Lymphoma Disease Discovery and Definition

Division Of Clinical Sciences - Nci

Investigators

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Abstract

Histiocytic sarcomas may occur de novo -- referred to as primary histiocytic sarcoma -- or in the context of a prior lymphoid malignancy or mediastinal germ cell tumor, designated secondary histiocytic sarcoma. Our initial efforts focused on primary histiocytic sarcoma. To better characterize the genetic landscape of these tumors, we previously performed an integrated genomic analysis of 21 cases utilizing whole exome sequencing, whole transcriptome sequencing and copy number analysis. We previously identified genetic alterations within the RAS-RAF-MAPK pathway in all cases. In recent work we turned our attention to secondary histiocytic sarcoma. We performed whole exome sequencing in 16 cases to evaluate the spectrum of mutations that occur in secondary histiocytic sarcoma, and both similarities and differences with primary histiocytic sarcoma. Six of the cases were associated with follicular lymphoma, with the remainder associated with chronic lymphocytic leukemia, both B-cell and T-cell acute lymphoblastic leukemia, and peripheral T-cell lymphoma, NOS, in 1 case. In prior publications we had demonstrated a clonal relationship between secondary histiocytic sarcoma and the associated lymphoid malignancy through common translocations, e.g. BCL2/IGH or through identical IG or TCR gene rearrangements. In our new work we show that secondary histiocytic sarcoma also shares a similar mutational profile with its associated malignancy. We identified shared mutations in CREBBP or KMT2D in all follicular lymphoma-associated secondary histiocytic sarcoma cases in our cohort, key events in nodal FL. However, we also found evidence of clonal divergence, with abnormalities in the B-cell lymphoma that were absent in the histiocytic tumor. Importantly, primary histiocytic sarcoma and secondary histiocytic sarcoma share mutations in RAS-MAPK pathway genes, which were shown in 14/16 cases. These involved KRAS (8/16), BRAF (2/16), NRAS (2/16), MAP2K1 (1/16) and NF1 (1/16). In this respect primary histiocytic sarcoma and secondary histiocytic sarcoma are similar, and confirms the importance of the RAS pathway in histiocytic and dendritic cell neoplasms, whether primary or secondary. Our study provides further evidence of a common neoplastic precursor in all cases tested and, in the case of follicular lymphoma, gives additional insight into the stage of lymphomagenesis at which clonal divergence and transdifferentiation may occur. In other recent work we showed that t(14;18)-negative follicular lymphoma is genetically a heterogeneous disorder with features that differ from conventional follicular lymphoma, nodal marginal zone lymphoma, and pediatric-type follicular lymphoma. The most distinct genetic alteration is the presence of STAT6 mutations, which usually co-occurred either with TNFRSF14 and/or CREBBP alterations revealing alternative oncogenic pathways. The genetic alterations seem to influence the morphology of t(14;18)-negative follicular lymphoma (follicular vs diffuse). Moreover, CD23 expression in t(14;18)-negative follicular lymphoma seems to be secondary to activating STAT6 mutations. Nevertheless, there is a group of t(14;18)-negative follicular lymphoma with low genomic complexity that warrants further study. Plasmablastic lymphoma is an aggressive B-cell lymphoma with an immunoblastic/large cell morphology and plasmacytic differentiation. The differential diagnosis with Burkitt lymphoma (BL), plasma cell myeloma (PCM) and some variants of diffuse large B-cell lymphoma (DLBCL) may be challenging due to the overlapping morphological, genetic and immunophenotypic features. Furthermore, the profile of chromosomal alterations is not well known. To characterize the genetic and molecular heterogeneity of these tumors, we investigated thirty-four plasmablastic lymphomas using an integrated approach, including fluorescence in situ hybridization, targeted gene sequencing and copy-number arrays. characterized by high genetic complexity including MYC translocations (87%), gains of 1q21.1-q44, trisomy 7, 8q23.2-q24.21, 11p13-p11.2, 11q14.2-q25, 12p and 19p13.3-p13.13, losses of 1p33, 1p31.1-p22.3, 13q and 17p13.3-p11.2, and recurrent mutations of STAT3 (37%), NRAS and TP53 (33%), MYC and EP300 (19%) and CARD11, SOCS1 and TET2 (11%). Pathway enrichment analysis suggested a cooperative action between MYC alterations and MAPK (49%) and JAK-STAT (40%) signaling pathways. Of note, EBV-negative plasmablastic lymphoma cases had higher mutational and copy-number load and more frequent TP53, CARD11 and MYC mutations whereas EBV-positive plasmablastic lymphoma tended to have more mutations affecting the JAK-STAT pathway. In conclusion, these findings further unravel the molecular heterogeneity of plasmablastic lymphoma identifying novel molecular targets. Monomorphic posttransplant lymphoproliferative disorders (PTLD) have been defined as lymphoid or plasmacytic proliferations that fulfil criteria for one of the B-cell or T/NK-cell neoplasms recognized in immunocompetent hosts in the current WHO Classification. Low grade B-cell neoplasms have historically been excluded from this category, although rare reports of marginal zone lymphoma have been described. We reported nine cases of posttransplant EBV-negative marginal zone lymphoma, all arising in solid organ transplant (SOT) recipients (four renal, three liver, one cardiac, and one liver, pancreas, & small bowel). Seven were extranodal marginal zone lymphoma of MALT type, all of which had gastrointestinal (GI) involvement (four colon, one duodenum, one stomach, and one oropharynx/base of tongue). Notably, the preferential involvement of intestine distinguishes posttransplant extranodal marginal zone lymphoma from sporadic cases. Immunoglobulin light chain restriction was seen in all cases, with PCR showing a monoclonal pattern in seven of eight cases with successful amplification of PCR products. A clonally unrelated recurrence was seen in one case. Next generation sequencing identified recurrent mutations previously reported in marginal zone lymphoma in 3/5 cases. Marginal zone lymphoma was diagnosed at least one year after SOT (median time to presentation, 84 months; range, 13 to 108 months). Median age was 44 (range, 9 to 73 years); male: female ratio 5:4. Mean follow-up was 33.4 months, with an indolent clinical course observed. A subset responded to reduction in immunosuppression and anti-CD20 therapy alone. These data support designation of EBV-negative marginal zone lymphoma as an uncommon form of monomorphic PTLD.