Myeloid/Lymphoid Neoplasms with PDGFRB Rearrangement

Revision as of 11:38, 14 November 2023 by Bailey.Glen (talk | contribs) (→‎Gene Mutations)
(diff) ← Older revision | Latest revision (diff) | Newer revision → (diff)


editPREVIOUS EDITION
This page from the 4th edition of Haematolymphoid Tumours is being updated. See 5th edition Table of Contents.

Primary Author(s)*

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

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)[1]. Since that time, over 20 fusion partners have been described[2][3]. Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRB are rare, accounting for less than 2% of all myelodysplastic/myeloproliferative neoplasms (MDS/MPN)[3].

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[4].

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[5].

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)[6].

Immunophenotype

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

Chromosomal Rearrangements (Gene Fusions)

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 (SNV/INDEL)

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[7].

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[8].

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[4]. 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[5].

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%[9]. 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[10].

Links

PDGFRB

References

  1. 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.
  2. 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.
  3. 3.0 3.1 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.
  4. 4.0 4.1 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.
  5. 5.0 5.1 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
  6. 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.
  7. 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.
  8. Chang, C. C., & Ohgami, R. S. (Eds.). (2018). Precision molecular pathology of myeloid neoplasms. Springer.
  9. 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.
  10. 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.

Notes

*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.