Lymphocyte Predominance Hodgkin's Disease Research Articles

Transformation of Hodgkin’s disease to high-grade B-cell lymphoma: Remission after Rituximab monotherapy

We demonstrate the usefulness of immunotherapy with the CD20 antibody Rituximab in a case of transformation of Hodgkin's disease (HD) to high-grade non-Hodgkin's lymphoma (NHL). A 45-year-old women suffering from lymphocyte predominant HD of paragranuloma type (stage IVb) since 1995 showed mediastinal relapse despite of 6 cycles of chemotherapy following the COPP/ABVD-protocol in 1998. Again complete remission could be achieved after escalated BEA-COPP II therapy in May 1998. Six months later chest radiograph and CT depicted pulmonary nodules. The non-typical resection of the lung revealed pulmonary involvement of a high-grade T-cell rich large B-cell lymphoma with 100% of the tumoral cells CD20 positive. Since the symptoms occurred shortly after the BEA-COPP-escalated protocol chemotherapy resistance had to be assumed. Because of this problems and supported by the refusal of a high-dose chemotherapy with stem-cell transplantation by the patient we decided to perform a mono-immunotherapy with the monoclonal CD20 antibody Rituximab. Today, 14 months later, the patient is still in complete remission including the absence of B symptoms. Immunotherapy against CD20 positive cells in cases of sequential HD and NHL seems to be an effective therapy in chemotherapy resistant cases because of the suspected clonally relation of both diseases.

Characterization of NF-κB Expression in Hodgkin's Disease: Inhibition of Constitutively Expressed NF-κB Results in Spontaneous Caspase-Independent Apoptosis in Hodgkin and Reed-Sternberg Cells

Although the neoplastic cells of classical Hodgkin's disease (CHD) demonstrate high levels of constitutively active nuclear NF-κB, the precise physiologic and clinical significance of NF-κB expression is currently undefined. Expression of active NF-κB p65(Rel A) was evaluated in patient samples of CHD and nodular lymphocyte predominance Hodgkin's disease. The action of the chemical NF-κB inhibitors gliotoxin and MG132 and the effect of NF-κB inhibition utilizing an adenovirus vector carrying a dominant-negative IκBα mutant (Ad5IκB) were then demonstrated in CHD cell lines (L428, KMH2, and HS445). Hodgkin and Reed-Sternberg (HRS) cells from all patient and cell line specimens showed strong immunopositivity for active p65(Rel A). Expression was also seen in lymphocytic/histiocytic cells from all cases of nodular lymphocyte predominance Hodgkin's disease. After chemical NF-κB inhibition, p65(Rel A) was significantly reduced in nuclear extracts from cultured HRS cells as revealed by electrophoretic mobility shift assays. Furthermore, chemical NF-κB inhibition resulted in time- and concentration-dependent apoptosis in HRS cells. With the exception of MG132-induced apoptosis in HS445, apoptosis by chemical NF-κB inhibition was not significantly altered by preincubation with various caspase inhibitors (z-DQMD-FMK, z-DEVD-FMK, z-VAD-FMK, z-VEID-FMK, and z-IETD-FMK). Regardless of the chemical inhibitor used, no significant change in caspase-3 functional activity was found in CHD cell lines. HRS cells infected with Ad5IκB also showed a marked increase in spontaneous apoptosis compared with wild type adenovirus-infected and control cells. Overall, the inhibition of active NF-κB in HRS cells resulting in spontaneous caspase-independent apoptosis demonstrates a critical role for NF-κB in HRS cell survival and resistance to apoptosis.

Lymphocyte predominance Hodgkin disease is characterized by recurrent genomic imbalances

Single-cell polymerase chain reaction (PCR) has been used as a tool to demonstrate clonality and B-cell origin of Reed-Sternberg (RS) cells in Hodgkin disease (HD). An analogous approach was used to investigate genomic imbalances in a (cyto)genetically poorly characterized subentity: lymphocyte predominance Hodgkin disease (LPHD). Nineteen cases of LPHD were selected for a comparative genomic hybridization (CGH) study. CGH was performed with degenerate oligonucleotide primed-PCR (DOP-PCR)-amplified DNA from 4-5 microdissected CD20+ malignant cells. All analyzed cases revealed a high number of genomic imbalances (average 10.8 per case), involving all chromosomes but the excluded 19, 22, and Y, indicating a high complexity of LPHD. The majority of detected aberrations were recurrent. Gain of 1, 2q, 3, 4q, 5q, 6, 8q, 11q, 12q, and X, and loss of chromosome 17 were identified in 36.8% to 68.4% of the analyzed cases. Some of them have also been found in non-Hodgkin lymphoma (NHL), and possibly represent secondary changes associated with disease progression. Gain of 2q, 4q, 5q, 6, 11q, however, are much more rarely observed in NHL and could be more specifically associated with LPHD. Particularly interesting is a frequent overrepresentation of chromosome arm 6q, a region usually deleted in NHL. Rearrangement of the BCL6 gene (3q27) demonstrated by cytogenetics and fluorescence in situ hybridization in 2 cases in this study suggests its contribution in pathogenesis of LPHD. In conclusion, the data show a consistent occurrence of genomic alterations in LPHD and highlight genomic regions that might be relevant for development and/or progression of this lymphoma entity.

T-cell-rich B-cell lymphoma: a clinicopathologic study of eight cases.

T-cell-rich B-cell lymphoma (TCRBCL) is a recently recognized and ill-defined form of non-Hodgkin's lymphoma (NHL), with no generally accepted diagnostic criteria and with limited information regarding its incidence, cellular origin, morphologic spectrum and biologic behavior. The recent findings suggest that TCRBCL could be a biologically distinct disease characterized by male preponderance, advanced-stage disease initially and high incidence of extranodal localization, especially in the bone marrow. For the time being, proper diagnosis rests on the immunohistochemical identification of the scattered large malignant B-cells amid a sea of small reactive T-lymphocytes. In this study, the clinicopathologic features of 8 patients (pts) with TCRBCL are presented. The male to female ratio was 5/3, and the median age was 52 years (32-67). The disease was advanced in most patients: 5 pts with stage IV and 2 pts with stage III. The patients presented with generalized lymphadenopathy (5), splenomegaly and/or hepatomegaly (4) and bone marrow involvement (4). The diagnosis of TCRBCL was initially established in 6 pts, while the remaining 2 pts were initially diagnosed as having Hodgkin's disease (of mixed cellularity in 1 pt and lymphocytic predominance in another). Revision of the 2 samples comprising immunohistochemistry enabled diagnosis of TCRBCL. Immunohistomorphologically the present series can be differentiated from other types of lymphoma such as lymphocyte-predominant Hodgkin's disease and peripheral T-cell lymphoma.

B-cell development in progressively transformed germinal centers: similarities and differences compared with classical germinal centers and lymphocyte-predominant Hodgkin disease

AbstractProgressively transformed germinal centers (PTGCs) are histologic structures mainly composed of small resting B cells and intermingled proliferating centroblast-like cells. The B-cell differentiation processes within PTGCs and their relation to classical germinal centers (GC) and to lymphocyte-predominant Hodgkin disease (LPHD), with which PTGCs are often associated, are largely unknown. To address these issues, single small resting (Ki67−) and proliferating (Ki67+) centroblast-like cells were isolated from 7 PTGCs of 5 lymph nodes, and rearranged immunoglobulin genes were amplified and sequenced. Most small resting B cells were clonally unrelated, and most carried unmutated immunoglobulin gene rearrangements resembling mantle zone B cells. Small resting B cells with mutated immunoglobulin gene rearrangements may represent centrocytes, memory B cells, or both. Among the centroblast-like Ki67+ cells, expanded B-cell clones were observed in 6 of 7 PTGCs analyzed. Clonally related V region genes showed extensive intraclonal diversity, and the mutation pattern indicated stringent selection of the cells for the expression of functional antigen receptors. Thus, somatic hypermutation, clonal expansion, and selection occur also in the disorganized PTGC microenvironment, as in classical GCs. In lymph nodes affected by PTGCs, no clonal expansion across the borders of individual PTGCs was observed, distinguishing PTGCs from LPHD.

Down-regulation of BOB.1/OBF.1 and Oct2 in classical Hodgkin disease but not in lymphocyte predominant Hodgkin disease correlates with immunoglobulin transcription

AbstractIn contrast to the tumor cells (L&H cells) of lymphocyte predominant Hodgkin disease (LPHD), Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin disease (cHD) are unable to transcribe immunoglobulin, despite the presence of rearranged immunoglobulin genes. Although initial studies have suggested crippling immunoglobulin gene mutations to be the cause of absent immunoglobulin expression in cHD, recent work of our group has demonstrated an impaired activation of the immunoglobulin promoter as a superior mechanism. As immunoglobulin transcription is mainly regulated by the B-cell transcription factors Oct2 and BOB.1/OBF.1, we analyzed 35 cases of LPHD, 32 cases of cHD, and 2 Hodgkin disease cell lines for the expression of these transcription factors and also in parallel for immunoglobulin expression. Our results demonstrate an absence of Oct2 and/or BOB.1/OBF.1 in cHD and a striking overexpression of Oct2 in LPHD. Immunoglobulin expression was lacking in cHD but present in LPHD. Furthermore, the reintroduction of BOB.1/OBF.1 and Oct2 into cultured HRS cells restored the activity of cotransduced immunoglobulin promoter constructs. Our findings dismiss the concept that the different immunoglobulin expression in cHD and LPHD is due to disrupting mutations of immunoglobulin V genes in cHD but is most likely due to a down-regulation of Oct2 and/or BOB.1/OBF.1. This study further revealed Oct2 as a new and valuable marker for the identification of L&H cells and their distinction from HRS cells. The impairment of immunoglobulin transcription with a down-regulated synthesis of Oct2 and BOB.1/OBF.1 is the first established general recurrent defect found in HRS cells.

Workshop R: Tumor Immunology, Abstract R1 bis R30

SummaryR. 1 Serum anti-p53 Ig-autoantibodies in patients with advanced gastrointestinal cancerR. 2 T cells expressing a chimeric anti-CD20/CD3ζR. 3 Characterization of tumor infiltrating immune cells in pancreatic carcinomaR. 4 Adoptive tumor therapy with T lymphocytes enriched by an IFN-γ capture assayR. 5 Tumor growth despite induction of potent tumor specific CD8 T cellsR. 6 Eradication of adenocarcinoma with CpG-DNA-activated CD4+ T cells from non-transgenic mice is strictly dependent on a Th1 phenotypeR. 7 Naturally occurring T cell response against mutated p21 ras protein in pancreatic carcinomaR. 8 A novel immune escape mechanism of renal cell carcinoma attributable to abnormal HLA-G expressionR. 9 Functional and structural analysis of tumor-specific T cellsR. 10 Identification of renal cell carcinoma associated genes and antigensR. 11 Combination of T cell therapy and trigger of inflammation induces remodeling of the vasculature and tumor eradicationR. 12 Immunotherapy directed against α-fetoprotein results in autoimmune liver disease during liver regenerationR. 13 Inhibition of metalloproteinases enhances the internalization of anti-CD30 antibody Ki-3 and the cytotoxic activity of Ki-3 immunotoxinR. 14 Upregulation of the chemokine receptor CCR7 in classical but not in lymphocyte predominant Hodgkin's disease correlates with distinct dissemination of neoplastic cells in lymphoid organsR. 15 Expression and recognition of HLA-G in a β2-microglobulin-negative tumor cell lineR. 16 Unexpected induction of unresponsiveness by vaccination with transformed Salmonella typhimuriumR. 17 Chemokine receptor expression on neoplastic and non-neoplastic T cells in mycosis fungoidesR. 18 Identification of prostate stem cell antigen-derived peptides as specific targets for CD8+ cytotoxic T cells in prostate cancer patientsR. 19 Heterogeneous expression of MAGE-A genes in occult disseminated tumor cells: A novel multimarker RT-PCR for diagnosis of micrometastatic diseaseR. 20 Tumor MHC downregulation can lead to T cell-dependent immunityR. 21 Ras-dependent inducible and constitutive expression of T cell death associated gene 51R. 22 P-glycoprotein positive multi-drug resistant ovarian carcinoma cells exert increased complement resistanceR. 23 EBNA1-specific CD4+ T cells recognize EBV associated malignancies of latency I and IIIR. 24 Apoptotic tumor cells induce a protective tumor immune response in vivoR. 25 Migration inhibitory factor participates in the tumorigenesis of malignant human gliomasR. 26 Analysis of interleukin-4-mediated cellular interactions during the generation of anti-tumor cytotoxic T lymphocytesR. 27 Complementary methods for the identification of tumor-specific T cell epitopesR. 28 Immunotherapy of experimental tumors by glycodendronsR. 29 Protective effects of gene therapy with interleukin-12p40 in a murine tumor modelR. 30 Targeting of human gamma-glutamyltransferase with mAb 138H11 in a new renal cell carcinoma mouse model

Lymphocyte predominance Hodgkin's disease: the use of bcl-6 and CD57 in diagnosis and differential diagnosis.

Distinction of lymphocyte predominance Hodgkin's disease (LPHD) from other forms of lymphoma often requires immunohistochemistry (IHC). Most previously published recommended panels include markers to define the large neoplastic cells (for example, CD20, J chain, CD45) as well as the non-neoplastic background cells (CD21, CD45RO, CD57, TiA 1). In the present study we examine the practical use of a double IHC method designed to look simultaneously at two germinal center specific cell types: bcl6+ cells and [bc16+, CD57+] co-positive cells. All 10 nodular LPHD had bcl6+ large cells and numerous CD57+ small background cells, including [bcl6+CD57+] cells in rosettes. One case of LPHD with large cell transformation contained numerous bcl6+ large cells both singly (in areas of typical LPHD) and in sheets (in foci of large cell transformation), many CD57+ small cells but few [bcl6+CD57+] co-positive cells and no rosettes. In none of the five cases of florid progressive transformation of germinal centers were true rosettes seen, although all contained variable numbers of bcl6+ large cells and CD57+ cells. Lymphocyte-rich classic Hodgkin's disease LRCHD cases were notable for bcl6 reactivity in Reed-Sternberg cells in all cases, numerous background small bcl6+ lymphocytes, and rare CD57+ cells. Two phenotypic profiles were associated with the 10 cases of T cell-rich B cell large cell lymphoma (TCRBCL). In the first, group "A," six of six cases had bc16- large cells and few CD57+ small cells, and none had significant numbers of [bcl6+, CD57+] co-positive cells. In the second, group "B," four of four cases had bcl6+ large cells with numerous CD57+ and [bcl6+, CD57+] co-positive cells. These findings not only show that LPHD can be distinguished from its morphologic mimics through identification of specific germinal center cell types, but also identifies a second group of TCRBCL (group "B") whose phenotype suggests it might be an architectural variant of nodular LPHD.

Historical review of lymphomas.

Historical review of lymphomas.

The Mi15 monoclonal antibody (anti-syndecan-1) is a reliable marker for quantifying plasma cells in paraffin-embedded bone marrow biopsy specimens

Plasmocyte selective monoclonal antibodies (MAb) recognizing syndecan-1 have recently been described. They belong to a new cluster, CD138. Using the MAb MI15, we investigated the expression of syndecan-1 in routinely paraffin-embedded tissues. Nontumoral lymph nodes (25 cases) and bone marrow biopsy specimens (63 cases) showed strong membrane staining of plasma cells only, allowing accurate analysis of the nuclear structure. The MI15 positivity correlated with kappa and lambda light chain expression in the cytoplasm. The percentages of plasma cells calculated in bone marrow biopsy specimens after MI15 staining were, respectively, 2.1% (range, 1% to 4%) in normal bone marrows, 8.5% (range, 5 to 17) in reactive plasmocytosis, and 4.66% in monoclonal gammapathy of undetermined significance (MGUS) patients (range, 1 to 13), in the same range but slightly higher than those obtained on smears or on hematoxylin and eosin (H&E)-stained sections. In multiple myeloma (40 cases), all plasma cell types were marked, and Mi15 MAb gave additional information in 8 of 40 (20%) patients. In lymph nodes, Mi15 MAb reacted with Reed-Sternberg cells of dassical Hodgkin's disease in 23 of 31 cases (74%) with variable intensity. In contrast, nodular lymphocyte predominance Hodgkin's disease (10 cases), most B cell lymphomas (88 of 107 cases) and all T cell lymphomas (30 cases) were negative. In B cell lymphomas, plasmocytomas (8 cases), plasmocytic lymphomas (2 cases), and 5 of 13 cases of immunoblastic lymphoma with plasmocytoid differentiation were stained. In lymphoplasmocytoid lymphomas (4 lymph nodes and 20 bone marrow biopsy specimens), only mature plasma cells were positive. Moreover, a wide distribution of syndecan-1 was observed in normal and tumoral epithelial tissues. Finally, Mi15 MAb appears to be a reliable marker for identifying and quantifying normal and tumoral plasma cells in paraffin-embedded bone marrow and lymph node samples.

Reed-Sternberg Cell Genome Expression Supports a B-Cell Lineage

AbstractThe malignant Reed-Sternberg cell of Hodgkin's disease, first described a century ago, has resisted in-depth analysis due to its extreme rarity in lymphomatous tissue. To directly study its genome-wide gene expression, approximately 11,000,000 bases (27,518 cDNA sequences) of expressed gene sequence was determined from living single Reed-Sternberg cells, Hodgkin's tissue, and cell lines. This approach increased the number of genes known to be expressed in Hodgkin's disease by 20-fold to 2,666 named genes. The data here indicate that Reed-Sternberg cells from both nodular sclerosing and lymphocyte predominant Hodgkin's disease were derived from an unusual B-cell lineage based on a comparison of their gene expression to approximately 40,000,000 bases (105 sequences) of expressed gene sequence from germinal center B cells (GCB) and dendritic cells. The data set of expressed genes, reported here and on the World Wide Web, forms a basis to understand the genes responsible for Hodgkin's disease and develop novel diagnostic markers and therapies. This study of the rare Reed-Sternberg cell, concealed in its heterogenous cellular context, also provides a formidable test case to advance the limit of analysis of differential gene expression to the single disease cell.

Reed-Sternberg Cell Genome Expression Supports a B-Cell Lineage

The malignant Reed-Sternberg cell of Hodgkin's disease, first described a century ago, has resisted in-depth analysis due to its extreme rarity in lymphomatous tissue. To directly study its genome-wide gene expression, approximately 11,000,000 bases (27,518 cDNA sequences) of expressed gene sequence was determined from living single Reed-Sternberg cells, Hodgkin's tissue, and cell lines. This approach increased the number of genes known to be expressed in Hodgkin's disease by 20-fold to 2,666 named genes. The data here indicate that Reed-Sternberg cells from both nodular sclerosing and lymphocyte predominant Hodgkin's disease were derived from an unusual B-cell lineage based on a comparison of their gene expression to approximately 40,000,000 bases (10(5) sequences) of expressed gene sequence from germinal center B cells (GCB) and dendritic cells. The data set of expressed genes, reported here and on the World Wide Web, forms a basis to understand the genes responsible for Hodgkin's disease and develop novel diagnostic markers and therapies. This study of the rare Reed-Sternberg cell, concealed in its heterogenous cellular context, also provides a formidable test case to advance the limit of analysis of differential gene expression to the single disease cell.

Further investigation of the role of HLA-DPB1 in adult Hodgkin's disease (HD) suggests an influence on susceptibility to different HD subtypes.

It has been suggested in a number of studies that susceptibility to adult Hodgkin's disease (HD) is influenced by the HLA class II region, and specifically by alleles at the HLA-DPB1 locus. Since HD is diagnostically complex, it is not clear whether different HLA-DPB1 alleles confer susceptibility to different HD subtypes. To clarify this we have extended a previous study to type DPB1 alleles in 147 adult HD patients from a single centre. We have analysed patients with nodular sclerosing (NS), mixed cellularity (MC) or lymphocyte predominant (LP) HD, and gender in relation to HLA-DPBI type, in comparison with 183 adult controls. The results confirmed previously reported associations of DPB1*0301 with HD susceptibility (relative risk (RR) = 1.42; 95% confidence interval (CI) 0.86–2.36) and DPB1*0201 with resistance to HD (RR = 0.49; CI 0.27–0.90). However, analysis by HD subtype and gender showed that *0301-associated susceptibility was confined to females with HD (RR = 2.46; CI 1.02–5.92), and *0201-associated resistance to females with NS-HD (RR = 0.28; CI 0.10–0.79). Susceptibility to NS-HD was also associated in females with *1001 (RR = 11.73; CI 1.32–104.36), and resistance with *1101 (RR = 0.08; CI 0.01–0.65). In contrast, susceptibility to LP-HD was associated in males with *2001 (RR = 32.14; CI 3.17–326.17), and to MC-HD with *3401 (RR = 16.78; CI 2.84–99.17). Comparison of DPB1-encoded polymorphic amino-acid frequencies in patients and controls showed that susceptibility to MC-HD was associated with Leucine at position 35 of DPB1 (RR = 8.85; CI 3.04–25.77), Alanine-55 (RR = 15.17; CI 2.00–115.20) and Valine-84 (RR = 15.94; CI 3.55–71.49). In contrast, Glutamic acid 69 was significantly associated with resistance to MC-HD (RR = 0.14; CI 0.03–0.60). Certain DPB1 alleles and individual DPβ1 polymorphic amino acid residues may thus affect susceptibility and resistance to specific HD subtypes. This may be through their influence on the binding of peptides derived from an HD-associated infectious agent, and the consequent effect on immune responses to the agent. © 1999 Cancer Research Campaign

Characterization of the Interleukin-1β-Converting Enzyme/Ced-3-Family Protease, Caspase-3/CPP32, in Hodgkin's Disease: Lack of Caspase-3 Expression in Nodular Lymphocyte Predominance Hodgkin's Disease

Apoptosis (programmed cell death) serves an important role in the normal morphogenesis, immunoregulation, and homeostatic mechanisms in both normal and neoplastic cells. Caspase-3/CPP32, a member of the ICE/Ced-3-family of cysteine proteases, is an important downstream mediator of several complex proteolytic cascades that result in apoptosis in both hematopoietic and nonhematopoietic cells. Previous studies have demonstrated that caspase-3 is commonly expressed in classical Hodgkin's disease (CHD); however, the biological significance of its expression in Hodgkin's disease is unknown. In this report, the expression of caspase-3 in nodular lymphocyte predominance Hodgkin's disease (NLPHD) was evaluated by immunohistochemistry; in addition, we investigated the role of caspase-3 in CD95 (Fas)-mediated apoptosis in three CHD cell lines. Formalin-fixed, paraffin-embedded tissue sections from 11 cases of NLPHD were immunostained for caspase-3 using a polyclonal rabbit antibody that detects both the 32-kd zymogen and the 20-kd active subunit of the caspase-3 protease. Only 1/11 cases of NLPHD demonstrated caspase-3 immunopositivity in lymphocytic/histiocytic cells. Caspase-3 expression was also evaluated in three CHD cell lines, HS445, L428, and KMH2. Whereas caspase-3 expression was detected in HS445 and L428 cell lines, no expression was found in KMH2 cells by immunohistochemical staining. Treatment of HS445 and L428 cell lines for 72 hours with agonistic CD95 monoclonal antibody induced marked apoptosis that was significantly inhibited by pretreatment with the caspase-3 inhibitor, DEVD-FMK, as determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay and flow cytometric analysis of 7-amino-actinomycin D staining. In addition, a significant increase in caspase-3 activity as determined by an enzyme colorimetric assay was detected in HS445 and L428 cells after 48 hours of CD95 stimulation. In marked contrast, treatment of caspase-3-deficient KMH2 cells with anti-CD95 mAb did not demonstrate an increase in caspase-3 activity or induce apoptosis. These data demonstrate caspase-3 is important for CD95-mediated apoptosis in CHD cell lines. In addition, the majority of NLPHD cases examined in this study failed to express detectable levels of caspase-3, suggesting these tumor cells may be resistant to apoptotic stimuli dependent on caspase-3 activity. Furthermore, these data suggest the differential expression of caspase-3 noted between NLPHD and CHD may provide additional evidence that each is a unique disease entity.

Hodgkin's disease: immunoglobulin heavy and light chain gene rearrangements revealed in single Hodgkin/Reed-Sternberg cells.

AIM: To corroborate and investigate the nature of Hodgkin/Reed-Sternberg cells (H/R-S) of various subtypes of Hodgkin's disease. METHOD: Single H/R-S cells were micro-picked from frozen sections of tissues affected by...

T-cell-rich B-cell Lymphoma in the Cat

The clinical and pathological features of eight cases of feline T-cell-rich B-cell lymphoma are described. The disease occurred in older cats (mean age 11·4±3·9 years), which on initial examination generally showed enlargement of a single submandibular or cervical lymph node. After excision, there was no recurrence of the lesions at 6 months in three cats. In one further case, however, the lesion had recurred 6 months later; it was again excised but recurred after an additional 6 months. Microscopically, there was effacement of normal lymph node architecture by a nodular (n=4) or diffuse (n=4) proliferation of small to blastic lymphocytes, accompanied by a characteristic population of bizarre giant, or multinucleate, cells. The mitotic rate was low and mitoses were restricted to the atypical population. Immunophenotyping revealed the smaller lymphocytes to be a mixture of CD3+MHC Class II+T lymphocytes and BLA36+CD79variableMHC Class IIvariableB lymphocytes. The atypical cells were of the B-cell lineage (BLA36+MHC Class IIvariable). Polymerase chain reaction analysis revealed no proviral DNA products of feline leukaemia virus or feline immunodeficiency virus in tissue from any tumour, confirming that these neoplasms were not associated with either virus. The clinical, histological and immunophenotypic findings in these cats were identical with those of “nodular lymphocyte predominance (lymphocytic and histiocytic/L&H) Hodgkin's disease” in man.

Seasonal variation in the incidence of Hodgkin's disease.

Earlier literature suggested there may be a seasonal rhythm of onset of Hodgkin's disease. This issue has been re-examined using population-based prospectively-collected data with high ascertainment levels. The Data Collection Study (DCS) of the Leukaemia Research Fund (LRF) Centre for Clinical Epidemiology (University of Leeds) generated the information used, which was based on a population of 13.5 million--about one quarter of England and Wales--over 10 years. The RYE histopathological classification was employed. The findings show that in patients with nodular sclerosing histopathology there was a highly significant circannual rhythm with a low amplitude (extent of seasonal variation) and a peak in March. A significant, but different, rhythm with a high amplitude and a peak in August was found in lymphocyte predominant Hodgkin's disease. However, this finding is less certain, due to smaller numbers and a lower significance level. The main conclusion is that there is a highly significant seasonality in nodular sclerosing Hodgkin's disease. The findings provide further evidence that nodular sclerosing and lymphocyte predominant may be two different diseases. The differing seasonality rhythms may provide aetiological clues.

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).

A nurse with a rash on her neck

A nurse aged 55 years had flu-like symptoms and a vesicular rash on her neck, about 4X4 cm. She thought that the rash might be caused by irritation from a label inside the collar of her coat. The next day she noticed lymph-node enlargement on both sides of her neck. Because she worked in a surgical department, she asked a surgeon about the lumps. The surgeon at once thought of the possibility of malignant lymphoma and removed one of the lymph nodes for histopathological investigation. The pathologist diagnosed a high-grade B-cell non-Hodgkin's lymphoma. Computed tomography of her thorax and abdomen was negative, and lactate dehydrogenase was normal. 2 weeks later she was sent to a University Hospital for further investigations and treatment. A bone-marrow biopsy specimen was normal. By that time her other lymph nodes had returned almost to normal. Microscopy of the lymph node removed showed a partly effaced structure caused by paracortical expansion and proliferation of blasts (figure A). In some areas, sinuses were preserved and dilated, suggesting an inflammatory reaction. Immunohistochemical investigation showed many blasts positive for anti-CD20 (figure B) and anti-CD30 (figure C) in the expanded paracortex. Differential diagnoses were T-cell-rich B-cell lymphoma, lymphocyte-predominant Hodgkin's disease, and virus lymphadenitis. Serological investigations did not show any sign of virus infection. PCR investigation of DNA extracted from sections of the lymph-node biopsy showed a polyclonal reaction for immunoglobulin genes (IgH) and T-cell receptor genes (TCRγ).

The origin of Hodgkin and Reed/Sternberg cells in Hodgkin's disease.

One of the characteristic features of Hodgkin's disease (HD) is the presence of a small population of often bizarre-looking large mono- or multinucleated Hodgkin and Reed-Sternberg (HRS) cells within the affected tissue. Recent cytogenetic investigations, studies of Epstein-Barr virus (EBV) genomes present in HRS cells, and analyses of Ig gene rearrangements amplified from single, micromanipulated HRS cells show that these cells largely represent clonal populations. The finding of Ig gene rearrangements in HRS cells in most cases of HD identifies B cells as the precursors of HRS cells in most if not all cases. Furthermore, the presence and pattern of somatic mutations within the rearranged Ig genes show that HRS cells in classical (i.e. nodular sclerosis, mixed cellularity, and lymphocyte depletion HD) as well as lymphocyte predominant (LP) HD originate from germinal center (GC) B cells. Ongoing somatic mutation and evidence for selection link HRS cells from LP HD to a mutating, antigen-selected GC B cell. In classical HD, the finding of "crippling" mutations and lack of stringent selection for antigen receptor expression suggests that in this case HRS cells are derived from a compartment of GC B cells that were destined to die but escaped apoptosis by some transforming event. One candidate for the latter is EBV infection.