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Splenic marginal zone lymphoma (SMZL) is a B-cell neoplasm whose molecular pathogenesis remains fundamentally unexplained, requiring more precise diagnostic markers. Previous molecular studies have revealed 7q loss and mutations of nuclear factor κB (NF-κB), B-cell receptor (BCR) and Notch signalling genes. We performed whole-exome sequencing in a series of SMZL cases. Results confirmed that SMZL is an entity distinct from other low-grade B-cell lymphomas, and identified mutations in multiple genes involved in marginal zone development, and others involved in NF-κB, BCR, chromatin remodelling and the cytoskeleton.

We performed an immunogenetic analysis of 345 IGHV-IGHD-IGHJ rearrangements from 337 cases with primary splenic small B-cell lymphomas of marginal-zone origin. Three immunoglobulin (IG) heavy variable (IGHV) genes accounted for 45.8% of the cases (IGHV1-2, 24.9%; IGHV4-34, 12.8%; IGHV3-23, 8.1%). Particularly for the IGHV1-2 gene, strong biases were evident regarding utilization of different alleles, with 79/86 rearrangements (92%) using allele (*)04. Among cases more stringently classified as splenic marginal-zone lymphoma (SMZL) thanks to the availability of splenic histopathological specimens, the frequency of IGHV1-2(*)04 peaked at 31%. The IGHV1-2(*)04 rearrangements carried significantly longer complementarity-determining region-3 (CDR3) than all other cases and showed biased IGHD gene usage, leading to CDR3s with common motifs. The great majority of analyzed rearrangements (299/345, 86.7%) carried IGHV genes with some impact of somatic hypermutation, from minimal to pronounced. Noticeably, 75/79 (95%) IGHV1-2(*)04 rearrangements were mutated; however, they mostly (56/75 cases; 74.6%) carried few mutations (97-99.9% germline identity) of conservative nature and restricted distribution. These distinctive features of the IG receptors indicate selection by (super)antigenic element(s) in the pathogenesis of SMZL. Furthermore, they raise the possibility that certain SMZL subtypes could derive from progenitor populations adapted to particular antigenic challenges through selection of VH domain specificities, in particular the IGHV1-2(*)04 allele.

Since the initial description of splenic marginal zone lymphoma (SMZL) in 1992, an increasing number of publications have dealt with multiple aspects of SMZL diagnosis, molecular pathogenesis and treatment. This process has identified multiple inconsistencies in the diagnostic criteria and lack of clear guidelines for the staging and treatment. The authors of this review have held several meetings and exchanged series of cases with the objective of agreeing on the main diagnostic, staging and therapeutic guidelines for patients with this condition. Specific working groups were created for diagnostic criteria, immunophenotype, staging and treatment. As results of this work, guidelines are proposed for diagnosis, differential diagnosis, staging, prognostic factors, treatment and response criteria. The guidelines proposed here are intended to contribute to the standardization of the diagnosis and treatment of these patients, and should facilitate the future development of clinical trials that could define more precisely predictive markers for histological progression or lack of response, and evaluate new drugs or treatments.

Aims: Splenic marginal zone lymphoma (SMZL) has been characterized by a micronodular pattern of infiltration, biphasic cytology, follicular replacement and the presence of marginal zone differentiation. Here we describe four cases with some distinctive features, such as diffuse splenic infiltration, lack of micronodules, marginal zone cytology, p53 inactivation and cutaneous involvement., Methods and Results: In the course of a review of cases of SMZL, we recognized the existence of a subset of four cases of splenic B-cell lymphoma, with predominantly red pulp involvement, absence of follicular replacement, and a monomorphous population of tumoral cells resembling marginal zone B-cells, with scattered nucleolated blast cells. The immunophenotype (bcl2+, CD5-, CD10-, CD43-, CD23-, cyclin D1-, IgD- (3/4)) was consistent with SMZL. Bone marrow infiltration (4/4) and peripheral blood involvement (2/4) showed similar findings to those described for SMZL in these locations. However, unlike classical SMZL, 2/4 had cutaneous involvement, and 4/4 cases showed either p53 mutation or anomalous p53 staining (p53+, p21-). CONCLUSIONS; In spite of a diffuse pattern of splenic infiltration, cutaneous involvement and p53 alterations, these cases have findings that overlap with those corresponding to classic SMZL (symptomatology, morphology of bone marrow, lymph nodes, peripheral blood involvement, and immunophenotype). We suggest that these cases be considered a putative variant of SMZL.

Splenic marginal zone lymphoma (SMZL) is considered to be an indolent extranodal B-cell lymphoma. Despite its low aggressivity, histologic progression has been described in sporadic reports, although the frequency, characteristics, and underlying molecular abnormalities of this phenomenon are largely unknown. We review here the clinical, morphologic, immunohistochemical, and molecular features of a series of 12 SMZL cases that showed progression to large B-cell lymphoma (LBCL). The most frequent location of secondary LBCL was in peripheral lymph node. This occurred between 12 and 85 months after diagnosis of SMZL. However, in two cases LBCL was diagnosed at the initial stage of the disease (one spleen tumoral nodule and one hilar lymph node). The histologic and immunophenotypic features of these cases were similar to those of transformed LBCL at other sites. In four cases the immunoglobulin heavy chain gene polymerase chain study revealed the same rearrangement pattern in both primary and secondary tumors, thereby confirming their identity and excluding the possibility of a second malignancy. As is the case with other low-grade lymphoproliferative disorders, SMZL may undergo high-grade transformation. These 12 cases represent 13% of our series of SMZL with adequate follow-up. The incidence of large cell transformation in SMZL seems to be lower than in follicular lymphoma (25-60%) and mantle cell lymphoma (11-39%), although it is similar to the frequency of transformation in B-chronic lymphocytic lymphoma/small lymphocytic lymphoma (1-10%). The mean proliferative index (MIB1 staining) in initial SMZL specimens of cases with LBCL transformation was 28.6%, higher than that of MIB1 staining in the overall SMZL series (21.8%), although not statistically significantly so. p53 or p16INK4a inactivation in this series was observed in only one case, in contrast with the situation observed in chronic lymphocytic leukemia, follicular lymphoma, and mantle cell lymphoma. It seems that progression in SMZL is mainly independent of p53 or p16INK4a inactivation. The frequency of the 7q deletion in this series was 3 of 7 (42%). 7q loss may play an alternative role in the inactivation of the p53 and p16INK4a pathway, thereby favoring tumoral progression.

Splenic marginal zone lymphoma (SMZL) has recently been recognized in the World Health Organization classification of hematological diseases as distinct type of non-Hodgkin's lymphoma. In contrast to the well-established chromosomal changes associated with other B-cell non-Hodgkin's lymphoma, few genetic alterations have been found associated with SMZL. The aim of our study was to analyze by comparative genomic hybridization (CGH) the chromosomal imbalances in 29 patients with SMZL and to correlate these findings with clinical and biological characteristics and patient outcome. In 21 cases, cytogenetic studies were simultaneously performed. Most of the patients (83%) displayed genomic imbalances. A total of 111 DNA copy number changes were detected with a median of four abnormalities per case (range, 1 to 12). Gains (n = 92) were more frequent than losses (n = 16), while three high-level amplifications (3q26-q29, 5p11-p15, and 17q22-q25) were observed. The most frequent gains involved 3q (31%), 5q (28%), 12q and 20q (24% each), 9q (21%), and 4q (17%). Losses were observed in 7q (14%) and 17p (10%). SMZL patients with genetic losses had a shorter survival than the remaining SMZL patients (P < 0.05). In summary, chromosomal imbalances in regions 3q, 4q, 5q, 7q, 9q, 12q, and 20q have been detected by CGH in SMZL. Patients with SMZL displaying genetic losses by CGH had a short survival.

Splenic marginal zone lymphoma (SMZL) has been recognized as a distinctive type of small B cell lymphoma, and defined on the basis of its morphological, phenotypic, clinical and molecular characteristics. In spite of this, the borders of the entity, the homogeneity of the cases and the presumably cell origin of SMZL remain controversial issues. The frequency of mutation in the 5' non-coding region of the bcl-6 gene has been used as a marker of germinal center derivation, which may be used to establish the molecular heterogeneity of different non-Hodgkin lymphoma (NHL) types. This roughly parallels the characteristics and frequency of the somatic hypermutations found in the immunoglobulin heavy chain variable region (IgVH) genes. This study analyzed mutations of bcl-6 in the 5' non-coding region in 22 SMZL cases and, for the purpose of comparison with different B cell subsets, in microdissected germinal centers, mantle zones and marginal zone subpopulations from reactive splenic lymphoid follicles. A majority of the SMZL cases studied, 19/22 (87%), bear unmutated bcl-6 gene, while mutation was only observed in 3/22 (13%) cases. Analysis of normal B cell subpopulations showed bcl-6 hypermutation in 3/10 (30%) germinal center clones, 5/14 (35%) marginal zone clones; and unmutated sequences in all clones derived from mantle cells. The frequency of these mutations in normal spleen confirms previous findings on the hypermutation IgVH process in normal B cell populations. The data presented here support the existence of molecular heterogeneity in this entity, and give additional results in favor of the hypothesis that, in spite of initial morphological observations, a significant proportion of SMZL cases could derive from an unmutated naive precursor, different from the marginal zone, and possibly located in the mantle zone of splenic lymphoid follicles. Thus the marginal zone differentiation of these tumors could be related more with the splenic microenvironment than it is to the histogenetic characteristics of the tumor.

Background and Objectives: Splenic marginal zone B-cell lymphoma (SMZBCL) has clinical, immunophenotypic and histologic features distinct from other B-cell malignancies, but few chromosome studies have been previously reported. In the present study we performed conventional cytogenetics and in situ hybridization studies in 47 patients with SMZBCL., Design and Methods: We studied 47 cases of splenic marginal zone B-cell lymphoma combining conventional cytogenetics and in situ hybridization (ISH) techniques using centromeric probes (chromosomes 3 and 12), locus specific probes (7q31 and 17p13) and cross-species color banding fluorescent ISH probes (RxFISH). The diagnosis of SMZBCL was ascertained in all cases after studying, morphologically and immunologically, peripheral blood and splenectomy specimens., Results: A clonal chromosome abnormality detected by conventional cytogenetics and/or FISH was found in 33/47 patients (70%) being identified in 18 (18/33, 55%) as a complex abnormality. The most frequently recurrent abnormalities were: gain of 3q (10 cases), del(7q) (12 cases), and involvement of chromosomes 1, 8 and 14. No patient showed translocation t(11;14) (q13;q32) or t(14;18) (q21;q32). Trisomy 3 was detected in eight cases (8/47, 17%). Two novel cytogenetic abnormalities involving 14q32, t(6;14)(p12;q32) and t(10;14) (q24;q32) were reported. Deletion of 17p13 (P53) was observed by FISH in one case. Only one patient showed a gain of 3q or trisomy 3 and deletion 7q in the same karyotype., Interpretation and Conclusions: Our findings support the interpretation that two forms of SMZBCL could be considered, one with gain of 3q and the other with deletions at 7q.

The most cases of splenic marginal zone lymphoma (SMZL) seem to respond favorably to splenectomy. The diagnosis of this lymphoma is mainly based on the recognition of a micronodular pattern of splenic involvement with marginal zone differentiation. However, it is possible to find so-called "marginal zone differentiation" in splenic involvement by other small B-cell lymphomas, particularly mantle cell lymphoma (MCL) and follicular lymphoma. We report a case of blastic MCL, large cell/anaplastic variant with a high level of clinical aggressiveness, showing biphasic cytology and a micronodular pattern which resembles SMZL. A single biopsy corresponding to this case shows two phases of tumoral progression in a MCL, a rare finding in MCL. In conclusion, the differential diagnosis of SMZL must take the possibility of a blastic MCL with biphasic cytology into account, as the case here., (Copyright 1999 Wiley-Liss, Inc.)

Splenic marginal zone lymphoma (SMZL) is a recently described and distinctive type of splenic lymphoma and is characterized by an indolent clinical course. By analyzing a large series of SMZL cases, we recognized the existence of a subset of 6 cases characterized by an aggressive clinical course that led to death caused by the tumor in 5 of 6 cases, whereas the remaining patient showed signs of tumor progression. The morphological, immunohistological, and molecular study of these cases has allowed us to detect precise distinctive features of this SMZL variant. The cases included here were characterized by massive splenomegaly and a morphological picture showing a micronodular pattern of splenic involvement with follicle replacement, biphasic cytology, and marginal zone differentiation. Unlike classical SMZL cases, a conspicuous component of larger lymphocytes was distributed in the marginal zone ring, occasionally overrunning it, with isolated presence of the same cells within the central small cell component and also in the red pulp. The bone marrow and peripheral lymph nodes showed similar histological findings to those described for SMZL in these locations. The genetic and molecular study of these cases showed no alterations specific to other lymphoma types, such as t14;18 and t11;14. Instead of this, it showed 7q loss in 3 of 5 cases, p53 inactivation in 2 of 6 cases, cyclinD1 overexpression in 2 of 6 cases, and the presence of translocations involving the 1q32 region in 2 of 4 cases. The recognition of this aggressive variant, besides offering a prognostic indication, could lead to a more suitable form of clinical management of these patients. Further molecular studies would clarify the role of the different genetic alterations found.

Splenic marginal zone lymphoma (SMZL) has been recognized as an entity defined on the basis of its morphological, phenotypic, and clinical characteristic features. Nevertheless, no characteristic genetic alterations have been described to date for this entity, thus making an exact diagnosis of SMZL difficult in some cases. As initial studies showed that chromosome region 7q22-32 is deleted in some of these cases, we analyzed a larger group of SMZL and other lymphoproliferative disorders that may partially overlap with it. To better define the frequency of 7q deletion in SMZL and further identify the deleted region, polymerase chain reaction analysis of 13 microsatellite loci spanning 7q21-7q36 was performed on 20 SMZL and 26 non-SMZL tissue samples. The frequency of allelic loss in SMZL (8/20; 40%) was higher than that observed in other B-cell lymphoproliferative syndromes (2/26; 7.7%). This difference was statistically significant (P < 0.05). The most frequently deleted microsatellite was D7S487 (5/11; 45% of informative cases). Surrounding this microsatellite the smallest common deleted region of 5cM has been identified, defined between D7S685 and D7S514. By comparative multiplex polymerase chain reaction analysis, we detected a homozygous deletion in the D7S685 (7q31.3) marker in one case. These results suggest that 7q31-q32 loss may be used as a genetic marker of this neoplasia, in conjunction with other morphologic, phenotypic, and clinical features. A correlation between 7q allelic loss and tumoral progression (death secondary to the tumor or large cell transformation) in SMZL showed a borderline statistical significance. The observation of a homozygous deletion in this chromosomal region may indicate that there is a tumor suppressor gene involved in the pathogenesis of this lymphoproliferative neoplasia.

Aims: Studies of the genetic characteristics of splenic marginal zone lymphoma (SMZL) have failed to identify genetic changes specific to this tumour. Microsatellite instability is a type of genomic instability associated with different types of human cancer. Although microsatellite instability is rare in B cell non-Hodgkin's lymphomas, it has been found in some specific subsets, such as marginal zone lymphomas arising in mucosa associated lymphoid tissue (MALT), where an association with p53 mutation has been described. Because it has been proposed that SMZL and MALT are close in histogenetic terms, this study investigated the comparative frequency of microsatellite instability and p53 mutation in patients with SMZL and MALT lymphomas., Methods: Microsatellite instability was investigated using seven microsatellite marker loci in 14 patients with SMZL and 20 patients with MALT lymphomas. In an attempt to clarify the role of p53 gene mutation in the pathogenesis of SMZL, exons 5-8 were also investigated by polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) and direct sequencing in a total of 20 patients with SMZL and 22 patients with MALT lymphomas., Results: Microsatellite instability was not detected in patients with SMZL, although five of 20 patients with MALT lymphomas had microsatellite instability. The frequency of p53 mutation was low in both series (two of 20 patients with SMZL and one of 22 patients with MALT lymphomas). No significant association was found between p53 mutation and microsatellite instability., Conclusions: These results indicate that microsatellite instability is not associated with the molecular pathogenesis of SMZL, confirming the relatively increased frequency of microsatellite instability in MALT lymphomas, and perhaps suggesting that MALT and SMZL have different mechanisms of tumorigenesis.

Aims: Splenic marginal zone lymphoma (SMZL) is characterized by a micronodular infiltrate of the splenic white pulp, centred on pre-existing follicles, with a peripheral rim of 'marginal' zone B-cells, always accompanied by a variable degree of red pulp infiltration. These histological features can be closely mimicked by a variety of other small B-cell lymphomas when they involve the spleen, which makes recognition of SMZL difficult. We therefore have compared the histopathological and immunohistochemical features of other non-Hodgkin's lymphoma (NHL) types with those of SMZL., Methods and Results: We selected cases of splenic involvement by different types of B-cell lymphoma, including mantle cell lymphoma (MCL), follicular lymphoma (FL), immunocytoma (IM) and lymphocytic lymphoma (B-CLL). A micronodular pattern and marginal zone differentiation were both found to be frequently present in FL and MCL, and with lesser frequency in IM and B-CLL. The main morphological feature useful for differential diagnosis was the cytological composition of the white pulp tumoral nodules. SMZL is distinguished by characteristic dimorphic cytology, different from the monomorphic cytology of MCL, and the distinctive mixture of centroblasts and centrocytes which is the rule in FL. B-CLL could also be identified on the basis of the polymorphic cytology including small lymphocytes and prolymphocytes, whereas cases diagnosed as IM show prominent plasmacytic differentiation, lacking the features of the other lymphoma types. Immunohistochemistry was particularly useful for the differential diagnosis. Thus the recognition of MCL was facilitated by the identification of cyclin D1 and CD43 reactivity, while FL could be recognized by the lack of IgD expression or the distinctive pattern of Ki67 staining found in SMZL. B-CLL cells were CD23+, CD43+., Conclusion: The results of this study provide morphological and immunohistological information useful in the recognition of the different varieties of NHLs when involving the spleen and the differential diagnosis of SMZL.

Splenic marginal zone lymphoma (SMZL) is a recently recognized primary splenic lymphoma. SMZL can be associated with peripheral lymphocytosis, in which some cells have a villous morphology (splenic lymphoma with villous lymphocytes [SLVL]). Several recent studies suggested involvement of the bcl-1 locus and/or the cyclin D1 gene, located on chromosome 11q, in SMZL/SLVL. Translocation t (11;14) is associated with rearrangement of the bcl-1 locus and overexpression of the cyclin D1 gene. Both the translocation and cyclin D1 protein expression are characteristic of mantle cell lymphoma (MCL) and are rare in other lymphoid neoplasms; thus, their detection is useful in the diagnosis of MCL. Because the differential diagnosis of low-grade lymphoma in the spleen can be difficult, it is important to assess the frequency of cyclin D1 expression in SMZL to determine its usefulness in differential diagnosis from MCL. We analyzed the expression of cyclin D1 nuclear protein in paraffin sections using an immunoperoxidase technique in 17 cases diagnosed as SMZL. In eight cases, the presence of cyclin D1 mRNA was also assessed by Northern blot analysis. None of the 17 cases of typical SMZL showed expression of cyclin D1 mRNA or protein. In contrast, four cases used as controls showed either expression of cyclin D1 protein or mRNA or both. We conclude that assessment of cyclin D1 protein expression can be useful in distinguishing SMZL from MCL involving the spleen.

We have studied 19 cases of splenic marginal zone B-cell lymphoma (SMZBCL) combining cytological features, conventional cytogenetics, and in situ hybridization (ISH) techniques. A clonal chromosome abnormality was found in 11/19 patients (58%). The more frequent recurrent abnormalities were: del(3), del (7q), and involvement of chromosomes 1, 3, 7 and 8. No patient showed the translocation t(11;14)(q13;q32). An outstanding finding was the low incidence of trisomy 3 (36%) compared to patients with MALT lymphoma. These findings support the interpretation that SMZBCL is a distinct lymphoproliferative disorder.

Splenic marginal zone lymphoma (SMZL) has recently been proposed as a distinctive type of low-grade B-cell lymphoma. Although there is general agreement that this entity exists, its precise definition is blurred by uncertainty in differential diagnosis from other low-grade B-cell lymphomas. There is even more uncertainty as to the histology of splenic hilar and peripheral lymph nodes involved by SMZL. We therefore reviewed the histological and immunohistochemical features of 19 of these lymph nodes (14 hilar and five peripheral) from 14 cases of classical SMZL and compared them with the features of lymph nodes involved by other B-cell lymphomas. The morphology and immunohistology of the lymph nodes resemble those found in the white pulp of the spleen, showing a distinctive pattern, different from that which is observed in other B-cell lymphomas. In these cases, the overall architecture of the lymph nodes is effaced and replaced by a nodular infiltrate, although the sinuses are preserved in most hilar lymph nodes. Some of the nodules contain a central reactive follicular center, around which there is a broad zone of small lymphocytes. In other cases, the central area is partially infiltrated or, more commonly, totally replaced by these small lymphocytes, which in the periphery of the nodules showed a pale, slightly larger cytoplasm. Scattered nucleolated blasts are present, largely confined to the periphery of the nodules. The tumoral cells express immunoglobulin (Ig)D, IgM, and Ig light chain restriction and show a low proliferation fraction. These findings confirm that SMZL is a real entity, and not merely a morphological pattern of splenic infiltration by different types of low-grade B-cell lymphoma.

The recognition and classification of the different varieties of splenic low-grade B-cell lymphomas have been hampered by the rarity of histological studies of surgical splenectomy specimens of B-cell lymphoma. In an effort to characterize the recently described splenic marginal zone lymphoma (SMZL), we conducted a survey of 13 patients with this type of tumor using the criteria defined by Schmid for its recognition (Schmid et al., Am J Surg Pathol 1992;16:455-66). Primary splenic high-grade lymphomas, T-cell lymphomas, and secondary infiltration by other recognized low-grade B-cell lymphomas, with the exception of splenic lymphoma with villous lymphocytes, were excluded. This selection gave rise to a homogeneous group of tumors with similar clinical, histological, immunohistochemical, and molecular features. Our study showed the critical parameters for their recognition to be morphological, including macroscopic micronodularity and the constant presence of white- and red-pulp infiltration, marginal zone pattern, and plasmacytic differentiation. No t(14;18) or PRAD-1/cyclin D1 overexpression was detect able in any case. Clinically, the tumors were widespread with a protracted evolution. Nodal infiltration by SMZL in our cases was morphologically similar to monocytoid B-cell lymphoma. SMZL could constitute the largest group of primary splenic malignant lymphomas, partially overlapping with splenic lymphoma with villous lymphocytes. Specific molecular markers for SMZL have yet to be defined. Because of the limited number of cases, the question of therapy for this group of lymphomas must remain open for the future.