A Novel PDGFRβ Rearrangement in Systemic Mastocytosis with an Associated Haematologic Neoplasm

Dear Editor,

Systemic mastocytosis (SM) is a heterogeneous neoplasm characterized by the clonal proliferation of abnormal mast cells that accumulate in one or more extracutaneous organs [1]. As per the 2016 WHO classification of tumors of the hematopoietic and lymphoid tissues, five variants of systemic mastocytosis are recognized including Systemic mastocytosis with an associated hematological neoplasm (SM-AHN) [2]. The associated malignancy can be a myeloid, lymphoproliferative, or plasma cell neoplasm. In most cases, a myeloid malignancy such as myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), myelodysplastic/myeloproliferative neoplasms (e.g., chronic myelomonocytic leukemia), and acute myeloid leukemia (AML), is diagnosed [3, 4].

A number of cytogenetic abnormalities including the t(8;21)(q22;q22), the deletion 20q as well as trisomy 9 have been reported in SM-AHN [5]. Myeloid/lymphoid neoplasms with eosinophilia are associated with recurrent rearrangements of PDGFRα, PDGFRβ, FGFR1, ETV6 and JAK2. Patients with rearrangement of PDGFRα or PDGFRβ respond to tyrosine kinase inhibitors similar to that seen in CML.

A 33 year old male presented with complaints of itching associated with erythematous rash followed by postinflammatory hyperpigmentation along with cough, fever and weight loss (10 kg) of 8 months duration. On examination he had a livedoid rash on the extremities and a reticulate rash on the chest extending to the upper abdomen, bilateral cervical lymphadenopathy and hepatomegaly (palpable 3 cms below costal margin). Investigations revealed a haemoglobin of 10.8 g/dL, total white blood cell (WBC) count of 6.7 × 10⁹/L with differential count showing eosinophilia (Neutrophils 26; Lymphocytes 22; Monocytes 4; Eosinophils 48; Basophils 0) and platelet count of 109 × 10⁹/L. Bone marrow aspirate showed a hypercellular marrow with moderate eosinophilia, mild plasmacytosis and non-specific reactive changes. The trephine biopsy showed a normocellular marrow with trilineage hematopoiesis, mild increase in eosinophils and focal perivascular aggregates of CD25+ mast cells. Radiological imaging for the persistent cough showed mediastinal, hilar and abdominal lymphadenopathies. Endobronchial ultrasound guided transbronchial biopsy from a subcarinal lymph node showed atypical mast cell infiltrate consistent with mastocytosis. Further work up for mastocytosis including mast cell tryptase and C KIT mutation were negative.

Conventional cytogenetic analysis (GTG banding) was performed according to standard protocols. Karyotype analysis of unstimulated bone marrow cultures showed an insertion of part of the long(q) arm chromosome 4 into chromosome 5q in all 20 cells analyzed with gain of the X chromosome in 6 cells- 46,XY,ins(4;5)(q32;q21q32.1)[14]/47,idem, + X[6] (Fig. 1a).

Fig. 1.

a G-banded karyogram showing a derivative chromsome 5 due to a possible insertion into 5q31-32. b FISH analysis using a dual color breakapart probe showing rearrangement of the PDGFRβ gene on chromosome 5, band q32 due to an insertion shown in inverted DAPI view to illustrate the insertion. The derivative chromosome 5 shows a split signal (1 red/1 green) while 1 fusion (yellow) is seen on the normal chromosome 5. c FISH analysis using a whole chromosome paint for chromosome 4 (Spectrum green) shows the insertion of part of 4q sequences into 5q

Matched metaphase fluorescence in situ hybridization (FISH) was performed on destained slides using the PDGFRβ dual color break apart probe (Metasystems, Germany) to confirm the karyotype findings. Rearrangement of the PDGFRβ gene was confirmed using a dual color break apart probe which was positive for rearrangement of the PDGFRβ gene (Fig. 1b) and appeared to be due to an insertion into 5q. Sequential FISH using a whole chromosome paint 4 showed the rearrangement to be the result of insertion of chromosome 4 sequences into 5q (Fig. 1c)- 46,XY,ins(4;5)(q32;q21q31.1).ish ins(4;5)(5′PDGFRβ+, WCP4+; WCP4+, 3′PDGFRβ+)[10].

Based on the clinical and laboratory parameters, the patient was diagnosed to have indolent systemic mastocytosis with cutaneous involvement. After completion of the work up, he was initially started on a short course of steroid (1 mg/kg/day × 1 week), with which the eosinophilia improved, but symptoms persisted. He was subsequently started on Imatinib (200 mg daily once). He showed dramatic improvement with Imatinib with complete resolution of the cough, lymphadenopathy and skin lesions. Presently he is on Imatinib for 2 months and is doing well.

Durable responses to imatinib have been described in rare patients with atypical myeloproliferative diseases. In most instances these imatinib-responsive diseases have been associated with fusion genes involving PDGFRα/β.

The t(4;5) has been reported in 3 cases to date, a 45-year-old female patient with a-MPN with basophilia and eosinophilia [6], a 61-year-old male patient with systemic mast cell disease (SMCD) and an associated chronic basophilic leukemia [7], and a 45-year-old male patient with a SMCD with eosinophilia [8]. This is the first report to show an insertion as a mechanism of PDGFRβ gene rearrangement in SM. Although, the partner gene on chromosome 4 could not be identified with certainty, a likely candidate may be the Protein kinase, cGMP-dependent, type II (PRKG2) gene on chromosome 4, band q21.21 [8]. This must be confirmed by molecular studies. The PRKG2 gene has been previously described in MPN as well as in SMCD [7]. Irrespective of the partner gene involved, neoplasms with rearrangements involving the PDGFRβ gene appear to be sensitive to treatment with Imatinib.

This disease variant should be considered in SM patients without codon 816 KIT mutations and with cytogenetic abnormalities involving 5q31-32. This case illustrates the importance of cytogenetic analysis when evaluating patients with SM-AHN.