Intravascular Large B-Cell Lymphoma Genomic Profile Is Characterized by Alterations in Genes Regulating NF-κB and Immune Checkpoints

Abstract

Intravascular large B-cell lymphoma (IVLBCL) is an uncommon lymphoma with an aggressive clinical course characterized by selective growth of tumor cells within the vessels. Its pathogenesis is still uncertain and there is little information on the underlying genomic alterations. In this study, we performed a clinicopathologic and next-generation sequencing analysis of 15 cases of IVLBCL using a custom panel for the detection of alterations in 68 recurrently mutated genes in B-cell lymphomagenesis. Six patients had evidence of hemophagocytic syndrome. Four patients presented concomitantly a solid malignancy. Tumor cells outside the vessels were observed in 7 cases, 2 with an overt diffuse large B-cell cell lymphoma. In 4 samples, tumor cells infiltrated lymphatic vessel in addition to blood capillaries. Programmed death-ligand 1 (PD-L1) was positive in tumor cells in 4 of 11 evaluable samples and in macrophages intermingled with tumor cells in 8. PD-L1 copy number gains were identified in a higher proportion of cases expressing PD-L1 than in negative tumors. The most frequently mutated gene was PIM1 (9/15, 60%), followed by MYD88 L265P and CD79B (8/15, 53% each). In 6 cases, MYD88 L265P and CD79B mutations were detected concomitantly. We also identified recurrent mutations in IRF4, TMEM30A, BTG2, and ETV6 loci (4/15, 27% each) and novel driver mutations in NOTCH2, CCND3, and GNA13, and an IRF4 translocation in 1 case each. The mutational profile was similar in patients with and without evidence of hemophagocytic syndrome and in cases with or without dissemination of tumor cells outside the vessels. Our results confirm the relevance of mutations in B-cell receptor/nuclear factor-κB signaling and immune escape pathways in IVLBCL and identify novel driver alterations. The similar mutational profile in tumors with extravascular dissemination suggests that these cases may also be considered in the spectrum of IVLBCL.

The Genetic Profile of Large B-Cell Lymphomas Presenting in the Ocular Adnexa

“…40%) [ 1 ]. However, the frequency of MYD88 variants in our cohort of primary OA-DLBCL-NOS does not match that of LBCL of immune-privileged sites (60–78%) [ 24 , 25 , 26 , 27 ], or extranodal LBCLs with high non-GCB frequencies, including primary breast DLBCL-NOS (39–56%) [ 28 , 29 ], primary cutaneous DLBCL, leg type (75–79%) [ 30 , 31 ], intravascular LBCL (44–57%) [ 32 , 33 , 34 ], or primary sinonasal DLBCL-NOS (approx. 50%) [ 35 ].…”

“…50%) [ 35 ]. Nevertheless, in primary OA-DLBCL-NOS, we now identify frequent pathogenic variants in several of the genes that either link primary OA-DLBCL-NOS to the MCD subtype and NF-κB activation [ 7 , 8 ], or which are mutated in several of the abovementioned extranodal lymphomas [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 34 , 35 ], including CD79B (n = 3, 21%), the proto-oncogene PIM1 (n = 3, 21%), putative tumor suppressor TBL1XR1 (n = 3, 21%), and putative tumor suppressor SETD1B (n = 3, 21%). Several large genetic studies including both nodal and extranodal DLBCL-NOS have reported comparable mutational frequencies in PIM1 (11–28%), and slightly lower frequencies in CD79B (5–15%), TBL1XR1 (3–13%), and SETD1B (8–10%) [ 6 , 8 , 9 , 10 , 36 ].…”

Large B-Cell Lymphomas in the 5th Edition of the WHO-Classification of Haematolymphoid Neoplasms—Updated Classification and New Concepts

“…Pathogenetically, the lack of expression of adhesion molecules, including integrins and chemokine receptors, prevents vascular adhesion and transvascular migration of the tumor cells [ 191 , 192 , 193 , 194 , 195 ]. Mutations in MYD88 , CD79B , SETD1B , and HLA-B have been reported [ 196 , 197 , 198 , 199 ], and structural alterations in CD274 ( PD-L1 ) and PDCD1LG2 ( PD-L2 ) genes are recurrent [ 198 ]. Therefore, IVLBCL, biologically, has some similarities with IP-LBCL.…”

Cutaneous Intravascular Hematolymphoid Entities: A Review

“…The United States Surveillance, Epidemiology, and End Results (SEER) 2000-2013 data study reported an age-adjusted incidence rate of 0.095 cases per million [3,4]. The median age at diagnosis is between 60 and 70 years old [1][2][3]6,9], with no sex predilection [1][2][3][4]6,9,10]. In the past, most patients were diagnosed with IVLBCL at autopsy [2,9]; however, recent data suggest approximately 80% of diagnoses are now made while patients are alive [6,11,12].…”

“…The median age at diagnosis is between 60 and 70 years old [1][2][3]6,9], with no sex predilection [1][2][3][4]6,9,10]. In the past, most patients were diagnosed with IVLBCL at autopsy [2,9]; however, recent data suggest approximately 80% of diagnoses are now made while patients are alive [6,11,12].…”