Myeloid/Lymphoid Neoplasms Associated With Eosinophilia and Rearrangements of PDGFRA, PDGFRB, or FGFR1 or With PCM1-JAK2

Abstract

Objectives To summarize cases submitted to the 2019 Society for Hematopathology/European Association for Haematopathology Workshop under the category of myeloid/lymphoid neoplasms with eosinophilia and PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2 rearrangements, focusing on recent updates and relevant practice findings. Methods The cases were summarized according to their respective gene rearrangement to illustrate the spectrum of clinical, laboratory, and histopathology manifestations and to explore the appropriate molecular genetic tests. Results Disease presentations were heterogeneous, including myeloproliferative neoplasms (MPNs), myelodysplastic syndromes (MDSs), MDS/MPN, acute myeloid leukemia, acute B- or T-lymphoblastic lymphoma/acute lymphoblastic lymphoma (ALL/LBL), or mixed-lineage neoplasms. Frequent extramedullary involvement occurred. Eosinophilia was common but not invariably present. With the advancement of RNA sequencing, cryptic rearrangements were recognized in genes other than PDGFRA. Additional somatic mutations were more frequent in the FGFR1-rearranged cases. Cases with B-ALL presentations differed from Philadelphia-like B-ALL by the presence of an underlying MPN. Cases with FLT3 and ABL1 rearrangements could be potential candidates for future inclusion in this category. Conclusions Accurate diagnosis and classification of this category of myeloid/lymphoid neoplasms has important therapeutic implications. With the large number of submitted cases, we expand our understanding of these rare neoplasms and improve our ability to diagnose these genetically defined disorders.

T-Cell Lymphoblastic Lymphoma Arising in the Setting of Myeloid/Lymphoid Neoplasms with Eosinophilia: LMO2 Immunohistochemistry as a Potentially Useful Diagnostic Marker

“…According to the current 2017 World Health Organization (WHO) classification, these disorders represent a distinct, but highly heterogeneous category, comprising cases with rearrangement of platelet-derived growth factor receptor (PDGFR)-alpha (PDGFRA), PDGFR-beta (PDGFRB) and fibroblast growth factor receptor 1 (FGFR1); a provisional entity identified by the presence of pericentriolar material 1-janus kinase 2 (PCM1-JAK2) rearrangement is also included [ 1 , 2 , 3 , 4 ]. A pluripotent stem cell is thought to be affected and disease presentation is very heterogeneous, including myeloproliferative neoplasms (MPN), myelodysplastic/myeloproliferative neoplasms (MDS/MPN), acute myeloid leukemia (AML), T- or B-LBL and mixed-phenotype acute leukemia [ 1 , 2 , 3 , 4 ]. The diagnosis of these entities requires the identification of the specific gene fusion, with cytogenetic and molecular tests, leading to overexpression of an aberrant tyrosine kinase or cytokine receptor [ 1 , 2 , 3 , 4 ].…”

“…A pluripotent stem cell is thought to be affected and disease presentation is very heterogeneous, including myeloproliferative neoplasms (MPN), myelodysplastic/myeloproliferative neoplasms (MDS/MPN), acute myeloid leukemia (AML), T- or B-LBL and mixed-phenotype acute leukemia [ 1 , 2 , 3 , 4 ]. The diagnosis of these entities requires the identification of the specific gene fusion, with cytogenetic and molecular tests, leading to overexpression of an aberrant tyrosine kinase or cytokine receptor [ 1 , 2 , 3 , 4 ]. PDGFRA and PDGFRB rearrangements may be cryptic, but fluorescence in situ hybridization (FISH) and/or RNA/DNA sequencing, either targeting or high-throughput next generation sequencing (NGS)-based are useful tools for diagnosis [ 1 , 2 , 3 , 4 ].…”

“…The diagnosis of these entities requires the identification of the specific gene fusion, with cytogenetic and molecular tests, leading to overexpression of an aberrant tyrosine kinase or cytokine receptor [ 1 , 2 , 3 , 4 ]. PDGFRA and PDGFRB rearrangements may be cryptic, but fluorescence in situ hybridization (FISH) and/or RNA/DNA sequencing, either targeting or high-throughput next generation sequencing (NGS)-based are useful tools for diagnosis [ 1 , 2 , 3 , 4 ]. The identification of the underlying molecular abnormality is crucial, having important therapeutic implications, given the responsiveness of some of these disorders to tyrosine-kinase inhibitors (TKIs) [ 1 , 2 , 3 , 4 , 5 ].…”

“…PDGFRA and PDGFRB rearrangements may be cryptic, but fluorescence in situ hybridization (FISH) and/or RNA/DNA sequencing, either targeting or high-throughput next generation sequencing (NGS)-based are useful tools for diagnosis [ 1 , 2 , 3 , 4 ]. The identification of the underlying molecular abnormality is crucial, having important therapeutic implications, given the responsiveness of some of these disorders to tyrosine-kinase inhibitors (TKIs) [ 1 , 2 , 3 , 4 , 5 ]. The response to TKIs is different according to the fusion gene identified, as PDGFRA- and PDGFRB-rearranged cases are responsive, in the majority of cases, to imatinib, which represents the first line therapy, whereas FGFR1-rearranged cases do not respond to imatinib [ 3 , 5 ].…”

“…The identification of the underlying molecular abnormality is crucial, having important therapeutic implications, given the responsiveness of some of these disorders to tyrosine-kinase inhibitors (TKIs) [ 1 , 2 , 3 , 4 , 5 ]. The response to TKIs is different according to the fusion gene identified, as PDGFRA- and PDGFRB-rearranged cases are responsive, in the majority of cases, to imatinib, which represents the first line therapy, whereas FGFR1-rearranged cases do not respond to imatinib [ 3 , 5 ]. Although lymphoma-like aggressive chemotherapy and hematopoietic stem cell transplantation (HSCT) are considered the best therapeutic option for FGFR1-positive cases, prognosis is very poor in these cases.…”