Alexandra Traverse-Glehen

Splenic marginal-zone lymphoma: a distinct clinical and pathological entity

In the World Health Organization classification system, splenic marginal-zone lymphoma (splenic MZL) is described as an indolent B-cell lymphoma, which generally presents as splenomegaly with involvement of the bone marrow and peripheral blood. Presence of disease in peripheral lymph nodes and extranodal locations is uncommon. Splenic MZL is characterised by micronodular infiltration of the spleen with marginal-zone differentiation; the immunophenotype is usually IgM+ IgD+/- cytoplasmic-Ig-/+ pan B antigens+ CD5- CD10- CD23- CD43-/+ cyclin D1-; and the most common genetic abnormalities are deletions at 7q22-7q32. Most patients with splenic MZL live for a long time but classic prognostic factors cannot distinguish between patients who are likely to have good and poor outcomes. However, immunological events, such as haemolytic anaemia and immune thrombocytopenia, or the presence of a monoclonal component, are significantly associated with shorter survival. Splenectomy is considered the first-line treatment of choice for splenic MZL; it results in only partial remission, but responses are generally sufficient for correcting cytopenia, improving quality of life, and increasing survival.

Target cells of Epstein-Barr-virus (EBV)-positive post-transplant lymphoproliferative disease: similarities to EBV-positive Hodgkin's lymphoma.

BACKGROUND Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disease (PTLD) encompasses a histologically broad range of lesions, arising from the expanded pool of EBV-infected B cells in the immunocompromised host. Identification of the precise cellular origin of these tumours could clarify their pathogenesis. METHODS Of 13 cases of EBV-positive cases of PTLD characterised by histological analysis, pattern of EBV gene expression, and clinical course, 11 had monoclonal or biclonal lesions in which we determined the progenitor B cell by immunoglobulin heavy chain (IgH) genotyping. RESULTS Two tumours had a naive B cell genotype and two showed patterns of IgH somatic mutation typical of antigen-selected (post-germinal-centre) memory cells. All four arose early post-transplant and expressed the markers of EBV transformation--Epstein-Barr nuclear antigen (EBNA) 2 and latent membrane protein (LMP) 1. However, seven tumours, either of early or late onset and including some with downregulated EBNA 2 and LMP 1, arose from post-germinal cells with randomly mutated or sterile IgH genotypes usually incompatible with B-cell survival in vivo. INTERPRETATION PTLD can arise from a broad range of target B cells and not only from the pool of antigen-selected memory cells that EBV generally colonises in immunocompetent individuals. Tumour development seems frequently associated with the EBV-induced rescue and expansion of B cells that have failed the physiological process of germinal centre selection into memory. This finding shows an unexpected connection between pathogenesis of PTLD and that of EBV-positive Hodgkins lymphoma, another B-cell malignancy of atypical post-germinal-centre cell origin.

CD5 expression identifies a subset of splenic marginal zone lymphomas with higher lymphocytosis: a clinico-pathological, cytogenetic and molecular study of 24 cases

Background Classically, splenic marginal zone B-cell lymphoma is characterized by the absence of CD5 expression. Cases of apparent splenic marginal zone B-cell lymphoma showing CD5 expression, as diagnosed by blood studies, have been described; however, in the absence of histological evidence, the correct diagnosis of these cases is controversial because of possible confusion with other CD5-positive small B-cell neoplasms. Design and Methods We report a series of 24 CD5-positive, t(11;14)-negative cases of splenic marginal zone B-cell lymphoma diagnosed by flow cytometry studies of blood and histologically proven on spleen sections. Clinical data as well as morphological, immunological, cytogenetic and molecular characteristics were assessed to evaluate the similarities and differences of these cases with those of classical CD5-negative splenic marginal zone B-cell lymphoma. Results The CD5 expression detected in blood by flow cytometry was confirmed in most cases by immunohistochemistry on spleen sections. In general, cases of CD5-positive and CD5-negative splenic marginal zone B-cell lymphoma did not appear different and, in particular, they showed similar karyotypic changes such as 7q deletion, trisomy 3, trisomy 18 and biased IGHV usage (i.e. VH1-2). The main differences were a higher lymphocyte count at diagnosis (8.15×109/L versus 3.90×109/L; P=0.005) and more frequent diffuse bone marrow infiltration (34% versus 8%; P=0.03) in the CD5-positive group. A tendency to a more mutated IGHV status in the CD5 positive cases was observed (80% versus 54.5%; (P=0.11). No significant differences in outcome were found in relation to CD5 expression. Conclusions This study confirms the existence of cases of CD5-positive splenic marginal zone B-cell lymphoma and shows that these cases are closely related to classical splenic marginal zone lymphoma. Whether or not CD5-positive splenic marginal zone B-cell lymphoma constitutes a true subset obviously requires the study of more cases.

Molecular profiling provides evidence of primary mediastinal large B-cell lymphoma as a distinct entity related to classic Hodgkin lymphoma: implications for mediastinal gray zone lymphomas as an intermediate form of B-cell lymphoma.

Expanding on prior studies that have used molecular profiling to elucidate the heterogeneity of diffuse large B-cell lymphomas (DLBCLs), two recent studies (Rosenwald et al and Savage et al) have characterized a third molecularly distinct subtype of DLBCL, primary mediastinal (thymic) large B-cell lymphoma (PMLBCL). Both groups found distinct gene expression patterns that were able to reliably diagnose PMLBCL and distinguish it from other DLBCLs. Notably, the signature gene expression profile of PMLBCL was more closely related to classic Hodgkin lymphoma (CHL) than other DLBCL subtypes. These studies provide further evidence that PMLBCL and nodular sclerosis CHL may represent related tumors on either ends of a continuum, whose interface includes an intermediate form of disease, mediastinal gray zone (MGZL) lymphoma. MGZLs are tumors that have a transitional morphology and phenotype, combining features of both PMLBCL and nodular sclerosis CHL, and provide a diagnostic challenge to pathologists. These studies provide insights into the biology of PMLBCL and CHL and demonstrate the utility of genomic technologies in defining and diagnosing hematopoietic tumors. The ability to map specific pathologic signal transduction pathways regulating hematopoietic differentiation, proliferation, and apoptosis through genomic or proteomic technologies promises to provide the basis for the development of individualized molecularly targeted therapies for specific tumors.

Breast implant-associated anaplastic large cell lymphoma: two distinct clinicopathological variants with different outcomes

BACKGROUND ALK-negative anaplastic large cell lymphoma associated with breast implant (i-ALCL) has been recently recognized as a distinct entity. Among 43 830 lymphomas registered in the French Lymphopath network since 2010, 300 breast lymphomas comprising 25 peripheral T-cell lymphomas (PTCL) were reviewed. Among PTCL, ALK-negative ALCL was the most frequent and all of them were associated with breast implants. PATIENTS AND METHODS Since 2010, all i-ALCL cases were collected from different institutions through Lymphopath. Immuno-morphologic features, molecular data and clinical outcome of 19 i-ALCLs have been retrospectively analyzed. RESULTS The median age of the patients was 61 years and the median length between breast implant and i-ALCL was 9 years. Most implants were silicone-filled and textured. Implant removal was performed in 17 out of 19 patients with additional treatment based on mostly CHOP or CHOP-like chemotherapy regimens (n = 10/19) or irradiation (n = 1/19). CHOP alone or ABVD following radiation without implant removal have been given in two patients. The two clinical presentations, i.e. effusion and less frequently tumor mass correlated with distinct histopathologic features: in situ i-ALCL (anaplastic cell proliferation confined to the fibrous capsule) and infiltrative i-ALCL (pleomorphic cells massively infiltrating adjacent tissue with eosinophils and sometimes Reed-Sternberg-like cells mimicking Hodgkin lymphoma). Malignant cells were CD30-positive, showed a variable staining for EMA and were ALK negative. Most cases had a cytotoxic T-cell immunophenotype with variable T-cell antigen loss and pSTAT3 nuclear expression. T-cell receptor genes were clonally rearranged in 13 out of 13 tested cases. After 18 months of median follow-up, the 2-year overall survival for in situ and infiltrative i-ALCL was 100% and 52.5%, respectively. CONCLUSIONS In situ i-ALCLs have an indolent clinical course and generally remain free of disease after implant removal. However, infiltrative i-ALCLs could have a more aggressive clinical course that might require additional therapy to implant removal.

Double-hit and double-protein-expression lymphomas: aggressive and refractory lymphomas

Double-hit lymphoma (DHL) is a subgroup of aggressive lymphomas with both MYC and BCL2 gene rearrangements, characterised by a rapidly progressing clinical course that is refractory to aggressive treatment and short survival. Over time, the definition was modified and now includes diffuse large B-cell lymphoma (DLBCL) with MYC translocation combined with an additional translocation involving BCL2 or BCL6. Some cases that have a similar clinical course with concomitant overexpression of MYC or BCL2 proteins were recently characterised as immunohistochemical double-hit lymphomas (ie, double-protein-expression lymphomas [DPLs]). The clinical course of these DPLs is worse than so-called standard DLBCL but suggested by some studies to be slightly better than DHL, although there is overlap between the two categories. Present treatment does not allow cure or long-term survival in patients with genetic or immunohistochemical double-hit lymphomas, but several new drugs are being developed.

Clinicopathologic characteristics and outcome of diffuse large B-cell lymphomas presenting with an associated low-grade component at diagnosis.

PURPOSE Some diffuse large B-cell lymphomas (DLBCL) present at diagnosis with associated morphologic features of small B-cell non-Hodgkins lymphoma (NHL) and may arise from the transformation of a previously unknown indolent low-grade lymphoma. The characteristics and prognosis of these particular DLBCL are not well known. PATIENTS AND METHODS The strict morphologic review of consecutive DLBCL patients diagnosed over 12 years in our department (Hematology Department, Centre Hospitalier Lyon-Sud, Lyon, France) allowed to retrieve 60 DLBCL that could be have occurred from the transformation of marginal zone B-cell NHL (32 patients), follicular NHL (22 patients), and small lymphocytic NHL (6 patients). We compared them to 180 matched patients of de novo DLBCL. RESULTS Patients median age was 55 years and presented the following clinical characteristics: poor performance status in 33%, disseminated disease in 97%, more than one extranodal site in 50%, and increased lactate dehydrogenase level in 55%. Complete remission with multidrug chemotherapy regimens was achieved in 60% of the patients, but 48% relapsed: 28% with aggressive and 20% with indolent histology, respectively. Overall survival (OS) and freedom-from-progression rates at 5 years were 57% and 33%, respectively. The matched-control analysis showed that patients with transformed NHL at diagnosis had lower complete response to chemotherapy (P = .004) and higher progression rate (P = .03), whereas no difference was observed in OS (P = .21). CONCLUSION Compared to de novo DLBCL, transformed NHL at diagnosis have similar overall survival but lower complete response to initial treatment and higher risk of indolent relapses.

Long-term follow-up analysis of 100 patients with splenic marginal zone lymphoma treated with splenectomy as first-line treatment

Abstract Splenectomy is considered as one of the first-line treatments for symptomatic patients with splenic marginal zone lymphoma (SMZL). Between 1997 and 2012, 100 hepatitis C virus-negative patients with SMZL were treated by splenectomy as first-line treatment. At 6 months, all patients but three recovered from all cytopenias. The median lymphocyte count at 6 months and 1 year was 11.51 × 109/L and 6.9 × 109/L, respectively. Median progression-free survival (PFS) was 8.25 years. The 5-year and 10-year overall survival (OS) rates were 84% and 67%, respectively. Histological transformation occurred in 11% of patients, and was the only parameter significantly associated with a shorter time to progression (p = 0.0001). Significant prognostic factors for OS were age (p = 0.0356) and histological transformation (p = 0.0312). In this large retrospective cohort, we confirmed that splenectomy as first-line treatment in patients with SMZL corrected cytopenias and lymphocytosis within the first year and was associated with a good PFS.

Aberrant T-cell antigen expression in classical Hodgkin lymphoma is associated with decreased event-free survival and overall survival

Hodgkin/Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) rarely express T-cell-associated antigens (TCA), but the clinical significance of this finding is uncertain. Fifty cHLs expressing any TCA on the HRS cells (TCA-cHL) were identified in two cohorts (National Cancer Institute, n = 38; Basel, n = 12). Diagnostic pathology data were examined in all cases with additional T-cell receptor γ rearrangements (TRG@) polymerase chain reaction (PCR) in a subset of cases. The outcome data were compared with a cohort of cHLs negative for TCA (n = 272). Primary end points examined were event-free survival (EFS) and overall survival (OS). The median age in the TCA-cHL group was 40 years (range, 10-85 years). Seventy percent presented in low stage (stage I/II) at presentation with nodular sclerosis (NS) histology predominating in 80% of cases. Among the TCA, CD4 and CD2 were most commonly expressed, seen in 80.4% and 77.4% of cases, respectively. TRG@ PCR was negative for clonal rearrangements in 29 of 31 cases. During a median follow up of 113 months, TCA expression predicted shorter OS (adjusted hazard ratio [HRadj] = 3.32 [95% confidence interval (CI): 1.61, 6.84]; P = .001) and EFS (HRadj = 2.55 [95% CI: 1.45, 4.49]; P = .001). TCA-cHL often display NS histology, lack T-cell genotype, and are independently associated with significantly shorter OS and EFS compared with TCA-negative cHLs.

Hairy cell leukaemia‐variant and splenic red pulp lymphoma: a single entity?

Supported in part by: Ministero della Salute (Ricerca Finalizzata I.R.C.C.S., ‘Alleanza Contro il Cancro’ and Rete Nazionale Bio-Informatica Oncologica/RN-BIO), Rome; Ricerca Scientifica Applicata, Regione Friuli Venezia Giulia, Trieste (‘Linfonet’ Project); Associazione Italiana contro le Leucemie, linfomi e mielomi (A.I.L.), Venezia Section, Pramaggiore Group; Novara-A.I.L. Onlus, Novara; Associazione Italiana per la Ricerca sul Cancro (A.I.R.C.; Investigator Grant IG-8701), Milan, Italy.