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Peter G Isaacson

Publications and source records attributed to Peter G Isaacson.

At least 19 recordsLinked to original sources
PubMed2006

Distinct comparative genomic hybridisation profiles in gastric mucosa-associated lymphoid tissue lymphomas with and without t(11;18)(q21;q21).

t(11;18)(q21;q21) occurs specifically in mucosa-associated lymphoid tissue (MALT) lymphoma and the translocation generates a functional API2-MALT1 fusion product that activates nuclear factor (NF)kappaB. t(11;18) positive lymphomas usually lack the chromosomal aberrations and microsatellite alterations frequently seen in the translocation-negative MALT lymphomas. To further understand their genetic differences, we investigated gastric MALT lymphomas with and without t(11;18) by comparative genomic hybridisation. In general, both chromosomal gains and losses were far more frequent in t(11;18)-negative (median = 3.4 imbalances) than t(11;18)-positive cases (median = 1.6 imbalances), with gains being more frequent than losses. Recurrent chromosomal gains involving whole or major parts of a chromosome were seen for chromosomes 3, 12, 18 and 22 (23%, 19%, 19% and 27% respectively). Discrete recurrent chromosomal gains were found at 9q34 (11/26 = 42%). Bioinformatic analysis of genes mapping to 9q34 revealed potential targets. Among them, TRAF2 and CARD9 are known interaction partners of BCL10, playing a role in NFkappaB activation. Interphase fluorescent in situ hybridisation confirmed genomic gain of the TRAF2, CARD9 and MALT1 loci in 5/6 and 2/2 cases showing chromosomal gains at 9q34 and 18q21 respectively. The results further highlight the genetic difference between MALT lymphomas with and without t(11;18). Moreover, our findings suggest that genomic gain of genes that modulate NFkappaB activation, such as MALT1, TRAF2 and CARD9, may play a role in the pathogenesis of the translocation-negative MALT lymphoma.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Gastrointestinal lymphoma: where morphology meets molecular biology.

Primary gastrointestinal lymphomas are best exemplified by mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach and enteropathy-type T-cell lymphoma (ETL). Both lymphomas were initially recognized on morphological grounds and their identification as distinct clinicopathological entities has subsequently been vindicated following integrated immunophenotypic, molecular, and cellular biological investigations. Delineation of the phenotypic, molecular, and biological properties of these lymphomas at various clinicopathological stages of their development has also provided critical information for the clinical management of patients with these diseases. Here, the histopathology and recent advances in phenotypic and molecular characterization of gastric MALT lymphoma and ETL and their applications in diagnosis and clinical management are reviewed.

Chromosome Aberrations↗
PubMed2005

MALT lymphoma with t(14;18)(q32;q21)/IGH-MALT1 is characterized by strong cytoplasmic MALT1 and BCL10 expression.

Mucosa-associated lymphoid tissue (MALT) lymphoma is specifically associated with t(11;18)(q21;q21), t(1;14)(p22;q32) and t(14;18)(q32;q21). t(11;18)(q21;q21) fuses the N-terminus of the API2 gene to the C-terminus of the MALT1 gene and generates a functional API2-MALT1 product. t(1;14)(p22;q32) and t(14;18)(q32;q21) bring the BCL10 and MALT1 genes respectively to the IGH locus and deregulate their expression. The oncogenic activity of the three chromosomal translocations is linked by the physiological role of BCL10 and MALT1 in antigen receptor-mediated NFkappaB activation. In this study, MALT1 and BCL10 expression was examined in normal lymphoid tissues and 423 cases of MALT lymphoma from eight sites, and their expression was correlated with the above translocations, which were detected by molecular and molecular cytogenetic methods. In normal B-cell follicles, both MALT1 and BCL10 were expressed predominantly in the cytoplasm, high in centroblasts, moderate in centrocytes and weak/negative in mantle zone B-cells. In MALT lymphoma, MALT1 and BCL10 expression varied among cases with different chromosomal translocations. In 9/9 MALT lymphomas with t(14;18)(q32;q21), tumour cells showed strong homogeneous cytoplasmic expression of both MALT1 and BCL10. In 12/12 cases with evidence of t(1;14)(p22;q32) or variants, tumour cells expressed MALT1 weakly in the cytoplasm but BCL10 strongly in the nuclei. In all 67 MALT lymphomas with t(11;18)(q21;q21), tumour cells expressed weak cytoplasmic MALT1 and moderate nuclear BCL10. In MALT lymphomas without the above translocations, both MALT1 and BCL10, in general, were expressed weakly in the cytoplasm. Real-time quantitative RT-PCR showed a good correlation between MALT1 and BCL10 mRNA expression and underlining genetic changes, with t(14;18)(q32;q21)- and t(1;14)(p22;q32)-positive cases displaying the highest MALT1 and BCL10 mRNA expression respectively. These results show that MALT1 expression pattern is identical to that of BCL10 in normal lymphoid tissues but varies in MALT lymphomas, with high cytoplasmic expression of both MALT1 and BCL10 characterizing those with t(14;18)(q32;q21).

Adaptor Proteins, Signal Transducing↗
PubMed2005

Update on MALT lymphomas.

Gastric mucosa associated lymphoid tissue (MALT) lymphoma is a histologically distinct tumour derived from MALT acquired as a result of Helicobacter pylori infection. Eradication of H. pylori causes clinical regression of the lymphoma in 75% of cases. In seeking to identify those cases resistant to this therapy, and in the interests of further understanding the biology of MALT lymphoma, genetic alterations of MALT lymphomas have been investigated. Three translocations, t(11;18)(q21;q21), t(1;14)(p22;q32) and t(14;18)(q32;q21) are specifically associated with MALT lymphoma and the genes involved have been identified. T(11;18) results in a chimeric fusion between the API2 and MALT1 genes and is specifically associated with gastric MALT lymphomas that do not respond to eradication of H. pylori. T(1;14) and t(14;18) deregulate BCL10 and MALT1 expression, respectively. These three chromosomal translocations that involve different genes appear to share common oncogenic properties by targeting the same nuclear factor kappa B (NF kappa B) oncogenic pathway.

Humans↗
PubMed2005

Plasmablastic lymphoma in HIV-positive patients: an aggressive Epstein-Barr virus-associated extramedullary plasmacytic neoplasm.

AIDS-associated aggressive B-cell lymphomas often have plasmacytoid features. Plasma cell neoplasms in HIV patients were commonly described to have atypical morphology and an aggressive clinical course in the literature. We reviewed 14 cases of neoplasms with marked plasmacytic differentiation in HIV-positive patients to determine their clinicopathologic features. Of these, 13 of 14 had homogeneous morphology and were generally CD45(+), CD20-, PAX-5-, and CD138(+). All were positive for Epstein-Barr virus-encoded RNA (EBER) but lacked EBV late membrane proteins (LMP). Human herpes virus 8 (HHV8) DNA was detected in 6 of 10 cases by nested PCR, but HHV8 latent nuclear antigen (LNA) was absent. The 13 patients ranged in age from 28 to 44 years (median, 41 years) (11 male patients; 2 female patients). All patients had extramedullary and 11 of 13 had extranodal tumor at the initial presentation; 2 had distant marrow involvement. The most commonly involved location was the oral cavity (6 of 13 cases), followed by bone and soft tissue (4 of 13), and the gastrointestinal tract (3 of 13). All 11 patients with follow-up died within 34 months (median, 7 months). The 14th patient who had a nodal disease with more undifferentiated morphology and expression of the HHV8 LNA protein was alive without disease at last follow-up (>72 months), probably representing a novel HHV8(+) lymphoma. We conclude that most plasmacytic tumors in HIV-positive individuals are extramedullary, clinically aggressive EBV(+) tumors identical to plasmablastic lymphoma that does not have the clinical features of plasma cell myeloma.

Adult↗
PubMed2004

Atypical marginal zone hyperplasia of mucosa-associated lymphoid tissue: a reactive condition of childhood showing immunoglobulin lambda light-chain restriction.

Mucosa-associated lymphoid tissue (MALT) lymphomas usually arise at sites of acquired MALT and are uncommon in native MALT (eg, Peyer patches and tonsil). Malignancy in these low-grade lymphomas is often inferred by immunoglobulin light-chain restriction and expression of CD43; molecular genetic evidence is sought only if these are in doubt. We report 6 cases (4 tonsils, 2 appendixes) of marginal zone (MZ) hyperplasia in children aged 3 to 11 years that, despite histologic and immunophenotypic features indicative of lymphoma, were polyclonal by molecular analysis. No lymphoma-directed therapy was given and patients remain alive and well (5 cases, median follow-up 35.3 months). The involved tonsil and appendix showed florid MZ hyperplasia with prominent intraepithelial B cells (IEBCs). The MZ B cells and IEBCs showed a high-proliferation fraction and a CD20(+), CD21(+), CD27(-), immunoglobulin (Ig) superfamily receptor translocation-associated 1-positive (IRTA-1(+)), CD43(+), multiple myeloma oncogene 1 (MUM-1), IgM(+)D(+) phenotype. Polymerase chain reaction (PCR), cloning, and sequencing of rearranged IgH and Iglambda genes (whole tissue sections [6 cases]; microdissected cells [2 cases]) showed that the MZ B cells and IEBCs were polyclonal and the IgH genes nonmutated. In contrast, MZ (intraepithelial) B cells of 6 control tonsils had a similar immunophenotype, except for expression of CD27 and polytypic light chains, whereas molecular studies showed that they were polyclonal with mutated Ig genes.

Appendix↗
PubMed2004

Cerebral CD8+ lymphocytosis in HIV-1 infected patients with immune restoration induced by HAART.

In HIV infected persons, highly active antiretroviral therapy (HAART) has reduced both the morbidity and incidence of several disorders. Its effects on direct HIV-induced damage to the CNS remain controversial. In addition, HAART may provoke an "immune reconstitution inflammatory syndrome" (IRIS). Herein we report two patients who, despite HAART, developed a diffuse encephalopathy. Their clinical, radiological and neuropathological features are described. Immunohistochemical and PCR analyses were used to detect HIV and to exclude other viruses in brain tissue. The unusual inflammatory reaction in the brain tissue was defined by immunohistochemistry. Both patients had advanced HIV disease with low CD4 counts and high HIV "viral loads" before starting HAART. In both, HAART induced an increase in CD4 count and a marked reduction in HIV viral load, which was accompanied, in patient one, by worsening of pre-existing, and, in patient two, by development of, acute encephalopathy. At post-mortem examination, the brain of patient one showed HIV encephalitis. In addition, the brains of both patients revealed HIV-DNA by PCR, diffuse microglial hyperplasia and massive and diffuse perivascular and intraparenchymal infiltration by CD8+/CD4- lymphocytes. We suggest that the rapid immune reconstitution induced by HAART in these two patients led to a redistribution of lymphocytes into peripheral blood. This was followed by recruitment of CD8+ lymphocytes into the brain, which resulted in the diffuse infiltration described. The appearances in patient two further suggest that HIV brain infection, even without encephalitis, is sufficient to trigger this response.

Adult↗
PubMed2004

t(1;14) and t(11;18) in the differential diagnosis of Waldenström's macroglobulinemia.

Waldenström's macroglobulinemia is caused by several B-cell proliferative disorders including lymphoplasmacytic lymphoma, marginal zone B-cell lymphoma, B-cell chronic lymphocytic leukemia and multiple myeloma. Differential diagnosis between lymphoplasmacytic lymphoma and extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue is particularly difficult as there is a considerable overlap in histological presentation. We report a case of Waldenström's macroglobulinemia with involvement of the peripheral blood, bone marrow and stomach. Serum chemistry revealed an IgM of 5.4 g/dl, but Bence-Jones protein in urine was negative. Abnormal lymphoid cells were detected in both blood and the bone marrow. Flow cytometry of the bone marrow aspirate showed that majority of cells were CD20(+), CD38(+), expressing immunoglobulin lambda light chain, but CD5(-) and CD10(-). Gastric biopsies revealed infiltration of the gastric mucosa by small lymphoid cells showing plasmacytoid differentiation and occasional Dutcher bodies. Lymphoepithelial lesions and Helicobacter pylori were not seen. Thus, the differential diagnosis between lymphoplasmacytic lymphoma and mucosa-associated lymphoid tissue lymphoma was raised. To resolve this, we performed BCL10 immunohistochemistry and reverse transcriptional polymerase chain reaction (RT-PCR) for the API2-MALT1 fusion transcript of t(11;18)(q21;q21). Both bone marrow and gastric biopsies showed strong BCL10 nuclear staining, similar to that seen in t(1;14)(p22;q32) positive mucosa-associated lymphoid tissue lymphoma, but absence of the API2-MALT1 fusion transcript. To further ascertain whether the detection of t(1;14)(p22;q32) and t(11;18)(q21;q21) can be reliably used for the differential diagnosis between lymphoplasmacytic lymphoma and mucosa-associated lymphoid tissue lymphoma, we screened for these translocations by BCL10 immunohistochemistry in 58 lymphoplasmacytic lymphomas and RT-PCR for t(11;18)(q21;q21) in 40 lymphoplasmacytic lymphomas, respectively. None of the lymphoplasmacytic lymphomas studied harbored these translocations. Thus, detection of t(1;14)(p22;q32) and t(11;18)(q21;q21) is useful in the differential diagnosis between lymphoplasmacytic lymphoma and mucosa-associated lymphoid tissue lymphoma.

ADP-ribosyl Cyclase↗
PubMed2004

CD10 expression in extranodal dissemination of angioimmunoblastic T-cell lymphoma.

Angioimmunoblastic T-cell lymphoma (AITL) is a systemic disease that often has evidence of extranodal involvement at presentation. In a recent study of lymph nodes in AITL, we showed that the neoplastic T cells in most cases can be identified by aberrant expression of CD10. The aim of this study was to investigate whether CD10 expression by the neoplastic T cells is maintained in extranodal sites. Ten cases of AITL with histologic and immunophenotypic evidence of extranodal dissemination were studied. Seven cases of peripheral T-cell lymphoma unspecified (PTLu), that included biopsies of involved extranodal sites, two cases of enteropathy type T-cell lymphoma (ETTL), and one case of extranodal NK/T lymphoma, nasal type were selected as controls. Diagnostic lymph node biopsies and biopsies of extranodal sites were reviewed. PCR for T-cell clonality and single layer immunostaining for CD3, CD20, CD10, and CD21 and double layer immunostaining for CD20/CD10 were performed. All 10 cases of AITL had characteristic histologic features and molecular evidence of the disease in lymph node biopsies. In these cases, aberrant CD10 expression was maintained in the lung, cecum, tonsil, nasopharynx, and one of six involved bone marrow trephines. In these extranodal biopsies, the distribution of CD10-positive tumor cells correlated with that of the follicular dendritic cell meshwork (FDC). The five bone marrow trephines that lacked aberrant CD10 expression were devoid of morphologic and immunohistochemical evidence of FDC. In these five cases, there was evidence of aberrant CD10 expression in other involved sites that had FDC. The neoplastic cells in PTLu, ETTL, and extranodal NK/T lymphoma, nasal type were CD10 negative. Our data show that aberrant CD10 expression is a useful phenotypic marker for diagnosis of AITL in most involved extranodal sites, except bone marrow, and suggest a possible role of FDC in the pathogenesis of AITL.

Adult↗
PubMed2004

t(11;18)(q21;q21) of mucosa-associated lymphoid tissue lymphoma results from illegitimate non-homologous end joining following double strand breaks.

t(11;18)(q21;q21) is the most frequent chromosomal aberration specifically associated with mucosa-associated lymphoid tissue (MALT) lymphoma. The translocation fuses the API2 gene to the MALT1 gene and generates a functional API2-MALT1 transcript. The breakpoint of the fusion gene is well characterized at the transcript level but poorly understood at the genomic level and the mechanism underlying the translocation is unknown. We identified the genomic breakpoint in 19 t(11;18)-positive MALT lymphoma cases by polymerase chain reaction and sequencing and analysed the junctional sequences. The breakpoints were scattered in intron 7 and exon 8 of the API2 gene, and introns 4, 6, 7 and 8 of the MALT1 gene. Comparative sequence analysis between the API2-MALT1 fusion on der(11) and the MALT1-API2 fusion on der(18) showed extensive alterations including deletions, duplications and non-template-based insertions at the fusion junctions in all cases examined. An extensive sequence search failed to reveal any known sequence motifs that might be associated with chromosomal recombination or any novel consensus sequences at or near the breakpoints on both der(11) and der(18) except in one case, in which Alu repeats spanned the breakpoint of the MALT1-API2 fusion. Our results suggest that t(11;18) may result from illegitimate non-homologous end joining following double strand breaks.

Base Sequence↗
PubMed2004

Translocation t(11;18)(q21;q21) is not predictive of response to chemotherapy with 2CdA in patients with gastric MALT lymphoma.

BACKGROUND: t(11;18)(q21;q21) resulting in the API2-MALT1 fusion transcript is an exclusive finding in extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). While it has recently been demonstrated as a negative predictor for gastric MALT lymphoma undergoing eradication of Helicobacter pylori, nothing is known about the relation between t(11;18)(q21;q21) status and response to chemotherapy. We have therefore performed a retrospective analysis of t(11;18)(q21;q21) in patients undergoing chemotherapy with the nucleoside analogue cladribine (2CdA) for gastric MALT lymphoma. PATIENTS AND METHODS: Eighteen cases of gastric MALT lymphoma treated with 2CdA were reviewed, and 17 could be investigated for t(11;18)(q21;q21) by reverse-transcription polymerase chain reaction and fluorescence in situ hybridization. t(11;18)(q21;q21) was correlated with response to chemotherapy. RESULTS: Of the 17 patients with gastric MALT lymphoma treated with 2CdA, 9 were at stage IE, 2 at stage IIE and 6 at stage IV. Eight cases with stage IE lymphoma were first treated with H. pylori eradication, but none of them showed histological regression during a minimum follow-up of 12 months, and they were subsequently treated with primary chemotherapy. One patient received chemotherapy due to absence of H. pylori infection. Another patient initially rated as stage IE whose gastric lymphoma did not respond developed spread to the lung during follow-up after eradication. All the remaining 13 cases were treated by chemotherapy at the time of diagnosis. Out of these 17, 8 patients (47%) were found to carry t(11;18)(q21;q21). One patient, who was negative for t(11;18)(q21;q21), progressed during chemotherapy and died 5 months after initiation of treatment. One patient each with and without t(11;18)(q21; q21) had a partial response lasting for 14 and >18 months, respectively. One t(11;18)(q21;q21)-positive patient had stable disease for >16 months. The remaining patients achieved a complete remission (CR) following treatment; 6 were positive for t(11;18)(q21;q21), while the remaining 6 were negative. Two patients [1 positive and 1 negative for t(11;18)(q21;q21), respectively] have developed a local relapse following CR and were salvaged by radiotherapy. CONCLUSION: Our findings suggest that the presence of the API2-MALT1 fusion transcript resulting from t(11;18)(q21;q21) does not adversely affect the response of gastric MALT lymphoma to chemotherapy with 2CdA. 2CdA appears to be an attractive agent for treatment of gastric MALT lymphoma unresponsive to H. pylori eradication, including those positive for t(11;18)(q21;q21).

Adult↗
PubMed2003

Phenotype and genotype of interfollicular large B cells, a subpopulation of lymphocytes often with dendritic morphology.

We describe large B cells, many of which have a stellate or dendritic morphology, found in the interfollicular T-cell-rich areas of human peripheral lymphoid tissue. These B cells probably require CD40/CD40 ligand signaling for their generation and have a unique phenotype and a post-germinal center pattern of immunoglobulin gene mutation. The only comparable B cell is the "asteroid" cell of the thymic medulla. Their anatomic location and pattern of gene mutation suggest that these cells may represent the cell of origin of some human large-cell lymphomas. Studies in experimental animals should help to elucidate the role of these cells in the immune response.

Antigens↗
PubMed2003

Variable frequencies of t(11;18)(q21;q21) in MALT lymphomas of different sites: significant association with CagA strains of H pylori in gastric MALT lymphoma.

t(11;18)(q21;q21) is a specific chromosomal translocation associated with mucosa-associated lymphoid tissue (MALT) lymphoma. It fuses the amino terminal of the API2 gene to the carboxyl terminal of the MALT1 gene and generates a chimeric fusion product. Although the translocation is frequently detected in gastric and pulmonary MALT lymphoma, its incidence in MALT lymphomas from other sites is largely unknown. It also remains unknown whether the occurrence of the translocation is influenced by the nature of preceding diseases associated with MALT lymphomas. We screened for t(11; 18)(q21;q21) in 417 cases of MALT lymphoma from 8 major sites by reverse transcription-polymerase chain reaction. t(11;18)(q21;q21) was found at highest frequencies in MALT lymphomas from the lung (38%) and stomach (24%), and at moderate frequencies in those from the conjunctiva (19%) and orbit (14%). However, the translocation was found only rarely in MALT lymphomas from the salivary gland (1%) and was absent in those from the thyroid, skin, liver, and other rare sites, and in immunoproliferative small intestinal disease (IPSID). In gastric MALT lymphoma, t(11;18)(q21;q21) was significantly associated with infection by CagA-positive strains of Helicobacter pylori. As CagA-positive strains of H pylori are much more potent in induction of host inflammatory responses, including activation of neutrophils, which release highly genotoxic oxygen reactive species, we therefore examined neutrophil infiltration in recognized precursors of MALT lymphoma including H pylori-associated gastritis, lymphoepithelial sialadenitis, and Hashimoto thyroiditis. Neutrophil infiltration was prominent in H pylori-associated gastritis but not in lymphoepithelial sialadenitis and Hashimoto thyroiditis. Our results demonstrate that t(11;18)(q21; q21) occurs at markedly variable frequencies in MALT lymphoma of different sites and suggest that the occurrence of the translocation is influenced by the nature of premalignant diseases associated with MALT lymphoma. Oxidative damage might play a role in development of t(11;18)(q21; q21).

Adaptor Proteins, Signal Transducing↗
PubMed2003

Splenic marginal zone lymphoma.

Splenic marginal zone lymphoma (SMZL) is an indolent lymphoproliferative disease accounting for approximately 1% of all lymphomas. SMZL presents with marked splenomegaly, and often accompanied by circulating atypical 'villous lymphocytes' and is also known as splenic lymphoma with villous lymphocytes. Histologically, the spleen in SMZL is characterised by a nodular infiltrate based on pre-existing white pulp but also involving the red pulp. Within the white pulp, the infiltrate has a biphasic morphology comprising an inner zone of small lymphocytes and a peripheral (marginal) zone of larger lymphoid cells. Usually the splenic lymph nodes and bone marrow are also involved by a vaguely nodular infiltrate of similar nature. Immunophenotypically, the tumor cells has a mature B-cell phenotype and frequently express IgM and IgD but typically lack CD5, CD23, CD43, CD10, Bcl-6 and cyclin D1. Analysis of immunoglobulin heavy-chain gene variable regions suggest that some cases of SMZL arise form postfollicular B cells but others from naïve B cells. Genetic studies have shown abnormalities of a number of chromosomes however 7q31-32 allelic loss appears to be characteristic. Histological differential diagnosis include a number of entities such as lymphoid hyperplasias, other marginal zone lymphomas, mantle cell lymphoma, follicular lymphoma, and B-CLL.

Adult↗