Pediatric-type follicular lymphoma (PTFL) is a variant of FL with distinctive clinico-pathological features, previously characterized in our group. The molecular pathogenesis of this disease has been unknown, although prior studies had indicated it differed from classical follicular lymphoma as seen in adults. Patients are predominantly young males presenting with localized lymphadenopathy; the tumor shows high grade cytology and lacks both BCL2 expression and t(14;18) translocation. In this study we examined 42 PTFL (40 males and 2 females; mean age: 16 years, (range 5-31) for genetic aberrations using a variety of techniques. Copy number analysis was performed with the Oncoscan protocol for formalin fixed paraffin embedded (FFPE) tissues. Next generation sequencing (NGS) analysis was done on the Ion Torrent platform. An Ion AmpliSeq Custom Panel covering twelve genes that have been shown to be frequently mutated in FL was used. The panel covered 98.24% of all exons of TNFRSF14, KMT2D (MLL2), FOXO1, EP300, MEF2B, HIST1H1B-E and GNA13 as well as hot spot regions of EZH2 (exon 16) and CREBBP (exons 24-38 and 30) For comparison 11 cases of conventional t(14:18)-negative FL in adults were investigated. Gains and losses and copy number neutral loss of heterozygosity (CNN-LOH) regions were evaluated and visually inspected using Nexus Biodiscovery version 7.5 software. Morphologically, PTFL cases had follicular growth pattern without diffuse areas and characteristic immunophenotype. All cases showed monoclonal IG rearrangement. PTFL displays low genomic complexity when compared with t(14;18)-negative FL (mean 0.77 vs 9 CNA/case, P0.001). Both groups presented 1p36 alterations including TNFRSF14 but copy number neutral loss of heterozygosity (CNN-LOH) of this locus was more frequently observed in PTFL (40% vs 9% P=0.075). TNFRSF14 was the most frequently affected gene in PTFL (21 mutations and 2 deletions), identified in 54% of cases followed by KMT2D mutations in 16%. Other histone-modifying genes were rarely affected. In contrast, t(14;18)-negative FL displayed a mutational profile similar to t(14;18)-positive FL. In eight PTFL cases (19%), no genetic alterations were identified, beyond IG monoclonal rearrangement. The genetic landscape of PTFL suggests that TNFRSF14 mutations accompanied by CNN-LOH of the 1p36 locus in over 70% of mutated cases, as additional selection mechanism, might play a key role in the pathogenesis of this disease. The genetic profiles of PTFL and t(14;18)-negative FL in adults indicate that these are two different disorders. In a separate study our group analyzed patterns of histological progression in chronic lymphocytic leukemia (CLL). Hodgkin/Reed-Sternberg (HRS) cells in the setting of chronic lymphocytic leukemia (CLL) exist in two forms: type I with isolated HRS cells in a CLL background (Hodgkin-like lesion), and type II with typical classic Hodgkin lymphoma (CHL), a variant of Richter transformation (CHL-RT). The clinical significance of the two morphological patterns is unclear, and their biological features have not been compared. Moreover, the clinical significance of the Type I lesion and whether it should be aggressively treated has been questioned. We retrospectively reviewed 77 cases: 26 of type I and 51 of type II CHL-RT; 3 cases progressed from type I to type II. We examined clinical features, EBV status, and clonal relatedness after microdissection. Median age for type I was 62 years vs. 73 years for type II (P=.01). 27% (type I) vs. 73% (type II) had a history of CLL. HRS cells were positive for EBV in 71% (55/77), similar in type I and II. Clonality analysis was performed in 33 cases (type I and type II combined): HRS cells were clonally related to the underlying CLL in 14 and unrelated in 19. ZAP-70 expression of the CLL cells, but not EBV status or morphological pattern was correlated with clonal relatedness: all 14 clonally related cases were ZAP-70-negative while 74% (14/19) of clonally unrelated cases were ZAP-70-positive. Overall median survival (types I and II) after diagnosis was 44 months. Advanced age was an adverse risk factor for survival, but not histological pattern, type I vs type II. HRS-like cells in a background of CLL carries a similar clinical risk to that of CHL-RT, and may progress in CHL in some cases. Our study provides evidence for the aggressive treatment of both forms of histological progression. Our group described marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT type) arising in the dura of the meninges in 1997. It was unknown how this tumor relates to MALT lymphomas in other extranodal sites. We performed genome-wide DNA copy number and targeted mutational analysis of 14 dural MZL to determine the genetic landscape of this entity. Monoallelic and biallelic inactivation of TNFAIP3 by mutation (n=5) or loss (n=1) was observed in 6/9 (67%) dural MZL exhibiting plasmacytic differentiation, including 3 IgG4+ cases. In contrast, activating NOTCH2 mutations were detected in 4/5 (80%) dural MZL displaying variable monocytoid morphology. Inactivating TBL1XR1 mutations were identified in all NOTCH2 mutated cases. Recurrent mutations in KLHL6 (n=2) and MLL2 (n=2) were also detected. Gains at 6p25.3 (n=2) and losses at 1p36.32 (n=3) were common chromosomal imbalances, with loss of heterozygosity (LOH) of these loci observed in a subset of cases. Translocations involving the IGH or MALT1 genes were not identified. Our results indicate genetic similarities between dural MZL and other MZL subtypes. However, recurrent and mutually exclusive genetic alterations of TNFAIP3 and NOTCH2 appear to be associated with distinct disease phenotypes in dural MZL. Primary central nervous system (CNS) lymphomas are relatively rare with the most common subtype being diffuse large B-cell lymphoma. Primary CNS T-cell lymphomas (PCNSTL) account for fewer than 5% of CNS lymphomas. We reported the clinical, morphologic, immunophenotypic, and molecular characteristics of 18 PCNSTLs. Median age was 58.5 years (range, 21 to 81 y), with an M:F ratio of 11:7. Imaging results showed that 15 patients had supratentorial lesions. Most cases studied had a cytotoxic phenotype with expression of TIA1 (13/15) and granzyme-B (9/13). Polymerase chain reaction analysis of T-cell receptor gamma rearrangement confirmed a T-cell clone in 14 cases with adequate DNA quality. Next-generation sequencing showed somatic mutations in 36% of cases studied; 2 had more than 1 mutation, and none showed overlapping mutations. These included mutations in DNMT3A, KRAS, JAK3, STAT3, STAT5B, GNB1, and TET2 genes, genes implicated previously in other T-cell neoplasms. The outcome was heterogenous; 2 patients are alive without disease, 4 are alive with disease, and 6 died of disease. In conclusion primary central nervous system lymphomas of T-cell origin are histologically and genomically heterogenous with frequent phenotypic aberrancy and a cytotoxic phenotype in most cases. This study should help in the accurate diagnosis of this rare tumor type.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIASC000550-36
Application #
9344090
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
36
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Clinical Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Perry, Anamarija M; Bailey, Nathanael G; Bonnett, Michelle et al. (2018) Disease Progression in a Patient With Indolent T-Cell Lymphoproliferative Disease of the Gastrointestinal Tract. Int J Surg Pathol :1066896918785985
Clot, Guillem; Jares, Pedro; Giné, Eva et al. (2018) A gene signature that distinguishes conventional and leukemic nonnodal mantle cell lymphoma helps predict outcome. Blood 132:413-422
Marshall, Vickie A; Labo, Nazzarena; Hao, Xing-Pei et al. (2018) Gammaherpesvirus infection and malignant disease in rhesus macaques experimentally infected with SIV or SHIV. PLoS Pathog 14:e1007130
Roswarski, Joseph; Roschewski, Mark; Lucas, Andrea et al. (2018) Phase I dose escalation study of the anti-CD2 monoclonal antibody, siplizumab, with DA-EPOCH-R in aggressive peripheral T-cell lymphomas. Leuk Lymphoma 59:1466-1469
Bouska, A; Zhang, W; Gong, Q et al. (2017) Combined copy number and mutation analysis identifies oncogenic pathways associated with transformation of follicular lymphoma. Leukemia 31:83-91
Reddy, Anupama; Zhang, Jenny; Davis, Nicholas S et al. (2017) Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma. Cell 171:481-494.e15
Jaffe, Elaine S (2017) The Microscope as a Tool for Disease Discovery-A Personal Voyage. Annu Rev Pathol 12:1-24
Scott, David W; Abrisqueta, Pau; Wright, George W et al. (2017) New Molecular Assay for the Proliferation Signature in Mantle Cell Lymphoma Applicable to Formalin-Fixed Paraffin-Embedded Biopsies. J Clin Oncol 35:1668-1677
Schmidt, Janine; Ramis-Zaldivar, Joan Enric; Nadeu, Ferran et al. (2017) Mutations of MAP2K1 are frequent in pediatric-type follicular lymphoma and result in ERK pathway activation. Blood 130:323-327
Brett, Francesca M; Flavin, Richard; Chen, Daphne et al. (2017) EBV driven natural killer cell disease of the central nervous system presenting as subacute cognitive decline. Hum Pathol (N Y) 10:64-68

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