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Biomedical subjects

A C Wotherspoon

Publications and source records attributed to A C Wotherspoon.

At least 19 recordsLinked to original sources
PubMed2000

BCL10 gene mutation in lymphoma.

BCL10 is directly involved in t(1;14)(p22;q32) of mucosa-associated lymphoid tissue (MALT) lymphoma. Wild-type BCL10 promoted apoptosis and suppressed malignant transformation in vitro, whereas truncated mutants lost the pro-apoptotic activity and exhibited gain of function enhancement of transformation. We studied 220 lymphomas for genomic BCL10 mutation by polymerase chain reaction-single-strand conformational polymorphism and DNA sequencing. Nineteen mutations were found in 13 lymphoma specimens, as follows: 8 of 120 (6.7%) mucosa-associated lymphoid tissue (MALT) lymphomas, 4 of 42 (9.5%) follicular lymphomas, and 1 of 23 (4.3%) diffuse large B-cell lymphomas. No mutations were found in 14 mantle cell lymphomas or 21 T-cell lymphomas. High-grade MALT lymphoma tended to show a slightly higher mutation frequency (2 of 25, 8%) than low-grade MALT tumor (6 of 95, 6.3%). Among low-grade gastric MALT lymphoma, mutations were found in 3 of 11 tumors that did not respond to Helicobacter pylori eradication therapy, but none were found in 22 tumors that regressed completely after H pylori eradication. All 14 potentially pathogenic mutations were distributed in the carboxyl terminal domain of BCL10. Deletion accounted for 10 of these mutations; 10 of 14 mutations caused truncated forms of BCL10. Western blot analysis of a mutant case confirmed the presence of truncated BCL10 products of anticipated size. Our results suggest that BCL10 mutation may play a pathogenic role in B-cell lymphoma development, particularly in aggressive and antibiotic unresponsive MALT lymphomas, and may further implicate the biologic importance of the carboxyl terminal of the molecule. (Blood. 2000;95:3885-3890)

Adaptor Proteins, Signal Transducing↗
PubMed2000

A critical review of the effect of Helicobacter pylori eradication on gastric MALT lymphoma.

Low-grade B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) are thought to arise within organized lymphoid tissue in the gastric mucosa that is most frequently acquired in response to Helicobacter pylori infection. This close association between the organism and the lymphoma is further reflected by the demonstration that the proliferation of the lymphoma cells can be driven by the presence of H. pylori organisms through a complex path of cellular interactions involving specific T cells. From these observations it was suggested that removal of one of the proliferative drives to the neoplastic cells in the form of eradication of the organism might induce a remission in the tumor. Several large multicenter studies are now underway to consider this question, and interim reports suggest that long-term remissions can be induced in low-grade MALT lymphomas in 70% to 80% of cases. The lymphomas that are most likely to respond to H. pylori eradication are those that are located superficially within the gastric mucosa. It has been suggested that certain genetic abnormalities, such as t(11;18) and the Bcl-10 mutation, may be associated with lack of response to this therapy. Recurrences of low-grade lymphoma are encountered in patients treated by H. pylori eradication, but these appear to be infrequent and may be self-limiting and spontaneously regress without further therapy.

Helicobacter Infections↗
PubMed2000

Extramedullary plasmacytoma presenting with myasthenia gravis and mediastinal mass.

A 68-year-old woman presented with myasthenia gravis and an anterior mediastinal mass, which proved to be an extramedullary plasmacytoma in the thymus with associated extracellular light chain deposition. Further specimens revealed plasma cell proliferation in an internal thoracic lymph node and in a subsequent colectomy specimen, indicating systemic disease. This case demonstrates the rare association between a plasmacytoma in the thymus and myasthenia gravis.

Aged↗
PubMed2000

Low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) of thymus.

This report describes a low-grade B-cell lymphoma of mucosa associated lymphoid tissue (MALT) involving the thymus of a 63-year-old woman with features suggestive of a connective tissue disease. Sections of the thymic lesion and of a lung biopsy performed at the same operation were examined histologically and by immunohistochemistry using the monoclonal antibodies CD45, CD20, CD79a, CD3, CD45RO, and AE1/AE3. Polymerase chain reaction (PCR) for immunoglobulin heavy chain gene rearrangement was also performed. The dense infiltrate of small lymphoid cells intimately admixed with ramifying epithelial elements, some of which had undergone cystic change, closely resembled a thymoma. The lymphoid infiltrate comprised centrocyte-like cells, small lymphocytes, plasma cells, and blasts. Most of the lymphoid cells were immunoreactive with the B-cell markers CD20 and CD79a, and PCR showed clonal immunoglobulin heavy chain gene rearrangement. The lung biopsy showed dense infiltration by small lymphoid cells, morphologically suggestive of lymphoid interstitial pneumonia. However, PCR showed a weak band in the amplification for immunoglobulin heavy chain gene rearrangement, identical to that within the thymus and suggesting either recirculation of cells to accumulated MALT or subhistological lymphoma. MALT lymphoma may rarely involve the thymus, and pathologists should be aware of this to avoid misdiagnosis as a thymoma. Immunohistochemical and/or molecular studies are of value in this regard. MALT lymphomas of the thymus, common with those arising in other organs, may develop in the setting of a connective tissue disease.

Biopsy↗
PubMed1999

Surgery plus chemotherapy or chemotherapy alone for primary intermediate- and high-grade gastric non-Hodgkin's lymphoma: the Royal Marsden Hospital experience.

Primary gastric lymphomas (PGL) have traditionally been treated with surgery followed by chemotherapy or radiotherapy. Surgery was thought to improve staging, optimise local disease control and reduce risk of perforation or bleeding, but recent studies question its role. In this study, patients with intermediate- or high-grade PGL who received chemotherapy from 1985 to 1996 at the Royal Marsden Hospital were identified using a prospectively accrued database. A total of 37 patients (6 with low-grade mucosa-associated lymphoid tissue lymphoma (MALT-L), 9 with high-grade MALT-L, 20 with diffuse large B-cell (DLBC) lymphoma and 2 other histologies), 17 of whom had localised disease, were treated with either surgery plus chemotherapy or chemotherapy alone. 5-year overall survival for localised and advanced PGL was 94 and 50%, respectively, with no differences between the two treatments over a 53 months median follow-up. No perforations or serious bleeding occurred. Surgery is associated with important morbidity and we detected no benefit of surgery prior to chemotherapy in this limited series of patients.

Adult↗
PubMed1998

Local recurrence of a primary pancreatic lymphoma 18 years after complete remission.

Primary pancreatic lymphoma is exceedingly rare, with fewer than 40 patients reported in the English literature, mostly in single case publications. It comprises under 0.2 per cent of pancreatic tumours in one surgical series, but represents a disease that may be curable even in advanced stages and thus should be distinguished from other pancreatic malignancies. We report on a patient with lymphoma initially presenting in the pancreas in 1978, achieving complete remission (CR) and re-presenting with pancreatic lymphoma 18 years after treatment, with immunohistochemical and molecular studies suggesting recurrence of the original phenotype.

Adult↗
PubMed1998

High-dose chemotherapy and autologous transplantation in lymphomatous polyposis in second remission: three case reports and literature review.

Lymphomatous polyposis is a rare primary gastrointestinal lymphoma. It morphologically and immunohistochemically resembles mantle cell lymphoma, with which it shares a disappointing response rate and duration following conventional anthracyclin-containing combination chemotherapy, with a short median survival and virtually no long-term survivors. We report the use of high-dose chemotherapy with autologous stem cell transplantation in second partial remission in three patients with lymphomatous polyposis treated at the Royal Marsden Hospital. All patients achieved a complete response, and one patient remains well and disease-free 64 months following transplantation and 76 months after diagnosis.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Prolonged disease-free survival in relapsed/refractory low-grade lymphoma treated with fludarabine: a report of four cases.

We report four patients with relapsed or refractory follicular (three) and lymphoplasmacytic (one) lymphoma who achieved complete remission (CR) with fludarabine (FDR) lasting from 3.2 to 6 years. One had stage III and three stage IV and were resistant to chlorambucil and/or anthracycline. FDR was well tolerated, the only complication being herpes zoster infection in three patients, which was controlled with aciclovir. One patient developed a gastric MALT lymphoma from a different clone than the follicular lymphoma. In conclusion, some patients with refractory low-grade lymphoma achieve long-term CR with FDR: therefore this agent may be considered as alternative to stem-cell transplantation.

Adult↗
PubMed1998

Helicobacter pylori infection and gastric lymphoma.

Gastric lymphoma of mucosa associated lymphoid tissue (MALT) has characteristic clinicopathological features that are different from nodal-type B cell lymphomas. Before a lymphoma can arise within the stomach, MALT has to be acquired as part of a response to an immunological stimulus. In most instances, gastric MALT is acquired in response to infection by Helicobacter pylori. There are several features of MALT lymphoma, such as plasma cell differentiation and follicular colonisation, that suggest that these lymphomas, although demonstrated on the basis of clonality studies to be neoplastic, retain some immunological drive. In vitro studies have shown that co-culturing cells derived from low grade MALT lymphomas with H. pylori results in tumour cell proliferation in a T cell dependant manner. Clinical studies have taken this discovery further and shown that patients with early low grade gastric MALT lymphoma treated with anti-Helicobacter therapy can show regression of their tumours. It is now generally accepted that eradication of H. pylori is a central component of the management of MALT lymphoma.

Helicobacter Infections↗
PubMed1998

True histiocytic lymphoma: a morphologic, immunohistochemical, and molecular genetic study of 13 cases.

We describe the morphologic, immunohistologic, and genotypic characteristics of 13 cases of true histiocytic lymphomas. Six cases presented with primary gastrointestinal involvement, five with lymphadenopathy, the other sites involved being the bone marrow and the skin. The neoplastic cells displayed large abundant eosinophilic cytoplasm, occasionally vacuolated with folded or bizarre-shaped nuclei with prominent nucleoli. Mitotic figures were numerous. Multinucleated cells were common. The pattern of growth was usually diffuse and noncohesive. Spindle cell sarcoma-like areas were evident in five cases, with a prominent foam cell component in four cases. All cases expressed histiocyte-associated markers (CD68, lysozyme, alpha-1-antitrypsin), CD45 or CD45RO, and were negative for CD1a, epithelial, and B- and T-cell lineage-specific markers. Reactivity for S-100 was observed in a variable proportion of cells in 11 cases. The proliferation fraction varied from 3 to 88%. Genotypic analysis for T-cell receptor or immunoglobulin gene rearrangement demonstrated a germline configuration in all cases. We demonstrate that true histiocytic lymphoma is a rare distinctive pathologic entity that may be defined by immunohistochemical criteria and that recognition among histiocytic disorders is important for clinical and prognosis reasons.

Adult↗
PubMed1998

Gastric lymphoma of mucosa-associated lymphoid tissue and Helicobacter pylori.

Although the majority of primary gastric lymphomas are of high-grade non-Hodgkin's type, a significant number are low-grade B cell lymphomas. The recognition that the majority of the latter have characteristic clinicopathological features that are different from those of their nodal counterparts has led to the suggestion that these lymphomas arise specifically from within organized extranodal lymphoid tissue; this tissue resembles that seen constitutively in the intestine (mostly located in the terminal ileum as Peyer's patches) and is termed mucosa-associated lymphoid tissue (MALT). The paradox of this proposal is that there is no MALT in the gastric mucosa in normal individuals from which a primary lymphoma can arise. However, it has been shown that organized lymphoid tissue with all the features of MALT can be acquired in the gastric mucosa, and this is seen most frequently, but not exclusively, in association with infection by Helicobacter pylori (H. pylori). Subsequent studies have confirmed a close association between H. pylori infection and gastric MALT lymphoma with the infection preceding the development of the lymphoma. In vitro studies have demonstrated that there is an immunologically based drive to tumor cell proliferation in low-grade gastric MALT lymphomas associated with the presence of H. pylori. Clinical studies have shown that, at least in early lesions, eradication of the organism can result in tumor regression in 60 to 92% of cases.

Cell Division↗
PubMed1997

Ongoing immunoglobulin gene mutations in mantle cell lymphomas.

Mantle cell lymphomas (MCL) frequently show a vaguely follicular growth pattern. This phenomenon is thought to result from the colonization of reactive B-cell follicles by tumour cells. In view of the unique property of the germinal centre environment, antigen stimulation may play a role in the expansion of the tumour. To assess this, we have examined ongoing Ig mutations, which are genetic markers of B cells in persistent response to antigen stimulation, in five MCLs including two cases derived from the gastrointestinal tract known as lymphomatous polyposis (LP). We have specifically analysed Ig ongoing mutations in tumour cells from multiple lesions in one case and in tumour cells microdissected from colonized follicles in two cases. The consensus Ig VB sequences in four MCLs were identical, or almost identical (three cases 100%, one case 99% homology), to the published germlines, which in each case were those frequently employed by autoantibodies. The consensus Ig VH sequence in the remaining case displayed 95.5% homology to the closest published germline. This may represent derivation from an unknown VH germline or a rare instance of somatic mutations. Extensive sequencing of the rearranged Ig genes revealed ongoing mutations within the tumour clone in two cases: one was a LP with multiple lesions of the gastrointestinal tract and the other was a nodal MCL in which tumour cells from colonized follicles were analysed. Our results indicate that MCLs are derived from pre-germinal centre B cells, possibly autoreactive B-cell clones. The ongoing mutations identified suggest a possible involvement of antigen stimulation in the clonal expansion of a proportion of MCLs.

Base Sequence↗
PubMed1997

Histologic, molecular, and radiologic characterization of resolving cerebral posttransplant lymphoproliferative disorder.

Lymphoproliferative disorders (LPDs) are commoner in pediatric versus adult immunosuppressed transplant recipients, and frequently involve the central nervous system. In these circumstances, the justification for biopsy is heavily influenced by the likely diagnostic yield. The present study centers on a 12-y-old renal transplant patient who developed multifocal cerebral LPD and had serial magnetic resonance (MR) examinations during the course of her illness from which she has completely recovered upon reduction of immunosuppression. She underwent stereotaxic biopsy, which was analyzed by both immunocytochemistry and polymerase chain reaction to examine the general question of how to release the maximum amount of information contained within, as well as to obtain a tissue diagnosis in this particular case. We show that a combination of these methods permits identification of the immunophenotype, lineage, clonality, viral involvement, and origin of abnormal cellular infiltrates. The biopsy also showed a novel histologic pattern of LPD, comprising numerous benign T cells obscuring a tiny clone of B cells. The MR examinations documented, for the first time, the differences in signal that accompany clinical resolution at both biopsied and nonbiopsied sites, showing that the latter may be associated with reduction, but not elimination, of MR signal abnormality. We conclude: 1) a combination of conventional and polymerase chain reaction analysis offers the greatest diagnostic yield from stereotaxic biopsies, even when the available tissue is minimal; 2) a focal polyclonal T cell infiltrate should prompt further investigation to exclude an underlying B cell lesion.

Adult↗
PubMed1997

Gastric MALT lymphoma and Helicobacter pylori.

The majority of low grade gastric lymphomas arise within acquired organized lymphoid tissue, which has all the features of MALT. This MALT is specifically acquired most commonly in response to infection of the gastric mucosa by H pylori. The lymphocytes within this MALT are therefore programmed to respond to this organism and the neoplastic cells of the lymphoma that may develop within this acquired MALT retain the ability to respond to the immunological proliferative drive associated with the continued presence of the organism. Following the removal of this immunological drive by eradication of the organism in vivo, the lymphoma shows clinical and histological regression. The time required to see this response is unknown and there are some lymphomas that fail to respond to simple Helicobacter eradication. In some cases, there is continued molecular evidence of the presence of the lymphoma clone in low levels and the significance of this remains unknown. These factors are presently under detailed examination, and several clinical trials to assess the response of a large series of low grade gastric MALT lymphomas to anti-Helicobacter therapy and the requirement for additional chemotherapy are at present in progress.

Gastric Mucosa↗
PubMed1996

Intestinal dissemination of gastric mucosa-associated lymphoid tissue lymphoma.

Despite increasing identification of concurrent gastric and intestinal lymphomas of mucosa-associated lymphoid tissue (MALT), the clonal relationship between the two tumors and their sequential development are poorly understood. It is also unknown whether the development of these concurrent tumors is closely associated with direct antigen stimulation, which is thought to play an important role in the clonal expansion of low-grade MALT lymphomas. To investigate these, we have studied six cases of concurrent gastric and intestinal MALT lymphomas by polymerase chain reaction (PCR) amplification, cloning, and sequencing of the rearranged Ig gene, a strategy that has been widely used for analysis of clonality and antigen-driven properties of B-cell malignancies. In each case, an identical or nearly identical complementarity determining region (CDR) 3 sequence was observed between the dominant clones of concurrent gastric and intestinal MALT lymphomas. In four of six cases examined, sufficient Ig variable region sequence information was obtained to permit analysis of somatic mutations. The mutation patterns in one case suggest that the intestinal lesion is secondary to the gastric tumor, and the mutation patterns in two cases indicate that the gastric and intestinal lesions are derived from different tumour subclones, which emerge after expansion of a common early tumor clone. Furthermore, three of four cases showed ongoing Ig mutations among different PCR clones at each site. These results show that concurrent gastric and intestinal MALT lymphomas are derived from the same clone and suggest that the intestinal lesions result from dissemination of gastric tumours. Antigen stimulation may play a role in tumor evolution, particularly at an early stage.

Amino Acid Sequence↗
PubMed1996

Diagnosis and posttreatment follow-up of Helicobacter pylori-positive gastric lymphoma of mucosa-associated lymphoid tissue: histology, polymerase chain reaction, or both?

The differential diagnosis between Helicobacter pylori (H pylori-associated chronic gastritis and low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue (MALT) and the assessment of endoscopic biopsy specimens after treatment of lymphoma can be problematic. Although immunocytochemistry can be used to identify clonal B-cell populations, which are characteristic of MALT lymphoma, its application to small biopsy specimens and the subsequent interpretation can be difficult. The polymerase chain reaction (PCR) can detect clonal B-cell populations by analysis of the Ig heavy chain gene in routinely fixed paraffin-embedded material and might provide a useful tool in the assessment of these specimens. We have investigated the value of histology and PCR in the diagnosis of lymphoma and its followup in formalin-fixed paraffin-embedded gastric endoscopy biopsy specimens from 69 sequential patients selected on the basis of a dense mucosal lymphoid infiltrate associated with H pylori infection. Histologic evidence of MALT lymphoma was identified in 13 cases, 9 of which showed PCR-detected monoclonality. In 12 of 13 cases, H pylori was eradicated, and in 11 of 12 cases, histologic regression of the lymphoma followed. PCR evidence of monoclonality disappeared in 6 of 9 originally monoclonal cases. This was synchronous with histologic remission in 1 case, but lagged in the remaining 5 cases by up to 28 months. Two of the 3 of the 9 cases originally monoclonal by PCR that have not shown molecular regression have monoclonal-amplified products 17 and 24 months after negative histology. In 3 cases, the histology of the biopsies was considered indeterminate or discordant. In 1 of these cases, the histologic features were obscured by crush artefact. In a second case, there was molecular evidence of monoclonality in the absence of histologic features suggestive of lymphoma; this persisted after H pylori eradication. An additional single case originally diagnosed as reactive developed a PCR detectable clonal population 29 months after original evaluation in the absence of histologic features of lymphoma but in the presence of persistent H pylori infection. These findings suggest that the histologic assessment of gastric biopsies remains the method of choice for the diagnosis of lymphoma in gastric endoscopic biopsies with a dense mucosal lymphoid infiltrate. PCR provides a useful technique to support the diagnosis if clonal amplification products are found. The significance of PCR detected clonality in the absence of histologic evidence of lymphoma in uncertain but may represent a stage of tumor progression/regression when the clonal population is insufficient to be detected by conventional histology. This is supported by the evidence that PCR-detectable monoclonality can persist after treatment and the disappearance of histologically detectable lymphoma.

Adolescent↗