in cases of peripheral T-cell lymphoma and nodular sclerosis Hodgkin's disease.     

BAFF-R, the major B cell-activating factor receptor, is expressed on most mature B cells and B-cell lymphoproliferative disorders

B cell-activating factor receptor (BAFF-R) is one of three known receptors for BAFF, a critical regulator of B- and T-cell function. In mice, BAFF-R is required for B-cell maturation and survival, and in mice and humans, the overproduction of BAFF is associated with autoimmune disease. We sought to determine the normal pattern of BAFF-R expression at specific stages of B- and T-cell development and whether this pattern of expression corresponds with related B- and T-cell neoplasms. Most circulating human B cells and a small subset of T cells are BAFF-R-positive. In reactive lymphoid tissues, BAFF-R is expressed by B cells colonizing the mantle zones, by a subset of cells within germinal centers, and rare cells in the interfollicular T-cell zone. BAFF-R is also expressed by B cells colonizing the splenic marginal zone. Seventy-seven (78%) of 116 cases of B-cell lymphoproliferative disorders were BAFF-R-positive by immunohistochemical and/or flow cytometric immunophenotypic analysis, including most cases of mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, chronic lymphocytic leukemia, hairy cell leukemia, and diffuse large B-cell lymphoma. In contrast, cases of precursor B lymphoblastic lymphoma, Burkitt lymphoma, and nodular lymphocyte-predominant Hodgkin lymphoma exhibit weak to negative staining for BAFF-R. All cases of classical Hodgkin lymphoma and T-cell lymphomas were BAFF-R-negative, including all cases of anaplastic large cell lymphoma, adult T-cell leukemia/lymphoma, angioimmunoblastic T-cell lymphoma, and peripheral T-cell lymphoma, unspecified. These findings highlight BAFF-R as a marker of both normal and neoplastic B cells and raise the possibility that BAFF-R expression is necessary for the survival of a subset of neoplastic B lymphocytes analogous to its known role in promoting normal B-cell maturation and survival.     

Monoclonal antibodies reactive in routinely processed tissue sections of malignant lymphoma, with emphasis on T-cell lymphomas

The immunoreactivity of eight monoclonal antibodies was evaluated on 45 routinely processed lymphomas (22 T-cell lymphomas, 11 B-cell lymphomas, and 12 cases of Hodgkin's disease). Two antibodies reactive with leukocyte common (T200) antigens (PD7/26 and 2B11) stained most of the B- and T-cell lymphomas but did not stain the Reed-Sternberg cells and variants in Hodgkin's disease. Two antibodies known to stain B cells (LN-1 and LN-2) reacted with some of the B-cell lymphomas, but LN-2 also reacted with the neoplastic cells in six of 22 T-cell lymphomas and with the Reed-Sternberg variants in eight of 12 cases of Hodgkin's disease. The granulocyte antibody anti-Leu M1 reacted with most cases of Hodgkin's disease but also reacted with two of 11 B-cell non-Hodgkin's lymphomas. An antibody to epithelial membrane antigen (anti-EMA) stained some cases of T-cell lymphoma, B-cell lymphoma, and Hodgkin's disease. Leu 7 was expressed in one T-cell lymphoma and in one case of Hodgkin's disease. A novel antibody reactive with T cells (L60) stained all cases of T-cell lymphoma but also stained some cases of B-cell lymphoma and one case of Hodgkin's disease. We conclude that none of these antibodies, when used alone on routinely fixed paraffin-embedded material, is completely sensitive and specific for T-cell lymphoma, B-cell lymphoma, or Hodgkin's disease. However, a panel of antibodies is useful in distinguishing Hodgkin's disease from non-Hodgkin's lymphoma and in suggesting the B- or T-cell phenotype of non-Hodgkin's lymphomas.     

T-cell/histiocyte-rich large B-cell lymphoma is a disseminated aggressive neoplasm: differential diagnosis from Hodgkin's lymphoma

AIMS: An accurate diagnosis of T-cell/histiocyte-rich large B-cell lymphoma needs to take into consideration those forms of Hodgkin's lymphoma also characterized by a predominance of small lymphocytes and histiocytes, i.e. nodular lymphocyte predominance Hodgkin's lymphoma and lymphocyte-rich classical Hodgkin's lymphoma. We have studied the clinical, phenotypic and genetic features of a series of 12 cases of T-cell/histiocyte-rich large B-cell lymphoma along with 18 cases of Hodgkin's lymphoma for comparative purposes. METHODS AND RESULTS: Of the Hodgkin's lymphoma cases, there were 11 lymphocyte predominance type and seven classic type. T-cell/histiocyte-rich large B-cell lymphomas presented usually in advanced stages (III or IV in 11/12 cases), frequently with 'B' symptoms (6/9 cases), and followed a more aggressive course than Hodgkin's lymphoma (4/8 patients died due to the tumour in T-cell/histiocyte-rich large B-cell lymphoma versus 0/15 in Hodgkin's lymphoma). T-cell/histiocyte-rich large B-cell lymphoma cases showed diffuse effacement of the nodal architecture by a proliferation of scattered large atypical B-cells obscured by a background of small T-lymphocytes (more CD8+, TIA1+ than CD57+). Five cases showed also a prominent histiocytic component. The large B-cells expressed CD45 and often EMA (6/10 cases). On the other hand, CD 30, CD15 and latent infection by Epstein-Barr virus (EBV) were generally lacking. bc l6 and CD10 were, respectively, detected in 6/6 and 1/5 cases. Conventional polymerase chain reaction (PCR) showed monoclonal immunoglobulin heavy chain (IgH) gene rearrangements in all T-cell/histiocyte-rich large B-cell lymphomas studied (5/5), but did not detect any case with t(14;18) involving the major breakpoint region (0/4). CONCLUSIONS: The differential diagnosis of T-cell/histiocyte-rich large B-cell lymphoma from Hodgkin's lymphoma is facilitated by the integration of different immunophenotypic, molecular and clinical findings. T-cell/histiocyte-rich large B-cell lymphoma is a monoclonal neoplasm of bc l6+ B-cells with a phenotypic profile similar to lymphocyte predominance Hodgkin's lymphoma, suggesting a germinal centre origin and a possible relation to this disease. Therefore, in order to distinguish it from lymphocyte predominance Hodgkin's lymphoma, characterization of the reactive background, IgH gene rearrangement studies by conventional PCR and clinical features are more useful. In contrast, T-cell/histiocyte-rich large B-cell lymphoma can be distinguished from classical Hodgkin's lymphoma thanks to the presence of monoclonal IgH rearrangement and the CD 30-CD15-CD45+EMA+ immunophenotypic profile of the neoplastic cells in T-cell/histiocyte-rich large B-cell lymphoma.     

CD40 ligand is constitutively expressed in a subset of T cell lymphomas and on the microenvironmental reactive T cells of follicular lymphomas and Hodgkin's disease.

Although CD40 has been extensively studied in B- and T-cell non-Hodgkin's lymphomas (NHLs)/leukemias, and more recently in Hodgkin's disease (HD), little is known about the expression of its ligand (CD40L) in lymphoproliferative disorders other than T-cell NHLs/leukemias. A series of 121 lymphoma/leukemia samples, including 35 cases of HD, 34 T-cell and 39 B-cells NHLs, 2 cases of adult T-cell leukemia/lymphoma, and 11 cases of T-cell acute lymphoblastic leukemia, were evaluated for CD40L expression by immunostaining of frozen tissue sections and flow cytometry with the anti-CD40L monoclonal antibody M90. CD40L was constitutively expressed by neoplastic cells in 15 of 36 (42%) T-cell NHLs/adult T-cell leukemia/lymphomas, almost invariably those displaying the CD4+/CD8- phenotype, whereas no CD40L-expressing tumor cells could be found in B-cell NHL and HD. Among T-cell acute lymphoblastic leukemias, CD40L was detected only on 2 cases displaying a stem-cell-like phenotype. In follicular B-cell lymphomas a large number of CD40L-expressing CD3+/CD4+ T lymphocytes were found admixed with tumor cells within the neoplastic follicles and in their surrounding areas. In the nonfollicular B-cell lymphomas, CD40L-positive CD3+/CD4+ T lymphocytes were few or absent. In all HD subtypes other than the nodular lymphocytic predominance, CD40L-expressing CD3+/CD4+ T lymphocytes were numerous in the HD-involved areas and were mainly located in close proximity to the Reed-Sternberg cells. Our data indicate that in human lymphomas CD40L is preferentially expressed by a restricted subset of T-cell lymphomas, mostly with CD4 immunophenotype. Finally, we have provided morphological evidence that CD40L may play an important role in the cell contact-dependent interaction of tumor B-cells (CD40+) within the neoplastic follicles or Reed-Sternberg cells (CD40+) in HD-involved areas and the microenvironmental CD3+/CD4+/CD40L+ T lymphocytes.     

Preferential expression of the mucosal homing receptor integrin alpha 4 beta 7 in gastrointestinal non-Hodgkin's lymphomas.

Recent studies have identified the integrin alpha 4 beta 7 as a mucosal homing receptor that mediates lymphocyte migration to the intestinal mucosa by binding to MAdCAM-1, a vascular recognition molecule (addressin) selectively expressed on mucosal endothelium. In the present study, we have assessed the expression of alpha 4 beta 7 on B- and T-cell non-Hodgkin's lymphomas of different primary localization and on related normal lymphocytes. Among B-lineage lymphomas, expression of alpha 4 beta 7 was present in the majority of cases of malignant lymphomatous polyposis of the intestine and low-grade lymphoma of the mucosa-associated lymphoid tissue/monocytoid B-cell lymphoma and in some cases of precursor B-cell lymphoma. CLL/small lymphocytic lymphoma, (nodal) mantle cell lymphoma, follicular center cell lymphoma, Burkitt's lymphoma, and diffuse large B-cell lymphoma were virtually always alpha 4 beta 7 negative, as was the case when localized in the mucosa-associated lymphoid tissue. The normal B cells of the follicle mantles and part of the B cells of the extrafollicular B-cell compartment of lymphoid tissues expressed moderate levels of alpha 4 beta 7. By contrast, follicular center cells were alpha 4 beta 7 negative. Among T-lineage lymphomas, expression of alpha 4 beta 7 was also strongly related to the primary localization; in mucosal, nodal, and cutaneous T cell lymphomas the percentage of positive cases was 56%, 17%, and 0%, respectively. All cases of precursor T-cell lymphoma were alpha 4 beta 7 negative. High expression of alpha 4 beta 7 was found on a subset of peripheral blood memory T cells as well as on lymphocytes in the intestinal mucosa. We conclude that non-Hodgkin's lymphomas that are related to mucosa-associated B- and T-lymphocyte populations selectively express the mucosal homing receptor alpha 4 beta 7. The presence of this receptor underscores their distinctive character and may play an important role in determining their characteristic mucosal dissemination pattern.     

Distribution of lymphocytes with interleukin-2 receptors (TAC antigens) in reactive lymphoproliferative processes, Hodgkin''s disease, and non-Hodgkin''s lymphomas. An immunohistologic study of 300 cases.

The authors investigated the distribution of interleukin-2 receptors (TAC antigen) in the lymph nodes of 300 patients with lymphoproliferative disorders. They used fresh-frozen sections to evaluate a possible correlation between the immunophenotype of specific lymphoid disorders and the presence or absence of TAC expression and to determine whether the TAC positivity of lymphoid cells contributes to the characterization of lymphoproliferative processes. All of the cases had previously been studied with a large screening panel of monoclonal antibodies and polyclonal antisera. Among 85 patients with a variety of benign reactive processes, the lymph nodes from 47 contained TAC-bearing lymphocytes in various patterns of distribution. Of 41 patients with Hodgkin's disease, 37 had TAC-bearing lymphocytes. Of 26 B-cell, well-differentiated lymphocytic lymphomas (WDL), 14 were diffusely TAC-positive and one had TAC-bearing cells in random distribution. Six cases of intermediate lymphocytic lymphoma were also studied, and three showed randomly distributed TAC-bearing lymphocytes. Of 19 patients with follicular or follicular and diffuse, poorly differentiated lymphocytic (PDL) lymphoma, 14 were TAC-positive. All 3 diffuse PDL lymphomas studied were TAC-negative. Among 23 cases of B-cell and 5 cases of T-cell mixed cell lymphoma, 15 and three, respectively, had TAC-positive lymphocytes. Of 39 large cell lymphomas (B-cell, 33; T-cell, 6), 14 were TAC-positive. All 13 cases of hairy cell leukemia were diffusely positive. Of 23 T-lymphoblastic lymphomas, only 1 showed positive TAC reactivity, which was focal. Of 5 cases of cutaneous T-cell lymphoma, 2 had TAC-bearing lymphocytes. Our study indicates that the TAC antigen is not lineage-specific, and that it may be expressed by lymphoid cells regardless of their phenotype.     

Expression of the diffuse B-cell lymphoma family molecule SWAP-70 in human B-cell neoplasms: immunohistochemical study of 86 cases.

SWAP-70 is a recently discovered member of the Dbl (diffuse B-cell lymphoma) family of signal transduction molecules that is abundantly expressed in B cells. SWAP-70 mediates lipid second-messenger signals to the cytoskeletal-organizing GTPase Rac, functioning as a guanine-nucleotide exchange factor. SWAP-70 is strongly expressed in germinal center B cells, with low-level expression in resting B-cells. Expression of SWAP-70 in neoplastic B cells has not been described. We report the immunohistochemical expression of SWAP-70 in 86 B-cell neoplasms. SWAP-70 was strongly expressed in 59 of the 86 cases: 2 of 10 (20%) precursor B-cell lymphoblastic leukemias, 2 of 2 (100%) precursor B-cell lymphoblastic lymphomas, 2 of 4 (50%) mantle cell lymphomas, 7 of 9 (78%) Burkitt lymphomas, 9 of 9 (100%) diffuse large B-cell lymphomas, 8 of 8 (100%) follicular lymphomas, 6 of 6 (100%) nodular lymphocyte predominant Hodgkin lymphomas, 0 of 8 (0%) classic Hodgkin lymphomas, 12 of 13 (92%) chronic lymphocytic leukemias, 3 of 3 (100%) nodal marginal zone lymphomas, 5 of 5 (100%) extranodal marginal zone lymphomas, 1 of 2 (50%) splenic marginal zone lymphomas, 2 of 3 (66%) hairy cell leukemias, and 0 of 4 (0%) plasma cell neoplasms. All 4 T-cell lymphomas were nonreactive for SWAP-70: 0 of 3 peripheral T-cell lymphomas and 0 of 1 anaplastic large cell lymphoma. These results suggest that a spectrum of neoplastic B cells maintains activation of this signal transduction pathway. This is the first report of the expression of a Dbl family molecule in human lymphoma and leukemia tissues.     

Immunohistochemical determination of CD23 expression in Hodgkin's disease using paraffin sections

The leukocyte antigen CD23 is expressed during B-cell development, and functions as an IgE receptor and a lymphocyte growth factor. We studied the expression of CD23 in paraffin sections of lymphoid tissue using the monoclonal antibody BU38. Fifteen cases of Hodgkin's disease, ten reactive lymph nodes, eight B-cell, and seven T-cell non-Hodgkin's lymphomas were analysed immunohistologically. CD23 positivity was seen on follicular dendritic cells and a small number of lymphocytes in reactive nodes. Thirteen of the 15 cases of Hodgkin's disease showed CD23 expression in both neoplastic cells and reactive lymphocytic infiltrate. The antigen was demonstrated in four of the B-cell and one of the T-cell tumours. CD23 may be important in mediating the mixed cellular infiltrate characteristic of Hodgkin's lymphoma.     

Programmed death 1 expression in variant immunoarchitectural patterns of nodular lymphocyte predominant Hodgkin lymphoma: comparison with CD57 and lymphomas in the differential diagnosis

Recent studies have exploited an antibody directed against programmed death 1 expressed by follicular helper T-cells in the diagnosis of nodular lymphocyte predominant Hodgkin lymphoma. We had previously described clinically relevant, variant immunoarchitectural patterns of nodular lymphocyte predominant Hodgkin lymphoma and, in this study, sought to address the diagnostic utility of programmed death 1 in comparison with CD57 in variant nodular lymphocyte predominant Hodgkin lymphoma. Immunohistologic staining for programmed death 1 was carried out on biopsies of 67 patients with variant nodular lymphocyte predominant Hodgkin lymphoma. Thirty-four additional cases of nodular lymphocyte predominant Hodgkin lymphoma with associated diffuse areas, de novo T-cell and histiocyte-rich large B-cell lymphoma, and lymphocyte-rich classic Hodgkin lymphoma were also studied. Our results show that programmed death 1 positivity was found in the majority of nodular lymphocyte predominant Hodgkin lymphoma cases with a classic nodular architecture (87%) as compared with 50% for CD57 and was particularly helpful in identifying extranodular large atypical cells. Nodular lymphocyte predominant Hodgkin lymphoma with diffuse areas showed a gradual decrease in programmed death 1 reactivity from nodular to diffuse areas, although a significant proportion (40%-50%) of cases retained programmed death 1 positivity also in diffuse areas. In addition, T-cell and histiocyte-rich large B-cell lymphoma and lymphocyte-rich classic Hodgkin lymphoma displayed programmed death 1 positivity in a significant subset of cases (33%-40%). In conclusion, our study supports the utility of programmed death 1 in the diagnosis of nodular lymphocyte predominant Hodgkin lymphoma and shows greater sensitivity of staining of programmed death 1 as compared with CD57 across all variants of nodular lymphocyte predominant Hodgkin lymphoma. Loss of programmed death 1 reactivity did not correlate with diffuse areas, progression, or the ability to differentiate nodular lymphocyte predominant Hodgkin lymphoma from T-cell and histiocyte-rich large B-cell lymphoma. These findings suggest the need for continued vigilance in the diagnosis of nodular lymphocyte predominant Hodgkin lymphoma and its immunoarchitectural variants as well as related lymphomas in their differential diagnosis.     

Leu 7 (CD57) reactivity distinguishes nodular lymphocyte predominance Hodgkin's disease from nodular sclerosing Hodgkin's disease, T-cell-rich B-cell lymphoma and follicular lymphoma.

Several recent reports have suggested that nodular lymphocyte predominance Hodgkin's disease (NLPHD) may be distinct from other forms of Hodgkin's disease and may be more closely related to B-cell non-Hodgkin's lymphoma. This is primarily based on immunophenotypic studies that have shown that the L & H cells in NLPHD demonstrate a B-cell phenotype. In 1989, Poppema reported that the T cells in NLPHD differ from T cells in other forms of Hodgkin's disease in that they demonstrate reactivity for Leu 7 (CD57). In this study we tested the hypothesis that Leu 7 (CD57) reactivity of small lymphocytes in NLPHD is an immunophenotypic feature that distinguishes NLPHD from nodular sclerosing Hodgkin's disease and from certain B-cell lymphomas that may histologically simulate NLPHD, namely T-cell-rich B-cell lymphoma and follicular lymphoma. Using an image analysis method, we found Leu 7 (CD57) reactivity in an average of 18.9% of the small lymphocytes in the nodules of NLPHD compared with 3.9% in nodular sclerosing Hodgkin's disease, 4.3% in T-cell-rich B-cell lymphoma, and 2.1% in follicular lymphoma. Moreover, Leu 7 (CD57)-reactive small lymphocytes often showed a distinctive pattern in NLPHD, forming a ring of cells around the large L & H cells. While scattered Leu 7 (CD57)-reactive lymphocytes were found in the other disorders, the percentage of reactive cells and the pattern of reactivity were significantly different in NLPHD. These results suggest that Leu 7 (CD57) reactivity may be used as an additional immunophenotypic criterion in distinguishing NLPHD from nodular sclerosing Hodgkin's disease, T-cell-rich B-cell lymphoma, and follicular lymphoma. The clinical and biological significance of Leu 7 (CD57) reactivity of small lymphocytes in NLPHD merits further investigation.     

IL-2 receptor expression in human lymphoid lesions. Immunohistochemical study of 166 cases.

Interleukin-2 (IL-2) receptor expression is a feature of T-cell activation and T-cell neoplasia. Expression of the IL-2 receptor in human lymphoid lesions was studied in a series of 166 immunophenotyped cases, including nodal and extranodal reactive lymphoid proliferations (44 cases), low-grade B-cell lymphomas (27 cases), intermediate and high grade B cell lymphomas (42 cases), peripheral T-cell lymphomas (13 cases), Hodgkin's disease (12 cases), histiocytic proliferations (15 cases), nonhematopoietic tumors (16 cases), and miscellaneous lesions (7 cases). Low levels of receptor expression were seen in reactive lymphoid lesions, low-grade B-cell lymphomas, and nonhematopoietic tumors (20%, 7%, and 25% of cases, respectively, with greater than 10% positive cells). High levels of receptor expression were seen in cases of peripheral T-cell lymphoma and histiocytic proliferations (86% and 100% of cases, respectively, with greater than 10% positive cells). Intermediate levels of expression were seen in Hodgkin's disease (including Reed-Sternberg cells) and some cases of intermediate and high-grade B-cell lymphomas (58% and 50% of cases, respectively, with greater than 10% positive cells). IL-2 receptor expression is not confined to T-cell neoplasia, but is also a feature of neoplastic and nonneoplastic histiocytic proliferations, Hodgkin's disease, and some intermediate and high-grade B-cell lymphomas. Biologic and therapeutic implications are discussed.     

Genotypic analysis of large cell lymphomas which express the Ki-1 antigen

The monoclonal antibody Ki-1 reacts with Reed-Sternberg cells in Hodgkin's disease and with the tumour cells in a minority of large cell non-Hodgkin's lymphomas. This study describes the results of immunophenotypic and DNA analysis in 30 cases of non-Hodgkin's lymphoma, all of which expressed the Ki-1 antigen. The genotypic analysis has been undertaken using both immunoglobulin and T-cell receptor gene probes. Sixteen cases were shown by this method to be of monoclonal T-cell origin, six of B-cell origin, while in eight cases there was no evidence of either T- or B-cell lineage. This confirms previous immunohistological data indicating that non-Hodgkin's lymphomas which express the Ki-1 antigen may be of either T-cell or B-cell origin.     

Specific phenotyping of T-cell proliferations in formalin-fixed paraffin-embedded tissues. Use of antibodies to the T-cell receptor beta F1.

Antibody beta F1 to a common framework determinant of the beta subunit of the T-cell receptor (TCR) was used as a specific phenotypic marker for T-cell differentiation in malignant lymphomas. Sensitivity of immunoperoxidase staining in paraffin sections was enhanced by pronase pretreatment, overnight incubation of primary antibody in Tween 20, and use of streptavidin horseradish peroxidase complexes to amplify the reaction. All 43 cases of B-cell lymphoma were negative for TCR. Reed Sternberg (RS) cells in 3 of 20 cases of Hodgkin's disease exhibited cell membrane staining for TCR (all nodular sclerosis type), further evidence that some RS cells may be T-cell derived. Twenty-nine of 44 cases of T-cell lymphoma expressed TCR (66%). These included 11 of 12 cases of peripheral T-cell lymphoma (PTCL) of small and mixed cell type, 8 of 9 cases of lymphoepithelioid cell (Lennert's) lymphoma, and 2 of 4 cases of T-cell lymphoblastic lymphoma. Loss of immunoreactivity for TCR occurred in lymphomas of large or activated T-cell type, including 7 of 9 cases of T-cell immunoblastic lymphoma and 3 of 4 cases of large cell PTCL. Antibody beta F1 is a specific and relatively sensitive marker of T-cell phenotype in formalin-fixed paraffin sections of malignant lymphomas.     

Rare expression of T-cell markers in classical Hodgkin's lymphoma.

Hodgkin's and Reed-Sternberg cells of classical Hodgkin's lymphoma are primarily of B-cell origin, although there are instances of T-cell antigen expression suggesting T-cell origin. We comprehensively analyzed expression of various T-cell antigens in 259 classical Hodgkin's lymphoma cases using the tissue microarray technique. Expression of the T-cell antigens CD2, CD3, CD4, CD5, CD7 and CD8 was assessed by immunohistochemistry. Hodgkin's and Reed-Sternberg cells of T-cell marker-positive cases were microdissected and analyzed by a multiplex polymerase chain reaction for clonal immunoglobulin heavy chain- and T-cell receptor gamma gene rearrangements. In all, 12 cases (5%) expressed at least one T-cell marker in the following order: CD2 in 11 cases, CD4 in five, CD3 in two, and CD5 and CD8 in one case each; there were no CD7-positive cases, and five cases (2%) expressed more than one T-cell antigen. In positive cases, a mean fraction of 40% of the Hodgkin's and Reed-Sternberg cells (range 20-100%) expressed the analyzed T-cell markers. Two cases (<1%) evidenced clonal T-cell receptor gamma gene rearrangement. Phenotypic expression of T-cell antigens in Hodgkin's and Reed-Sternberg cells of classical Hodgkin's lymphoma is rare (5%), while genotypically, less than 1% of classical Hodgkin's lymphomas are of possible T-cell origin. Therefore, T-cell antigen expression on Hodgkin's and Reed-Sternberg cells is aberrant in the majority of cases and only infrequently classical Hodgkin's lymphomas are of T-cell origin.     

The Leukocyte Semaphorin CD100 Is Expressed in Most T-Cell, but Few B-Cell, Non-Hodgkin’s Lymphomas

The 150-kd transmembrane protein CD100 is the first semaphorin protein shown to be expressed in lymphoid tissue. CD100 is present in the interfollicular T cell zones and is also expressed by B cells in the germinal centers of secondary lymphoid follicles, but not in the mantle zones. The CD100 molecule was recently cloned, and CD100 transfectants were shown to induce homotypic aggregation of human B cells and improve their viability in vitro, suggesting that CD100 may play a role in lymphocyte aggregation and germinal center formation. We studied the expression of CD100 in 138 clinical cases representing a range of lymphoproliferative disorders, to determine whether this molecule is expressed in these neoplastic processes. In general, we found CD100 expression to be common in peripheral T-cell non-Hodgkin’s lymphomas but rare in B-cell non-Hodgkin’s lymphomas. CD100 expression was not detectable in low-grade B-cell non-Hodgkin’s lymphomas, including cases of small lymphocytic lymphoma (18 cases), marginal zone lymphoma (10 cases), and mantle cell lymphoma (10 cases), as might be expected for these neoplasms that are not of follicular center cell origin. Surprisingly, we found that the vast majority of follicular lymphomas (37 of 40 cases) as well as diffuse large-cell lymphomas of B-cell type (35 cases) did not express CD100. The neoplastic cells in 3 of 11 cases of predominantly large-cell-type follicular lymphoma did express CD100. In contrast, all five cases of high-grade, small non-cleaved (Burkitt-like) B-cell lymphoma were immunoreactive for CD100 expression, as were 18 of 20 cases (90%) of malignant T cell neoplasms. Northern blot analysis of CD100 expression correlated with immunohistochemical findings. Absence of expression of CD100 by neoplastic follicular center B cells is a common feature in follicular lymphomas, but expression of CD100 by T cells is maintained in T-cell lymphoproliferative disorders.