Laboratory Assessment of Patients with Hypereosinophilic Syndrome

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Eosinophilic gastrointestinal diseases (EGIDs) are single-organ hypereosinophilic syndromes (HESs) characterized by eosinophilic inflammation involving any segment of the gastrointestinal (GI) tract and include eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, and eosinophilic colitis. Peripheral eosinophilia (500/mm3) is common in patients with EGID, and some patients present with peripheral hypereosinophilia (absolute eosinophil count AEC, 1500/mm3). It is important to exclude other subtypes of HESs that may progress to multisystem involvement or require alternative therapies in the evaluation of such cases. We studied a patient who first presented with isolated, biopsy-proven EGID, but was later found to harbor FIP1L1-PDGFRA fusion gene, a hallmark of chronic eosinophilic leukemia. A 32-year-old man presented in 2012 to an outside institution complaining of abdominal pain and diarrhea. Initial AEC was 3000/mm3. Esophagogastroduodenoscopy (EGD) and colonoscopy were performed, with biopsies revealing eosinophilic infiltration of the esophagus, terminal ileum, and colon. He was treated for presumed EGID with oral budesonide capsules and cromolyn, with persistent symptoms in the setting of increasing peripheral eosinophilia (AEC, 4800/mm3). Additional evaluation revealed elevated serum tryptase (56.1 g/L) and B12 (1367 pg/mL) levels. Peripheral blood flow cytometry did not show any evidence of a clonal process, and testing for parasitic infection, including Strongyloides stercoralis IgG, was unrevealing. A bone marrow biopsy was performed. The specimen contained scant marrow but showed increased eosinophils with a focal aggregate of CD25-positive mast cells, a finding that is usually suggestive (but not diagnostic) of systemic mastocytosis. Fluorescence in situ hybridization (FISH) assay was negative for FIP1L1-PDGFRA, and molecular testing was negative for D816V KIT mutation that is present in over 95% of patients with systemic mastocytosis. He was treated with prednisone (20-50 mg daily) beginning in early 2017 with persistent symptoms and AEC ranging from 5800 to 10,700/mm3. He was referred to the Clinical Center, National Institutes of Health for further evaluation. At his initial visit, he complained of persistent abdominal pain and diarrhea. Physical examination was notable only for splenomegaly, which was subsequently confirmed by computed tomography scan. Laboratory assessment revealed persistent eosinophilia (AEC, 6300/mm3) and elevated serum tryptase level (19.7 ng/mL). Despite a 5-year interval from the time of initial presentation, the patient's clinical symptoms were stable, and additional laboratory and diagnostic testing, including routine chemistries, serum troponin, EKG, echocardiography, pulmonary function tests, and computed tomography scan, showed no evidence of new end-organ involvement. Repeat bone marrow biopsy confirmed normal cellularity with increased eosinophils and atypical mast cell aggregates. RT-PCR assay detected the FIP1L1-PDGFRA fusion rearrangement in both peripheral blood and bone marrow. Allele-specific PCR testing for D816V KIT was negative. Patient was diagnosed with FIP1L1-PDGFRA positive chronic eosinophilic leukemia. Imatinib therapy (400 mg daily) resulted in clinical improvement and resolution of peripheral eosinophilia (AEC, 200/mm3) within 1 week of initiation of therapy and prednisone was tapered and discontinued. Bone marrow examination performed after 6 weeks on imatinib monotherapy was normocellular without eosinophilia or mast cell aggregates. Repeat EGD and colonoscopy with biopsies at the same visit demonstrated normal architecture of the esophagus, stomach, and small and large intestine, with the notable absence of eosinophils. Molecular testing for FIP1L1-PDGFRA fusion in blood and bone marrow became negative by 13 weeks after initiation of imatinib therapy, and the imatinib dose was decreased to 100 mg daily in early 2019. The patient has continued to do well, maintaining clinical, hematologic, and molecular remission since that time. The present case provides evidence that isolated eosinophilic GI involvement can occur in patients with PDGFRA-positive myeloid neoplasms and may mimic the presentation of EGID with peripheral eosinophilia. Clues to the diagnosis include the lack of response to corticosteroid therapy and other features of myeloid neoplasms, including splenomegaly and elevated serum tryptase and B12 levels. Laboratory evaluation of these patients should include testing for the FIP1L1-PDGFRA gene fusion product via FISH or RT-PCR, although false-negative results can occur, particularly with FISH assays (as in our patient). Although PDGFRA-positive myeloid neoplasms typically follow an aggressive course with high mortality in the absence of treatment, the FIP1L1-PDGFRA fusion is very sensitive to imatinib mesylate, with nearly all patients achieving durable clinical, hematological, and molecular remission. Thus, imatinib therapy should be instituted promptly even in asymptomatic patients once the diagnosis is confirmed. In situations in which confirmatory testing is unavailable, treatment should be initiated on the basis of clinical suspicion.