HAEM5:Myeloid/lymphoid neoplasm with FGFR1 rearrangement: Difference between revisions

Systemic symptoms are common, including fatigue, fever, weight loss and night sweats. Some patients can be asymptomatic. Patients often present with peripheral blood eosinophilia without basophilia <ref name=":2" />.  Cases with lymphoma features present as lymph nodes involvement and mediastinal mass; cases with myeloproliferative features present as splenomegaly and hypermetabolism. Cases can also present as acute myeloid leukaemia or myeloid sarcoma <ref name=":1" /> <ref>{{Cite journal|last=Abruzzo|first=Lynne V.|last2=Jaffe|first2=Elaine S.|last3=Cotelingam|first3=James D.|last4=Whang-Peng|first4=Jacqueline|last5=Duca|first5=Vincent Del|last6=Medeiros|first6=L. Jeffrey|date=1992|title=T-Cell Lymphoblastic Lymphoma With Eosinophilia Associated With Subsequent Myeloid Malignancy:|url=http://journals.lww.com/00000478-199203000-00003|journal=The American Journal of Surgical Pathology|language=en|volume=16|issue=3|pages=236–245|doi=10.1097/00000478-199203000-00003|issn=0147-5185}}</ref> <ref>{{Cite journal|last=Vega|first=Francisco|last2=Medeiros|first2=L. Jeffrey|last3=Bueso-Ramos|first3=Carlos E.|last4=Arboleda|first4=Patricia|last5=Miranda|first5=Roberto N.|date=2015|title=Hematolymphoid Neoplasms Associated With Rearrangements of PDGFRA, PDGFRB, and FGFR1|url=https://academic.oup.com/ajcp/article/144/3/377/1760716|journal=American Journal of Clinical Pathology|language=en|volume=144|issue=3|pages=377–392|doi=10.1309/AJCPMORR5Z2IKCEM|issn=1943-7722}}</ref>. Extranodal sites of disease include tonsil, lung, and breast in small subsets of patients <ref name=":2" />.   

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==Sites of Involvement==

Immunophenotypic analysis is not helpful in chronic phase disease. However, in lymphoblastic leukemia/lymphoma and in acute myeloid transformation, immunophenotypic analysis is important to distinguish the lineage origins, such as B- or T- lineage, or myeloid lineage <ref name=":0" />. Please refer to the above section "Morphologic Features".

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==Chromosomal Rearrangements (Gene Fusions)==

Various translocations with an 8p11 breakpoint are found. Depending on the partners, a variety of fusion genes with part of ''FGFR1'' from 8p11 can be formed, encoding aberrant tyrosine kinases. Note: Some precise mapping has positioned ''FGFR1'' locus to 8p12, instead of 8p11 <ref>{{Cite journal|last=Mozziconacci|first=Marie-Joëlle|last2=Carbuccia|first2=Nadine|last3=Prebet|first3=Thomas|last4=Charbonnier|first4=Aude|last5=Murati|first5=Anne|last6=Vey|first6=Norbert|last7=Chaffanet|first7=Max|last8=Birnbaum|first8=Daniel|date=2008|title=Common features of myeloproliferative disorders with t(8;9)(p12;q33) and CEP110–FGFR1 fusion: Report of a new case and review of the literature|url=https://linkinghub.elsevier.com/retrieve/pii/S0145212607004444|journal=Leukemia Research|language=en|volume=32|issue=8|pages=1304–1308|doi=10.1016/j.leukres.2007.11.012}}</ref>.

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* Individual Region Genomic Gain/Loss/LOH

* Characteristic Chromosomal Patterns

Unlike myeloid/lymphoid neoplasms with ''[[Myeloid/Lymphoid Neoplasms with PDGFRA Rearrangement#cite ref-:0 1-4|PDGFRA]]'' or ''PDGFRB'' rearrangement, the prognosis for this ''FGFR1'' associated entity is poor even for patient in the chronic phase, due to the high incidence of transformation. There is no established tyrosine kinase inhibitor therapy for myeloproliferative neoplasms with ''FGFR1'' rearrangement. Midostaurin (PKC412) was reported to be effective in one case <ref>{{Cite journal|last=Chen|first=J.|last2=DeAngelo|first2=D. J.|last3=Kutok|first3=J. L.|last4=Williams|first4=I. R.|last5=Lee|first5=B. H.|last6=Wadleigh|first6=M.|last7=Duclos|first7=N.|last8=Cohen|first8=S.|last9=Adelsperger|first9=J.|date=2004|title=PKC412 inhibits the zinc finger 198-fibroblast growth factor receptor 1 fusion tyrosine kinase and is active in treatment of stem cell myeloproliferative disorder|url=http://www.pnas.org/cgi/doi/10.1073/pnas.0404438101|journal=Proceedings of the National Academy of Sciences|language=en|volume=101|issue=40|pages=14479–14484|doi=10.1073/pnas.0404438101|issn=0027-8424|pmc=PMC521956|pmid=15448205}}</ref>, and interferon has induced cytogenetic response in several cases <ref name=":1" /> <ref>{{Cite journal|last=Holmes|first=A L|last2=Raper|first2=R N|last3=Heilig|first3=J S|date=1998|title=Genetic analysis of Drosophila larval optic nerve development.|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1460051/|journal=Genetics|volume=148|issue=3|pages=1189–1201|issn=0016-6731|pmc=1460051|pmid=9539434}}</ref>. Nevertheless, haematopoietic stem cell transplantation should be considered even for patients in chronic phase.

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==Individual Region Genomic Gain / Loss / LOH==

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A variety of translocations involving 8p11 breakpoint. Secondary cytogenetic abnormalities also occur, most commonly trisomy 21 <ref name=":0" />.

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==Gene Mutations (SNV / INDEL)==

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Normal FGFR1 is a transmembrane protein with an extracellular ligand-binding domain, a transmembrane domain and a cytoplasmic tyrosine kinase domain. In inactive state, FGFR1 presents as monomers in cell membrane. Binding with ligands--the fibroblast growth factors (FGFs), induces dimerization and a conformational change that partially activates the enzymatic activity leading to transphosphorylation of the key tyrosine residue, an increase in enzymatic activity, phosphorylation of additional tyrosines and subsequent phosphorylation of downstream target substrates. The signaling pathways include Ras/MAPK, P13K, PLCÁ and STAT proteins. Fusion proteins with FGFR1 mimic the initial tyrosine kinase activation and thus possess constitutive tyrosine kinase activity to activate multiple signal transduction pathways in myeloid/lymphoid neoplasms <ref>{{Cite journal|last=Ollendorff|first=Vincent|last2=Guasch|first2=Géraldine|last3=Isnardon|first3=Daniel|last4=Galindo|first4=Rémy|last5=Birnbaum|first5=Daniel|last6=Pébusque|first6=Marie-Josèphe|date=1999|title=Characterization of FIM-FGFR1, the Fusion Product of the Myeloproliferative Disorder-associated t(8;13) Translocation|url=http://www.jbc.org/lookup/doi/10.1074/jbc.274.38.26922|journal=Journal of Biological Chemistry|language=en|volume=274|issue=38|pages=26922–26930|doi=10.1074/jbc.274.38.26922|issn=0021-9258}}</ref><ref>{{Cite journal|last=Jiang|first=Guoqiang|last2=den Hertog|first2=Jeroen|last3=Hunter|first3=Tony|date=2000|title=Receptor-Like Protein Tyrosine Phosphatase α Homodimerizes on the Cell Surface|url=https://mcb.asm.org/content/20/16/5917|journal=Molecular and Cellular Biology|language=en|volume=20|issue=16|pages=5917–5929|doi=10.1128/MCB.20.16.5917-5929.2000|issn=1098-5549|pmc=PMC86069|pmid=10913175}}</ref><ref>{{Cite journal|last=Mason|first=Ivor J.|date=1994|title=The ins and outs of fibroblast growth factors|url=https://linkinghub.elsevier.com/retrieve/pii/0092867494905207|journal=Cell|language=en|volume=78|issue=4|pages=547–552|doi=10.1016/0092-8674(94)90520-7}}</ref><ref>{{Cite journal|last=Smedley|first=Damian|last2=Demiroglu|first2=Asuman|last3=Abdul-Rauf|first3=Munah|last4=Heatht|first4=Carol|last5=Cooper|first5=Colin|last6=Shipley|first6=Janet|last7=Cross|first7=Nicholas C.P.|date=1999|title=ZNF198-FGFR1 Transforms Ba/F3 Cells to Growth Factor Independence and Results in High Level Tyrosine Phosphorylation of STATS 1 and 5|url=https://linkinghub.elsevier.com/retrieve/pii/S1476558699800268|journal=Neoplasia|language=en|volume=1|issue=4|pages=349–355|doi=10.1038/sj.neo.7900035|pmc=PMC1508104|pmid=10935490}}</ref>.

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==Genetic Diagnostic Testing Methods==