Myeloid Neoplasm with PDGFRA Rearrangement Manifesting as a Retromolar Pad Mass

Abstract

Myeloid neoplasms with PDGFRA rearrangement are rare, and most commonly present with features of chronic eosinophilic leukemia; however, they rarely manifest as acute myeloid or lymphoblastic leukemia. Patients typically present with symptoms of hypereosinophilia including cardiovascular and pulmonary symptoms. An increase in mast cells is also a common feature of this disease, and there may be elevated serum tryptase with significant clinical overlap with systemic mastocytosis. Here, we present an unusual case of a myeloid neoplasm with PDGFRA rearrangement manifesting as a retromolar pad mass in a patient with a prior diagnosis of systemic mastocytosis. This case highlights the possibility of soft tissue involvement by myeloid neoplasms with PDGFRA rearrangement in the oral cavity. The identification of this entity is of significant clinical importance because many patients can be effectively treated with tyrosine kinase inhibitors.

Introduction

“Myeloid/lymphoid neoplasms with eosinophilia and gene rearrangement” is a rare category of hematologic malignancy. These neoplasms typically manifest as chronic myeloid neoplasms with eosinophilia, but can rarely present as lymphoid neoplasms or acute myeloid leukemia [1]. They are defined by gene rearrangements involving PDGFRA, PDGFRB or FGFR1, and are characterized by bone marrow involvement [1]. Here we present an unusual case of a myeloid neoplasm with PDGFRA rearrangement with soft tissue involvement that was diagnosed by a retromolar pad mass biopsy, along with a relevant literature review.

Case report

A 70-year-old man reported 1–2 weeks of swelling of the right retromolar pad. Twelve years prior, he was found to have a mildly elevated white blood cell count (14.5 K/μL; reference range: 4.5–11 K/μL), with marked eosinophilia (absolute eosinophil count 8.4 K/μL; reference range: 0.12–0.3 K/μL). His hematocrit (44.3%; reference range 41–53%) and platelet count (209 K/μL; reference range 150–350 K/μL) were normal. Imaging studies showed mild splenomegaly, and a positron emission tomography (PET) scan showed no definite focal hypermetabolic abnormalities. Troponin levels were not measured, but an echocardiogram reportedly demonstrated normal biventricular size and systolic function, with no significant valvular abnormalities.

A bone marrow biopsy was also performed at the time of his initial presentation. Per report, the biopsy showed hypercellular bone marrow with multifocal, dense paratrabecular mast cell infiltrates that expressed CD117 and mast cell tryptase, as well as eosinophilia with no increase in blasts. Flow cytometry studies performed on the bone marrow reportedly showed no phenotypic evidence of excess blasts, myeloid dysmaturation, or non-Hodgkin lymphoma. Both fluorescence in situ hybridization (FISH) studies for inv(16) and molecular studies for KIT mutations were negative. A diagnosis of systemic mastocytosis was rendered. Since KIT mutational analysis was negative, tyrosine kinase inhibitor therapy was not initiated. Serum tryptase reportedly peaked at approximately 35 ng/mL. The patient was asymptomatic at the time of the original work-up, and remained asymptomatic over the years.

During a routine dental visit 12 years after the work-up for eosinophilia was initiated, the patient’s dentist noted a 2.5 cm firm mass in the right retromolar pad, distal to tooth number 31. The mucosa overlying the mass was normal in color without any ulceration or exudate. Radiologic evaluation of the area was reportedly within normal limits. A 6 mm punch biopsy of the center of the retromolar pad mass was performed.

The punch biopsy showed an infiltrative proliferation of atypical mononuclear cells involving fibrovascular tissue (Fig. 1). The mononuclear cells were medium to large in size with an abundant amount of clear or lightly eosinophilic cytoplasm, irregular nuclear borders, and open chromatin with inconspicuous nucleoli. There were numerous admixed eosinophils, which had a somewhat patchy distribution. A panel of immunostains demonstrated that the mononuclear cells were positive for CD4 (dim), CD43, CD68, lysozyme, and myeloperoxidase, with partial dim expression of CD33 (Fig. 2). The neoplastic cells were negative for CD1a, CD3, CD7, CD20, CD21, CD30, CD34, CD45, CD79a, CD123, CD117, CD163, MUM1, TdT, and S100. CD117 and calretinin highlighted infrequent singly-scattered mast cells, and only very rare mast cells were highlighted by mast cell tryptase [1, 2]. The Ki-67 proliferation index was increased in a patchy distribution, ranging from 20 to 80% (Fig. 1). FISH studies were performed to evaluate for a myeloid neoplasm with PDGFRA rearrangements. The FISH studies identified a FIP1L1-PDGFRA fusion in 85% of cells, as well as 5q deletion/monosomy 5 in 30% of cells and trisomy 8 in 39% of cells.

Fig. 1.

An H&E stain of the retromolar pad punch biopsy at a 20 ×, b 400 × and c 1000 × (oil) showed an infiltrate of medium to large mononuclear cells (arrow) with numerous admixed eosinophils (arrow head) involving fibrovascular tissue. d These abnormal cells had a high Ki-67 proliferation index by immunohistochemistry (400 ×)

Fig. 2.

Immunostains performed on the punch biopsy showed that the atypical mononuclear cells expressed a CD43, b CD68, c myeloperoxidase, d lysozyme, e weak CD4, and f partial weak CD33. All images 400 ×

The morphologic, immunophenotypic, and cytogenetic findings were consistent with a diagnosis of a myeloid neoplasm with PDGFRA rearrangement. The patient was treated with imatinib therapy, with complete resolution of his oral lesion. Additional clinical information is not available for review at the time of the composition of this manuscript.

Discussion

This case represents an unusual manifestation of a myeloid neoplasm with a PDGFRA rearrangement as an oral soft tissue mass. The patient presented with an asymptomatic eosinophilia that persisted for years, which was thought to represent systemic mastocytosis. In retrospect, the findings were likely due to myeloid neoplasm with PDGFRA rearrangement, though the original bone marrow biopsy is no longer available for review. Ultimately, the diagnosis was facilitated by the development of soft tissue mass.

Myeloid neoplasms with PDGFRA rearrangement are usually characterized by a cryptic deletion on chromosome 4q12 that results in a FIP1L1-PDGFRA gene fusion [3]. Patients typically present with features of chronic eosinophilic leukemia, including fatigue, pruritus, and respiratory, cardiac, or gastrointestinal symptoms [4, 5]. Serum tryptase levels are usually elevated (> 12 ng/mL), as well [4]. There is a notable male predominance (17:1) in patients with this gene fusion, and most patients present between the ages of 25 and 55 [6, 7]. The differential diagnosis may include other myeloid neoplasms with associated eosinophilia, including systemic mastocytosis, chronic eosinophilic leukemia, myeloid/lymphoid neoplasms with other recurrent gene rearrangements (i.e., PDGFRB, FGFR1, PCM1-JAK2), acute myeloid leukemia, chronic myeloid leukemia, or Langerhans cell histiocytosis [8]. Of note, molecular and/or cytogenetic testing is often necessary for the definitive subclassification of these neoplasms.

While tissue infiltration by eosinophils may be seen in myeloid neoplasms with PDGFRA rearrangement, involvement of the bone marrow is characteristic, and the diagnosis is typically rendered via blood and bone marrow evaluation. Extramedullary involvement by myeloid neoplasm with a PDGFRA rearrangement is relatively rare, but has been reported as soft tissue masses involving the scapula, chest wall, scalp, and spine [6, 7, 9–11]. As in the current case, these extramedullary proliferations may be composed of sheets of immature myeloid cells, which is compatible with a myeloid sarcoma; however, it is critically important to make a diagnosis of myeloid/lymphoid neoplasms with PDGFRA rearrangement rather than myeloid sarcoma, not otherwise specified, because myeloid neoplasms with PDGFRA rearrangement respond to tyrosine kinase inhibitors.

Treatment is indicated in all patients with a known FIP1L1-PDGFRA gene fusion in order to stabilize the eosinophilia and prevent the progression of cardiac disease and other end organ damage. Responses to imatinib in myeloid neoplasms with PDGFRA rearrangement are excellent, with 100% of patients reportedly achieving a durable complete hematologic response within one month of initiating therapy, and nearly all patients achieving a complete molecular response within one year on therapy [10, 12]. In addition to hematologic and molecular responses, the majority of patients also have improvement in end organ damage. One exception is patients who have already developed cardiac damage; however, imatinib therapy may help to prevent the progression of cardiac disease [12].

Interestingly, the dose of imatinib needed to achieve and maintain a hematologic response is as low as 100 mg per day for the majority of patients, which is significantly less than the conventional doses of 400–800 mg used for the treatment of BCR-ABL1-positive chronic myeloid leukemia (CML) [10]. However, higher doses of imatinib up to 400 mg may be necessary to achieve a complete molecular response in some patients. As with CML, patients are generally treated indefinitely due to the high risk of relapse with cessation of therapy [11], but there is emerging evidence that treatment discontinuation may be possible in select cases with careful monitoring [13]. While the vast majority of patients respond to treatment, there have been reports of both primary resistance and secondary resistance, owing to the development of specific gene mutations including T6741 and D842V [14–16]. A variety of other TKIs, including sorafenib and midostaurin, have demonstrated efficacy in patients with the T6741 mutation, and ponatinib is the only TKI that has demonstrated efficacy for the D842V mutation [16–18].

The acquisition of the additional chromosomal abnormalities (5q deletion/monosomy 5 and trisomy 8) that were identified in a subset of cells in this case have been reported in other patients with myeloid neoplasm with PDGFRA rearrangement. This finding is reported to be associated with disease progression, including evolution to acute myeloid leukemia [5].

In summary, here we report a case of a myeloid neoplasm with PDGFRA rearrangement with involvement as a soft tissue mass in the oral cavity. Unusual manifestations and the clinical overlap with systemic mastocyotosis can make the diagnosis of this entity challenging; however, it is important for pathologists and clinicians to recognize myeloid neoplasms with PDGFRA rearrangement because they can be effectively treated with tyrosine kinase inhibitors.

Funding

This work was supported in part by the Sidney Kimmel Comprehensive Cancer Center grant from the National Institutes of Health (P30 CA006973; A.S.D., J.A.W., B.D.S.).

Compliance with Ethical Standards

Conflict of interest

All authors declare that they have no conflict of interest to disclose.

Ethical Approval

This manuscript constitutes a retrospective analysis of one clinical case (a “case report”). The Johns Hopkins Medicine Institutional Review Board does not require review of case reports, as case reports do not meet the Department of Health and Human Services definition of “research” (https://www.hopkinsmedicine.org/institutional_review_board/guidelines_policies/guidelines/case_report.html). HIPAA identifiers (including unique patient characteristics) are not included in the manuscript.

Informed Consent

Consent for publication was verbally obtained from the patient.