Nodular Lymphocyte Predominance Research Articles

Pathological Findings in Human Autoimmune Lymphoproliferative Syndrome

The defects in lymphocyte apoptosis that underlie the autoimmune lymphoproliferative syndrome (ALPS) are usually attributable to inherited mutations of the CD95 (Fas) gene. In this report, we present the histopathological and immunophenotypic features seen in the lymph nodes (n = 16), peripheral blood (n = 10), bone marrow (n = 2), spleen (n = 3), and liver (n = 2) from 10 patients with ALPS. Lymph nodes showed marked paracortical hyperplasia. Interfollicular areas were expanded and populated by T cell receptor-alphabeta CD3+ CD4-CD8- (double-negative, DN) T cells that were negative for CD45RO. CD45RA+ T cells were increased in all cases studied. The paracortical infiltrate was a result of both reduced apoptosis and increased proliferation, as measured by in situ detection of DNA fragmentation and staining with MIB-1, respectively. The paracortical proliferation may be extensive enough to suggest a diagnosis of malignant lymphoma. Many of the paracortical lymphocytes expressed markers associated with cytotoxicity, such as perforin, TIA-1, and CD57. CD25 was negative. In addition, most lymph nodes exhibited florid follicular hyperplasia, often with focal progressive transformation of germinal centers; in some cases, follicular involution was seen. A polyclonal plasmacytosis also was present. The spleens were markedly enlarged, more than 10 times normal size. There was expansion of both white pulp and red pulp, with increased DN T cells. DN T cells also were observed in liver biopsies exhibiting portal triaditis. In the peripheral blood, the T cells showed increased expression of HLA-DR and CD57 but not CD25. CD45RA+ T cells were increased in the four cases studied. Polyclonal B cell lymphocytosis with expansion of CD5+ B cells was a characteristic finding. Taken together, the histopathological and immunophenotypic findings, particularly in lymph nodes and peripheral blood, are sufficiently distinctive to suggest a diagnosis of ALPS. Of note, two affected family members of one proband developed lymphoma (T-cell-rich B-cell lymphoma and nodular lymphocyte predominance Hodgkin's disease, respectively).

Transcription Factor B-Cell–Specific Activator Protein (BSAP) Is Differentially Expressed in B Cells and in Subsets of B-Cell Lymphomas

The paired box containing gene PAX-5 encodes the transcription factor BSAP (B-cell-specific activator protein), which plays a key role in B-lymphocyte development. Despite its known involvement in a rare subtype of non-Hodgkin's lymphoma (NHL), a detailed examination of BSAP expression in NHL has not been previously reported. In this study, we analyzed normal and malignant lymphoid tissues and cell lines, including 102 cases of B-cell NHL, 23 cases of T- and null-cell NHL, and 18 cases of Hodgkin's disease. Normal lymphoid tissues showed strong nuclear BSAP expression in mantle zone B cells, less intense reactivity in follicular center B cells, and no expression in cells of the T-cell-rich zones. Monocytoid B cells showed weak expression, whereas plasma cells and extrafollicular large transformed B cells were negative. Of the 102 B-cell NHLs, 83 (81%) demonstrated BSAP expression. All of the 13 (100%) B-cell chronic lymphocytic leukemias (B-CLLs), 21 of (100%) mantle cells (MCLs), and 20 of 21 (95%) follicular lymphomas (FLs) were positive. Moderate staining intensities were found in most B-CLL and FL cases, whereas most MCLs showed strong reactions, paralleling the strong reactivity of nonmalignant mantle cells. Eight of 12 (67%) marginal zone lymphoma cases showed negative or low BSAP levels, and 17 of 24 (71%) large B-cell lymphomas displayed moderate to strong expression. None of the 23 T- and null-cell lymphomas reacted with the BSAP antisera, whereas in Hodgkin's disease, 2 of 4 (50%) nodular lymphocytic predominance and 5 of 14 (36%) classical cases showed weak nuclear or nucleolar BSAP reactions in a fraction of the tumor cells. Western blot analysis showed a 52-kD BSAP band in B-cell lines, but not in non-B-cell or plasma cell lines. We conclude that BSAP expression is largely restricted to lymphomas of B-cell lineage and that BSAP expression varies in B-cell subsets and subtypes of B-cell NHL. The high levels of BSAP, especially those found in large-cell lymphomas and in some follicular lymphomas, may be a consequence of deregulated gene expression and suggest a possible involvement of PAX-5 in certain B-cell malignancies. This is a US government work. There are no restrictions on its use.

Transcription Factor B-Cell–Specific Activator Protein (BSAP) Is Differentially Expressed in B Cells and in Subsets of B-Cell Lymphomas

AbstractThe paired box containing gene PAX-5 encodes the transcription factor BSAP (B-cell–specific activator protein), which plays a key role in B-lymphocyte development. Despite its known involvement in a rare subtype of non-Hodgkin's lymphoma (NHL), a detailed examination of BSAP expression in NHL has not been previously reported. In this study, we analyzed normal and malignant lymphoid tissues and cell lines, including 102 cases of B-cell NHL, 23 cases of T- and null-cell NHL, and 18 cases of Hodgkin's disease. Normal lymphoid tissues showed strong nuclear BSAP expression in mantle zone B cells, less intense reactivity in follicular center B cells, and no expression in cells of the T-cell–rich zones. Monocytoid B cells showed weak expression, whereas plasma cells and extrafollicular large transformed B cells were negative. Of the 102 B-cell NHLs, 83 (81%) demonstrated BSAP expression. All of the 13 (100%) B-cell chronic lymphocytic leukemias (B-CLLs), 21 of (100%) mantle cells (MCLs), and 20 of 21 (95%) follicular lymphomas (FLs) were positive. Moderate staining intensities were found in most B-CLL and FL cases, whereas most MCLs showed strong reactions, paralleling the strong reactivity of nonmalignant mantle cells. Eight of 12 (67%) marginal zone lymphoma cases showed negative or low BSAP levels, and 17 of 24 (71%) large B-cell lymphomas displayed moderate to strong expression. None of the 23 T- and null-cell lymphomas reacted with the BSAP antisera, whereas in Hodgkin's disease, 2 of 4 (50%) nodular lymphocytic predominance and 5 of 14 (36%) classical cases showed weak nuclear or nucleolar BSAP reactions in a fraction of the tumor cells. Western blot analysis showed a 52-kD BSAP band in B-cell lines, but not in non–B-cell or plasma cell lines. We conclude that BSAP expression is largely restricted to lymphomas of B-cell lineage and that BSAP expression varies in B-cell subsets and subtypes of B-cell NHL. The high levels of BSAP, especially those found in large-cell lymphomas and in some follicular lymphomas, may be a consequence of deregulated gene expression and suggest a possible involvement of PAX-5 in certain B-cell malignancies.This is a US government work. There are no restrictions on its use.

Histologic Features and Differential Diagnosis of Nodular Lymphocyte Predominance Hodgkin's Lymphoma (NLPHL)

Histologic Features and Differential Diagnosis of Nodular Lymphocyte Predominance Hodgkin's Lymphoma (NLPHL)

Platelet-derived endothelial cell growth factor/thymidine phosphorylase immunohistochemical expression in lymphoid tissue and lymphoid malignancies

The catabolic enzyme thymidine phosphorylase (TP) plays a crucial role in nucleic acid metabolism by regulating the availability of thymidine. Platelet-derived endothelial cell growth factor (PD-ECGF) is an angiogenic factor that was recently shown to be TP. The angiogenic properties of PD-ECGF/TP are attributable to a reduction of thymidine levels that results in a promotion of endothelial cell proliferation. Early studies showed a higher concentration of TP in macrophages than in parenchymal cells and in neoplastic than in nonneoplastic tissues. We examined the immunohistochemical expression of PD-ECGF/TP in reactive lymphoid tissues (lymph node and tonsil), as well as in a series of 20 cases of Hodgkin's disease and 31 cases of non-Hodgkin's lymphomas. Macrophages, sinus lining cells, and cells with dendritic morphology, of both follicular dendritic and interdigitating reticular cell type, presented a prominent nuclear and cytoplasmic positivity in reactive lymphoid tissue and in malignant lymphomas. Small lymphocytes and the neoplastic population were always negative, whereas endothelial staining was variable and showed no correlation to the type or grade of the lymphomas. In Hodgkin's disease (with the exception of the nodular lymphocyte predominance type) and some cases of high-grade non-Hodgkin's lymphomas, the positive dendritic cells formed a dense meshwork closely surrounding the neoplastic population. Our results suggest that the reported upregulation of PD-ECGF/TP activity in lymphoid malignancies is attributable to the nonneoplastic population, especially to cells of dendritic morphology.

Reed-Sternberg Cells of Classical Hodgkin's Disease React With the Plasma Cell-Specific Monoclonal Antibody B-B4 and Express Human Syndecan-1

AbstractAlthough the cellular origin of Reed-Sternberg (RS) cells of classical Hodgkin's disease (HD) has been a controversial issue for many years, recent immunophenotypic and molecular studies have suggested that RS cells of a subset of classical HD cases may be related to B cells. To further define the immunophenotypic features and the differentiation stage of RS cells, a series of 56 HD samples, including both nodular lymphocyte predominance (LP) (eight cases) and classical HD (nodular sclerosis [NS], 32 cases; mixed cellularity [MC], 16 cases) with a non-T–cell phenotype, were evaluated for the immunohistochemical expression of the B-B4 antigen, a specific marker for terminally differentiated B cells. Because the cDNA of the B-B4 antigen encodes syndecan-1, a member of a family of transmembrane heparan sulfate proteoglycans thought to be involved in binding cells of the B lineage to the interstitial matrix, the B-B4 immunoreactivity was correlated with the expression of syndecan-1 in HD-derived cell lines (L428, KM-H2), as detected by both reverse transcriptase polymerase chain reaction (RT-PCR) studies and Western blotting. Our results show that B-B4 reacts with RS cells and their morphological variants of all cases of classical HD, irrespective of their antigenic phenotype (B, undetermined), albeit at a varying degree of cellular expression. Notably, a high reactivity and staining intensity for the B-B4 monoclonal antibody (MoAb) was restricted to tumor cells from NS HD. In cases of the latter subtype, B-B4 positivity was also found in sclerosis-trapped spindle cells (fibrocytes/fibroblasts). Conversely, the putative tumor cells of nodular LP HD were consistently unreactive with the B-B4 MoAb. Finally, we have demonstrated by RT-PCR, flow cytometry, and Western blotting that cultured RS cells, of B and undetermined phenotype, express syndecan-1 mRNA and produce a form of syndecan-1, recognized by the B-B4 MoAb, which is predominantly associated with glycosaminoglycans and is present at the cell surface. Our detection of the plasma cell-specific antigen B-B4 (syndecan-1) on tumor cells of classical HD further supports that RS cell progenitors may be related to germinal/postgerminal center mature B cells and suggests that expression of syndecan-1 may contribute to some of the typical biologic and histopathologic features of classical HD, with a special regard to the NS subtype.

Reed-Sternberg Cells of Classical Hodgkin's Disease React With the Plasma Cell-Specific Monoclonal Antibody B-B4 and Express Human Syndecan-1

Although the cellular origin of Reed-Sternberg (RS) cells of classical Hodgkin's disease (HD) has been a controversial issue for many years, recent immunophenotypic and molecular studies have suggested that RS cells of a subset of classical HD cases may be related to B cells. To further define the immunophenotypic features and the differentiation stage of RS cells, a series of 56 HD samples, including both nodular lymphocyte predominance (LP) (eight cases) and classical HD (nodular sclerosis [NS], 32 cases; mixed cellularity [MC], 16 cases) with a non-T–cell phenotype, were evaluated for the immunohistochemical expression of the B-B4 antigen, a specific marker for terminally differentiated B cells. Because the cDNA of the B-B4 antigen encodes syndecan-1, a member of a family of transmembrane heparan sulfate proteoglycans thought to be involved in binding cells of the B lineage to the interstitial matrix, the B-B4 immunoreactivity was correlated with the expression of syndecan-1 in HD-derived cell lines (L428, KM-H2), as detected by both reverse transcriptase polymerase chain reaction (RT-PCR) studies and Western blotting. Our results show that B-B4 reacts with RS cells and their morphological variants of all cases of classical HD, irrespective of their antigenic phenotype (B, undetermined), albeit at a varying degree of cellular expression. Notably, a high reactivity and staining intensity for the B-B4 monoclonal antibody (MoAb) was restricted to tumor cells from NS HD. In cases of the latter subtype, B-B4 positivity was also found in sclerosis-trapped spindle cells (fibrocytes/fibroblasts). Conversely, the putative tumor cells of nodular LP HD were consistently unreactive with the B-B4 MoAb. Finally, we have demonstrated by RT-PCR, flow cytometry, and Western blotting that cultured RS cells, of B and undetermined phenotype, express syndecan-1 mRNA and produce a form of syndecan-1, recognized by the B-B4 MoAb, which is predominantly associated with glycosaminoglycans and is present at the cell surface. Our detection of the plasma cell-specific antigen B-B4 (syndecan-1) on tumor cells of classical HD further supports that RS cell progenitors may be related to germinal/postgerminal center mature B cells and suggests that expression of syndecan-1 may contribute to some of the typical biologic and histopathologic features of classical HD, with a special regard to the NS subtype.

So-called large-cell lymphoma associated with nodular lymphocyte predominance Hodgkinʼs disease may represent several different entities

So-called large-cell lymphoma associated with nodular lymphocyte predominance Hodgkinʼs disease may represent several different entities

Nodular Lymphocyte Predominance Hodgkin's Disease: Long-Term Observation Reveals a Continuous Pattern of Recurrence

We evaluated the presenting clinical characteristics and outcome of 68 patients with nodular lymphocyte predominance Hodgkin's disease (NLP-HD), in order to delineate the pattern of evolution of the disease. The male to female ratio was 46/22 and median age 35 yrs (range, 14–86). Eight patients had a history of benign hyperplasia on lymph node biopsies performed 6 to 36 months before the diagnosis of NLP-HD. Early stage disease accounted for 75% of cases. One patient had a coexistent non-Hodgkin's lymphoma (NHL). Treatment was as follows: radiotherapy in 26, chemotherapy in 23, combined modality in 19. CR rate was 93% (63/68). 18 patients relapsed as HD and 5 developed NHL. The cumulative risk of NHL was 9% at 10 yrs. During remission, 4 patients had 5 episodes of follicular hyperplasia histologically documented. Overall survival rate was 71% at 10 yrs and and 63% at 15 yrs. Freedom from progression (FFP) declined from 67% at 5 yrs to 45% at 10 yrs, because of late relapses. Localized disease predicted for a better FFP (p = 0.01), but was not associated with a reduced risk of recurrence over time.NLP-HD is characterized by an indolent course with a constant pattern of relapse over time, also in patients with early stage disease at diagnosis. In addition to relapse as NLP-HD, patients may evolve into a NHL or develop benign lymph nodal hyperplasia. Careful long-term follow up is needed for these patients.

Epstein Barr Virus in Argentine Pediatric Hodgkin's Disease

Since Hodgkin's disease (HD) is an heterogeneous condition with diverse histological and epidemiological subgroups, it seemed worthwhile to investigate the Argentine pediatric pattern. Moreover, the presence of Epstein Barr virus (EBV) infection occurs at different ages depending on the development status of the country. Thus, it was interesting to assess the relation between EBV and HD in the Argentine pediatric population. The age distribution profile of our pediatric HD patients showed a peak in early childhood which declined towards adolescence, closely resembling EBV infection pattern. Male: female ratio of the studied population was 3.2:1 and the histological subtype distribution disclosed that mixed cellularity HD (MCHD) was the most common, an epidemiological profile shared with other developing countries. Fifty percent of assessed HD cases were associated with EBV. showing a significantly higher prevalence in the 3-6 year-old group, indicating a non-random distribution. EBV was also present in most of MCHD cases and in some nodular lymphocyte predominance HD (nLPHD) but entirely absent in nodular sclerosis HD (NSHD). Both EBV subtypes, namely EBV-1 and EBV-2, were detected in studied HD cases. EBV-HD association in the Argentine pediatric population reveals typical epidemiological features indicating EBV as the aetiologic agent or, alternatively as a cofactor in a considerable percentage of such HD cases.

Immunoglobulin light chain staining in paraffin-embedded tissue using a heat mediated epitope retrieval method.

We have compared light chain immunohistochemistry in reactive lymphoid tissue and a series of paraffin-embedded B-cell lymphomas using standard trypsin digestion with a heat mediated epitope retrieval method. Fifty-seven B-cell lymphomas (18 high grade, 29 low grade and 10 cases of nodular lymphocyte predominance Hodgkin's disease), two reactive lymph nodes and eight tonsils fixed for known times between 12 h and 2 years were studied. Paraffin-embedded tissue was stained with polyclonal anti-kappa and anti-lambda antibodies. For each antibody staining was performed on two sections, one treated with trypsin digestion and one with microwave heating. Sections were scored from 0 to + + + with 0 representing poor staining and + + + excellent staining. A score of ++ was considered satisfactory. Light chain restriction was recorded if present. Satisfactory staining was obtained in 34/59 cases using trypsin digestion and 56/59 cases using heat retrieval. Light chain restriction was demonstrated in 32/57 (56%) B-cell lymphomas using trypsin digestion and 52/57 (91%) using heat retrieval. Satisfactory staining was obtained in tonsils fixed for up to 48 h using trypsin digestion and up to 2 years using heat retrieval. We have shown that for light chain immunostaining a heat mediated epitope retrieval method produces more consistent and satisfactory results and is effective over a greater range of fixation times than traditional trypsin digestion.

Anomalous retinoblastoma protein expression in Sternberg-Reed cells in Hodgkin's disease: a comparative study with p53 and Ki67 expression.

Retinoblastoma (Rb) tumour-suppressor protein plays a critical role in cell cycle control. Rb inactivation is a frequent phenomenon in tumours of different cell lineages, in which the absence of Rb protein has been considered to be a marker of Rb disregulation. We used modern immunohistochemical techniques to study the expression of Rb protein in a large series of 130 patients with Hodgkin's disease. Simultaneously, Western blot was used to analyse a more restricted group (12 patients) to confirm the immunohistochemical results and to clarify the phosphorylation status of Rb protein. As the level of Rb expression varied according to cell cycle stage, we also performed immunostaining for Ki67, a protein present in proliferating cells. To make comparison possible, we first characterised the amount and phosphorylation status of Rb protein in reactive lymphoid tissue and phytohaemagglutinin (PHA)-stimulated lymphocytes. The presence of p53 in Sternberg-Reed cells was also included in the study, as both proteins (p53 and Rb) have been found to be closely associated in cell cycle control. PHA-stimulated peripheral blood lymphocytes showed a parallel increase in Rb and cell cycle progression, together with progressive Rb phosphorylation. In reactive lymphoid tissue there was also a clear correlation between Rb expression and the Ki67 proliferation index (R = 0.96, P = 0.038). When analysing Hodgkin's disease samples, a clear difference emerges between cases of nodular lymphocyte predominance, which preserve the relationship between Rb and Ki67 expression (r = 0.8727, P = 0.000), and classical forms of Hodgkin's disease (nodular sclerosis and mixed cellularity), which display a strong deviation from this pattern. Two main anomalies were found: (1) One group of 21/130 cases with partial or total loss of Rb protein expression, which could reflect the existence of genetic alterations, or an altered transcriptional or translational regulation of Rb gene. (2) Another group with an abnormally high Rb/Ki67 ratio, which could support conflicting interpretations: (i) excess Rb protein for controlling cell cycle progression; or (ii) adhesion of Rb protein to other cellular or viral proteins, such as p53 and MDM2. The results of this study indicate an anomalous pattern of expression of Rb in classical forms of Hodgkin's disease, and suggest the possibility of undertaking functional studies (E1A adhesion, p16 expression) with the aim of better characterising the status of Rb protein, and correlating these findings with clinical course in Hodgkin's disease patients.

Bcl-6 protein expression in nodular lymphocyte predominance Hodgkinʼs disease (nLPHD)

Bcl-6 protein expression in nodular lymphocyte predominance Hodgkinʼs disease (nLPHD)

Nodular Lymphocyte Predominance Hodgkin's Disease: A Monoclonal or Polyclonal B-Cell Disorder?

Nodular lymphocyte predominance Hodgkin's disease (NLPHD) is characterized by the presence of atypical putatively neoplastic cells (L & H cells) with a B-cell phenotype. A proportion of patients with NLPHD develop a simultaneous or subsequent large cell B lymphoma (LCL) that is thought to evolve directly from the L & H cells of NLPHD. However, the clonal nature of L & H cells remains controversial, and the relationship between NLPHD and complicating LCL has not been fully established. In an attempt to determine the clonality of L & H cells and to clarify the link between NLPHD and complicating LCL, we used polymerase chain reaction (PCR) to analyze 33 cases of NLPHD, including 15 cases with simultaneous or subsequent LCL, for clonal immunoglobulin (lg) heavy chain variable region (VH) gene rearrangements. PCR amplifications with consensus primers covering framework 2 or framework 3 to joining region were performed on paraffin-embedded tissue sections and, in 12 cases, on microdissection-enriched L & H cells. No clonal Ig rearrangements were detected. In eight of the 15 LCL, monoclonal IgVH regions were amplified, four of which were cloned and sequenced. Clone specific primers were designed based on the unique N region sequences. These allowed detection of LCL clones at a sensitivity up to 1,000 times greater than the consensus primers, as determined by dilution assays. However, no LCL clones were detected in the preceding NLPHD, including microdissection-enriched L & H cells. Our results suggest that populations of L & H cells do not carry monoclonal Ig rearrangements and provide no evidence for a clonal link between NLPHD and complicating LCL.

A pathologic study of Hodgkin's disease in Korea and its association with Epstein-Barr virus infection.

The incidence of Hodgkin's disease (HD) in Korea and other Asian countries is much lower than in western countries and its association with the Epstein-Barr virus has not been well characterized. We evaluated the clinical, morphologic, and immunohistochemical features of 87 patients with Hodgkin's disease and also analyzed patients for Epstein-Barr virus (EBV) using in situ hybridization for EBV DNA, RNA, and latent membrane protein (LMP1). There were 68 males and 19 females, with a mean age of 38 years. Mixed cellularity was the most prevalent subtype. Expression of EBV RNA (EBER:EBV-encoded RNA) was detected in 60 of 87 cases (69%): 1 of 1 (100%) with lymphocyte predominance, nodular; 4 of 7 (57%) with lymphocyte predominance, diffuse; 10 of 17 (59%) with nodular sclerosis; 38 of 51 (75%) with mixed cellularity; and 7 of 11 (64%) with lymphocyte depletion. Positivity was higher in advanced clinical stages; 4 of 7 patients (57%) with Stage I; 6 of 12 patients (50%) with Stage II: 7 of 9 patients (75%) with Stage III; and 5 of 5 patients (100%) with Stage IV HD EBV DNA was detected in 9 of 25 cases tested (36%). LMP1 was seen in 39 of 87 cases (45%). EBER and LMP1 positivity were higher in children and older adults than in adults aged between 15-50 years. Immediate early mRNAs (BHLF:Bam H-fragment, lower strand frame) was seen in a single patient. HD in Korea showed a high incidence of mixed cellularity subtype and a high prevalence of EBV. EBV was detected in all subtypes, including a case of nodular lymphocytic predominance, and in all age groups, and showed correlation with mixed cellularity subtype and higher clinical stage. The expression of EBER and LMP were more frequently seen in children and older adults, suggesting a lowered immune surveillance in those age groups or a different pathophysiology of HD among different age groups.

Distinctive Expression Pattern of the BCL-6 Protein in Nodular Lymphocyte Predominance Hodgkin's Disease

The BCL-6 gene encoding a nuclear-located Kruppel-type zinc finger protein is rearranged in about 30% diffuse large B-cell lymphomas and is expressed predominantly in normal germinal center B cells and related lymphomas. These findings suggest that BCL-6 may play a role in regulating differentiation of normal germinal center B cells and that its deregulated expression caused by rearrangements may contribute to lymphomagenesis. This prompted us to investigate the expression of the BCL-6 protein in Hodgkin's disease (HD), focusing on the nodular lymphocyte predominance subtype (NLPHD), which differs from classical HD by virtue of the B-cell nature of the malignant cell population (so-called L&H cells) and its relationship with germinal centers. Forty-one HD samples (19 NLPHD, 12 nodular sclerosis, and 10 mixed cellularity) were immunostained with the monoclonal antibodies PG-B6 and PG-B6p that react with a fixative-sensitive and a formalin-resistant epitope on the aminoterminal region of the BCL-6 gene product, respectively. Strong nuclear positivity for the BCL-6 protein was detected in tumor (L&H) cells in all cases of NLPHD. In contrast, BCL-6 was expressed only in a small percentage of Hodgkin and Reed-Sternberg cells in about 30% of classical HD cases. Notably, the nuclei of reactive CD3+/CD4+ T cells nearby to and rosetting around L&H cells in NLPHD were also strongly BCL-6+, but lacked CD40 ligand (CD40L) expression. This staining pattern clearly differed from that of classical HD, whose cellular background was made up of CD3+/CD4+ T cells showing the BCL-6-/CD40L+ phenotype. These results further support the concept that NLPHD is an histogenetically distinct, B-cell-derived subtype of HD and suggest a role for BCL-6 in its development.

T‐cell rich B‐cell non‐Hodgkin's lymphoma: a progressed form of follicle centre cell lymphoma and lymphocyte predominance Hodgkin's disease

T-cell rich B-cell non-Hodgkin's lymphoma (T-cell rich B-cell lymphoma) is a morphological variant of diffuse large B-cell lymphoma. It is important to recognize this variant in the differential diagnosis of T-cell non-Hodgkin's lymphoma. The main differential diagnosis of T-cell rich B-cell lymphoma, nodular and diffuse lymphocyte predominance Hodgkin's disease (lymphocyte predominance Hodgkin's disease), is, however, even more difficult and differentiating criteria are still not satisfactorily defined. Moreover, T-cell rich B-cell lymphoma may not represent a clinicopathological entity. Twelve cases of T-cell rich B-cell lymphoma, selected on the basis of morphology and limited immunohistochemistry without previous knowledge of clinical data, were studied by immunohistochemistry and polymerase chain reaction for bcl-2 rearrangements to investigate the histogenetic background. In three of 12 cases, bcl-2 rearrangements were found, strongly suggesting a follicle centre cell origin. In three other cases, a documented history of definite nodular lymphocyte predominance Hodgkin's disease 29 months to 20 years prior to the diagnosis of the lymphoma was present. No differences in growth pattern, residual nodularity, tumour cell distribution, cellular morphology and composition, or immunophenotypical differences were noted in these six cases as compared to the remaining cases. These data underscore the histogenetic diversity in T-cell rich B-cell lymphoma and identify it as a progressed form of lymphoma derived from entities as diverse as follicle centre cell lymphoma and nodular lymphocyte predominance Hodgkin's disease. Moreover, it shows a complete morphological overlap with the diffuse form of lymphocyte predominance Hodgkin's disease and may actually encompass this disease entity.

Pathologic Features of Nodular Lymphocyte Predominance Hodgkinʼs Disease in Extranodal Sites

We describe the gross and histologic features of nodular lymphocyte predominance Hodgkin's disease (NLPHD) occurring in extranodal sites. Fifty-one specimens of NLPHD from 16 patients were studied. The sites of involvement were the spleen, liver, tonsil, salivary glands, skin, colon, soft tissue, and bone marrow, and the morphologic features were similar to those described in node-based NLPHD, including characteristic lymphocytic and/or histiocytic (L&H) cells that were easily identified in a background of a nodular proliferation of small lymphocytes and histiocytes. In the spleen, the normal architecture was generally preserved, and the tumor was found predominantly in the white pulp; the red pulp was rarely involved. In the liver, the tumor involved both the portal and parenchymal areas. In the tonsil, the lympohproliferation closely resembled the typical appearance of NLPHD in a lymph node. In all specimens with materials available for immunohistochemical studies, there were demonstrable L&H cells with an immunophenotype similar to node-based NLPHD, that is, CD45-positive, CD20-positive, and CD15-negative. The unique morphologic and immunologic characteristics of NLPHD are preserved in extranodal sites and allow its distinction from classic Hodgkin's disease and other lymphoproliferative malignancies that may occur in extranodal sites.

Mantle irradiation alone for selected patients with laparotomy-staged IA to IIA Hodgkin's disease: preliminary results of a prospective trial.

To determine the feasibility of omitting prophylactic paraaortic irradiation in selected patients with laparotomy-staged (pathologically staged [PS]) IA to IIA Hodgkin's disease. We initiated a prospective single-arm trial in October 1988 to study the role of mantle irradiation alone in selected PS IA to IIA patients with Hodgkin's disease. A total of 37 patients have been entered onto this trial. Entrance criteria included nodular sclerosis (NS) or lymphocyte predominance (LP) histology, absence of B symptoms, disease limited above the carina, and a negative laparotomy. Results of treatment of 23 patients in the prospective trial, monitored off treatment for > or = 1 year, are presented. Twenty-three additional PS IA to IIA patients, treated with mantle irradiation alone from 1970 to 1987, were analyzed as a comparison group. The median follow-up durations were 32 and 113 months, respectively, for the two groups. The 4-year actuarial rates of freedom from relapse and overall survival are 83% and 100%, respectively, for the prospective trial. The 10-year actuarial rates of freedom from relapse and overall survival are 83% and 89%, respectively, for retrospectively studied patients. There have been five recurrences among 46 patients who received mantle irradiation alone, all with a component of relapse below the diaphragm. These early results support the use of mantle irradiation alone in selected PS IA to IIA patients with NS or LP histology. Relapses, although rare, have occurred predominantly below the diaphragm. This suggests the need for continued long-term surveillance of abdominal and pelvic nodes in this group of treated patients.

Extranodal lymphocyte predominance Hodgkin's disease. Clinical and pathologic features.

Although B-cell nodular lymphocyte predominance Hodgkin's disease (nodular paragranuloma, LPHD) typically presents at low stage, reported series have identified a minor population of patients with advanced disease. Clinicopathologic findings in 13 cases of LPHD are described that had extranodal manifestations. The B-cell immunophenotype was confirmed in all cases with paraffin-section immunostains. Nine patients presented with extranodal disease; distribution was in Waldeyer's ring (n = 2), spleen (n = 3), spleen and liver (n = 3), or bone marrow (n = 1). Three cases, clinically stage III/IV at presentation, had involvement of bone marrow (n = 2) or bone marrow, liver and spleen (n = 1) at relapse. One patient presented with clinical stage IIe disease and had involvement of spleen at relapse. Follow-up was available for 11 patients (range 4 months to 11 years; mean, 5 years). One patient died of disease and one died with disease because of therapeutic complications. Six patients were disease-free and three had persistent or recurrent LPHD. Microscopically, LPHD was difficult to recognize in extranodal sites and could easily be mistaken for low-grade non-Hodgkin's lymphoma or conventional Hodgkin's disease. Certain morphologic and immunophenotypic findings were effective in avoiding such diagnostic confusion. Thorough staging evaluation appears warranted for LPHD because it may be responsive to therapy, even in advanced stage or after relapse. Although LPHD is unexpected in extranodal samplings, the wary pathologist can suspect its presence on the basis of characteristic histopathologic features. Confirmation of the diagnosis may require paraffinsection immunostains.