Ulcers and Eosinophils: A Rare Presentation of PDGFRA-Rearranged Myeloid Neoplasm Responding to Imatinib

Abstract

Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase fusions (M/LN-eo-TK) are uncommon but highly treatable disorders. Among them, FIP1L1::PDGFRA–driven disease is distinguished by marked eosinophilia and multisystem involvement that can rapidly reverse with targeted therapy. We describe a 50-year-old man with uncontrolled diabetes who presented with progressive dyspnea, abdominal discomfort, and painful necrotic scrotal ulcers. Laboratory testing revealed leukocytosis with a striking absolute eosinophil count of 22.1 × 10³/µL, while imaging showed pulmonary infiltrates, small-bowel inflammation, and splenomegaly. Bone marrow examination demonstrated hypercellularity with prominent eosinophilic proliferation. Fluorescence in situ hybridization confirmed a PDGFRA rearrangement with CHIC2 deletion, establishing the diagnosis of FIP1L1::PDGFRA-positive M/LN-eo-TK. Imatinib was initiated at 400 mg daily, later reduced to 200 mg, leading to a rapid normalization of eosinophil counts and resolution of systemic and dermatologic manifestations within 2 weeks. The case highlights how delayed recognition of clonal eosinophilia can permit extensive organ injury, whereas early molecular testing and prompt initiation of imatinib yield dramatic clinical and hematologic remission. Persistent hypereosinophilia, particularly with cutaneous or gastrointestinal involvement, should prompt evaluation for PDGFRA-rearranged disease to enable early intervention and prevent irreversible tissue damage.

Introduction

Myeloid/lymphoid neoplasms with eosinophilia and tyrosine‑kinase fusions (M/LN‑eo‑TK) represent a distinct and uncommon group of hematologic malignancies defined by recurrent rearrangements of genes such as PDGFRA, PDGFRB, FGFR1, and JAK2. These entities were incorporated into the World Health Organization classification due to their clonality, potential for organ damage and marked sensitivity to tyrosine‑kinase inhibitor therapy (TKIs).^1,2 Among these, the FIP1L1::PDGFRA fusion is the most frequently recognized lesion, occurring primarily in male patients and accounting for the vast majority of cases presenting with pronounced hypereosinophilia.^3,4 The fusion activates a constitutively active PDGFRA kinase, driving eosinophil proliferation and infiltration of multiple organs including skin, lung, gastrointestinal tract, and heart.

Clinically, FIP1L1‑PDGFRA–associated M/LN‑eo‑TK often manifests with marked eosinophilia (>1.5 × 10⁹/L), splenomegaly and variable hematologic findings, while signs of organ infiltration may include dermatologic ulcerations, pulmonary infiltrates, gastrointestinal inflammation, and end‑organ dysfunction.^5,6 The identification of the fusion via fluorescence in situ hybridization (FISH) or reverse‑transcription polymerase chain reaction (RT‑PCR) enables a definitive diagnosis and underpins the remarkable therapeutic efficacy of imatinib, often at low doses, leading to rapid hematologic and clinical remission.^2,7 Because delayed recognition may result in irreversible tissue damage, early detection and treatment are essential in optimizing outcomes in these patients. ¹

Herein, we present the case of a 50‑year‑old male who developed hypereosinophilia, necrotic dermatologic ulcers, and multiorgan involvement, in whom a diagnosis of FIP1L1::PDGFRA–rearranged myeloid/lymphoid neoplasm with eosinophilia was established and treated with imatinib, resulting in a rapid and profound clinical response.

Case Presentation

A 50-year-old male with a history of poorly controlled diabetes mellitus presented to the emergency room with a 3-day history of diffuse, nonspecific abdominal pain. He denied associated symptoms such as nausea, vomiting, fever, or changes in bowel movements. This abdominal pain was preceded by a seven-month history of a chronic, nonproductive cough, and shortness of breath with exertion. Despite multiple visits to urgent care centers, where he was diagnosed with allergies, asthma, or flu, he experienced no improvement with prescribed treatments.

In addition, he reported a 30-pound weight loss over the past year and the appearance of skin lesions on his lower extremities, which had been attributed to his diabetes. Over the past 8 months, these lesions would appear spontaneously, manifesting as erythematous pinpoint ulcerations and more diffuse skin irritations. Three weeks before this emergency room visit, he developed a painful ulcerative lesion on the left scrotal region.

On physical examination, the pulmonary exam revealed extensive bilateral crackles at both lung bases. The abdominal exam showed diffuse epigastric tenderness across all quadrants, without rebound tenderness or guarding, with normal bowel sounds, and a palpable spleen.

Skin examination of the midback, lower extremities, and left hip demonstrated various changes consistent with urticarial and nummular dermatitis, along with crusted erythematous papules resembling pruriginous papules. Additionally, two well-demarcated necrotic lesions, measuring 4 cm and 2 cm, were noted on the anterior left scrotum, accompanied by painful, tender diffuse erythema and swelling of the left scrotum (Figures 1 and 2).

Figure 1.

Necrotic, well-defined ulcers on the left hemiscrotum with black eschar bases, violaceous borders, and surrounding erythema. Findings are consistent with ischemic or vasculitic skin lesions associated with PDGFRA-related hypereosinophilic disease.

Figure 2.

Hyperpigmented macules and patches over the midback, right leg, and left hip, some with central violaceous tones, consistent with postinflammatory changes from prior cutaneous eosinophilic inflammation. No active ulceration or scaling is visible.

A CT scan with IV contrast of the chest, abdomen, and pelvis was significant for bibasilar pulmonary infiltrates, an enlarged spleen measuring 18 cm, and inflammatory changes suspicious for mild small bowel enteritis. The complete blood count (CBC) showed a leukocyte count of 38.2 × 10/µL, an absolute eosinophil count (AEC) of 22.1 × 10³/µL, hemoglobin of 13.7 g/dL, and platelet count of 125 × 10³/µL. A previous CBC in 2021 had shown a normal WBC of 8 × 10³/µL, but an AEC of 2 × 10³/µ/L documenting hypereosinophilia was present for at least 3 years prior.

A subsequent bone marrow biopsy and aspirate were done to evaluate the hypereosinophilia which demonstrated markedly hypercellular bone marrow with >90% cellularity with maturing trilineage hematopoiesis. There was a marked predominance of myeloid elements exhibiting increased eosinophilic differentiation. Mild atypia was noted in a subset of erythroid elements and megakaryocytes, but there was no increase in blasts noted. Flow cytometry confirmed the increase in eosinophils, but no other immunophenotypic abnormalities were noted. Molecular analysis demonstrated the presence of PDGFRα (4q12) rearrangement with the signal pattern of 1GRA-1GA indicative of CHIC2 gene deletion. A diagnosis of hypereosinophilic disorder of clonal neoplastic pathology was made; specifically consistent with myeloid/lymphoid neoplasm with eosinophilia and tyrosine kinase gene fusion (M/LN-eo-TK). The patient was begun on Imatinib 400 mg per day for 2 weeks and then for 200 mg per day maintenance. Two weeks later his WBC had decreased to 3.78 × 10³/µL and the AEC to 0.27 × 10³/µL. The scrotal lesions healed completely (Figure 3) and his chronic cough, abdominal discomfort, and shortness of breath had resolved completely.

Figure 3.

Marked improvement of the left hemiscrotal ulcer after imatinib therapy, showing resolution of necrosis with healthy granulation tissue, partial re-epithelialization, and minimal residual erythema or edema.

Discussion

Eosinophils, also known as eosinophilic granulocytes, were first identified by Paul Ehrlich in 1879. Ehrlich, a Nobel Prize laureate and a pioneering figure in many scientific fields, began his research career with hematological staining techniques and is credited with developing the precursor to the gram stain method. Eosinophils were identified as bilobed, nucleated, granular cells that stain deeply with the acidic dye eosin, which is the source of their name. ⁸ They were also previously referred to as acidophils due to their affinity for acidic dyes.

The eosinophil life cycle includes phases in the bone marrow, blood, and tissues. ⁹ These cells are produced in the bone marrow and make up 2% to 5% of circulating leukocytes. After entering the bloodstream, eosinophils remain in circulation for 8 to 18 h but can persist in tissues for up to 6 to 7 days. ¹⁰

Thus, eosinophils are primarily tissue-dwelling, with a tissue-to-blood ratio of about 100:1. ¹¹ Compared to other cell types, eosinophils are more prevalent in several areas, including the lamina propria of the gastrointestinal tract, the lung parenchyma, the cortico-medullary region of the thymus (near CD4/CD8 negative thymocytes), the bulbous end of developing terminal end buds in mammary glands, the endometrium of the uterus, and the interstitial spaces of adipose tissue and skeletal muscle. ¹⁰ Eosinophils do not perform their functions in the blood; instead, they use the bloodstream as a transit route from the bone marrow to the tissues. Once they reach the tissues, eosinophils play a variety of crucial roles, such as defending against parasitic infections in the gut, responding to allergens in the lungs, and supporting a Th2 environment in the adipose tissue. ¹⁰

Eosinophils typically comprise less than 5% of circulating leukocytes and eosinophilia is defined as greater than 500 cells per microliter (≥0.5 × 10⁹/L) [12]. Mild eosinophilia is classified as 0.5 to 1.5 × 10⁹/L, moderate as 1.5 to 5 × 10⁹/L, and severe as greater than 5 × 10⁹/L.^12,13 Mild eosinophilia is typically asymptomatic, but when levels exceed 1.5 × 10⁹/L, tissue and organ damage may result. Eosinophilia may be transient, episodic, or persistent. Persistent hypereosinophilia (HE) was previously defined as an absolute eosinophil count greater than 1.5 × 10⁹/L for at least 4 weeks, but the 2021 Working Conference revised this definition, stating that “persistent” hypereosinophilia (HE) should be recorded on at least two separate occasions, with a minimum interval of 2 weeks between them, ¹³ while the WHO has proposed a 4-week interval. ¹⁴

In patients with persistent or recurrent hypereosinophilia (HE), eosinophils can infiltrate tissues and release mediators and cytotoxic proteins, potentially causing significant organ damage and leading to hypereosinophilic syndrome (HES). ¹³ Conversely, some patients may have persistent HE without noticeable organ damage. These individuals should be carefully monitored and regularly evaluated during follow-up to identify potential HE-related complications.^13,15

Hypereosinophilia (HE) encompasses a spectrum of conditions and may be secondary or reactive (due to parasitic infections, drug reactions, or autoimmune disorders) or primary/clonal, such as myeloid neoplasms harboring PDGFRA, PDGFRB, or FGFR1 rearrangements, or chronic eosinophilic leukemia.^{1 -3} Familial or hereditary forms also exist, and a subset remains of undetermined significance when no clear etiology is identified. ⁴ Distinguishing among these categories is vital because reactive forms often respond to treatment of the underlying condition, whereas clonal HE carries distinct diagnostic, prognostic, and therapeutic implications.^2,5

Eosinophil-related diseases are typically diagnosed by detecting an elevated number of eosinophils in peripheral blood and/or in biopsy samples from affected tissues or organs. The pathophysiology driven by eosinophils often results in tissue destruction and alteration, characterized by proinflammatory, prothrombotic, and profibrotic effects. Eosinophils are distinguished by their unique granules, which contain proteins that can be highly toxic to cells, tissues, and organs. Although eosinophils are not usually present in most human tissues, their involvement in disease is typically revealed through cell infiltration observed in histopathologic examinations. Nevertheless, eosinophils can lose their structural integrity and release granules and granule proteins at inflammation sites, which may lead to their role in tissue damage being underrecognized or overlooked. ¹⁶

Hypereosinophilia (HE) can be classified into 4 distinct categories: familial (hereditary) HE (HEFA), HE of unknown significance (HEUS), secondary (reactive) HER) where the eosinophilia is nonclonal and secondary to overproduced cytokine release, and primary (clonal, neoplastic) HE which is HE driven by neoplastic pathology (clonal) eosinophils (HEN). ¹³

Eosinophilic disorders driven by clonal neoplastic pathology are further categorized into 3 groups: (1) myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (M/LN-eo-TK), (2) eosinophilia associated with myeloid malignancies such as chronic myeloid leukemia (CML) or acute myeloid leukemia (AML) with inversion of chromosome 16, and (3) chronic eosinophilic leukemia (CEL), not otherwise specified (NOS). ¹⁷

The most common genetic alteration within the M/LN-eo-TK subgroup is a rearrangement of PDGFRA which was detected in our patient. ¹⁷ This PDGFRA rearrangement is due to an interstitial deletion of approximately 800 kilobase pairs on chromosome 4q12, which incorporates the CHIC2 gene and results in a fusion between the FIP1L1 and PDGFRA genes, creating an abnormal FIP1L1::PDGFRA fusion protein. This abnormal fusion protein constitutively activates tyrosine kinase and that drives unregulated proliferation of the eosinophilic lineage. The fusion protein is detected through FISH or RT-PCR given that conventional karyotyping does not reveal this cryptic deletion.^17,18 There is a male-to-female ratio of 17:1 with a median age in the late 40s with elevated white blood cell count (WBC), and marked eosinophilia in greater than 95% of patients. HE with PDGFRA fusion is exquisitely sensitive to imatinib even at low doses (100 mg/day). ¹⁹

While some patients with HER and HEN may have marked and persistent HE over several years, they may not demonstrate clinical or laboratory signs of organ damage (HES). ¹³ However, the most common symptoms in PDGFRA HE with HES are skin manifestations (57%) with pruritis in 16% and dermographism seen in 11%. ²⁰ Skin involvement is a frequent manifestation of hypereosinophilic syndrome (HES), particularly in lymphocytic variants, while PDGFRA-driven myeloproliferative forms more often present with ulcerative or necrotic lesions.^{1 –3} The pathogenesis involves direct eosinophilic infiltration and cytotoxic granule-mediated tissue injury, including fibrosis and thrombosis.^4,5 In our case, the patient’s necrotic ulcers and rapid resolution following imatinib therapy mirror previously described PDGFRA-associated dermatologic patterns, reinforcing the potential for targeted treatment to reverse cutaneous damage.^6,7

Our patient had dermatologic manifestations corresponding with the onset of HE. It is unclear what accounts for the pathophysiology of the dermatologic manifestations and if they are the result of nonspecific toxic substance release or eosinophilic infiltration of the skin. There is one report of concurrent molecular evidence of the FIP1L1-PDGFRA fusion gene detected both in peripheral blood and skin tissue in a patient with erythematous papules, macules, hyperpigmentation, and dermographism. ²¹

Conclusion

This case highlights the critical need to consider myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase fusions (M/LN-eo-TK), particularly those involving PDGFRA rearrangements, in patients presenting with persistent hypereosinophilia, especially when accompanied by cutaneous ulcers or signs of multisystem involvement. In such presentations, reliance solely on clinical findings can delay diagnosis; therefore, early molecular testing using fluorescence in situ hybridization (FISH) or reverse transcription polymerase chain reaction (RT-PCR) is essential to identify clonal eosinophilic disorders. The identification of a PDGFRA fusion not only clarifies the diagnosis but also enables targeted treatment with imatinib, which, even at low doses, can induce rapid hematologic remission and prompt resolution of systemic and dermatologic manifestations. Longitudinal review of white blood cell differentials over time, rather than isolated snapshots, is equally crucial to recognize evolving eosinophilia that may signal an underlying clonal process. Given the potential for irreversible tissue damage in untreated cases, timely intervention is paramount. This case reinforces a practical diagnostic and therapeutic approach to eosinophilic syndromes: prioritize early detection, confirm molecular drivers, and initiate appropriate therapy swiftly. In doing so, clinicians can significantly improve prognosis and mitigate long-term morbidity in this otherwise aggressive but highly treatable hematologic entity.