Bailey.Glen: Created page with "{{Under Construction}} ==Primary Author(s)*== Christopher Sullivan, MD, MPH and Daynna J. Wolff, PhD TOC ==Cancer Category/Type== Myeloid Neoplasms/Acute myeloid leuke..."

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Created page with "{{Under Construction}} ==Primary Author(s)*== Christopher Sullivan, MD, MPH and Daynna J. Wolff, PhD __TOC__ ==Cancer Category/Type== Myeloid Neoplasms/Acute myeloid leuke..."

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==Primary Author(s)*==

Christopher Sullivan, MD, MPH and Daynna J. Wolff, PhD

__TOC__

==Cancer Category/Type==

Myeloid Neoplasms/Acute myeloid leukemia

==Cancer Sub-Classification / Subtype==

Myeloid/Lymphoid Neoplasms with PDGFRB Rearrangement

==Definition / Description of Disease==
Gene fusions with PDGFRB were first described by Golub et al. in 1994 in a patient with features consistent with chronic myelomonocytic leukemia (CMML)<ref>Golub TR, Barker GF, Lovett M, Gilliland DG. Fusion of PDGF receptor-beta to a novel Ets-like gene, Tel, in chronic myelomonocytic leukemia with t(512) chromosomal translocation. Cell. 1994;77(2):307–16.</ref>. Since that time, over 20 fusion partners have been described<ref>Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J, Kutok J, Clark J, Galinsky I, et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 .Genes as a therapeutic target of imatinib in idiopathic Hypereosinophilic syndrome. N Engl J Med. 2003;348(13):1201–14.</ref><ref name=":0">Vega F, Medeiros LJ, Bueso-Ramos CE, Arboleda P, Miranda RN. Hematolymphoid neoplasms associated with rearrangements of PDGFRA, PDGFRB, and FGFR1. Am J Clin Pathol. 2015;144(3):377–92.</ref>. Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRB are rare, accounting for less than 2% of all myelodysplastic/myeloproliferative neoplasms (MDS/MPN)<ref name=":0" />.

==Synonyms / Terminology==

Chronic myelomonocytic leukemia with eosinophilia associated with t(5;12); myeloid neoplasms with PDGFRB rearrangement; myeloid neoplasms associated with PDGFRB rearrangement.

==Epidemiology / Prevalence==

This neoplasm is considerably more common in men than in women (male-to-female ratio: 2:1) and occurs over a wide age range (8-72 years), with peak incidence in middle-aged adults and a median age of onset in the late 40s<ref name=":1">Steer, E. J., & Cross, N. C. (2002). Myeloproliferative disorders with translocations of chromosome 5q31–35: role of the platelet-derived growth factor receptor Beta. ''Acta haematologica'', ''107''(2), 113-122.</ref>.

==Clinical Features==
Patients typically present with splenomegaly; hepatomegaly is less frequent. Lymphadenopathy may also be seen. Skin and cardiac infiltration may be present at diagnosis with resulting cardiac damage. Serum tryptase levels may be elevated.

==Sites of Involvement==

MPN associated with t(5;12)(q32;p13.2) is a multisystem disorder. The peripheral blood and bone marrow are always involved. The spleen is enlarged in most cases. Tissue infiltration by eosinophils and cytokine release, humoral factors, or granule contents by eosinophils can contribute to tissue damage in several organs<ref name=":2">Swerdlow SH, Campo E, Harris NL, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. In: Bosman FT, Jaffe ES, Lakhani SR, Ohgaki H, eds. World Health Organization Classification of Tumours. Lyon, France: IARC; 2008</ref>.

==Morphologic Features==
In patients with abnormalities of PDGFRB, peripheral blood and bone marrow is almost always involved. Leukocytosis is typical with monocytosis and eosinophilia. Rarely, basophilia is also prominent. Anemia and thrombocytopenia may also be present. Overall, the features are typically suggestive of CMML with eosinophilia; however, some patients present with features more in keeping with aCML or CEL. Rarely, they present with features of ALL, AML, and juvenile myelomonocytic leukemia (JMML)<ref>Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J, Kutok J, Clark J, Galinsky I, et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 .Genes as a therapeutic target of imatinib in idiopathic Hypereosinophilic syndrome. N Engl J Med. 2003;348(13):1201–14.</ref>.

==Immunophenotype==

The mast cells show expression of CD2 and CD25, which is also found in most mast cell disease.

==Chromosomal Rearrangements (Gene Fusions)==

{| class="wikitable sortable"
|-
!Translocation!!Fusion Gene!!Hematological Diagnosis
|-
|t(5;12)(q32;p13.2)
|ETV6-PDGFRB
|CMML with eosinophilia, CEL
|-
|t(1;3;5)(q36;q11.2)||WDR48-PDGFRB||CEL
|-
|der(1)t(1;5)(p34;q32),
der(5)t(1;5)(p34;q15),

der(11)ins(11;5)(p13;q15q32)
|CAPRIN1-PDGFRB||CEL
|-
|t(1;5)(q21.3;q32)
|TPM3-PDGFRB
|
|-
|t(1;5)(q21.2;q32)
|PDE4DIP-PDGFRB
|MDS/MPN with eosinophilia
|-
|t(2;5)(p16.2;q32)
|SPTBN1-PDGFRB
|
|-
|t(4;5;5)(q21.2;q31;q32)
|PRKG2-PDGFRB
|Chronic basophilia leukemia
|-
|t(3;5)(p22.2;q32)
|GOLGA4-PDGFRB
|CEL or aCML with eosinophilia
|-
|Cryptic interstitial deletion of 5q
|TNIP1-PDGFRB
|CEL with thrombocytosis
|-
|t(5;7)(q32;q11.2)
|HIP1-PDGFRB
|CMML with eosinophilia
|-
|t(5;7)(q32;p14.1)
|HECW1-PDGFRB
|JMML
|-
|t(5;9)(q32;p24.3)
|KANK1-PDGFRB
|Essential thrombocythemia without eosinophilia
|-
|t(5;10)(q32;q21.2)
|CCDC6-PDGFRB
|aCML with eosinophilia or MPN with eosinophilia
|-
|Uninformative
|SART3-PDGFRB
|MPN with eosniophilia
|-
|t(5;12)(q32;q24.1)
|GIT2-PDGFRB
|CEL
|-
|t(5;12)(q32;p13.3)
|ERC1-PDGFRB
|AML without eosniophilia
|-
|t(5;12)(q32;p13.1)
|BIN2-PDGFRB
|aCML with eosinophilia
|-
|t(5;14)(q32;q22.1)
|NIN-PDGFRB
|Ph-negative CML (13% eosinophils)
|-
|t(5;14)(q32;q32.1)
|CCDC88C-PDGFRB
|CMML with eosinophilia
|-
|t(5;15)(q32;q15.3)
|TP53BP1-PDGFRB
|Ph-negative CML with prominent eosinophilia
|-
|t(5;16)(q32;p13.1)
|NDE1-PDGFRB
|CMML
|-
|t(5;17)(q32;p13.2)
|RABEP1-PDGFRB
|CMML
|-
|t(5;17)(q32;p11.2)
|SPECC1-PDGFRB
|JMML
|-
|t(5;17)(q32;q11.2)
|MYO18A-PDGFRB
|MPN with eosinophilia
|-
|t(5;17)(q32;q21.3)
|COL1A1-PDGFRB
|MDS or MPN with eosinophilia
|-
|t(5;20)(q32;p11.2)
|DTD1-PDGFRB
|CEL
|}

==Characteristic Chromosomal Aberrations / Patterns==

t(5:12)(q32;p13.2), translocation resulting in ETV6-PDGFRB.
==Gene Mutations==
Fusion results in the joining of the N-terminal domain of ETV6 to the tyrosine kinase-containing C-terminal of PDGFRB. This leads to oligomerization at the pointed domain, constituently active phosphorylation, and activation of STAT proteins<ref>Chen J, Williams IR, Kutok JL, Duclos N, Anastasiadou E, Masters SC, et al. Positive and negative regulatory roles of the WW-like domain in TEL-PDGFbetaR transformation. Blood. 2004;104(2):535–42.</ref>.

==Genes and Main Pathways Involved==
PDGFRB encodes a plasma membrane-spanning receptor with five extracellular immunoglobulin-like loops for ligand binding and a split intracellular tyrosine kinase domain. Signal transduction is very similar, with ligand binding inducing dimerization and autophosphorylation of the tyrosine kinase. In addition to its role in embryonic development, PDGFRB mediates chemotactic responses of monocytes, macrophages, and platelets to inflammatory processes. Overexpression has been implicated in solid tumors, such as medulloblastoma and chordoma<ref>Chang, C. C., & Ohgami, R. S. (Eds.). (2018). ''Precision molecular pathology of myeloid neoplasms''. Springer.</ref>.

==Diagnostic Testing Methods==

FISH (break-apart FISH with a PDGFRB probe) is indicated in all patients with a presumptive diagnosis of MPN with a 5q31-33 breakpoint, in particular if there is eosinophilia. However, FISH analysis does not always demonstrate rearrangement of PDGFRB even when such rearrangement is detectable on Southern blot anaylsis<ref name=":1" />. Molecular analysis is not indicated when no 5q31-33 breakpoint is found by conventional cytogenetic analysis, because almost all cases reported to date in which 20 metaphases were available for examination have had a cytogenetically detectable abnormality<ref name=":2" />.

==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==

Before the introduction of imatinib therapy, the median survival was <2 years. Most patients are now known to have excellent morphologic and molecular response to therapy with a recent study showing a 10-year overall survival of 90%<ref>Cheah CY, Burbury K, Apperley JF, Huguet F, Pitini V, Gardembas M, et al. Patients with myeloid malignancies bearing PDGFRB fusion genes achieve durable long-term remissions with imatinib. Blood. 2014;123(23):3574–7.</ref>. Furthermore, earlier diagnosis due to recognition of this entity will result in earlier initiation of appropriate therapy, preventing cardiac damage and blast phase. Primary and secondary resistance is uncommon; however, initial response typically occurs within 2 months, and if not seen by 3 months, consideration of another therapy is suggested. Whether or not therapy can be stopped in patients with long term molecular remission is still up for debate, with a recent article citing one patient in remission 4 years after therapy cessation<ref>Cerrano M, Crisà E, Gottardi E, Aguzzi C, Boccadoro M, Ferrero D. Long-term therapy-free remission in a patient with platelet-derived growth factor receptor beta (PDGFRB)- rearranged myeloproliferative neoplasm. Am J Hematol. 2016;91(9):E353.</ref>.

==Links==

[[PDGFRB]]

==References==
<references />

==Notes==
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HAEM4Backup:Myeloid/Lymphoid Neoplasms with PDGFRB Rearrangement - Revision history

Bailey.Glen: Created page with "{{Under Construction}} ==Primary Author(s)*== Christopher Sullivan, MD, MPH and Daynna J. Wolff, PhD __TOC__ ==Cancer Category/Type== Myeloid Neoplasms/Acute myeloid leuke..."

Bailey.Glen: Created page with "{{Under Construction}} ==Primary Author(s)*== Christopher Sullivan, MD, MPH and Daynna J. Wolff, PhD TOC ==Cancer Category/Type== Myeloid Neoplasms/Acute myeloid leuke..."