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Molecular lesions of signalling pathway genes in clonal B‐cell lymphocytosis with marginal zone features

2014; Wiley; Volume: 167; Issue: 5 Linguagem: Inglês

10.1111/bjh.13052

1365-2141

Alessio Bruscaggin, Sara Monti, Luca Arcaini, Antonio Ramponi, Sara Rattotti, Marco Lucioni, Marco Paulli, Gianluca Gaïdano, Davide Rossi,

CNS Lymphoma Diagnosis and Treatment

Clonal B-cell expansions whose immunophenotype is consistent with marginal zone (MZ) lymphoma, but presenting with isolated lymphocytosis in the absence of splenomegaly or lymph node enlargements, cannot be assigned to any of the entities recognized by the World Health Organization (WHO) classification of haematological malignancies (Swerdlow et al, 2008). After reviewing the clinico-pathological features of such cases, Xochelli et al (2014) proposed that these lymphoproliferations: (i) may represent the early stage of a splenic marginal zone lymphoma (SMZL) or of a splenic B-cell lymphoma/leukaemia unclassifiable (SLLU); and (ii) should be classified as a provisional entity, termed clonal B-cell lymphocytosis with marginal zone features (CBL-MZ) in future classifications of mature B-cell tumours. Along with clinico-pathological features, the WHO classification also utilizes genetic data to define distinct and provisional entities (Swerdlow et al, 2008). If CBL-MZ are to be considered the early stage of SMZL, they should share a common genetic profile with this lymphoma, including recurrent NOTCH2 mutations and, more generally, mutually exclusive lesions affecting signalling pathways involved in normal MZ differentiation (Kiel et al, 2012; Rossi et al, 2012; Parry et al, 2013; Martínez et al, 2014). Otherwise, if CBL-MZ represent the early phase of a SLLU, they might harbour MAP2K1 mutations and lack lesions of MZ differentiation genes (Waterfall et al, 2014). To unravel the genetics of CBL-MZ, mutations of the NOTCH2, NOTCH1, BIRC3, TNFAIP3, TRAF3, IKBKB, MYD88, CD79A, CD79B, CARD11, BRAF and MAP2K1 genes were investigated on peripheral blood (PB) samples (tumour representation >50%) from 16 CBL-MZ identified according to the criteria defined by Xochelli et al (2014), namely: (i) persistent monoclonal B-cell lymphocytosis in the PB; (ii) immnophenotypic features consistent with a MZ lymphoproliferation, including lack of CD5, CD10, and CD103 expression and a Matutes score <2; (iii) bone marrow (BM) infiltration by small lymphocytes with no or limited plasmacytic differentiation; (iv) absence of lymphadenopathy, splenomegaly or extranodal tissue organomegaly by computerized tomography scan. BM biopsies were reviewed by experienced haematopathologists. Patients provided informed consent in accordance with the Declaration of Helsinki. The study was approved by the Ethical Committee (Protocol Code CE 116/12). Median absolute lymphocyte count of CBL-MZ was 11·4 × 109/l (range: 4·5–23·9 × 109/l) and the median tumour B-cell count was 8·1 × 109/l (range: 3·4–19·8 × 109/l) (Table SI). According to current diagnostic criteria, 43% (7/16) could be classified as non-CLL type of monoclonal B-cell lymphocytosis (Marti et al, 2005). A small (<10 g/l) serum monoclonal component of IgM type was detected in 25% of cases (95% confidence interval [CI]: 9–49%; n = 4/16). After a median follow-up of 44 months, 18% (95% CI: 5–43%; n = 3/16) CBL-MZ cases had progressed into overt lymphoma (Table SI). Most cases (40%; 95% CI: 19–64%; n = 6/15) utilized the IGHV4-34 gene and expressed mutated immunoglobulins (80%; 95% CI: 54–93%; n = 12/15) (Table SI). Overall, this clinical picture is consistent with that of the CBL-MZ cases described by Xochelli et al (2014). Mutually exclusive lesions of genes belonging to the physiological programme of MZ differentiation occurred in 37% (95% CI: 18–61%; n = 6/16) of CBL-MZ cases (Fig 1), a prevalence that did not significantly differ from that observed in SMZL (P = 0·154) (Rossi et al, 2012). NOTCH2 mutations occurred in 13% (95% CI: 2–37%; n = 2/16) of cases, MYD88 mutations in 25% (95% CI: 9–49%; n = 4/16), and TNFAIP3 and CD79B mutations in 6% (95% CI: 0–30%; n = 1/16) each (Fig 1). Though the small number of cases prevents statistically supported conclusions, NOTCH2 mutations tended to cluster with cases showing an intrasinusoidal pattern of BM infiltration (28%; 95% CI: 7–64%; 2/7 vs. 0%; 95% CI: 0–34%; 0/9; P = 0·21), while MYD88 mutations tended to be enriched in cases secreting an IgM monoclonal component (50%; 95% CI: 15–85%; 2/4 vs. 16%; 95% CI: 3–46%; 2/12; P = 0·21) (Table SI). CBL-MZ lacked MAP2K1 mutations, which are recurrent in up to 50% SLLU (Waterfall et al, 2014). Overall, these data indicate that CBL-MZ and SMZL share a similar genotype, suggesting the involvement of a common oncogenic pathway in these disorders. This is consistent with the observation by Xochelli et al (2014) of recurrent 7q deletion in CBL-MZ, a cytogenetic abnormality that is also a marker in SMZL (Rinaldi et al, 2011). From a pathogenetic standpoint, the observation, that 43% (3/7) CBL-MZ presenting with small B-cell clones (<5·0 × 109/l) in the PB harbour mutations of MZ differentiation genes, indicates these mutations are early events and further document their role in the oncogenic process of MZ tumours. Predictors of CBL-MZ evolution to an overt lymphoma remain to be clarified, including the clinical impact of mutations on the rate of progression. Though the small sample size of our cohort precludes a robust statistical analysis, two out of four CBL-MZ patients harboring a MYD88 mutation in this series evolved into MZ lymphoma (SMZL and nodal marginal zone lymphoma, respectively) during disease course. This observation, though preliminary, is consistent with the adverse clinical implication of MYD88 mutations documented in another pre-malignant condition, namely IgM secreting MGUS, where subjects harbouring MYD88 mutations show a 5-fold increased risk of progression to overt lymphoma compared to wild type cases (Varettoni et al, 2013). Combined together, the findings reported by Xochelli et al (2014) and our own observations support: (i) the classification of CBL-MZ as a MZ tumour with preferential leukaemic dissemination; and (ii) the inclusion of CBL-MZ as a provisional entity in future classifications of haematological malignancies. This study was supported by Special Program Molecular Clinical Oncology 5 × 1000 No. 10007, My First AIRC Grant No. 13470, Associazione Italiana per la Ricerca sul Cancro Foundation Milan, Italy; Progetto Giovani Ricercatori 2010, Grant No. GR-2010-2317594, Ministero della Salute, Rome, Italy; Compagnia di San Paolo, Grant No. PMN_call_2012_0071, Turin, Italy; Fondazione Cariplo, Grant No. 2012-0689; Futuro in Ricerca 2012 Grant No. RBFR12D1CB, Ministero dell'Istruzione, dell'Università e della Ricerca, Rome, Italy. D.R., and G.G. designed the study, interpreted data and wrote the manuscript; A.B., and S.M. performed and interpreted molecular studies; L.A. and S.R. collected clinical data; A.R., M.L., and M.P. provided well characterized samples, performed pathological revision and contributed to data interpretation. The authors have no conflict of interest to disclose. Table SI. Clinical and molecular features of clonal B-cell lymphocytosis with marginal zone features Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.