Low-grade Marginal Zone Lymphoma Research Articles

A RARE CASE OF PRIMARY PLEURAL LOW GRADE MARGINAL ZONE NONHODGKIN'S LYMPHOMA: A CASE REPORT

A primary pleural based marginal zone low grade NHL is very rare. Primary pleural Lymphomas account for less than 0.5% off all Non-Hodgkin Lymphomas and DLBCL is the most common subtype of primary pleural lymphomas. Here, we report a rare case of marginal zone lymphoma of low grade with Mib index of 15-20% presenting as a pleural based mass in a middle age individual. A 52 years old male presented with right sided pleural effusion with pleural thickening of soft tissue density. Thoracoscopy showed pleural based mass lesion and pleural biopsy revealed low grade marginal zone NHL which is very rare with very few cases documented till date. Diagnosis was based on Bcl-2 and CD20 marker positivity on IHC. Treatment of such Low-grade Marginal zone lymphoma is with Bendamustine and Rituximab.

Development of Notch1 Positive T-Lineage Lymphomas or Splenic Marginal Zone Lymphomas with Pan-Hematopoietic or Pro-B Cell Specific Deletion of Trp53 with Distinct Differentially Dysregulated Pathways

Deletion of the tumor suppressor gene TP53 (Trp53 in mice) has been associated with the development of numerous human malignancies. TP53 acts as a central coordinator of the DNA damage response. In mice, pan-Trp53 deletion leads predominantly to the development of T-cell lymphomas, followed by B-cell lymphomas, sarcomas and teratomas. In order to dissect the role of Trp53 in the hematopoietic system, we created two different loss of function mouse models: Pan-hematopoietic Trp53 deletion using Vav1-Cre based deletion; and a B-cell-specific deletion was created using CD19-Cre.Vav1-p53CKO mice developed hematolymphoid malignancies with 100% penetrance by 12 months. Most malignancies observed were CD3e+ T-lineage lymphomas involving the thymus or spleen (37/45). Beyond 200 days, these mice predominantly developed mixed myeloid malignancies. The shift away from T-lineage malignancies in older mice may reflect aging-related decline of pre-malignant lymphoid progenitors and skewing to myeloid progenitors.Flow cytometric characterization of the T-lineage lymphomas identified a mix of tumors, including double-negative (CD4-CD8-), double-positive (CD4+CD8+), or single positive (CD4/CD8). In pre-malignant mice, Vav1-p53CKO thymocytes showed accelerated maturation with most of the cells in the DN4 stage, suggesting a bypass of the p53-dependent DN3 β-selection checkpoint. All T-lineage lymphomas showed overexpression of surface Notch1 as well as overexpression of Notch1 targets Hes1 and p21 at the transcript level. Consistent with prior data, normal murine thymocyte subsets showed high levels of expression of Notch1 target genes at the DN3 stage of development, which appears dysregulated in these T-lineage lymphomas. This Notch1 activation was found to be multifactorial with increased Mdm2 and decreased Numb levels seen in tumors. Overall, we demonstrate Notch1 activation and subsequent acceleration through the T-cell developmental stages in this model of pan-hematopoietic Trp53 deletion.The B-cell specific Trp53 knockout mice (CD19-P53CKO) (n=54) were followed up for up to 2 years. The majority (47/54) developed splenomegaly in an age-dependent manner. Histologic examination showed marginal zone expansion (6/54), frank low-grade marginal zone lymphoma (16/54) or diffuse splenic lymphoma (25/54). The disease was confined to the spleen in the case of lower-grade histology while higher grades correlated with liver and kidney involvement. Flow cytometric analysis of tumors showed B220+ CD19+ IgM+ cells. Interestingly, these tumors demonstrated low levels of Notch2 expression, which normally is highly expressed in marginal zone B-cells.In order to characterize pathogenesis, we sorted follicular and marginal zone B-cells from floxed P53 and pre-malignant CD19-P53CKO mice. RNA was isolated from all these fractions and the spleens of 5 CD19-P53KO mice with diffuse lymphoma and subjected to RNA-Seq. A comparison of the floxed p53 with the CD19-P53CKO fractions (follicular and marginal zone) revealed a highly similar transcriptome. On the other hand, p53-deficient lymphomas showed >10,000 genes significantly differentially expressed demonstrating the unique transcriptome which developed during malignant transformation.Pathway analysis of these genes using Gene Set Enrichment Analysis (GSEA) identified enrichment of PI3K, Rap1 and MAPK signaling pathways, which are associated with cellular proliferation. Overexpression of the PI3K pathway genes Ccne1, Sgk1, Mapk13 and Pik3cb were validated by qPCR in 10 independent tumor samples when compared to the splenic marginal zone fractions. In the B-cell lineage, Trp53 deficiency leads to the dysregulation of multiple genes involved in key cellular signaling pathways, including the PI3K/MAPK pathway.In summary, pan hematopoietic deletion of Trp53 led to T-lineage lymphoma in young mice and myeloid tumors in older mice; with activation of Notch1 signaling in the former. B-cell specific deletion of Trp53 led to splenic marginal zone and diffuse B-cell lymphoma with transcriptional dysregulation of key signaling molecules. Hence, tumorigenesis by Trp53 deletion is tightly linked to lineage and appears to dysregulate key signaling pathways that are operant in those lineages, potentially identifying novel strategies for therapeutic interventions in P53 dependent human hematolymphoid malignancies. DisclosuresNo relevant conflicts of interest to declare.

S3136 Metastatic Renal Cell Carcinoma Presenting as a Gastric Polyp – A Case Report

Introduction: Patients with renal cell carcinoma are metastatic in 1/3rd of the cases, however, metastasis to gastrointestinal tract is uncommon. We present a case of rare finding of metastatic renal cell carcinoma presenting as gastric polyp in a patient who presented with gastrointestinal bleeding. Case Description/Methods: A 70-year-old man with history of clear cell renal cell carcinoma (ccRCC) with metastatic mediastinal lymphadenopathy presented with melena and anemia. The patient had received Nivolumab and Ipilimumab in the past and was currently on Cabozatinib for the past fourteen months. Patient denied any use of non-steroidal anti-inflammatory drugs. Laboratory data was significant for a hemoglobin of 6.8 g/dL. An esophagogastroduodenoscopy showed two friable gastric polyps ranging from 8-10 mm in the body. Polyps were removed using a cold snare and endoclips were placed. Histopathological analysis demonstrated portions of gastric mucosa with central area of fibrinoid necrosis covering clusters of epithelial cells with pale to clear cytoplasm, with immunostains Pax2/8 consistent with metastatic renal cell carcinoma. Discussion: Metastasis of RCC to stomach presenting as gastric polyps is exceedingly rare. The gross appearance of these polyps appears to have a smooth surface and can be friable to contact. The size of the polyp can be variable. Clinical presentation includes gastrointestinal bleeding and abdominal pain as was the case in our patient. Small gastric polyps are often not biopsied, however, our case highlights that in patients with RCC, gastric polyps should be biopsied to rule out metastasis.Figure 1.: CT Abdomen: A, B revealed 2.9cm gastric ulcer in lesser curvature, fused distal body and tail of pancreas with stomach. Endoscopy: C, normal esophagus. D-H, ischemic ulceration with nodularity, blackened mucosa, non-obstructing, clean-based gastric ulcers in the entire stomach. I, normal duodenum. J Gastric lymphoma pathology, Lymphoma cells diffusely infiltrate between the gastric glands. Separation of gastric cells with architectural disruption. Round, oval, and irregular nuclei are present with scant cytoplasm. K. Concomitant component of low-grade marginal zone lymphoma (seen in 1/3 of cases). These cells arise from large cell transformation.

Primary Gastric Lymphoma, Epidemiology, Clinical Diagnosis, and Treatment.

Primary gastric lymphoma (PGL) is the most common extranodal non-Hodgkin lymphoma and represents a wide spectrum of disease, ranging from indolent low-grade marginal zone lymphoma or mucosa-associated lymphoid tissue (MALT) lymphoma to aggressive diffuse large B-cell lymphoma. The PGL is a relatively rare cancer and easily misdiagnosed due to its unspecific symptoms of the digestive tract. The medical literature and ongoing clinical trials were reviewed on the clinical presentation, diagnosis, prognosis, prevention, and treatment of PGL. Primary gastric lymphoma is an event in the course of cancer with a variable clinical presentation and a wide differential diagnosis. Chronic gastritis secondary to Helicobacter pylori (H pylori) infection has been considered a major predisposing factor for MALT lymphoma. Magnetic resonance imaging and endoscopic ultrasonography have helped in staging of these cancers. The clinical course and prognosis of this disease are dependent on histopathological subtype and stage at the time of diagnosis. A global therapeutic approach to the cure of PGL has completely changed over the past 10 years, including innovative and conservative options to reduce treatment toxicity. Due to the rarity of PGL, many aspects of this neoplasm are still controversial. The incidence of this disease is increasing, making it necessary for clinicians to understand the clinical symptoms, workup, and treatment of these lymphomas.

Letter re: Primary marginal zone lymphoma of the CNS presenting as a diffuse leptomeningeal process.

Similar to Gazzola et al.,1 we treated a patient with primary marginal zone leptomeningeal lymphoma. A 58-year-old man presented with headaches, papilledema, and confusion on a background of left face/arm paresthesias for 3 years, attributed to migraine. CT brain scan showed sulcal-pattern right frontal hyperdensity, suspicious for subarachnoid blood, but normal size ventricles. Catheter arteriogram was normal. MRI showed frontal, basal, and spinal leptomeningeal enhancement. Lumbar punctures showed persistently elevated CSF pressure (>30 cm H2O) and protein (3.95 g/L) with monoclonal B lymphocytes and reactive T cell. Leptomeningeal biopsy showed a low-grade B cell neoplasm. Biopsy flow cytometry showed CD19, CD20, CD22, and FMC7-positive, kappa light-chain restricted B cells interpreted as low-grade marginal zone lymphoma. The patient was given high-dose methotrexate, rituximab IV, and intrathecal methotrexate for 6 weeks without clear response, then intrathecal rituximab plus methotrexate, with some improvement in CSF and MRI abnormalities. Our patient similarly had 2–3 years of intermittent cortical symptoms, then confusion and neuroimaging suggested subarachnoid hemorrhage. In addition, our patient also developed pseudotumor cerebri,2 probably due to very high CSF protein, and had incomplete response to chemotherapy. He completed a course of low-dose (2 Gy x 2) craniospinal radiotherapy and is now headache-free. These observations expand the clinical spectrum of chronic low-grade leptomeningeal lymphoma.

Primary dural lymphoblastic B-cell lymphoma: a rare subtype of aggressive dural lymphoma

Lymphomas arising in the dura mater represent a rare subset of primary central nervous system lymphoma (PCNSL). The majority of primary dural lymphoma (PDL) are low-grade marginal zone lymphomas (MZL) characterized by an indolent course and favorable long-term outcomes. Primary aggressive dural lymphomas are exceedingly rare with a paucity of cases reported in the literature. Herein, we describe a case of primary lymphoblastic dural lymphoma. To our knowledge, this is the second report of an isolated dural B-lymphoblastic lymphoma (B-LBL) in an immunocompetent patient.

XIV. The pathology of transformation of indolent B cell lymphomas.

XIV. The pathology of transformation of indolent B cell lymphomas.

A peculiar case of the abscopal effect: radioactive iodine therapy incidentally palliating marginal zone lymphoma.

The abscopal effect is an extremely rare phenomenon occurring when irradiation or treatment of a primary tumor burden not only results in debulking of the targeted site but also reduces tumor size at distant sites from the intended treatment area. We present the abscopal effect occurring in a patient with low-grade marginal zone lymphoma who subsequently received radioactive iodine therapy for papillary thyroid carcinoma. She was 67 years old when a routine complete blood count at her primary care physician's office yielded a persistent leukocytosis of 14,500/μL with lymphocytosis of 9,870/μL. Immunophenotyping and fluorescence in situ hybridization (FISH) analysis confirmed low-grade marginal zone lymphoma. Over eight years, her peak leukocyte and lymphocyte counts were 24,100/μL and 18,100/μL, respectively. Subsequently, she was diagnosed with papillary thyroid carcinoma after presenting with a new complaint of dysphagia. A total thyroidectomy was performed, followed by 172.1 millicuries of oral I-131 sodium iodine radioactive ablation therapy. Following treatment, her leukocyte and lymphocyte counts were 3,100/μL and 1,100/μL, respectively. Over the next four years, her leukocyte and lymphocyte counts remained within normal limits and she remained symptom free. To our knowledge, there has never been a published report describing the use of radioactive iodine causing abscopal effect benefits for patients with underlying lymphoproliferative diseases.

FRI0138 Characterization of non-hodgkin lymphomas in rheumatic diseases

BackgroundNon-Hodgkin lymphomas (NHL) are 3 to 45 times more common in rheumatic diseases (RD) than in the general population. The spectrum of NHL varies in different studies.ObjectivesTo describe the most...

Synchronous Primary Pulmonary Marginal Zone B-Cell Lymphoma and Large B-Cell Lymphoma

SESSION TYPE: Pleural Case Report Posters

Gastrointestinal lymphomas: Pattern of distribution and histological subtypes: 10 years experience in a tertiary centre in South India

Gastrointestinal tract (GIT) is one of the major sites of extra-nodal lymphomas constituting 10-15% of all non-Hodgkin's lymphoma cases and about 30-40% of extra-nodal lymphomas. Considerable variation exists in the literature with respect to incidence of the various histological subtypes and sites of involvement. This study was undertaken to ascertain the anatomic distribution, histological subtypes and sites of all GIT lymphomas presenting to a tertiary referral hospital in southern India. The histological material of 361 patients over a period of 10 years (2001-2010), with histopathological diagnosis of lymphoma involving the GIT (both primary and secondary), was analyzed retrospectively. All lymphomas were reclassified according to the World Health Organization 2008 classification. These 361 cases include 336 primary and 25 cases of lymphomas, where the involvement was secondary. Primary lymphomas consisted of 267 males (79.64%) and 68 females (20.24%) with a male:female ratio of 3.93:1. The mean age was 45 years (range 3-88). Diffuse large B-cell lymphoma (DLBCL) was the commonest subtype (222 cases; 66.71%), followed by low-grade marginal zone lymphoma of the mucosa associated lymphoid tissue (MALT) type (34 cases; 10.12%) and Burkitt's lymphoma (35 cases; 10.48%). The commonest site was stomach (180 cases; 53.57%), followed by small intestine (79 cases; 23.51%) and large intestine (68 cases; 20.23%), respectively. There were some uncommon types of GIT lymphomas documented during the study. In this largest retrospective single centre study from India, we establish that the pattern of distribution of primary GIT lymphomas (PGLs) in India is similar to the western literature in that the stomach is the commonest site of PGL and DLBCL is the commonest histological subtype. Immunoproliferative small intestinal disease cases were seen in this study, which is uncommon in the west.

Abnormal Wnt signaling and stem cell activation in reactive lymphoid tissue and low-grade marginal zone lymphoma

The variable natural history of mucosa-associated lymphoid tissue (MALT) lymphoma poses a challenge in predicting clinical outcome. Since Wnt signaling, as indicated by nuclear localization of β-catenin, is believed to be key in stem cell activation and stem cell self-renewal, we explored the possibility that it might have a predictive value in marginal zone lymphoma. We chose to analyze pβ-catenin-S552 because its nuclear localization by immunohistochemistry appears to coincide with Wnt signaling-initiated tumorigenesis in intestinal and hematopoietic tissues. Wnt signaling and activation was studied in 22 tissue samples of extranodal marginal zone lymphoma, atypical lymphoid hyperplasia, reactive lymphoid hyperplasia, and normal lymphoid tissue to determine whether Wnt signaling could help distinguish MALT lymphoma from benign lesions. Compared to normal or reactive lymphoid tissue, we found increased nuclear expression of localized pβ-catenin-S552 in atypical lymphoid hyperplasia and extranodal marginal zone lymphoma. We show that the anti-pβ-catenin-S552 antibody may be useful in diagnosing and monitoring the progression of or response to therapy of MALT lymphoma.

BALTOMA (BRONCHUS-ASSOCIATED LYMPHOID TISSUE LYMPHOMA) PRESENTING AS ENLARGING GROUND GLASS OPACITIES

INTRODUCTION: Bronchus-associated lymphoid tissue lymphoma (BALToma) is a rare, low grade marginal zone lymphoma of the lung. Histologically, BALToma is characterized by the aggregation of extranodal, monoclonal B- lymphoid cells near the bronchial epithelium. The radiographic appearance of BALToma is variable, ranging from well circumscribed nodules, to dense consolidations with air bronchograms. We report two patients with histories of marginal zone lymphoma, who underwent resection of enlarging ground glass opacities (GGOs) found to be BALTomas.

A Phase II Trial of Darinaparsin in Advanced Lymphomas: Report on Safety and Activity.

Darinaparsin (ZIO-101) is a novel organic arsenic molecule that has a mechanism of action mediated by targeted disruption of mitochondrial function, modified signal transduction, and antiangiogenesis. It is active against diverse cancers in vitro. This Phase II multi-center trial is being conducted in patients diagnosed with advanced lymphomas that have received at least 1 prior therapy and require additional treatment. Patients receive 300 mg/m2 of darinaparsin intravenously for 5 consecutive days every 28 days (1 cycle) and are then evaluated for efficacy and safety by standard criteria. Treatment continues until toxicity or progression. To date the study has accrued 22 patients (15 non-Hodgkin's [NHL], 7 Hodgkin's); 12 are male and 10 are female. Median age at baseline was 60.5 years (range: 28–80), ECOG performance status was ≤2, and median number of prior therapies was 4 (range 2–6). Thirteen subjects have received at least 2 cycles of darinaparsin and are evaluable for efficacy. Of these, 1 (diagnosed with PTCL) has achieved a complete response (CR) and 3 (diagnosed with marginal zone transformed to diffuse large B-cell, marginal zone, and Hodgkin's nodular sclerosis, respectively) have achieved partial responses (PRs). These patients had been heavily pretreated (PTCL: CHOP, ICE, and EPOCH; marginal zone transformed to diffuse B-cell: RCHOP, RICE, RT and autologous bone marrow transplantation; marginal zone: rituximab, RCVP, and gemcitabine; and Hodgkin's: ICE, CBV, gemcitabine+ MDX-060, and stem cell transplant). In the patient with transformed diffuse large B-cell lymphoma who achieved PR, no evidence for macroscopic disease was present, but microscopic low-grade marginal zone lymphoma was detectable in random biopsies from normal-appearing gastric mucosa. In addition, 2 patients (diagnosed with PTCL and Hodgkin's, respectively) have achieved stable disease (SD). The only Grade 3 adverse event (AE) considered drug-related was wheezing. A total of 12 subjects have reported 37 serious adverse events (SAEs) while on study. Of these, only 2 had SAEs that were considered drug-related (neutropenic fever, fall). In conclusion, darinaparsin has been very well tolerated and has demonstrated promising activity in heavily pretreated patients diagnosed with advanced lymphoma. Initial responses (1 CR, 3 PRs, 2 SDs) have been observed among 13 evaluable patients. Accrual continues; additional safety and efficacy data will be reported.

Primary dural lymphomas: a review

Primary dural lymphoma (PDL) is a rare subtype of primary central nervous system lymphoma (PCNSL) that arises from the dura mater and differs biologically from other CNS lymphomas. The PDL is usually a low-grade marginal zone lymphoma (MZL), whereas other types of PCNSLs are usually high-grade, diffuse, large B-cell lymphomas. A PDL usually presents with single or multiple extraaxial masses that enhance diffusely with addition of contrast material and can be confused with meningioma. The MZLs respond well to local therapy such as surgery and radiation treatment. Most patients attain complete response and have good local disease control. Nevertheless, the risk of systemic relapse appears to be high, probably because the dura mater is outside of the blood-brain barrier.

Genetic Rearrangements of FOXP1 Are Restricted to a Subset of Agressive B Cell Lymphoma with Extranodal Presentation.

In most mature B-cell non-Hodgkin lymphoma (NHL) chromosomal translocations result in the transcriptional deregulation of an oncogene by juxtaposing it to regulatory sequences of genes that are constitutively expressed in mature B cells, most often the Ig genes. Recently, a novel recurrent translocation t(3;14)(p13;q32) that results in deregulation of the FOXP1 forkhead transcription factor has been reported in a variety of B cell lymphoma.Here we present the analysis of 275 B-cell NHL: 102 diffuse large B cell lymphoma (DLBCL) (49 nodal and 53 extranodal cases) 122 marginal zone lymphoma (MZL) from different localization (cutenous n= 9, salivary gland n= 13, pulmonary n=50, ocular adnexae n=36, thyroid n=8, gastric n=6), 30 follicular lymphoma (FL) and 21 mantle cell lymphoma (MCL). The presence of genetic aberrations involving the FOXP1 gene was studied by interphase fluorescence in situ hybridization (FISH) and FOXP1 protein expression - by immunohistochemistry using the JC12 monoclonal antibody.In total, 5 of 275(2%) lymphoma were found to carry a chromosomal breakpoint within the FOXP1 gene. Further FISH studies indicated the presence of a FOXP1/IgH translocation in only 2 of these samples, suggesting the likely involvement of other translocation partner. All samples that harbored a FOXP1 breakpoint represented aggressive B cell lymphoma with proliferation fraction of 70–90% defined by the Ki 67% labeling pattern. Cytogenetic analysis and/or FISH suggested a presence of the complex chromosomal rearrangements. Four of 5 tumors presented at extranodal sites: gastro-intestinal tract (N=3); thyroid gland (N=1). All samples expressed B-cell markers and lacked CD5 and CD10 - a phenotype consistent with a marginal zone derivation. Interestingly, we failed to identify a FOXP1 breakpoint in any of the “true” low grade MZL in our series.A gain of genomic material was found in 80 (29%) of these samples, indicated by detection of more than two FISH signals in a variable number of cells and/or cytogenetic data. In the vast majority of these cases trisomy 3 was further identified. All 5 samples that harbor FOXP1 chromosomal breakpoint showed strong nuclear labeling pattern when stained with JC12 monoclonal antibody. FOXP1 nuclear expression, in a variable number of the cells was detected in 95% of the cases with genomic gain/trisomy 3, however also in 40 % of the samples without evidence of any genetic aberrations in this locus, suggesting a range of mechanisms, regulating the FOXP1 expression.

A reassessment of primary thyroid lymphoma: high-grade MALT-type lymphoma as a distinct subtype of diffuse large B-cell lymphoma.

Primary lymphoma of the thyroid gland (PTL) is a relatively rare disease. During an 18-year period, 53 cases of primary non-Hodgkin's lymphoma involving this extranodal site were seen at our institutions. The aims of this study were to evaluate the spectrum of PTLs using current lymphoma classification concepts and immunocytochemical markers, determine whether features of MALT-type lymphoma were evident in PTL, and if there was any clinical significance of such a finding. The cases were retrospectively studied clinically, histologically and immunohistochemically. The tumours were classified according to the Revised European-American Lymphoma Classification of lymphoid malignancies (REAL classification). Thirty-eight patients were females, 15 were males and mean age at diagnosis was 66.3 years (range 38-90). Three cases were low-grade marginal zone lymphomas (low-grade MALT-type lymphomas). There were 45 diffuse large B-cell lymphomas (DLBCL) of which there were 27 DLBCL-NOS and 18 high-grade MALT-type lymphomas. Within the diffuse large B-cell lymphoma (DLBCL) category, cases were subdivided into those without (DLBCL-NOS) and those with features of 'high-grade' MALT-type lymphoma based on presence of a low-grade component or large cell lymphoepithelial lesions (HG MALT-type lymphoma). In addition there were three follicle centre lymphomas, one anaplastic large cell lymphoma and one peripheral T-cell lymphoma. Twenty cases were stage IE, 18 stage IIE, and four stage IV. All patients with low-grade MALT-type lymphoma are alive without disease. The 5-year survivals for DLBCL-NOS and HG MALT-type lymphoma were 75% and 25%, respectively. Univariate analysis (log rank) among the DLBCLs showed stage (P < 0.001) and subtype (P = 0.005) were associated with survival. Stage was associated with type of DLBCL, 65% of DLBCL-NOS being stage IE compared to 20% of HG MALT-type lymphomas. We conclude that primary thyroid lymphomas occur most commonly in elderly women and are frequently present in clinical stage IE and IIE. Low-grade MALT-type lymphomas are relatively uncommon but appear to have a favourable prognosis. DLBCL is the most common lymphoma and features of MALT can be seen in over one-third of cases. As a group, HG MALT-type lymphomas had a worse outcome than DLBCL-NOS, primarily due to higher clinical stage at diagnosis. These two subtypes of DLBCL appear to be distinct clinical and histological entities.

Lymphomas in Patients with Sjögren's Syndrome: Review of the Literature and Physiopathologic Hypothesis

The occurrence of non Hodgkin's lymphoma (NHL) is the most serious complication of Sjögren's syndrome (SS). Taking the opportunity to study 16 patients with lymphoma and an underlying SS, we performed a review of literature concerning SS and lymphoma and made an hypothesis on the physiopathology of lymphoproliferation in patients with SS.Lymphomas occurring in patients with SS are in most cases low grade marginal zone lymphomas (MZL). They arise frequently in mucosal extranodal sites, not only in the salivary glands but also the stomach and the lung. These lymphomas are not associated with viruses including hepatitis C virus (HCV), Epstein-Barr virus, human herpes virus 8 or human T lymphotropic virus-I, known to be present in other types of lymphomas. Some of the translocations or mutations of oncogenes or anti-oncogenes described in other lymphomas are also detected in SS-associated lymphomas.Lymphomas complicating SS share a number of characteristics with lymphomas complicating HCV infection. We make the asumption that, in both diseases, the first event of lymphomagenesis is the chronic stimulation, on the site of the disease, of polyclonal B-cells secreting rheumatoid factor (RF). Then, these RF B-cells may become monoclonal and disseminate in other organs. The monoclonal secreted RF complexed with polyclonal IgG may cryoprecipitate. The following step would be a chromosomal abnormality (e.g. trisomy 3) which would confer to these cells a low grade B-cell lymphoma compartment. A last event (e.g. mutation of p53) could transform this low grade B-cell lymphoma into a high grade large B-cell lymphoma. If this hypothesis was correct, most of B-cell lymphomas associated with SS should have a surface immunogiobulin with RF activity and should grow through an auto-antigen driven process.

Lymphomas in Patients With Sjögren's Syndrome Are Marginal Zone B-Cell Neoplasms, Arise in Diverse Extranodal and Nodal Sites, and Are Not Associated With Viruses

The occurrence of non-Hodgkin's lymphoma (NHL) is the most serious complication of Sjögren's syndrome (SS). We performed a study of 16 NHLs occurring in patients with an underlying SS. These lymphomas arose not only in salivary glands (7 cases) but also in other mucosal extranodal sites (the stomach [4 cases], the lung [3 cases], the skin [3 cases], the buccal mucosa [1 case], the thymus [1 case]) and in nodal sites (8 cases). Low-grade marginal zone lymphomas (MZL) were diagnosed in 12 of the 16 patients, 9 of mucosa-associated lymphoid tissues (MALT) type in mucosal sites and 3 exclusively nodal. The 4 other patients presented with a high-grade B-cell lymphoma that was probably a histological transformation of an underlying low-grade MZL at least in 3 of the cases involving skin, stomach, and parotid, respectively. A t(14; 18) translocation was detected in 1 of 8 lymphomas tested. We detected serum anti-p53 antibodies in 2 of the 14 studied patients. p53 protein was detected in 1 of 11 lymphomas tested. LMP protein and Eber RNAs of Epstein-Barr virus (EBV) were not detected in the 16 NHL biopsies. Using polymerase chain reaction, EBV was never detected except in 1 of 4 parotid lymphomas. No human T-lymphotropic virus 1 or human herpes virus 8 DNAs were detected in NHL biopsies. None of the patients had hepatitis C virus infection found using serological methods. Chemotherapy was usually efficient. In conclusion, lymphomas occurring in patients with an underlying SS are in most cases MZL. These lymphomas are not associated with viruses known to be present in other types of lymphomas. Some of the translocations or mutations of oncogenes or antioncogenes described in other lymphomas are detected in SS-associated lymphomas.

Lymphomas in Patients With Sjögren's Syndrome Are Marginal Zone B-Cell Neoplasms, Arise in Diverse Extranodal and Nodal Sites, and Are Not Associated With Viruses

AbstractThe occurrence of non-Hodgkin's lymphoma (NHL) is the most serious complication of Sjögren's syndrome (SS). We performed a study of 16 NHLs occurring in patients with an underlying SS. These lymphomas arose not only in salivary glands (7 cases) but also in other mucosal extranodal sites (the stomach [4 cases], the lung [3 cases], the skin [3 cases], the buccal mucosa [1 case], the thymus [1 case]) and in nodal sites (8 cases). Low-grade marginal zone lymphomas (MZL) were diagnosed in 12 of the 16 patients, 9 of mucosa-associated lymphoid tissues (MALT) type in mucosal sites and 3 exclusively nodal. The 4 other patients presented with a high-grade B-cell lymphoma that was probably a histological transformation of an underlying low-grade MZL at least in 3 of the cases involving skin, stomach, and parotid, respectively. A t(14; 18) translocation was detected in 1 of 8 lymphomas tested. We detected serum anti-p53 antibodies in 2 of the 14 studied patients. p53 protein was detected in 1 of 11 lymphomas tested. LMP protein and Eber RNAs of Epstein-Barr virus (EBV) were not detected in the 16 NHL biopsies. Using polymerase chain reaction, EBV was never detected except in 1 of 4 parotid lymphomas. No human T-lymphotropic virus 1 or human herpes virus 8 DNAs were detected in NHL biopsies. None of the patients had hepatitis C virus infection found using serological methods. Chemotherapy was usually efficient. In conclusion, lymphomas occurring in patients with an underlying SS are in most cases MZL. These lymphomas are not associated with viruses known to be present in other types of lymphomas. Some of the translocations or mutations of oncogenes or antioncogenes described in other lymphomas are detected in SS-associated lymphomas.