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Summary Extra‐nodal marginal zone B‐cell lymphoma (MZBL) of mucosa‐associated lymphoid tissue is an indolent lymphoma mostly affecting the gastrointestinal tract. The lymphoma initially has small‐cell morphology (SC‐MZBL) and often arises in the background of Helicobacter pylori‐induced gastritis. In some cases, a clonal malignant progression to large‐cell morphology (LC‐MZBL) is observed. Here, we studied the DNA methylation profile of 30 gastric MZBLs along their progression. Genome‐wide DNA methylation profiling, identified 7698 significantly differentially methylated loci during gastric MZBL progression (σ/σmax ≥0·4, q ≤ 0·001). LC‐MZBL showed hypermethylation in comparison to SC‐MZBL with an enrichment of regions involved in transcriptional regulation. In conclusion, our present data show that the morphological distinction between SC‐ and LC‐MZBL is reflected by characteristic DNA methylation profiles., publishedVersion

Clonal heterogeneity in multisited or recurrent lymphoid neoplasms is a phenomenon that has been increasingly studied in recent years. However, in mucosa-associated lymphoid tissue (MALT) lymphomas it remains largely unexplored. Patients diagnosed at our institution with multisited MALT lymphoma, from January 2009 to October 2018, were studied. Molecular studies were performed for the detection of clonally rearranged immunoglobulin by polymerase chain reaction.In all, 91 patients were included. Of those, 28 had a multisited disease and in 16 clonality studies were done. In eight cases, multifocal involvement was synchronous and in eight metachronous. Patients with non-gastric gastrointestinal tract involvement tended to disseminate within the same tract, without observing other specific dissemination patterns. Four cases (25%) had clonal heterogeneity at the different organs involved. All patients with late relapses (two patients) had different clones. The majority of patients with multisited MALT lymphomas presented with the same clone in the different involved organs, identifying a different clone in those with late relapses. These patients could represent de novo neoplasms, rather than a relapse. This could mean that some individuals might have a genetic predisposition to develop this type of lymphoma and it could also have clinical implications regarding therapeutic decisions.

Given the lack of consistent data regarding the clinico‐pathological features and clonal lymphomagenesis of patients with mucosa‐associated lymphoid tissue (MALT) lymphoma and histological transformation (HT), we have systematically analysed 379 patients (32% gastric, 68% extra‐gastric; median follow‐up 52 months) diagnosed with HT at the Medical University Vienna 1999–2017, and reassessed tissues of identified patients by polymerase chain reaction (PCR)‐based clonality analysis. HT was documented in 12/379 patients (3·2%) and occurred at a median time of 22 months (range; 6–202 months) after diagnosis of MALT lymphoma. By PCR‐based clonality analysis, we detected a clear‐cut clonal relationship of MALT lymphoma and diffuse large B‐cell lymphoma (DLBCL) in 8 of 11 analysed cases proving that the large majority of DLBCL following MALT lymphoma are clonally‐related and constitute a real transformation. Interestingly, HT occurred within the first 2·5 years after diagnosis in patients with clonal relationship, whereas time to aggressive lymphoma was longer in patients identified as clonally‐unrelated (most likely secondary) lymphoma (82–202 months), suggesting that HT is an early event in this disease. Survival of patients with HT was poor with 6/12 dying at 1·5–33 months after HT, however, patients with localized gastric transformation had a superior outcome with only 1/6 dying due to progression of lymphoma.

This study analysed incidence, patient outcome, immunophenotype and prognostic factors of histological transformation (HT) from extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) to diffuse large B-cell lymphoma (DLBCL) in 467 patients (median age, 61 years). The primary sites of MALT lymphoma were the stomach (43%), ocular adnexa (25%), lung (8%), systemic (8%) and other tissues (16%). HT occurred in 8% of MALT lymphomas. Risk of HT by 15 years was 5%: 4% in limited-stage diseases (n = 385) and 16% in advanced-stage diseases (n = 56) (P = 0·02). The median time to HT was 48 months (range, 4-139). Five-year progression-free survival (PFS) and overall survival (OS) rates after HT were 80% and 94%, respectively. Immunohistochemical results of DLBCL were as follows: germinal centre B-cell (GCB)/non-GCB, 37%/63%; CD10, 9%; BCL6, 59%; MUM1, 38%; MYC, 42%; BCL2, 35%; Ki67 ≥ 90%, 23%; and CD5, 3%. The majority (75%, 9/12) of GCB-type DLBCLs exhibited CD10(-) , BCL6(+) and MUM1(-) immunophenotypes; the remainder had CD10(+) immunophenotypes. Multivariate analysis revealed that only advanced stage at HT was a significant adverse factor for PFS (P = 0·037). Thus, overall risk of HT was low and prognosis after HT was favourable; however, in advanced-stage cases, risk of HT was relatively high and prognosis was unfavourable.

There are few large-scale reports of primary thyroid lymphoma (PTL). This study clinically and pathologically reviewed 171 patients with PTL and 24,553 patients with Hashimoto's disease at Ito Hospital between January 1990 and December 2004, to investigate the clinical features and the treatment outcomes of PTL. The median age of the patients with PTL was 67 years (range, 27-90 years). The pathological diagnosis of PTL patients included diffuse large B-cell lymphoma (DLBCL) (n=74), DLBCL with mucosa-associated lymphoid tissue (MALT) lymphoma (n=13), MALT lymphoma (n=80) and others (n=4). Of the 167 patients with B-cell lymphoma, treatment included combined modality therapy (CMT) (n=95), radiation therapy (RT) alone (n=60) and chemotherapy alone (n=6). Information on treatment was not available in six patients. Information on treatment response was available in 154 patients; 149 patients (97%) responded to treatment. According to the institutional treatment strategy of Ito Hospital, 45 of 54 patients with stage IE disease received RT alone, and 87 of 113 stage IIE patients received CMT. The 5-year overall survival rate was 85% (95% confidence interval, 79-91%). This study demonstrated that PTL showed good response to radiotherapy and chemotherapy and had a favourable prognosis.

The clinical features, morphology and immunophenotype of 20 cases of B non Hodgkin's lymphoma (B-NHL) with chromosome abnormalities involving 11q13-14 were studied, to determine if this abnormality was closely associated with a specific sub-type of B-NHL. A t(11;14)(q13;q32) was found in 11 cases of intermediately differentiated lymphocytic lymphoma (IDLL). A breakpoint in the major translocation cluster of the BCL-1 locus was found in six of these cases. These patients were male with lymphomatous involvement of the bone marrow, marked splenomegaly and frequently had mucosa associated lymphoid tissue involvement. One patient with IDLL had a t(8;11)(p21;q13) and a rearranged BCL-1 locus, suggesting that this may be a variant of t(11;14)(q13;q32). Diagnoses of IDLL, chronic lymphocytic leukaemia, lymphoplasmacytic lymphoma and monocytoid B cell lymphoma were made in all but one of the remaining cases. These cases had either a translocation involving 11q13-14 and various partner chromosomes or an 11q13 deletion. This study demonstrates that 11q abnormalities occur mainly in a group of low-grade B-NHL of non follicle centre cell lineage.

Analysis of complementary RNA molecules of junctional regions of rearranged T-cell-receptor-gamma genes show a pattern of conformational polymorphisms which is specific for an individual lymphocytic clone. In a blinded study we analysed formalin-fixed, paraffin-embedded histological specimens from gastrointestinal lymphomas and control tissues (lymphomas: pleomorphic T-cell 10, anaplastic large cell [Ki1+] 9, centroblastic 5, immunocytoma 1, B-CLL 2, Hodgkin's 2, centroblastic-centrocytic 1, MALT [mucosa associated lymphoid tissue] 1, T-cell acute lymphoblastic leukaemia 1, non-lymphoid or polyclonal lymphoid tissues 5). Junctional regions of rearranged TCR-gamma genes were amplified by the polymerase chain reaction and the products were transcribed into cRNA. Conformational patterns of cRNA molecules were analysed by polyacrylamide gel electrophoresis. 13/20 T-lineage lymphomas and the T-cell acute lymphocytic leukaemia displayed a distinct cRNA band pattern, all B-lineage lymphomas and the non-lymphoid control tissues were negative. Only one case of nasopharyngeal (lymphoepithelial, Schmincke-Regaud) carcinoma showed a faint cRNA banding pattern. This novel and non-radioactive assay allows for the rapid detection and molecular characterization of clonal lymphoid populations in minute histological biopsy specimens.