Laboratory Assessment of Patients with Hypereosinophilic Syndrome

嗜酸性胃肠道疾病(EGID)是以胃肠道(GI)任一段的嗜酸性炎症为特征的单器官高嗜酸性综合征(HESS)，包括嗜酸性食管炎、嗜酸性胃炎、嗜酸性胃肠炎和嗜酸性结肠炎。外周嗜酸性粒细胞增多(500/mm3)在EGID患者中很常见，一些患者表现为外周高嗜酸性粒细胞(绝对嗜酸性粒细胞计数AEC，1500/mm3)。在评估这类病例时，重要的是排除可能进展为多系统受累或需要替代治疗的其他HESS亚型。我们研究了一名患者，他最初表现为分离的、经活检证实的EGID，但后来被发现携带FIP1L1-PDGFRA融合基因，这是慢性嗜酸性白血病的标志。2012年，一名32岁的男子向外部机构报告腹痛和腹泻。初始AEC为3000/mm~3。进行了食管胃十二指肠镜(EGD)和结肠镜检查，活检发现食道、回肠末端和结肠有嗜酸性细胞浸润。他接受了口服布地奈德胶囊和色甘露治疗推定的EGID，并在外周嗜酸性粒细胞增多(AEC，4800/mm3)的背景下持续出现症状。进一步的评估显示血清类胰蛋白酶(56.1g/L)和B12(1367pg/ml)水平升高。外周血流式细胞术没有显示任何克隆过程的证据，寄生虫感染的检测，包括斯特里线虫免疫球蛋白，也没有揭示。进行骨髓活检。标本含有少量骨髓，但可见嗜酸性粒细胞增多，并有CD25阳性的肥大细胞聚集，这一发现通常提示(但不是诊断)系统性肥大细胞增多症。荧光原位杂交(FISH)检测FIP1L1-PDGFRA阴性，分子检测D816V KIT突变阴性，95%以上的系统性肥大细胞增多症患者存在D816V KIT突变。他从2017年初开始接受泼尼松(每天20-50毫克)治疗，出现持续症状，AEC从5800到10,700/mm3不等。 他被转介到国立卫生研究院临床中心进行进一步评估。在他第一次就诊时，他抱怨持续的腹痛和腹泻。体检仅在脾肿大方面值得注意，随后经计算机断层扫描证实。实验室评估显示持续的嗜酸性粒细胞增多症(AEC，6300/mm3)和血清类胰蛋白酶水平升高(19.7 ng/ml)。尽管患者最初出现症状的时间间隔为5年，但患者的临床症状稳定，其他实验室和诊断测试，包括常规化学、血清肌钙蛋白、EKG、超声心动图、肺功能测试和计算机断层扫描，均未显示新的终末器官受累的证据。重复骨髓活检证实细胞正常，嗜酸性粒细胞增多，不典型的肥大细胞聚集。RT-PCR检测外周血和骨髓中FIP1L1-PDGFRA融合重排。D816V试剂盒的等位基因特异性聚合酶链式反应为阴性。1例诊断为FIP1L1-PDGFRA阳性的慢性嗜酸性粒细胞白血病。伊马替尼治疗(每天400 mg)可在治疗开始后1周内改善和消除外周血嗜酸性粒细胞增多症(AEC，200/mm3)，并逐渐减少和停用强的松。伊马替尼治疗6周后，骨髓检查显示正常细胞，无嗜酸性粒细胞增多或肥大细胞聚集。重复EGD和结肠镜检查，并在同一就诊时进行活检，显示食道、胃、小肠和大肠结构正常，明显缺乏嗜酸性粒细胞。伊马替尼治疗开始后13周，血液和骨髓中FIP1L1-PDGFRA融合的分子检测转为阴性，2019年初伊马替尼剂量降至每天100毫克。自那时以来，患者一直表现良好，保持着临床、血液学和分子方面的缓解。 本病例提供的证据表明，PDGFRA阳性的髓系肿瘤患者可发生孤立的胃肠道嗜酸性粒细胞受累，其表现可能类似于外周嗜酸性粒细胞增多症。诊断的线索包括对皮质类固醇治疗缺乏反应和髓系肿瘤的其他特征，包括脾肿大和血清类胰蛋白酶和B12水平升高。对这些患者的实验室评估应包括通过FISH或RT-PCR检测FIP1L1-PDGFRA基因融合产物，尽管可能会出现假阴性结果，特别是FISH检测(如我们的患者)。尽管PDGFRA阳性的髓系肿瘤在缺乏治疗的情况下通常具有侵袭性，死亡率高，但FIP1L1-PDGFRA融合对甲磺酸伊马替尼非常敏感，几乎所有患者都获得了持久的临床、血液学和分子缓解。因此，伊马替尼治疗应立即开始，即使对无症状的患者，一旦诊断得到确认。在无法获得确证试验的情况下，应根据临床怀疑开始治疗。

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.