J Thromb Thrombolysis DOI 10.1007/s11239-014-1151-9
Hypereosinophilic syndrome as a cause of fatal thrombosis: two case reports with histological study Kumi Fujita • Hiroyasu Ishimaru • Kazuhiro Hatta Yoichiro Kobashi
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Ó Springer Science+Business Media New York 2014
Abstract Herein we present two cases of hypereosinophilic syndrome with a unique clinical presentation. One patient showed severe systemic thrombosis with splenic rupture and the other patient showed finger gangrene with various systemic symptoms. Both patients were examined histologically, and several characteristics were noted. First, fresh or organized thrombosis with marked eosinophilic infiltration was observed in the cavity and walls of the thrombosed vessels. Second, many eosinophils showed degranulation and were positive for eosinophilic cationic protein on immunohistological examination. Third, the structures of thrombosed vessels were well preserved, which is not observed in systemic vasculitis. These patients exhibited no neoplastic features and were treated with prednisolone with excellent therapeutic results. Keywords Hypereosinophilic syndrome Thrombosis Eosinophilic cationic protein
Introduction Hypereosinophilic syndrome (HES) is a group of disorders that results in damage to multiple organs and persistent eosinophilia without a specific cause such as parasite infection, allergic disorders, or malignancy [1–4]. Mural thrombosis of the cardiac wall is a typical finding in classic K. Fujita (&) Y. Kobashi Department of Diagnostic Pathology, Tenri Hospital, 200, Mishima-cho, Tenri-City, Nara, Japan e-mail:
[email protected] H. Ishimaru K. Hatta Department of General Medicine, Tenri Hospital, 200, Mishima-cho, Tenri-City, Nara, Japan
cases, but different clinical outcomes have been reported [5–7]. Although there are many case reports on HES, few reports have described the histological characteristics of HES in detail. In this study, we report two cases of HES and elucidate their characteristic histological profile.
Case reports Case 1 A 22–year–old woman was admitted to our hospital after presenting with pain in the left inguinal region. The patient underwent an appendectomy at 15 years of age and did not have a remarkable family history. The patient had been healthy until 1 month before admission, when she developed intermittent headaches and chest discomfort. Furthermore, she experienced acute onset of lower abdominal pain 1 week before admission and visited the emergency room of our hospital. The abdominal pain resolved after administration of antibiotics, but fever as well as pain in the left inguinal and lumbar regions persisted. On admission, the patient’s vital signs were as follows: blood pressure, 121/65 mm Hg; pulse rate, 66 beats/min; respiratory rate, 20 counts/min; and body temperature, 37.9 °C. The patient was alert. There was no skin eruption, and the heart and lungs appeared normal. The abdomen was slightly distended with hypoactive bowel sounds and without defense. Abdominal tenderness occurred, particularly around the left area. The laboratory tests results were as follows: hemoglobin, 10.3 g/dL; hematocrit, 34.7 %; platelet count, 63,000/ lL; white blood cell count, 16,000/lL (blood lymphocytes, 15.5 %; monocytes, 2.0 %; eosinophils, 37.0 %; basophils, 1.0 %; segmented neutrophils, 39.0 %; and band
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On day 3 after admission, the patient experienced syncope and worsened left abdominal pain. On day 5, computed tomographic (CT) scan and abdominal ultrasonography revealed thrombus formation from the trunk of the portal vein, superior mesenteric vein, splenic vein, and right hepatic vein to deep veins in the lower extremities (Fig. 1a). On day 6, the patient went into hypovolemic shock, and the CT scan revealed splenic rupture with intra–abdominal hemorrhage (Fig. 1b). Catheter embolization of the splenic artery was performed, followed by open surgery. We observed 5,000 mL of bloody peritoneal effusion with coagula, without any sign of inflammation. The gastrointestinal tract, liver, uterus, and adnexa on both sides appeared normal. Splenectomy was also performed. Prednisolone at 40 mg with anticoagulation therapy was initiated after the operation. Serum hypereosinophilia and multiple thromboses resolved, and the dose of prednisolone was gradually reduced. The patient was discharged on day 71 and has remained healthy since then; moreover, she gave birth 3 years after discharge. Case 2
Fig. 1 Contrast–enhanced computed tomography images. a Portal vein thrombosis detected on the portal vein phase. b Spleen rupture with massive intraabdominal hemorrhage
neutrophils, 5.5 %); C–reactive protein, 1.9 mg/dL; prothrombin time (PT), 13.2 s; PT–international normalized ratio, 1.45; activated partial thromboplastin time, 37.5 s; fibrinogen, 229 mg/dL; antithrombin III, 94 %; fibrinogen degradation products, 55 lg/dL; D–dimer, 31.0 lg/dL; blood urea nitrogen, 5.7 mg/dL; creatinine, 0.8 mg/dL; total cholesterol, 138 mg/dL; total protein, 6.7 g/dL; albumin, 3.5 g/dL; lactate dehydrogenase, 252 IU/L; aspartate aminotransferase, 21 IU/L; alanine aminotransferase, 25 IU/L; total bilirubin, 0.3 mg/dL; c-glutamyl transpeptidase, 13 IU/L; alkaline phosphatase, 407 IU/L; creatine kinase, 56 mg/dL; Na, 143 mmol/L; K, 3.9 mmol/ L; Cl, 107 mmol/L; rheumatoid factor, 0.9; and erythrocyte sedimentation rate, 16 mm/h. Proteinase 3–antineutrophil cytoplasmic antibody, myeloperoxidase–antineutrophil cytoplasmic antibody, anti–cardiolipin antibody, and lupus anticoagulant were unremarkable. Protein C activity was 51 % (normal range is 73–142 %), and protein S activity was 73 % (normal range is 60–150 %). The test results for blood, urine, and stool cultures were within normal limits. Screening test results for parasites were negative. No remarkable findings were observed on the chest radiograph, electrocardiograph, and ultrasound cardiograph.
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A 36–year–old male patient visited our hospital because of palsy and pain in the right middle finger. The patient had a subcutaneous mass lesion in the upper extremity and serum hypereosinophilia (white blood cell count, 15,400/lL; eosinophils, 21.0 %) at 33 years of age. Biopsies of the subcutaneous mass lesion and kidney were performed, and Kimura’s disease and membranous glomerulonephritis were diagnosed. Although magnetic resonance imaging of the head revealed a mass lesion in the sellar region when the patient was aged 35 years, the lesion subsided spontaneously without any therapy. Throughout the clinical course, the patient’s eosinophil count was as high as 2,000–3,000/lL. He was prescribed prednisolone at a dosage of 10 mg/day. On admission, the patient’s height was 175 cm and weight was 85 kg, and vital signs were: blood pressure, 128/84 mm Hg; pulse rate, 84 beats/min; body temperature, 36.3 °C; mental status: alert. The heart and lungs appeared normal. The pulse of the right radial artery and dorsalis pedis was hardly palpable on both sides. There was an ulcer in the right middle finger and a 7–cm nodule on the left thigh. The laboratory test results on admission were as follows: hemoglobin, 13.4 g/dL; hematocrit, 37.6 %; white blood cell count, 15,400/lL (blood lymphocytes, 24.0 %; monocytes, 4.5 %; eosinophils, 21.0 %; segmented neutrophils, 47.0 %; and band neutrophils, 3.0 %); platelets, 431,000/ lL; PT, 11.8 s (international normalized ratio, 1.22); activated partial thromboplastin time, 26.5 s; C–reactive protein, 1.9 mg/dL; erythrocyte sedimentation rate, 44 mm/h; blood urea nitrogen, 6.3 mg/dL; creatinine, 0.9 mg/dL; total
Hypereosinophilic syndrome as a cause of fatal thrombosis
Fig. 2 Histology of the spleen of case 1 a Macrostructure of the spleen. Ruptured spleen capsule with the presence of coagula. b A low–power field picture of the spleen (Loupe). Vessels with fresh or partially organized thrombi can be observed. Hemorrhage can be observed in the parenchyma and subcapsular regions. c, d The wall of the thrombosed vein is well preserved and a marked eosinophilic
infiltration was observed in and around the vessel wall; c hematoxylin and eosin staining; d Elastic van Gieson staining (original magnification at 920). e Marked eosinophilic infiltration was observed in and around the vessel wall (original magnification at 9200). f Eosinophils on the vessel wall are immunoreactive for ECP (original magnification at 9200)
protein, 6.3 g/dL; albumin, 4.1 g/dL; aspartate aminotransferase, 24 IU/L; alanine aminotransferase, 36 IU/L; lactate dehydrogenase, 252 IU/L; Na, 138 mmol/L; K, 3.3 mmol/ L; Cl, 102 mmol/L; IgE, 17,581 U/mL; rheumatoid factor, 67.6 IU/mL; myeloperoxidase–antineutrophil cytoplasmic antibody \10 EU; and proteinase 3–antineutrophil cytoplasmic antibody \10 EU. The urine test result was within normal limits; no remarkable findings were observed on the chest radiograph and electrocardiograph. Chromosome analysis showed a normal karyotype. Skin biopsy in the left femoral region was performed. Treatment with prednisolone (60 mg), cyclosporin A (100 mg), and prostaglandin E1 was initiated. The lesion in the left thigh showed improvement but that in the finger did not; therefore, the finger was amputated after 1 year. Since then, the patient has been healthy for more than 5 years.
Materials and methods Tissue samples were fixed in 10 % neutral–buffered formalin, embedded in paraffin, and cut into 4–micrometer– thick sections. Samples were stained with hematoxylin and eosin or Elastica van Gieson. Eosinophilic cationic protein (ECP) (EG2, Nichirei, Tokyo, Japan) was examined immunohistochemically in case 1. Pathological findings Case 1 Macroscopically, the spleen capsule ruptured, and coagula were present in the subcapsular region. The dimensions of the spleen were 16 9 11 9 5 cm, and the weight was
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Fig. 3 Micrograph of case 2. A vessel in the subcutaneous thrombosed tissue. A marked eosinophilic infiltration was observed in and around the vessel wall on hematoxylin and eosin staining (a), but the
vessel wall structure was well preserved on Elastic van Gieson staining (b) (original magnification at 920)
465 g. Histological examination revealed different venous thrombi, from fresh to old organized thrombi, in several venous vessels in the spleen. Marked eosinophilic infiltration was observed in the cavity and wall of the thrombosed vein, and eosinophil degranulation was observed. Immunohistological examination indicated the presence of ECP in the eosinophils within the thrombi. The arteries appeared normal. Furthermore, The structure of the vein with the thrombus was preserved, and fibrinoid necrosis was not observed (Fig. 2).
cases of eosinophilic leukemia with little evidence of neoplastic features, and therefore these patients were diagnosed with HES, which is a group of disorders that includes Loeffler’s endocarditis [1]. In 1975, Chusid et al. proposed the following diagnostic criteria for HES: (1) persistent eosinophilia with an eosinophil count of 1,500/ mm3 for more than 6 months or death associated with signs and symptoms of hypereosinophilic disease within these 6 months; (2) lack of evidence of parasitic, allergic, or other known causes of eosinophilia; and (3) presumptive signs and symptoms of organ involvement including hepatosplenomegaly, organic heart murmur, congestive heart failure, diffuse or focal central nervous system abnormalities, pulmonary fibrosis, fever, weight loss, and anemia [2]. The main clinical symptoms of HES are believed to be associated with thrombus formation. Endomyocarditis or myocarditis along with mural thrombus formation with marked eosinophilic infiltration is a typical form of HES [6]. However, venous thrombosis presents as the main clinical manifestation in some cases [7]. Poor prognosis is attributed to thrombosis itself. In the first case reported herein, the condition could have been fatal if the correct diagnosis and treatment were not provided, although the patient’s clinical course was shorter. In the second case, hypereosinophilia persisted for more than 6 months (i.e., long–term serum hypereosinophilia). Therefore, the two cases satisfied the criteria of HES proposed by Chusid et al. [2]. Moreover, peripheral
Case 2 A thrombus of the muscular artery was observed in the subcutaneous region upon histological examination. Many degranulated eosinophils were observed in the cavity and wall of the thrombosed vessel. The structure of the thrombosed vessel was preserved considerably. Fibrinoid necrosis was not observed (Fig. 3).
Discussion In 1965, Odeberg et al. reconsidered the diagnosis of eosinophilic leukemia and reported the concept of disseminated eosinophilic collagen disease [8]. The latter could be distinguished from the former because it was non– neoplastic. In 1968, Hardy and Anderson reported three
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thrombosis seemed to be the main clinical feature in these two cases, without evidence of cardiac involvement. The histological findings in these two cases showed common characteristics, including thrombosis with marked eosinophilic infiltration. Eosinophil degranulation and tissue necrosis were also observed. Degranulation of eosinophils suggested their role in thrombus formation. In case 1, the expression of ECP in eosinophils could be considered an indirect evidence of cytotoxicity of ECP. Furthermore, tissue damage by eosinophils might promote thrombosis. In 1982, Fauci et al. described the mechanism of tissue injury caused by eosinophils [3]. The space occupied by eosinophil accumulation leads to tissue damage due to the activity of eosinophils and other thromboembolic phenomena. Eosinophils contain granules with some cationic cytotoxic proteins such as ECP, major basic protein, eosinophil peroxidase, and eosinophil–derived neurotoxin [4]. In particular, the role of ECP in thrombosis is well described [9–11]. Thrombus formation can be explained by the activation of urokinase–induced plasminogen by ECP [10] or by the stimulation of activation factor XII by ECP [11]. It remains unclear whether eosinophilic proliferation in HES is a neoplasm population. Although it is difficult to confirm the clonality of eosinophils, some cases of HES with cytogenic abnormalities have been reported [12]. Since 2002, many researchers have reported that imatinib can be effective against HES [13, 14]. These studies revealed that some HES cases were associated with chromosomal abnormalities such as fusion of the genes coding for FLP1L1 and a receptor tyrosine kinase–platelet– derived growth factor receptor a (PDGFRa)—on chromosome 4q12. This indicates that HES is a neoplastic disease. However, a study by Jovanovic et al. revealed that only 11 % of the 376 patients with HES harbored the FLP1L1– PDGFRa fusion gene [15]. HES patients with chromosomal abnormalities do not necessarily follow the clinical course of patients with a malignant neoplasm like myeloproliferative disease, and some patients respond to corticosteroids, as observed in the patients reported herein [2– 5]. In our study, the second patient had normal chromosomes; however, the genetic examination was not performed in case 1. Both patients responded well to corticosteroid therapy along with anticoagulants, and their clinical course was excellent after more than 3 years of follow–up. These results can be used to differentiate a hypereosinophilic state from cases of malignant disorders. Genetic studies on HES should be conducted in the near future and patients with HES should have a long–term follow–up. HES should be considered as a group of thrombosis–associated disorders that can lead to poor prognosis even if HES is not neoplastic. This is important for the appropriate management of patients with HES.
Although there are many case reports on HES, only a few reports have described its histological characteristics in detail, which can be important for assessing complications associated with thrombosis and for differentiating HES from vasculitis syndromes such as eosinophilic granulomatosis with polyangiitis. Accordingly, pathologists should recommend appropriate treatment after the pathological diagnosis of HES.
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