title: Characterization of a variant of t(14;18) negative nodal diffuse follicular lymphoma with CD23 expression, 1p36/TNFRSF14 abnormalities, and STAT6 mutations.
abstract: A predominantly diffuse growth pattern and CD23 co-expression are uncommon findings in nodal follicular lymphoma and can create diagnostic challenges. A single case series in 2009 (Katzenberger et al) proposed a unique morphologic variant of nodal follicular lymphoma, characterized by a predominantly diffuse architecture, lack of the t(14;18) IGH/BCL2 translocation, presence of 1p36 deletion, frequent inguinal lymph node involvement, CD23 co-expression, and low clinical stage. Other studies on CD23+ follicular lymphoma, while associating inguinal location, have not specifically described this architecture. In addition, no follow-up studies have correlated the histopathologic and cytogenetic/molecular features of these cases, and they remain a diagnostic problem. We identified 11 cases of diffuse, CD23+ follicular lymphoma with histopathologic features similar to those described by Katzenberger et al. Along with pertinent clinical information, we detail their histopathology, IGH/BCL2 translocation status, lymphoma-associated chromosomal gains/losses, and assessment of mutations in 220 lymphoma-associated genes by massively parallel sequencing. All cases showed a diffuse growth pattern around well- to ill-defined residual germinal centers, uniform CD23 expression, mixed centrocytic/centroblastic cytology, and expression of at least one germinal center marker. Ten of 11 involved inguinal lymph nodes, 5 solely. By fluorescence in situ hybridization analysis, the vast majority lacked IGH/BCL2 translocation (9/11). Deletion of 1p36 was observed in five cases and included TNFRSF14. Of the six cases lacking 1p36 deletion, TNFRSF14 mutations were identified in three, highlighting the strong association of 1p36/TNFRSF14 abnormalities with this follicular lymphoma variant. In addition, 9 of the 11 cases tested (82%) had STAT6 mutations and nuclear P-STAT6 expression was detectable in the mutated cases by immunohistochemistry. The proportion of STAT6 mutations is higher than recently reported in conventional follicular lymphoma (11%). These findings lend support for a clinicopathologic variant of t(14;18) negative nodal follicular lymphoma and suggests importance of the interleukin (IL)-4/JAK/STAT6 pathway in this variant.
authors.affiliation: Department of Pathology, Hematopathology Section, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
authors.forename: Imran N
authors.initials: IN
authors.lastname: Siddiqi
authors.affiliation: Cancer Genetics, Inc., Rutherford, NJ, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Friedman
authors.affiliation: Department of Pathology, Hematopathology Section, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
authors.forename: Keegan Q
authors.initials: KQ
authors.lastname: Barry-Holson
authors.affiliation: Cancer Genetics, Inc., Rutherford, NJ, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Ma
authors.affiliation: Cancer Genetics, Inc., Rutherford, NJ, USA.
authors.forename: Venkata
authors.initials: V
authors.lastname: Thodima
authors.affiliation: Department of Medicine, Division of Hematology, University of Southern California, Los Angeles, CA, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Kang
authors.affiliation: Cancer Genetics, Inc., Rutherford, NJ, USA.
authors.forename: Raghavendra
authors.initials: R
authors.lastname: Padmanabhan
authors.affiliation: Cancer Genetics, Inc., Rutherford, NJ, USA.
authors.forename: Lizalynn M
authors.initials: LM
authors.lastname: Dias
authors.affiliation: Department of Medicine, Division of Hematology, University of Southern California, Los Angeles, CA, USA.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Kelly
authors.affiliation: Department of Pathology, Hematopathology Section, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
authors.forename: Russell K
authors.initials: RK
authors.lastname: Brynes
authors.affiliation: Cancer Genetics, Inc., Rutherford, NJ, USA.
authors.forename: Sitharthan
authors.initials: S
authors.lastname: Kamalakaran
authors.affiliation: Cancer Genetics, Inc., Rutherford, NJ, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Houldsworth
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics / Q000276:immunology; D002883:Chromosomes, Human, Pair 14; D002887:Chromosomes, Human, Pair 18; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D050438:Genes, Immunoglobulin Heavy Chain; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008224:Lymphoma, Follicular / Q000737:chemistry / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D017455:Receptors, IgE / Q000032:analysis*; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000235:genetics*; D050800:STAT6 Transcription Factor / Q000032:analysis / Q000235:genetics*; D014178:Translocation, Genetic
chemical_list: C000595707:BCL2 protein, human; D014408:Biomarkers, Tumor; D019253:Proto-Oncogene Proteins c-bcl-2; D017455:Receptors, IgE; D053240:Receptors, Tumor Necrosis Factor, Member 14; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C506028:TNFRSF14 protein, human