Expression of signal transducer and activator of transcription 3 (STAT3) in primary central nervous system diffuse large B-cell lymphoma: a retrospective analysis of 17 cases

Abstract

Most primary central nervous system lymphomas (PCNSL) occurring in immunocompetent patients are diffuse large B-cell lymphomas (DLBCL), characterized by poor prognosis. An activated B-cell (ABC) origin of PCNSL has been postulated based on bcl-6 and MUM-1 expression by majority of these tumors. ABC DLBCL has been functionally subdivided using gene expression profiling and immunohistochemical analysis into STAT3-high and STAT-3 low subsets. A potentially crucial difference between STAT3-high and STAT3-low ABC DLBCL is in the expression of bcl-2 family members. STAT3-high cases are generally bcl-2 low and STAT3-low cases show higher expression of bcl-2. Further mechanisms such as activation of nuclear factor-kappa B (NF-κB) activation seem to be responsible for upregulation of bcl-2 in ABC subtype of DLBCL with an adverse outcome. As deregulation of STAT-3 pathway is known to play a critical role in ABC DLBCL and majority of the PCNSL are of the ABC subtype we studied the immunohistochemical expression of STAT-3 proteins in PCNSL along with other traditional markers (CD10, bcl-6, MUM-1 and bcl-2) in 17 cases of PCNSL occurring in immunocompetent patients. Despite lack of STAT3 expression in all our cases, majority (70%) of the patients with bcl-2 positive PCNSL had an adverse outcome similar to that reported in systemic lymphomas of ABC subtype. Based on our observations we propose that PCNSL represents a distinct subset of ABC diffuse large B-cell lymphomas with low STAT3 expression and perhaps mechanisms other than interaction of STAT-3 and NF-κB pathways may play a role in upregulation of bcl-2 in PCNSL. To the best of our knowledge expression of STAT-3 protein in PCNSL which represents a distinct anatomical subset of ABC DLBCL with a dismal prognosis has not been studied before.

Frequent mutated B2M, EZH2, IRF8, and TNFRSF14 in primary bone diffuse large B-cell lymphoma reflect a GCB phenotype

“…Therefore, the revised (2016) WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues 29 recognizes extranodal DLBCL with specific anatomy as separate entities, such as intravascular large B-cell lymphoma, primary cutaneous DLBCL, primary cutaneous DLBCL-leg type, and primary DLBCL of the central nervous system (PCNSL), commonly representing an activated B-cell (ABC) phenotype. [30][31][32][33][34][35][36] Following this paradigm and because of their specific disease presentation and clinical behavior, we hypothesized that PB-DLBCL contains unique molecular characteristics. To address this theory, our study presents the first comprehensive GEP and targeted deep-sequencing analyses in a well-annotated and relatively large cohort of PB-DLBCL.…”

Stat3-positive tumor cells contribute to vessels neoformation in primary central nervous system lymphoma

“…A higher Stat3 activation in tumor cells is associated with lower survival rates of patients with several malignant tumors [ 14 – 17 ]. High levels of phosphorylated Stat3 (pStat3) protein were found in diffuse large B-cell lymphoma [ 18 , 19 ], while data on the expression of Stat3 in PCNSL are controversial [ 20 – 22 ]. Moreover, Stat3 favors proliferation and maintenance of CSCs, and its inhibition blocks tumor formation in glioblastoma [ 23 ].…”

Diffuse Large B-Cell Lymphoma of the Central Nervous System. Immunophenotype, Clinicopathological Features and Differential Diagnosis

“…In a recent study, Wang et al [26] found four cases of DLBCL with aberrant expression to CD 3, in one of the cases, the lymphoma occurred in the CNS in a 52-year-old woman; in the present study, expression of CD 3 was observed in a 47-year-old woman (Case 3) ( Figure 5); the biological significance and the mechanism for the CD 3 expression in DLBCL is not known; hence, we believe that other pan B markers such as CD 79ª, CD 138, PAX 5, and Mum-1 must be determined or molecular biology techniques must be implemented for the correct determination of the cell lineage of these unusual lymphomas. In the present series, three DLBCL in the SNC expressed Mum-1 and all expressed bcl-2 markers of bad prognosis; in a recent publication of 17 cases, expression of bcl2 and STAT-3 (Signal transducer and activator of transduction) was studied, emphasizing the low expression of this marker as a subtype of diffuse large B cell lymphoma originated from activated lymphocytes [27].…”

“…More than 460 expressed sequence tags were differentially expressed between PCNSL [27]. Regarding prognosis, several variables have been identified that affect survival negatively such as: age over 60 years, high serum levels of lactic dehydrogenase, hyperproteinorachia, and affectation of deep cerebral structures like periventricular regions, basal ganglia, brain stem, and cerebellum [28].…”