American Journal of Hematology 74:64–67 (2003)
Hypereosinophilia Associated With Cardiac Rhabdomyosarcoma Vincent Lo Re III,1* Kevin R. Fox,2 Victor A. Ferrari,3 Craig H. Scott,3 Plamen M. Kossev,4 and Jay R. Kostman1 1
Division of Infectious Diseases, Department of Internal Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 2 Division of Hematology and Oncology, Department of Internal Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 3 Division of Cardiovascular Medicine, Department of Internal Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 4 Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Hypereosinophilia, defined as an absolute eosinophil count exceeding 1,500/mm3, is caused by a limited number of disorders. Its association with malignancy is a rare occurrence that typically denotes extensive metastasis and a poor prognosis. Several theories have been proposed to explain the hypereosinophilia associated with malignancy, focusing on the production of eosinophilopoietic cytokines by tumors. We describe a patient with hypereosinophilia associated with a cardiac rhabdomyosarcoma, review the etiologies of hypereosinophilia, and discuss the possible mechanisms. Am. J. Hematol. 74:64–67, 2003. © 2003 Wiley-Liss, Inc. Key words: hypereosinophilia; eosinophilia; rhabdomyosarcoma
INTRODUCTION
An increase in the level of peripheral blood eosinophils accompanies a variety of diseases, but a marked accumulation of eosinophils encompasses a more limited list of conditions. The recognition of hypereosinophilia, defined by most authorities as an absolute eosinophil count above 1,500/mm3, can help clinicians focus their differential diagnoses [1]. Hypereosinophilia in malignancy is an uncommon occurrence that typically carries a poor prognosis. We present a case of hypereosinophilia associated with a cardiac rhabdomyosarcoma. CASE REPORT
A 20-year-old man with no significant past medical history presented to the hospital for continued evaluation of fever, severe leukocytosis, and hypereosinophilia. Three months prior to admission, the patient went camping for 1 week in the Adirondack Mountains of New York. During his trip, he ate cooked meats and drank only bottled water. Two days after his return, he developed a low-grade fever of 100.5°F, nausea, and intermittent diarrhea. His primary care physicians treated him © 2003 Wiley-Liss, Inc.
with a 5-day course of azithromycin, and his symptoms resolved. However, 2 days after the completion of the antibiotic therapy, he developed myalgias in his calves, arms, and lower back, and his low-grade fever returned. Two months prior to admission, the patient presented to his primary physician for evaluation of his fever and myalgias. His physical examination was remarkable only for conjunctival pallor. His white blood cell (WBC) count was 34,000/mm3 with 8% eosinophils (absolute eosinophil count ⳱ 2,720/mm3), and his hemoglobin was 8.8 g/dL. No prior complete blood count was available. A peripheral smear showed mature eosinophils and no blasts. Chest and abdominal computed tomographic
*Correspondence to: Vincent Lo Re III, M.D. (last name “Lo Re”), Division of Infectious Diseases, University of Pennsylvania School of Medicine, 502 Johnson Pavilion, Philadelphia, PA 19104. E-mail:
[email protected] Received for publication 14 September 2002; Accepted 15 April 2003 Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ajh.10373
Case Report: Hypereosinophilia Due to Rhabdomyosarcoma
(CT) scans were unremarkable, and he was referred to a hematologist for further work-up. One month prior to admission, he underwent a bone marrow biopsy that showed hypercellular marrow with myeloid hyperplasia. There were 3% eosinophils identified on the bone marrow aspirate differential. The Philadelphia chromosome was not present. The patient’s hematologist felt that his presentation was consistent with a BCR-negative myeloproliferative disorder and recommended treatment with imatinib, a protein tyrosine kinase inhibitor [2]. Despite 3 weeks of therapy with this agent, the patient’s WBC count continued to climb, and he began to experience intermittent heaviness in his chest. Treatment with imatinib was discontinued at this time, and he was subsequently admitted to the hospital for further evaluation. Upon admission, the patient primarily complained of worsening fatigue and mild generalized myalgias. His only medication was occasional acetaminophen, and he denied use of vitamins and other non-prescription health products. He had never traveled outside the United States, and he had no pet exposures. On physical examination, he appeared chronically ill and was febrile to 101.9°F. A new 2/6 holosystolic murmur was audible at the apex. There were no cutaneous lesions, rashes, or peripheral stigmata of subacute bacterial endocarditis. Other aspects of the physical examination were unremarkable. His WBC count was 57,500/mm3 with 52% neutrophils, 24% bands, 9% lymphocytes, and 15% eosinophils (absolute eosinophil count ⳱ 8,625/mm3). The hemoglobin was 7.4 g/dL, and the platelet count was 134,000/mm3. The peripheral smear again showed a preponderance of only mature eosinophils. The patient’s electrolytes, coagulation studies, liver function tests, and urinalysis were normal, and examinations of stool for ova and parasites were negative. A chest radiograph was unrevealing. An abdominal CT scan was performed and showed two lesions in the anterior and posterior spleen and a wedge-shaped defect in the right kidney consistent with splenic and renal infarcts (Fig. 1). In light of the multiple embolic phenomena suggested by the CT scan and the new heart murmur, a transthoracic echocardiogram was obtained to evaluate for potential cardiac sources of embolism. A 9.0 × 4.0 cm mobile multi-lobulated mass was noted in the left atrium, which extended from the midinteratrial septum to the tip of the anterior mitral valve leaflet (Fig. 2). The body of the mass was found to prolapse across the mitral valve to the mid-left ventricle during diastole, and moderate mitral regurgitation was present. The base of the mass was contiguous with the aortic root and extended into the left atrial appendage. Cardiology and cardiothoracic surgery consultations were obtained, but as the patient was being interviewed, he developed acute dysarthria and right-sided hemiple-
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Fig. 1. Abdominal computed tomographic scan revealing a right renal infarct (black arrow) and a posterior splenic infarct (white arrow).
Fig. 2. Transthoracic echocardiogram (parasternal long axis view) revealing 9.0 × 4.0 cm mobile mass (M) originating in the left atrium (LA) and prolapsing across the leaflets of the mitral valve (white arrows) into the mid-left ventricle (LV) during diastole. The base of the mass is contiguous with the aortic root (Ao).
gia. An emergent head CT scan revealed an acute left frontal lobe hemorrhage and an evolving right middle cerebral artery infarction. The patient was subsequently taken to the operating room for resection of the intracardiac mass. The histologic appearance of the frozen and formalin-fixed sections was that of a spindle cell neoplasm with significant cellular aplasia and extensive zonal necrosis. The tumor cells were positive for vimentin, sarcomeric actin, and S100 and negative for lymphoid and epithelioid markers. The morphology and the staining pattern were consistent with a diagnosis of rhabdomyosarcoma (Fig. 3). Postoperatively, the patient received local irradiation. How-
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Case Report: Lo Re et al. TABLE I. Disorders Commonly Associated With Hypereosinophilia* Idiopathic hypereosinophilic syndrome Asthma Drug reaction Eosinophilia–myalgia syndrome Toxic oil syndrome Cutaneous disease Bullous pemphigoid Episodic angioedema with eosinophilia Collagen vascular disease Churg–Strauss syndrome Eosinophilic fasciitis Radiation therapy Eosinophilic gastroenteritis Familial eosinophila
Fig. 3. Photomicrograph of a hematoxylin–eosin-stained section of the cardiac rhabdomyosarcoma, original magnifications 200× and 1000×, respectively (magnified area), showing spindle cell tumor with prominent nuclear atypia and abundant eosinophilic cytoplasm. Numerous eosinophils and neutrophils are infiltrating the tumor. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
ever, 4 weeks later, he developed a cutaneous metastasis to the right temple as well as metastatic involvement of the retroperitoneum. He elected to have palliative care. DISCUSSION
Eosinophilia occurs when the absolute eosinophil count exceeds the usual maximum level of 350/mm3 and is associated with a wide variety of conditions [3]. However, hypereosinophilia, defined as an absolute eosinophil count of over 1,500/mm3, is associated with fewer conditions (Table I), and its recognition can help narrow the differential diagnosis [1]. Hypereosinophilia is associated with helminthic infections [4], intrinsic asthma [5], and collagen vascular diseases such as Churg– Strauss syndrome [6] and eosinophilic fasciitis [7]. It has been seen in radiation therapy [6], cutaneous diseases such as bullous pemphigoid [5] and episodic angioedema with eosinophilia [8], and a number of drug reactions, most notably the eosinophilia–myalgia syndrome due to L-tryptophan [9] and the toxic oil syndrome due to rapeseed oil [6]. Eosinophilic gastroenteritis, characterized by eosinophilic infiltration of gastrointestinal tissue, has also been associated with hypereosinophilia [10]. In 1975, Chusid et al. [11] defined the idiopathic hypereosinophilic syndrome as hypereosinophilia that persists for more than 6 months without underlying cause and that is associated with extensive infiltrates of mature eosinophils in multiple organs. The idiopathic hypereosinophilic syndrome affects adults, particularly men, from 20 to 50 years of age, and primarily affects the brain, pro-
Parasitic infection Ascariasis Filariae Hookworms Paragonimiasis Schistosomiasis Strongyloidiasis Toxocariasis Trichinosis Malignancy Lymphoma Hodgkin’s disease T-cell lymphomas Leukemia Acute lymphoblastic Acute myelogenous Chronic myelogenous T cell Adenocarcinoma Ovarian
*Hypereosinophilia is defined as an absolute eosinophil count exceeding 1,500/mm3.
ducing encephalopathy, and the heart, causing endomyocardial fibrosis (Lo¨ffler’s endocarditis). Hypereosinophilia has occasionally been encountered in patients with a variety of malignancies. Rheinbach was the first to report such a case in 1883, describing a patient with a metastatic head and neck cancer who had a WBC count of 120,000/mm3 and 40% eosinophils [12]. In 1946, Isaacson and Rapoport [12] presented 34 cases of eosinophilia associated with malignant neoplasms, with more than half having hypereosinophilia (absolute eosinophil count > 1,500/mm3). This finding was more frequently identified with extensive metastatic tumors and was generally a poor prognostic sign. Tumor-associated hypereosinophilia has been found to be unrelated to the histologic type of tumor, but most frequently occurs in hematologic malignancies [13]. It has been well described in Hodgkin’s disease as well as in T-cell lymphomas, particularly T-cell lymphoblastic lymphoma and mycosis fungoides [13]. It has also been associated with cases of acute lymphoblastic leukemia, acute myelogenous leukemia, and chronic myelogenous leukemia [3,13]. Acute eosinophilic leukemia is a rare disorder that almost always presents with hypereosinophilia and is distinguished by the marked increase in immature eosinophils in the blood and bone marrow [5]. Hypereosinophilia is encountered with less frequency in malignancies of the head and neck, ovaries, uterus, breast, pancreas, lungs, liver, thyroid gland, and gastrointestinal tract [5,13,14]. Soft-tissue sarcomas are rarely associated with hypereosinophilia, and only 7 cases have been described in the literature [12,14–16]. When this patient first presented to the hospital, the recognition of his hypereosinophilia opened up a number
Case Report: Hypereosinophilia Due to Rhabdomyosarcoma
of diagnostic possibilities. Given his lack of international travel, absence of cutaneous manifestations, and minimal use of medications, we were able to eliminate many of the potential etiologies associated with hypereosinophilia. We thus narrowed our list to a malignancy and the idiopathic hypereosinophilic syndrome, a diagnosis of exclusion that should be determined only after all other causes of hypereosinophilia have been excluded. Ultimately, the abdominal CT findings suggested embolization from a cardiac source, and this prompted further examination of the patient’s heart with a transthoracic echocardiogram. The morphology and extension of the multi-lobulated mass was not characteristic for an atrial myxoma, and the constellation of findings suggested a primary cardiac malignancy. Rhabdomyosarcoma, a malignant skeletal muscle neoplasm, typically appears within the first two decades of life and may arise in any anatomic location. Cardiac rhabdomyosarcomas are uncommon, and only one prior case associated with hypereosinophilia has been described [16]. In that report, the patient presented with fatigue, fever, weight loss, and congestive heart failure. His peripheral WBC count was 90,000/mm3 with 57% eosinophils. The patient died within 24 hr of hospitalization. An autopsy revealed a necrotic tumor that had filled the right ventricular cavity, invaded into the myocardium, and metastasized to the hilar lymph nodes. Several explanations for the hypereosinophilia seen in malignancy have been proposed. One theory suggests that a necrotic tumor can produce cytokines that stimulate eosinophil production [17]. Another hypothesis is that tumors can produce or expose new antigens that trigger T cells to elicit eosinophil differentiation or chemotactic factors [13,17]. Finally, some investigators have suggested that metastases can trigger mast cells to release cytokines that promote the proliferation of eosinophils [3]. The identification of hypereosinophilia on a peripheral leukocyte count opens up a wide spectrum of diagnostic possibilities for clinicians. Malignancy should be consid-
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