Eosinophilia in a patient with aggressive systemic mastocytosis harboring a KIT D816V mutation: A case report

Abstract

Eosinophilia may result from three main causes: secondary (reactive), primary (clonal), and/or idiopathic. The diagnosis of idiopathic eosinophilia must be made based on excluding all reactive or clonal causes. However, some causes may be very rare so as to be misdiagnosed as idiopathic. We present the case of eosinophilia caused by aggressive systemic mastocytosis, originally recognized as idiopathic. Lymphadenopathy, dysmyelopoiesis, and hepatosplenomegaly gradually appeared and deteriorated with increasing eosinophils. This case carried KIT D816V mutation. The BCR::ABL fusion gene and the mutations in JAK2 V617F, PDGFRα, and PDGFRβ in bone marrow were all negative. PHF6, PPM1D, and TET2 mutations were demonstrable. The patient was prescribed to avapritinib. The condition was effectively controlled. However, the patient discontinued medication for economic reasons 5 months later. Disease progression happened and died 10 months after diagnosis. Our study indicates that gene mutation detection at diagnosis is helpful for patient accurate diagnosis and targeted therapy of such patients.

Introduction

Eosinophilia is defined as an elevation of the eosinophil count in peripheral blood above 0.5 × 10⁹/L. The definition of hypereosinophilia (HE) is an eosinophil count of 1.5 × 10⁹/L or greater persisting for at least 6 months, for which no underlying cause can be found. ¹ Eosinophilia may result from three main causes: secondary (reactive), primary (clonal), and/or idiopathic. The diagnosis of idiopathic eosinophilia must be made based on excluding all reactive or clonal causes. However, some causes may be very rare so as to be misdiagnosed as idiopathic. Systemic mastocytosis (SM) is a rare disease and the global cases are relatively scarce. ² Aggressive SM (ASM) is reported to account for only about 12% of SM. ³ Here, we report a case of eosinophilia caused by ASM in detail, originally recognized as idiopathic.

Case report

A 74-year-old male was admitted to hospital on August 25, 2021 with upper abdominal discomfort and eosinophilia for more than 4 months. Five years ago, he developed gastric carcinoma in situ and underwent subtotal gastrectomy. He remained stable in conjunction to the follow-up visit.

In early April 2021, this patient felt upper abdominal discomfort and went to hospital repeatedly. Blood routine and liver function results showed increased white blood cells (WBC) with prominent eosinophilia, followed by HE, anemia, thrombocytopenia, elevated glutamyltransferase (GGT), and alkaline phosphatase (ALP) (Table 1). Serum total immunoglobulin E was elevated (351.758 KIU/L, reference upper limit 100). Parasites were not found in stool. Serum allergens and parasites were negative. Serological tests for human immunodeficiency virus, hepatitis B virus (HBV), hepatitis C virus, cytomegalovirus, Epstein-Barr virus, and minvovirus 19 were negative. HBV testing showed that HBsAg and anti-HBc were all positive, but no HBV-DNA was detected. Ca-199 was elevated (98.2 U/mL), and the other tumor (especially gastric cancer) markers such as CEA, CA15-3, CA125, and CA72-4 were all within normal limits. Computed tomography (CT) in the lungs showed: (1) chronic bronchitis, emphysema, partial bronchiectasis in both lungs, and a few inflammatory foci in the upper lobe of the right lung, (2) multiple small nodules in both lungs, and (3) pleural thickening on both sides, a little pleural effusion on both sides in the lungs. Abdominal CT suggested cholecystitis and enlarged extra abdominal lymph nodes. Positron emission tomography-CT (PET-CT) displayed multiple enlarged lymph nodes between interportal lumen and mesenteric roots with the biggest 34.5 × 19.7 mm and SUV 4.48 (Supplemental Figure S1). Gastroscopy demonstrated a residual gastritis. Next-generation sequencing (NGS) results in peripheral blood indicated that no bacteria, fungi, viruses, parasites, mycobacteria, and chlamydia were detected. Bone marrow (BM) smear showed significantly increased eosinophils (19%; Supplemental Figure S2). The BCR::ABL fusion gene and the mutations in JAK2 V617F, PDGFRα, and PDGFRβ in BM by polymerase chain reaction were all negative. The diagnosis of an idiopathic eosinophilia syndrome besides cholecystitis was made in June 2021. Piperacillin tazobactam was administered for treating cholecystitis. Prednisone and imatinib were prescribed to control eosinophils.

Table 1.

Blood routine and liver function index results.

Date	WBC (×109/L)	E (×109/L)	Hb (g/L)	PLT (×109/L)	GGT (U/L)	ALP (U/L)
2020/4/14	9.2	0.9	119	91	14	138
2021/5/25	13.7	2.66	112	87	298	746
2021/6/17	16.1	5.15	105	81	430	780
2021/8/1	24.2	5.59	103	81	388	1263

WBC: white blood cells; E: eosinophils; Hb: hemoglobin; PLT: platelet; GGT: glutamyltransferase; ALP: alkaline phosphatase.

More than 2 months later, the patient still felt upper abdominal discomfort and developed progressive fatigue with a significant 5-kg weight loss, occasional chest tightness, and skin itching. On August 25, 2021, the patient was transferred to our hospital. Physical examination showed that the upper abdomen was slightly tender on palpation. No skin lesions were observed. Superficial lymph nodes were untouched. Laboratory data showed that WBC was higher (54.9 × 10⁹/L) and E reached 17.24 × 10⁹/L. GGT and ALP were 383 U/L and 1226 U/L, respectively. Abdominal CT suggested hepatosplenomegaly (Supplemental Figure S3). Laparoscopic lymphadenectomy was performed. The HE staining of the lymph node samples showed the existence of some lymph node structure, significant hyperplasia of spindle cells in the interfollicular area, and a false follicle-like structure with a large amount of eosinophil infiltration in some spindle cells. Immunohistochemistry showed that the spindle-form atypical cells were CD117+ and CD25+ (Figure 1). Serum trypsin level was not performed due to limited laboratory conditions. KIT D816V mutation was identified on the lymph node specimen by DNA sequencing techniques. We reexamined the previous BM specimen, indicating hyperplasia was extremely active, and mast cells were cytoplasma-rich, mildly eosinophilic cytoplasm with irregular morphology, expressing CD117, CD25, and CD30 (Supplemental Figure S4). Based on an ultra-deep 521-gene sequencing panel (Supplemental Table S1), NGS results in the lymph node specimen showed that mutations in KIT, PHF6, PPM1D, and TET2 were discovered (Table 2). The patient was eventually diagnosed as ASM. The case scored three points, according to the Mayo Alliance Prognostic System (MAPS), while five points by Mutation-Adjusted Risk Score (MARS). The two scoring systems both stratified the case as high-risk. Avapritinib was administered at 200 mg per day.

Figure 1.

(a–e) H&E staining showed the presence of some lymph node structures with significant hyperplasia of spindle-shaped atypical cells in the interfollicular area, and some spindle cells showed a false follicle-like structure with large amounts of eosinophil infiltration. (f) CD3 showed the residual interfollicular T cells. (g) CD20 showed the residual follicular structure. (h) LCA showed strong positive for residual follicles and weakly positive for spindle cells. (i, j) CD117 showed diffuse strong positive spindle-shaped atypical cells. (k, l) CD25 showed diffuse strong positive for spindle atypical cells. H&E: hematoxylin-eosin; LCA: leukocyte common antigen (CD45).

Table 2.

Next-generation sequencing results in the pathological tissue specimen.

Mutated gene	Transcript ID	NT alteration	AA alteration	VAF
KIT	NM_000222	c.2447A>T	p.D816V	22.05%
PHF6	NM_001015877	c.385C>T	p.R129x	68.38%
	NM_001015877	c.725delG	p.C242fs	1.76%
PPM1D	NM_003620	c.1714C>T	p.R572X	38.64%
TET2	NM_001127208	c.2188delA	p.T730fs	34.36%
	NM_001127208	c.4054G>T	p.E1352x	32.67%
	NM_001127208	c.5734C>T	p.H1912Y	1.00%

NT: Nucleotide; AA: Amino acid; VAF: Variant allele frequency.

During hospital stay, the patient repeatedly complained of fatigue, chest tightness, occasionally hypotension, abdominal pain, diarrhea, and night sweat. After more than 1 month, the symptoms improved significantly. As for laboratory data, the WBC and eosinophils dropped to normal after about 1 week. The platelets rose to near normal after about half a month, declined possibly due to avapritinib and recovered after dose reduction. GGT and ALP gradually decreased with the follow-up. However, anemia still persisted because of infection and diarrhea (Figure 2). Furthermore, KIT D816V allele burden in BM and serum trypsin level were not tested due to limited laboratory conditions. Regretfully, the patient discontinued medication for economic reasons five months later. Disease progression happened and died 10 months after diagnosis.

Figure 2.

Flowchart showed the changes of blood routine and liver function indexes after avapritinib treatment, including (a) WBC, (b) E, (c) Hb, (d) PLT, (e) GGT, and (f) ALP.

Discussion

Here, we presented a case of a patient with diagnosis of ASM. Eosinophilia/HE was a prominent clinical manifestation. Originally, we tried to explore the causes. However, we could not find any reactive or secondary reasons including allergies, parasitic or viral infections, and even the recurrence of gastric cancer. The BM examination did not prove to be clonal for a hematologic neoplasm such as chronic eosinophilic leukemia (CEL) or other myeloid neoplasms associated with eosinophilia such as myeloproliferative neoplasm (MPN) or myelodysplastic syndrome (MDS)/MPN. Moreover, we had not noticed the presence of mast cells due to a lack of clinical experience and the rarity of SM. Consequently, the eosinophilia/HE was misdiagnosed as idiopathic at first. Eventually, it cost almost half a year from the beginning of the disease to the date when the ASM diagnosis was made. This case was a typical ASM. The abnormal/clonal mast cells were detected in the intraperitoneal lymph nodes, expressing CD25 and carrying KIT D816V mutation. The case showed “B symptoms” including hepatosplenomegaly and lymphadenopathy. The case also had “C findings” such as anemia, thrombocytopenia, and liver function injury. Accordingly, the case fulfilled the criteria of ASM.^4,5

Although SM is a rare disease, marked and sustained eosinophilia is observed in a significant number of patients with SM (SM-eo). ⁶ Eosinophilia/HE is mainly seen in patients with advanced SM (17%/19%), which comprises ASM, SM with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia. It is not surprising that eosinophilia/HE is present in patients with SM-AHN, which may have CEL or other myeloid neoplasms associated with eosinophilia such as MPN or MDS/MPN. ⁷ Eosinophilia/HE may be demonstrable in ASM patients, but criteria for clonal eosinophil disorders are not fulfilled like in our case.

Eosinophilia can indicate an aggressive disease and the eosinophil count may correlate with organomegaly and dysmyelopoiesis. ⁸ In our case, lymphadenopathy, dysmyelopoiesis, and hepatosplenomegaly gradually appeared and deteriorated with increasing eosinophils. It is of great importance to apply clinical, molecular, and cytogenetic markers to make subcategory and risk stratification for an SM-eo. This case carried KIT D816V mutation like over 70% of ASM cases.^4,9 The BCR::ABL fusion gene and the mutations in JAK2 V617F, PDGFRα, and PDGFRβ in BM were all negative. Therefore, the case could not fulfill a clonal eosinophil disorder such as CEL or other MPN. MAPS discovers that SM patients with ASXL1, RUNX1, or NRAS mutated genes have poor outcome. ¹⁰ MARS uses SRSF2, ASXL1, and RUNX1 mutated genes as prognostic factors of SM. ¹¹ In our case, the genes mentioned above were not detected, while PHF6, PPM1D, and TET2 mutations were demonstrable, to be further explored. As to the treatment for ASM, avapritinib is highly selective against the KIT D816V mutation. ¹² Clinical studies have demonstrated a significant efficacy of avapritinib in ASM.^13–15 Our patient was prescribed to avapritinib and the condition was effectively controlled. Laboratory data improved significantly, except for hemoglobin due to infection and diarrhea. Regretfully, the patient discontinued medication for economic reasons 5 months later. Disease progression happened and died ten months after diagnosis.

Conclusion

In summary, we present an ASM patient with prominent eosinophilia treated with avapritinib. Our study highlights that the possibility of SM diagnosis should be considered in patients with unexplained eosinophilia, and gene mutation detection at diagnosis is helpful for patient accurate diagnosis and subsequent targeted therapy.

Supplemental Material

sj-docx-1-sco-10.1177_2050313X231197322 – Supplemental material for Eosinophilia in a patient with aggressive systemic mastocytosis harboring a KIT D816V mutation: A case report

Supplemental material, sj-docx-1-sco-10.1177_2050313X231197322 for Eosinophilia in a patient with aggressive systemic mastocytosis harboring a KIT D816V mutation: A case report by Lihong Cao, Hongyan Tong, Xing Liu, Qi Pan, Yingqing Xu, Jin Lai, Wenjun Zheng, Jian Huang, Zhaoming Wang, Shengli Ye, Liming Zhang, Jiayue Qin and Jie Jin in SAGE Open Medical Case Reports