Characterization of a variant of t(14;18) negative nodal diffuse follicular lymphoma with CD23 expression, 1p36/TNFRSF14 abnormalities, and STAT6 mutations

Mod Pathol. 2016 Jun;29(6):570-81. doi: 10.1038/modpathol.2016.51. Epub 2016 Mar 11.

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.

MeSH terms

  • Adult
  • Aged, 80 and over
  • Biomarkers, Tumor / analysis
  • Biomarkers, Tumor / genetics*
  • Chromosome Deletion
  • Chromosome Disorders / genetics*
  • Chromosome Disorders / immunology
  • Chromosome Disorders / pathology
  • Chromosomes, Human, Pair 1 / genetics
  • Chromosomes, Human, Pair 1 / immunology
  • Chromosomes, Human, Pair 14*
  • Chromosomes, Human, Pair 18*
  • DNA Mutational Analysis / methods
  • Female
  • Genes, Immunoglobulin Heavy Chain
  • Genetic Predisposition to Disease
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization, Fluorescence
  • Lymphoma, Follicular / chemistry
  • Lymphoma, Follicular / genetics*
  • Lymphoma, Follicular / immunology
  • Lymphoma, Follicular / pathology
  • Male
  • Middle Aged
  • Mutation*
  • Phenotype
  • Phosphorylation
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Receptors, IgE / analysis*
  • Receptors, Tumor Necrosis Factor, Member 14 / genetics*
  • STAT6 Transcription Factor / analysis
  • STAT6 Transcription Factor / genetics*
  • Translocation, Genetic*

Substances

  • BCL2 protein, human
  • Biomarkers, Tumor
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, IgE
  • Receptors, Tumor Necrosis Factor, Member 14
  • STAT6 Transcription Factor
  • STAT6 protein, human
  • TNFRSF14 protein, human

Supplementary concepts

  • Chromosome 1p36 Deletion Syndrome