Disease-biased and shared characteristics of the immunoglobulin gene repertoires in marginal zone B cell lymphoproliferations.

The B cell receptor immunoglobulin (Ig) gene repertoires of marginal zone (MZ) lymphoproliferations were analyzed in order to obtain insight into their ontogenetic relationships. Our cohort included cases with MZ lymphomas (n = 488), i.e. splenic (SMZL), nodal (NMZL) and extranodal (ENMZL), as well as provisional entities (n = 76), according to the WHO classification. The most striking Ig gene repertoire skewing was observed in SMZL. However, restrictions were also identified in all other MZ lymphomas studied, particularly ENMZL, with significantly different Ig gene distributions depending on the primary site of involvement. Cross-entity comparisons of the MZ Ig sequence dataset with a large dataset of Ig sequences (MZ-related or not; n = 65 837) revealed four major clusters of cases sharing homologous ('public') heavy variable complementarity-determining region 3. These clusters included rearrangements from SMZL, ENMZL (gastric, salivary gland, ocular adnexa), chronic lymphocytic leukemia, but also rheumatoid factors and non-malignant splenic MZ cells. In conclusion, different MZ lymphomas display biased immunogenetic signatures indicating distinct antigen exposure histories. The existence of rare public stereotypes raises the intriguing possibility that common, pathogen-triggered, immune-mediated mechanisms may result in diverse B lymphoproliferations due to targeting versatile progenitor B cells and/or operating in particular microenvironments. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

An Immunogenetic Signature of Ongoing Antigen Interactions in Splenic Marginal Zone Lymphoma Expressing IGHV1-2*04 Receptors.

PURPOSE: Prompted by the extensive biases in the immunoglobulin (IG) gene repertoire of splenic marginal-zone lymphoma (SMZL), supporting antigen selection in SMZL ontogeny, we sought to investigate whether antigen involvement is also relevant post-transformation. EXPERIMENTAL DESIGN: We conducted a large-scale subcloning study of the IG rearrangements of 40 SMZL cases aimed at assessing intraclonal diversification (ID) due to ongoing somatic hypermutation (SHM). RESULTS: ID was identified in 17 of 21 (81%) rearrangements using the immunoglobulin heavy variable (IGHV)1-2*04 gene versus 8 of 19 (40%) rearrangements utilizing other IGHV genes (P= 0.001). ID was also evident in most analyzed IG light chain gene rearrangements, albeit was more limited compared with IG heavy chains. Identical sequence changes were shared by subclones from different patients utilizing the IGHV1-2*04 gene, confirming restricted ongoing SHM profiles. Non-IGHV1-2*04 cases displayed both a lower number of ongoing SHMs and a lack of shared mutations (per group of cases utilizing the same IGHV gene). CONCLUSIONS: These findings support ongoing antigen involvement in a sizable portion of SMZL and further argue that IGHV1-2*04 SMZL may represent a distinct molecular subtype of the disease.

Splenic diffuse red pulp small B-cell lymphoma: revision of a series of cases reveals characteristic clinico-pathological features.

BACKGROUND: Splenic diffuse red pulp small B-cell lymphoma is an uncommon B-cell lymphoma, now recognized as a provisional entity in the 2008 update of the WHO Classification. Additional work is required to review this entity and establish its diagnostic features. DESIGN AND METHODS: We have retrospectively analyzed the disease features in a highly selected series of 17 patients diagnosed as splenic diffuse red pulp small B-cell lymphoma. RESULTS: The median age was 65.5 years (range 40-79 years) and there was a predominance of males (male/female ratio: 2.4). Clinical manifestations were mainly derived from splenomegaly. Splenectomy was the front-line treatment in 11 symptomatic patients; the remaining 6 received chemotherapy initially followed by splenectomy. After a mean follow-up of 72 months, the five-year overall survival was 93%. All cases showed a purely diffuse pattern of splenic infiltration by monomorphous small cells with small round nuclei and pale cytoplasm. All bone marrow biopsies showed tumoral infiltration, with intrasinusoidal infiltration. Peripheral blood cells were small to medium-sized, with clumped chromatin and round nuclear outline and villous cytoplasm. Neoplastic cells had a CD20(+), CD23(-), bcl6(-), Annexin A1- phenotype, with frequent expression of DBA44+ (15/17) and IgG (10/15). FCM data had a B-cell phenotype (CD19(+), CD20(+), CD22(+)) with FMC7 (10/11) and CD11c (5/8) expression. Clonal IgH rearrangement studies in 4 cases showed IgVH mutations in all cases, without VH1.2 usage. CONCLUSIONS: Our data suggest that splenic diffuse red pulp small B-cell lymphoma is a distinct entity with morphological and immunophenotypical features that differ from those of other splenic lymphomas.

Nodal and splenic marginal zone B cell lymphomas.

Splenic marginal zone lymphoma (SMZL) and nodal marginal zone lymphoma (NMZL) are newly defined, separate clinicopathological entities. Both are rare lymphoma types, with low reproducibility in the diagnosis, although a conjunction of molecular and clinical studies seems to be now facilitating a more accurate diagnosis and understanding of the neoplastic process. SMZL is a disease involving the spleen, bone marrow and peripheral blood since the initial manifestations of the disease. The diagnosis has been until very recently based on the pathological study of the spleen with the conjunction of the clinical features, although the integration of the morphology in bone marrow and peripheral blood with the immunophenotype and molecular characteristics of the tumour makes a more accurate diagnosis now possible. The most frequent molecular alteration found in SMZL is allelic loss at the 7q chromosomal region. SMZL is an indolent lymphoma, although there is small subset of patients in which it follows an aggressive course. Molecular studies of SMZL are starting to reveal new diagnostic and prognostic markers, and to identify new potentially useful therapeutic targets. Nodal marginal zone lymphoma is a B-cell neoplasm originated in the lymph node, whose histology resembles the nodal infiltration by MALT- or Splenic-type marginal zone lymphoma, in the absence of clinical evidence of extranodal or spleen disease. The lack of characteristic phenotypic or molecular diagnostic findings is still hampering the reproducibility of this diagnosis. Here we review the main morphological and immunophenotypical markers, discussing the differential with other overlapping entities, singularly follicular lymphoma. Specific therapeutic protocols and prognostic factors are required to more precisely define this tumour.

Nodal marginal zone lymphoma: a heterogeneous tumor: a comprehensive analysis of a series of 27 cases.

We have reviewed the clinical, morphologic, immunophenotypical, and molecular features of a series of 27 cases of nodal marginal zone lymphoma with the aim of defining this entity more precisely. The series was characterized by a relatively favorable clinical course, with a low clinical stage at diagnosis (59% patients with clinical stage I-II) and a 5-year overall survival probability of 79%. However, the disease persisted in a relatively large fraction of the patients, thus yielding a 5-year failure-free survival probability of 22%. Molecular and immunohistochemical analyses of the series revealed heterogeneity in the frequency of IgV(H) somatic mutation and in the expression of IgD, CD43, MUM1, and CD38. Apart from the absence of nuclear Bcl10, no clear distinction could be made from the expression profiling of other B-cell lymphomas claimed to be derived from marginal zone B cells. Additionally, the immunophenotype of the tumoral cells in all cases but one differed from that described in monocytoid B cells. It was characterized by a Bcl2-, p21+, cyclin E+ profile. The analysis of apoptosis-regulator proteins disclosed abnormalities in the expression of survivin and active caspase 3, which could partially explain the abnormal regulation of apoptosis observed in these tumors. Molecular and immunohistochemical data obtained in this study strongly imply that there is significant heterogeneity among the cases included in the category termed nodal marginal zone lymphoma.

Splenic marginal zone lymphoma: clinical characteristics and prognostic factors in a series of 60 patients.

A precise description of clinical features at presentation and analysis of clinical and biologic prognostic factors in splenic marginal zone lymphoma (SMZL) are still lacking. Here we describe the clinical and biologic features of a series of 60 SMZL patients diagnosed after splenectomy. Analysis for overall survival (OS), failure-free survival (FFS), and the probability of obtaining a response was performed using univariate and multivariate tests. The median age of the patient was 63 years (range, 35-84 years). Performance status according to the Eastern Cooperative Oncology Group (ECOG scale) was 0 = 16%, 1 = 58%, and 2 = 25%. Of the 60 patients, 53 (86.6%) were at Ann Arbor stage IV. All 60 patients received splenectomies, 29 of 60 also received chemotherapy, and 2 received spleen radiotherapy. A complete response (CR) was achieved by 38.3% of patients, and a partial response (PR) was achieved by 55%. Mean OS of the series was 103 months (range, 2-164 months); mean FFS was 40 months (range, 3-164 months). At 5 years from diagnosis, 39 patients (65%) were alive. Patients dying from the disease had a relatively aggressive clinical course, with a short survival (17.5 months [range, 2-72 months]). Significant prognostic factors in multivariate analysis were (1) (for OS and FFS) lack of response to therapy (CR versus noncomplete response [nCR]) and involvement of nonhematopoietic sites, and (2) (for the probability of obtaining CR) bone marrow involvement. Chemotherapy did not influence OS or FFS. p53 overexpression predicted a shorter OS in the univariate analysis. These data confirm the relative indolence of this disease, indicating the existence of a subset of more aggressive cases, which should stimulate the search for predictive biologic factors and alternative therapies.

Loss of heterozygosity of p16 correlates with minimal residual disease at the end of the induction therapy in non-high risk childhood B-cell precursor acute lymphoblastic leukemia.

We evaluated the incidence of MTS1/p16 deletions by loss of heterozygosity (LOH) analysis in 36 non-high risk B-cell precursor childhood acute lymphoblastic leukemia (BCP-ALL) and correlated these results with clinical features and with the presence of minimal residual disease (MRD) at the end of induction therapy. LOH was analyzed using three microsatellite markers flanking the p16 gene. MRD was studied by the polymerase chain reaction (PCR) for IgH and TCRdelta genes. All patients were classified and treated according to the BFM-86 protocol. A slower response to the induction treatment (MRD) was associated with LOH of p16 and worse clinical outcome. Thus, LOH of p16 may be a marker of chemotherapy resistance among the children classified as non-high risk BCP-ALL.

Analysis of the IgV(H) somatic mutations in splenic marginal zone lymphoma defines a group of unmutated cases with frequent 7q deletion and adverse clinical course.

This study aimed to correlate the frequency of somatic mutations in the IgV(H) gene and the use of specific segments in the V(H) repertoire with the clinical and characteristic features of a series of 35 cases of splenic marginal zone lymphoma (SMZL). The cases were studied by seminested polymerase chain reaction by using primers from the FR1 and J(H) region. The results showed unexpected molecular heterogeneity in this entity, with 49% unmutated cases (less than 2% somatic mutations). The 7q31 deletions and a shorter overall survival were more frequent in this group. Additionally a high percentage (18 of 40 sequences) of SMZL cases showed usage of the V(H)1-2 segment, thereby emphasizing the singularity of this neoplasia, suggesting that this tumor derives from a highly selected B-cell population and encouraging the search for specific antigens that are pathogenically relevant in the genesis or progression of this tumor.