[Show abstract][Hide abstract] ABSTRACT: There is a need for genetic biomarkers to guide prognosis and management of gastric mucosa-associated lymphoid tissue (MALT) lymphomas. We assessed the incidence and clinical significance of the MALT lymphoma-associated genetic abnormalities t(11;18)/API2-MALT1, t(1;14)/BCL10-IGH, t(14;18)/IGH-MALT1, t(3;14)/FOXP1-IGH, and extra copies of MALT1 and FOXP1 in gastric MALT lymphomas from Japan.
The presence of translocations and copy number changes involving MALT1, IGH and FOXP1 were assessed in 90 cases of gastric MALT lymphoma using interphase fluorescence in situ hybridisation (FISH). In cases carrying a MALT1 translocation, FISH for API2-MALT1 was performed, whereas in those carrying an IGH translocation, FISH was performed for BCL10, BCL6, BCL2, c-MYC and/or CCND1.
t(11;18)/API2-MALT1 was detected in 18 of 87 (21%) cases and was significantly associated with Helicobacter pylori-negativity, resistance to H pylori eradication and Bcl10 nuclear expression. Four of 68 (6%) cases carried a translocation involving IGH and FOXP1 (n = 1), BCL2 (n = 1) or an unknown partner (n = 2). Neither t(1;14)/BCL10-IGH nor t(14;18)/IGH-MALT1 was detected. Extra copies of MALT1 and FOXP1 were detected in 18 of 71 (25%) cases and 10 of 59 (17%) cases, respectively. The presence of extra copies of MALT1 was significantly associated with progression or relapse of lymphoma, and was an independent adverse prognostic factor for event-free survival as determined by multivariate analysis.
t(11;18)/API2-MALT1 is frequent, whereas IGH-involved translocations are rare in gastric MALT lymphoma in Japan. The presence of extra copies of MALT1, often suggestive of partial or complete trisomy 18, is a frequent genetic aberration in gastric MALT lymphoma, which appears to predict adverse clinical behaviour.
Gut 11/2007; 56(10):1358-63. DOI:10.1136/gut.2007.123729 · 14.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Strong uniform expression of FOXP1 protein occurs in a subgroup of non-germinal centre (GC) diffuse large B-cell lymphomas (DLBCL). We have investigated gene rearrangement as a potential mechanism for deregulated expression of FOXP1 however, using FISH FOXP1 translocations were not found in any case with over-expression of the protein.
[Show abstract][Hide abstract] ABSTRACT: In view of the certain anatomic site-dependent frequency of chromosomal translocations involved in extranodal marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) pathogenesis, 17 salivary gland MALT lymphoma cases were analyzed for MALT1 and FOXP1 translocations. B cell CLL/lymphoma 10 (BCL10) and forkhead box PA (FOXP1) protein expression were studied by immunohistochemistry and translocations identified using fluorescence in situ hybridization (FISH)-specific probes FOXP1, t(11;18)(q21;q21)/API2-MALT1 and t(14;18)(q32;q21)/IgH-MALT1. None of the 11 analyzed cases showed FOXP1 rearrangement or amplification. The t(11;18) was present in five of 13 cases and the t(14;18) in three of 13 cases. MALT1 translocations were mostly mutually exclusive except in a single case. FOXP1 protein expression showed differences in the proportion of tumor cells with nuclear expression but not in their intensity, with the exception of one case where very intense nuclear staining was noted. BCL10 nuclear expression was present in four of 17 cases, two of which lacked t(11;18). Our results suggest that MALT1-specific translocations and FOXP1 rearrangements are not commonly involved in pathogenesis. A case with strong FOXP1 protein expression indicates the possibility that the upregulation of FOXP1 expression is significant in a small subset of salivary gland MALT lymphomas. Also a single case in which both MALT1 translocations were present indicates that these are not always mutually exclusive.
Pathology International 02/2007; 57(1):47-51. DOI:10.1111/j.1440-1827.2007.02056.x · 1.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Over the last decade, fluorescence in situ hybridization (FISH) has become a firmly established technique in the diagnosis and assessment of lymphoid malignancies. However, this technique is not wide-ly used in the routine diagnostic evaluation of paraffin-embedded biopsies, most likely because of a perception that it is technically more demanding. There are also uncertainties regarding diagnostic thresholds and the way in which results should be interpreted. In this Review, we describe practical strategies for using FISH analysis to detect lymphoma-associated chromosomal abnormalities in routine paraffin-embedded lymphoma biopsies. Furthermore, we provide proposals on how FISH results should be interpreted (including how to calculate cutoff levels for FISH probes), recorded, and reported. An online appendix (available at http://jmd.amjpathol.org) details various simple, yet robust procedures for paraffin FISH analysis; it also provides additional information on the production of FISH probes, evaluating and reporting FISH results, sources for reagents and equipment, and troubleshooting. We hope that these suggestions will make FISH technology for the study of lymphoma biopsies more accessible to routine diagnostic and research laboratories.
[Show abstract][Hide abstract] ABSTRACT: The use of interphase fluorescence in situ hybridisation (FISH) to study cytogenetic abnormalities in routinely fixed paraffin wax embedded tissue has become commonplace over the past decade. However, very few studies have applied FISH to routinely fixed bone marrow trephines (BMTs). This may be because of the acid based decalcification methods that are commonly used during the processing of BMTs, which may adversely affect the suitability of the sample for FISH analysis. For the first time, this report describes the simultaneous application of FISH and immunofluorescent staining (the FICTION technique) to formalin fixed, EDTA decalcified and paraffin wax embedded BMTs. This technique allows the direct correlation of genetic abnormalities to immunophenotype, and therefore will be particularly useful for the identification of genetic abnormalities in specific tumour cells present in BMTs. The application of this to routine clinical practice will assist diagnosis and the detection of minimal residual disease.
[Show abstract][Hide abstract] ABSTRACT: Two microarray studies of mediastinal B cell lymphoma have shown that this disease has a distinct gene expression profile, and also that this is closest to the pattern seen in classical Hodgkin's disease. We reported previously an immunohistologic study in which the loss of intracellular B cell-associated signaling molecules in Reed-Sternberg cells was demonstrated, and in this study we have investigated the expression of the same components in more than 60 mediastinal B cell lymphomas. We report that these signaling molecules are frequently present, and in particular that Syk, BLNK and PLC-gamma2 (absent from Reed-Sternberg cells) are present in the majority of mediastinal B cell lymphomas. The overall pattern of B cell signaling molecules in this disease is therefore closer to that of diffuse large B cell lymphoma than to Hodgkin's disease, and is consistent with a common cell of origin as an explanation of the similar gene expression profiles.
[Show abstract][Hide abstract] ABSTRACT: Stimulation of lymphoid cells via their surface receptors triggers signalling pathways that terminate in the nucleus, where they induce alterations in gene transcription. Nuclear factor of activated T cells (NFAT) transcription factors, involved in a major Ca2+-dependent signalling pathway, normally reside in the cytoplasm but re-locate to the nucleus when activation of the pathway (e.g. following ligation of antigen receptors) leads to their dephosphorylation. This study found that one member of the NFAT family (NFATc1/NFAT2) can be detected in routine biopsy samples, where it is seen in essentially all lymphoid cells, but is absent from the great majority of non-haematopoietic cells. An immunohistological evaluation of NFATc1 in almost 300 lymphomas showed that most neoplastic lymphoid cells also express NFATc1 as a cytoplasmic constituent, although it is absent in classical Hodgkin's disease and plasma cell proliferations. Of particular interest was the finding that NFATc1 was relocated to the nucleus in a minority of lymphoid neoplasms (usually diffuse large B-cell lymphomas or Burkitt lymphoma), presumably reflecting activation of the NFAT pathway. It would be of interest to correlate this feature with patterns of gene expression and also with prognosis, since it may identify a subset of human lymphoma that is distinct in its molecular and clinical features.
British Journal of Haematology 03/2005; 128(3):333-42. DOI:10.1111/j.1365-2141.2004.05313.x · 4.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cutaneous biopsies are traditionally studied for the expression of cellular markers by immunoenzymatic techniques. However, immunofluorescent analysis is a valuable, and largely overlooked, ancillary technique that can resolve questions arising from conventional immunostaining, since it allows pairs of antigens to be simultaneously visualized. Furthermore, a novel technique, based on a combination of immunoperoxidase and immunofluorescent staining, allows three markers to be demonstrated together. Fluorescent microscopy also allows skin biopsies from lymphoma cases to be analyzed for chromosomal abnormalities by the fluorescent in situ hybridization (FISH) technique, which is now applicable to routine biopsy samples. In this review, we describe the technical aspects of immunofluorescent and FISH analysis of routine cutaneous biopsy samples.
American Journal of Dermatopathology 07/2004; 26(3):242-7. DOI:10.1097/00000372-200406000-00015 · 1.39 Impact Factor