Pediatric-Type Nodal Follicular Lymphoma in Children and Adults Is Nearly Genetically Silent and Biologically Distinct from Typical Follicular Lymphoma

Pediatric-type nodal follicular lymphoma (PTNFL) is a variant of follicular lymphoma (FL) characterized by localized presentation and excellent behavior despite its often high-grade histologic appearance. We recently identified high proliferation index and the absence of BCL2 , BCL6 , and IRF4 gene rearrangements as defining features of PTNFL in both children and adults (Louissaint, Blood 2012). In contrast to typical FL, children with PTNFL consistently have persistent remissions after surgical excision alone. Therefore, it is critically important to identify PTNFL in order to avoid unnecessary therapy. Considering the unique clinical behavior of PTNFL, we hypothesized that the mutational landscape of this disease would differ from that of typical FL. Twenty-four cases were collected from several institutions (MGH, Brigham & Women9s, Weill Cornell, Chicago Children9s, Boston Children9s, University of Pittsburgh, SUNY Downstate, and Stanford). PTNFL was defined by the following criteria: 1) nodal involvement, 2) architectural effacement by a clonal follicular proliferation, 3) high proliferation index and 4) absence of both MUM1/IRF4 expression and BCL2/BCL6 rearrangements by FISH. All cases presented with localized nodal involvement and demonstrated no evidence of recurrence or progression after chemotherapy (n=5), radiation (n=3) or surgical excision alone (n=13) (therapeutic approach to be confirmed in 3 cases), with a median follow-up of 33.1 months (range 10-124 months). Subjects ranged in age from 4-60 years, including 14 children (4-18 years; median 15) and 10 adults (20-60 years; median 29.5). Whole exome sequencing performed on 7 PTNFL cases showed a strikingly low mutation burden (7.1 non-silent mutations/exome), more than an order of magnitude lower than the exomic mutation burden of typical FLs (Green, PNAS 2015; Pasqualucci, Cell Rep 2015). Given these findings, we pursued targeted exome capture and next-generation sequencing for 112 genes previously reported to be recurrently mutated in FL across a panel of 20 PTNFLs. Targeted sequencing (mean depth, 250) again demonstrated very low mutation burden in PTNFL, with a median number of non-silent mutations of 1.67/case compared with 4 mutations/case (P TNFRSF14 was the most frequently mutated gene in PTNFL, with similar frequencies in PTNFL and limited-stage typical FL (29% vs. 41%; p=0.76). CREBBP mutations, which occur in most cases of advanced-stage FL, were seen in 82% of limited-stage typical FLs and only 4% of PTFLs (p e.g. BCL2 , MLL2 , GNA13 ) were also present in Disclosures South: Lineagen Corporation: Consultancy; ARUP Laboratories: Employment; Affymetrix: Consultancy, Honoraria; Illumina: Consultancy, Honoraria. Hasserjian: Promedior: Consultancy.