Recurrent Orogenital Ulcers: A Rare Case of Myeloid Neoplasm Associated with FIP1L1-PDGFRA Rearrangement with Rapid Response to Imatinib

Dear Editor, Orogenital ulceration is a common presentation encountered in dermatological practice. Myeloproliferative hypereosinophilic syndrome (HES) is one of the rarer causes of recurrent orogenital ulcerations. Myeloid HES has characteristic clinico-pathological features.[1] A distinctive feature of patients with myeloproliferative HES is mucosal ulceration.[2] Myeloid neoplasm with Factor Interacting with The PAPOLA gene encodes for poly(A) polymerase alpha (PAPα), and CPSF1–Platelet-Derived Growth Factor Receptor-α (FIP1L1-PDGFRA) gene rearrangement is a type of myeloproliferative HES with an excellent response to imatinib.[3] Since it is a rare entity, a high index of suspicion is needed for diagnosis. We present a case of myeloid neoplasm with FIP1L1-PDGFRA rearrangement presenting with recurrent orogenital ulcerations, which had been misdiagnosed as Behcet’s disease. A 36-year-old male from Bangladesh presented with recurrent painful oro-genital ulcers, erythematous skin lesions, and bilateral conjunctival congestion for the past five years. He complained of recurrent fevers and headaches for the preceding six months. He was being presumptively treated as Behcet’s disease with oral prednisolone and azathioprine at another centre, with minimal benefit. Cutaneous examination showed multiple erythematous papules and plaques with central hemorrhagic crusts and erosions on the chest, abdomen, and axillae [Figure 1a], and crusted erosions on the upper lip and undersurface of the tongue [Figure 1b]. Superficial ulcers with an erythematous base were seen on the glans and shaft of penis [Figure 1c]. The spleen was palpable up to the umbilicus. There was no hepatomegaly or lymphadenopathy, and the rest of the systemic examination was unremarkable. Differential diagnoses considered included Behçet’s disease, Herpes simplex infection, Crohn’s disease, immunobullous disorders, connective tissue disorders, and drug-induced ulcers. Tzanck smear from the oral erosions was negative for acantholytic cells and multinucleated giant cells. Blood investigations revealed peripheral eosinophilia [total white blood cell count (TC): 12600/mm3; absolute eosinophil count (AEC): 5544/mm3]. Prior AEC was 4200/mm3. Peripheral smear examination showed degranulated eosinophils with cytoplasmic vacuolations. Blood investigations revealed elevated vitamin B12 (>2000 pg/mL), negative anti nuclear antibody (ANA), normal liver and renal function tests, and no blood microfilariae. Stool was negative for parasites. Bone marrow biopsy showed marked myeloid hyperplasia with an increase in eosinophils and their precursors [Figure 2]. Skin and mucosal lesional biopsies revealed non-specific inflammatory infiltrates. Direct immunofluorescence from perilesional skin was negative, ruling out paraneoplastic pemphigus. HLA–B51 was negative. Bone marrow karyotyping was normal. Echocardiography was normal, while spirometry showed a restrictive pattern. The diagnostic criteria for HES were satisfied in our patient: persistent absolute eosinophil count >1,500/mm3, evidence of organ involvement, and exclusion of secondary causes.[3] Reverse transcriptase polymerase chain reaction testing for FIP1L1-PDGFRA rearrangement was performed and was positive, confirming the diagnosis of myeloproliferative HES.Figure 1: (a). Multiple erythematous papules and plaques with central hemorrhagic crusts and erosions on the chest, abdomen, and axillae. (b). Oral cavity showed crusted erosions on the upper lip and superficial erosions on the undersurface of tongue. (c). Superficial ulcers with an erythematous base were seen on the shaft of penis and glansFigure 2: Bone marrow biopsy showed solidly cellular marrow with marked myeloid hyperplasia with moderate increase in eosinophils and their precursors (20×)The patient was initiated on imatinib mesylate 100 mg once daily, with which there was complete resolution of mucosal, skin, ocular, and systemic symptoms as well as normalization of the eosinophil count (TC-5500; AEC-400/mm3) at 3 months [Figure 3].Figure 3: Oral cavity showing resolution of lesionsOrogenital ulceration is a frequent dermatological concern with varied etiologies, including Behçet’s disease, infections, and rare systemic conditions like myeloproliferative HES. HES is a rare disorder characterized by persistent eosinophilia (>6 months) and multi-system involvement. Myeloid neoplasm with FIP1L1-PDGFRA rearrangement is a distinct type of this hematopoietic neoplasm associated with a cryptic deletion on chromosome 4q12.[3] It has characteristic clinical and pathological features like weight loss, fatigue, hepatomegaly, splenomegaly, pruritus, pallor, bruising, and cardiac, respiratory, cutaneous, or gastrointestinal symptoms and signs.[1] Cutaneous involvement in HES includes both mucosal lesions and skin lesions. The skin lesions are heterogenous and can present as pruritic erythematous macules, papules, plaques, nodules, urticaria and angioedema, erythema annulare centrifugum, purpuric papules, livedo reticularis, etc. Splinter hemorrhages and nail fold infarcts have also been described.[2] Mucosal lesions are more common in myeloproliferative than lymphocytic HES and are associated with a more severe disease course.[4] They are painful, discrete ulcers on the non-keratinized unattached mucosal epithelium of the lips, sulci, lateral and ventral tongue, soft palate, and oropharynx. Similar lesions may also be present on the genital or conjunctival mucosae. Histopathological features of HES-related lesions are nonspecific, showing polymorphous infiltrates with lymphocytes, eosinophils, and plasma cells beneath ulcerated epithelium. Tissue eosinophilia may not always be present in all affected organs, as seen in our patient’s skin biopsies, possibly due to the heterogeneous tissue involvement or eosinophil degranulation.[5] Testing for FIP1L1-PDGFRA rearrangement should be considered in all patients with recurrent orogenital ulcers and skin lesions along with unexplained hypereosinophilia, especially when there is organ involvement, elevated serum tryptase, or myeloproliferative features, because of the striking therapeutic effectiveness of imatinib mesylate.[2] Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published, and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. Use of artificial intelligence (AI) The preparation of this manuscript was carried out entirely by the authors without the use of artificial intelligence technologies.