Case 19-2004 — A 12-Year-Old Boy with Fatigue and Eosinophilia
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《新英格兰医药杂志》
Presentation of Case
A 12-year-old boy was evaluated in the hematology clinic of this hospital because of fatigue and peripheral-blood eosinophilia. For one week, he had had fatigue that had caused him to miss school, and his appetite had decreased. He also had intermittent cramping, pain in his arms and legs, and anterior chest pain that was worse with movement, deep breathing, and coughing. The patient's mother noted that he had felt warm; the maximum documented temperature was 38.3°C. He had no nausea, vomiting, changes in stool or urinary habits, or night sweats. He took ibuprofen and acetaminophen, both of which resulted in limited improvement. He was seen by his family physician, and the results of a physical examination were normal. Laboratory tests were performed (Table 1 and Table 2). The result of a mononucleosis spot test was negative. The boy was referred to this hospital for further evaluation.
Table 1. Hematologic Laboratory Data.
Table 2. Blood Chemical Values.
He had previously been healthy. He had recovered spontaneously from a respiratory illness three weeks earlier, was doing well in school, and was physically active and did not have a history of hospitalizations, surgical procedures, or allergic reactions to drugs. There was no history of international travel. He was taking no medications at the time of the evaluation. He lived with his parents and siblings, and he had a dog, a lizard, and fish as pets. His mother had a history of ulcerative colitis, ascending cholangitis, and colon cancer that had been treated with a colectomy and that was in remission after treatment with chemotherapy. His father and siblings were healthy. His maternal grandfather had died of leukemia. Distant relatives had heart disease, melanoma, and ovarian cancer.
On physical examination, he appeared tired but not in acute distress. The weight was 33.9 kg, and the height was 146.2 cm. He was afebrile; the blood pressure was 102/50 mm Hg, the heart rate 120 beats per minute, and the respiratory rate 22 breaths per minute. His cheeks were flushed; the results of an examination of the head, ears, eyes, nose, and throat were otherwise normal. The neck was supple. A few lymph nodes, each less than 1.5 cm in diameter, were palpable in the inguinal regions. The lungs and heart were normal on auscultation. The abdomen was soft and nontender, with normal bowel sounds and no hepatosplenomegaly. Genitourinary, cutaneous, and neurologic examinations were normal, as was examination of his arms and legs.
Additional tests were ordered, including serologic tests for helminthic infections, quantitative immunoglobulin assays, and examination of a stool specimen for ova and parasites. A radiograph of the chest showed no abnormalities.
A diagnostic procedure was performed.
Differential Diagnosis
Dr. Mary S. Huang: This patient's clinical presentation was not immediately impressive. His symptoms were nonspecific, but his primary care physician recognized a marked contrast from the boy's baseline state and emphasized how uncharacteristic it was for this child to say he was not feeling well. For this reason, the physician ordered laboratory tests, which disclosed marked eosinophilia. As the consultant in hematology, I had to consider the differential diagnosis of eosinophilia. Normally, eosinophils constitute 1 to 3 percent of the peripheral-blood leukocytes, at a count of 350 to 650 per cubic millimeter. Eosinophilia can be categorized as mild (fewer than 1500 eosinophils per cubic millimeter), moderate (1500 to 5000 per cubic millimeter), or severe (more than 5000 per cubic millimeter).1,2 This patient had severe eosinophilia. The list of causes of eosinophilia shown in Table 3 is broad but not exhaustive.
Table 3. Causes of Eosinophilia.
Infectious Diseases
Worldwide, the most common cause of eosinophilia is infection.1 Severe eosinophilia is most commonly associated with helminthic infections.3,4 This patient had no history of international travel, but he was exposed to the household dog and he did eat meat. The most likely culprits in this setting would be Toxocara canis and trichinella.
T. canis, or dog roundworms, are generally transmitted by the oral–fecal route. Pica or close contact with a dog facilitates infection. A history of pica may not always be obvious, but as many as 10 to 30 percent of soil samples in public playgrounds and parks in the United States have been reported to be contaminated with toxocara eggs. The disease caused by this agent, visceral larva migrans, is associated with absolute eosinophil counts that are greater than 3000 per cubic millimeter and with hyperglobulinemia, fever, hepatosplenomegaly, pneumonitis, and pruritic rashes.4 This patient had malaise and fever but did not have hepatosplenomegaly, respiratory symptoms, or a rash. However, infection with toxocara or other helminths can be subtle or even asymptomatic, and the first sign can be eosinophilia that is discovered incidentally.
This patient had no history of eating undercooked or raw pork, but Trichinella spiralis must be considered as a possible causative agent. In addition to pork, beef — especially ground beef processed in the same facility as pork — can transmit the disease. Trichinosis can be a consideration in a patient with more than 7000 eosinophils per cubic millimeter who also has myalgias, periorbital edema, and fever. The eosinophilia is often preceded by diarrhea and abdominal pain. Approximately 100 cases of trichinosis are reported each year in the United States.4 Again, this patient's symptoms were not specific to this infection, but neither are they inconsistent.
This patient had no history of travel or contact with recent travelers. Occult exposures can occur, however, but this information may not be readily apparent during an interview with a patient or family. Infection remained a strong possibility in this patient. It is important to identify the specific infection, since some helminthic infections can cause late sequelae and specific therapy may be required to eradicate the infection.
Disorders of the Immune System
The second most common cause of eosinophilia in the United States is allergy or atopic disease. Discussion after the initial history taking revealed that the patient had food allergies, and in particular, that hives without respiratory symptoms developed after he ate cashews or pistachios. The illness in this case is not associated with specific symptoms suggestive of an allergic reaction. The patient had had no new exposures that might be implicated. Although allergic reactions can result in relatively high eosinophil counts, this severe degree of eosinophilia is sufficiently unusual that even if symptoms of allergy were present, other possible causes should be investigated.2
Lupus and rheumatoid arthritis can be associated with eosinophilia.5 The eosinophilia in this case was more severe than it usually is in patients with rheumatologic disease,6,7 however, and the boy had no signs or symptoms suggestive of this group of disorders.
He had a family history of ulcerative colitis, and eosinophilia to this degree has been reported in ulcerative colitis.8 His mother's diagnosis of ulcerative colitis was made only after her presentation with colon cancer, so she had been asymptomatic. The boy might also have had ulcerative colitis, but the diagnosis is relatively unlikely without gastrointestinal symptoms.
Toxins, Drugs, and Environmental Factors
Several drugs have been associated with a syndrome of drug reaction with eosinophilia and systemic symptoms (known as the DRESS syndrome). The most notorious are the anticonvulsant agents phenytoin, carbamazepine, and phenobarbital. Other drugs, including ranitidine and sulfonamide antibiotics, can also cause hypersensitivity syndromes with peripheral eosinophilia.9 Some drugs specifically promote the production of eosinophils, such as granulocyte colony-stimulating factor. It is worth mentioning both the eosinophilia–myalgia syndrome and the toxic-oil syndrome in this category. These syndromes have been associated, respectively, with the ingestion of tryptophan and cooking oil that contains aniline. The mechanism of this reaction is unclear, but it can be associated with severe eosinophilia, with an eosinophil count as high as 36,000 per cubic millimeter. This patient had no recent history of drug use or suspicious exposures and did not have associated clinical findings to support these causes of eosinophilia.
Endocrine Abnormalities
Endocrinologists cite idiopathic eosinophilia as a marker of adrenal insufficiency. It may be present in as many as 17 percent of patients,10 and although this diagnosis is unlikely in the case under discussion because of the severity of the eosinophilia, I mention it because of its clinical significance. In critically ill patients, the presence of eosinophilia may raise the possibility of adrenal insufficiency.11,12 Recognition of adrenal insufficiency in such patients directs the use of corticosteroid replacement therapy.
Inherited Disorders
Familial eosinophilia, which has an autosomal dominant mode of inheritance, was recognized in the early 1900s. No specific gene has been implicated, but in one kindred, linkage analysis targeted the region of 5q31-33, notably close to the genes for interleukin-3, interleukin-5, and granulocyte colony-stimulating factor, all of which are thought to be important in activating eosinophils.13 This patient had no family history of eosinophilia.
Hypereosinophilic Syndromes
Eosinophilia can be associated with disorders such as Churg–Strauss syndrome, Kimura's disease, Wells's syndrome, and Castleman disease, which are characterized by various combinations of specific skin findings, pulmonary symptoms, lymphadenopathy, and vasculitis.1,14,15,16 This patient had no findings consistent with these disorders.
Idiopathic hypereosinophilic syndrome was originally defined as the presence of an absolute eosinophil count above 1500 per cubic millimeter for more than six months (or death within six months after presentation — indicative of the potential severity of this entity), end-organ damage attributable to eosinophilia, and "no identifiable cause" of the eosinophilia. It was soon recognized that in some patients with idiopathic hypereosinophilic syndrome, leukemia subsequently developed. Within the past decade, many cases that would have fallen into the idiopathic category have been shown to have clonal cytogenetic abnormalities that are consistent with the presence of a malignant process, usually a myeloproliferative disorder or mast-cell disease.15,16,17 Some patients have an abnormal clonal population of T cells that secrete interleukin-5, which results in eosinophilia.18 A recent study found a fusion between the Fip1-like 1 gene and platelet-derived growth factor receptor in 9 of 16 patients with hypereosinophilic syndrome; the disease in these 9 patients responded to treatment with the tyrosine kinase inhibitor, imatinib.19
Cancer
Eosinophilia can be seen in association with many forms of cancer. It would be unusual for it to be this severe in a patient with Hodgkin's lymphoma or carcinomas. There are, however, some distinct hematopoietic cancers that occur in children that are associated with eosinophilia.
Acute lymphoblastic leukemia is the most common cancer in childhood, and in the majority of cases it is of the precursor B-cell type. Eosinophilia to the degree seen in the patient under discussion has been described in a small subset of cases of precursor B-cell acute lymphoblastic leukemia, associated with a translocation between chromosomes 5 and 14, which links the immunoglobulin heavy-chain locus on chromosome 14 with the interleukin-3 gene on chromosome 5. This translocation up-regulates the expression of interleukin-3, which stimulates eosinophilia.20,21 Because the eosinophilia is stimulated by cytokine production by the malignant cells, small numbers of leukemic cells can result in impressive eosinophilia. Patients who have this specific condition often do not have peripheral blasts or other cytopenias, and they have a relatively low percentage of blasts in the bone marrow.
Acute myeloid leukemia is classified into several subtypes on the basis of cytogenetic and other features. Acute myeloid leukemia with a pericentric inversion of chromosome 16 is associated with an increase in the number of eosinophils in the bone marrow, which are morphologically abnormal. There is no increase in the number of eosinophils in the peripheral blood.22
Finally, a recently described entity with severe peripheral-blood and bone marrow eosinophilia, precursor T-cell lymphoblastic lymphoma, and the subsequent development of myeloid leukemia is associated with the translocation t(8;13)(p11;q11).23 This breakpoint involves the fibroblast growth factor receptor 1 gene and ZNF198, a zinc finger protein gene. The pathophysiology of the eosinophilia in this disorder is unclear.
End-Organ Damage in Hypereosinophilic Syndromes
Multisystem organ damage can result from eosinophilia regardless of the underlying cause; the extent of the damage does not strictly correlate with the degree or duration of eosinophilia. The mechanism of injury is thought to be related to inflammatory mediators in the eosinophilic granules.14
L?ffler's endocarditis, the chief cause of illness and death associated with eosinophilia, has been described in children with acute lymphoblastic leukemia and other hypereosinophilic syndromes.24,25,26 Treatment of the underlying disease and resolution of the eosinophilia can arrest or reverse progressive heart damage14; therefore, it is critical to identify and appropriately treat the cause.
On the basis of the degree of eosinophilia and the history and physical examination of the patient under discussion, the two categories of disease I was most compelled to pursue were infection and leukemia. Of the leukemias to consider, I thought the most likely would be precursor B-cell acute lymphoblastic leukemia with the t(5;14) translocation. Serologic tests for the presence of several infections were ordered and an elective bone marrow aspirate and biopsy were scheduled.
Dr. Nancy Lee Harris (Pathology): Dr. D'Angelo, since you are the patient's family practitioner, please tell us what your thoughts were when you saw the patient.
Dr. Henry A. D'Angelo (Newton–Wellesley Family Practice): I know the boy well, and I am also his mother's doctor. The patient came into the office on a Monday, and what struck me most was that at church the day before the 30 minutes of standing up and sitting down had exhausted him to the extent that he had to lie in bed for the rest of the day. This apparent fatigue was so uncharacteristic of this normally energetic boy that I immediately ordered blood tests. His blood count had never previously been obtained. Shortly thereafter, I received a call from the laboratory at the hospital and was informed that he had a tremendously high eosinophil count. A couple of hours later, I spoke with Dr. Huang, and we arranged an appointment for the boy the next day.
Clinical Diagnosis
Acute lymphoblastic leukemia with eosinophilia or helminthic infection.
Pathological Discussion
Dr. Robert P. Hasserjian: Examination of the peripheral-blood smear revealed leukocytosis with marked eosinophilia (Figure 1). There was no monocytosis or basophilia, nor were blasts identified. The eosinophils had abnormal morphologic features, characterized by frequent forms with three nuclear lobes and uneven cytoplasmic granulation (Figure 1, inset).
Figure 1. Peripheral-Blood Smear.
There is leukocytosis with marked eosinophilia. The eosinophils include many abnormal forms with three nuclear lobes and uneven cytoplasmic granulation (Wright–Giemsa, x200; inset, x1000).
Smears of the bone marrow aspirate were markedly hypercellular. A differential count of 200 cells revealed 32 percent blasts, 52 percent eosinophils, 1 percent promyelocytes, 3 percent myeloid precursors, 1 percent basophils, 2 percent erythroid precursors, 8 percent lymphocytes, and 1 percent monocytes. The eosinophils were similar to those found in the peripheral-blood smear. The blasts were medium in size, with irregular nuclei, finely dispersed chromatin, small nucleoli, and scant, agranular cytoplasm (Figure 2A). Auer rods were not identified. Examination of the bone marrow biopsy specimens revealed a hypercellular marrow with markedly increased numbers of eosinophils and precursors along with some maturing erythroid elements and clusters of blasts (Figure 2B).
Figure 2. Bone Marrow Aspirate and Biopsy Specimen.
The bone marrow aspirate (Panel A) predominantly contains populations of maturing eosinophils and blasts with scant, agranular cytoplasm (Wright–Giemsa, x500; inset, x1000). The biopsy specimen (Panel B) is markedly hypercellular, with maturing eosinophils and erythroid elements amid clusters of medium-to-large blasts with irregular nuclei and distinct nucleoli (hematoxylin and eosin, x500).
Immunophenotyping of bone marrow cells by flow cytometry revealed a distinct population of cells expressing CD19, CD20, CD10, and terminal deoxynucleotidyl transferase and weakly expressing CD34 and CD33 — a pattern indicative of a precursor B-cell phenotype. It was a possibility that these cells represented benign normal bone marrow B-cell precursors (i.e., hematogones), but the uniform phenotype of this cell population and the lack of a maturation pattern typical of hematogones suggested that these cells could be characterized as malignant B-cell lymphoblasts (Figure 3).27 The weak expression of CD33, a marker usually associated with myeloid differentiation, would also be aberrant for hematogones.
Figure 3. Flow-Cytometric Analysis of Bone Marrow.
Immunophenotyping of bone marrow aspirate by flow cytometry shows a discrete population of CD10 and CD20 cells (circled, Panel A). The discrete nature of this cell population contrasts with the weaker intensity of CD10 expression and the continuous pattern of CD10 and CD20 expression in normal, maturing B-cell precursors (i.e., hematogones) seen on flow-cytometric analysis of bone marrow from a normal subject (Panel B).
Acute leukemias are broadly classified as acute myeloid leukemia, precursor B-cell acute lymphoblastic leukemia, and precursor T-cell acute lymphoblastic leukemia.28 Immunophenotyping is critical to definitive classification. In this case, the morphologic and immunophenotypic features confirmed a diagnosis of precursor B-cell lymphoblastic leukemia, associated with marked eosinophilia. Expression of a single myeloid marker (CD33) does not qualify this case as biphenotypic leukemia.
Cytogenetic studies are assuming an increasingly important role in the classification of leukemia; specific cytogenetic findings are the basis for the current classification of acute myeloid leukemia and provide critical prognostic information in precursor B-cell acute lymphoblastic leukemia and precursor T-cell acute lymphoblastic leukemia.29 Beyond providing prognostic information, cytogenetic abnormalities identify molecular lesions that underlie the pathogenesis of specific leukemia subtypes and that may be vulnerable to targeted therapy. Cytogenetic analysis of bone marrow from this patient revealed a 46,XY,t(5;14)(q31;q32),add(9) (p13) karyotype in 6 of 20 metaphases analyzed (Figure 4A). Fluorescence in situ hybridization studies using a dual-color probe confirmed that the t(5;14) translocation involved the immunoglobulin heavy-chain gene locus on chromosome 14 and was present in 10 percent of the bone marrow cells (Figure 4B).
Figure 4. Cytogenetic and Fluorescence in Situ Hybridization Analysis of the Bone Marrow.
Cytogenetic analysis of the patient's bone marrow revealed a 46,XY,t(5;14)(q31;q32),add(9)(p13) karyotype in 6 of 20 analyzed nuclei of cells in metaphase; the remaining nuclei of cells in metaphase were normal (46,XY). The arrows indicate the abnormal chromosomes 5 and 14 affected by the translocation of an abnormal chromosome 9, which contains additional material on its short arm (Panel A). Fluorescence in situ hybridization was performed on cells in interphase from the bone marrow aspirate with the use of dual-color probes flanking the breakpoint region of the immunoglobulin heavy-chain gene (Panel B); this site is affected by translocation in many B-cell neoplasms. The abnormal cell (lower cell) exhibits separation of the red and green signals, indicating a chromosomal rearrangement at this site in 10 of 100 nuclei of cells in interphase. One and two fused (yellow) signals are seen in the abnormal cell and the adjacent normal cell (upper cell), respectively, representing the normal, intact immunoglobulin heavy-chain gene (fluorescence microscopy, x500).
The t(5;14) translocation is a rare but recurrent mutation found in fewer than 1 percent of cases of B-cell acute lymphoblastic leukemia; in it, the interleukin-3 gene is joined to the immunoglobulin heavy-chain gene in a head-to-head fusion.21 The translocation leaves the interleukin-3 coding region intact and results in overproduction of interleukin-3 by the blasts, a change reflected by increased levels of serum interleukin-3.30 Interleukin-3 is a hematopoietic growth factor that stimulates the proliferation and differentiation of hematopoietic cells, including eosinophils. B-cell acute lymphoblastic leukemia with the t(5;14) translocation is typically characterized by marked eosinophilia, presumably a result of interleukin-3 overproduction by the blasts bearing the t(5;14) translocation.
The differential diagnosis in this case includes two other acute leukemias associated with eosinophilia, each of which has a characteristic cytogenetic translocation (Table 4). In T-cell lymphoblastic lymphoma with the t(8;13) translocation, the translocation is present in both the neoplastic T lymphoblasts and in the eosinophils of the associated myeloproliferative disorder.23 In a similar fashion, the eosinophils in acute myeloid leukemia with bone marrow eosinophilia are also neoplastic. It is not known whether the eosinophils also bear the t(5;14) translocation, but it is generally assumed that they are not part of the neoplastic clone and are reactive in nature. In this case, since the translocation was identified in only 10 percent of the bone marrow cells, whereas eosinophils comprised 52 percent of the cells in the bone marrow aspirate, it is likely that the translocation was limited to the blasts.
Table 4. Acute Leukemias Associated with Eosinophilia and Their Characteristic Cytogenetic Aberrations.
Dr. Howard Weinstein (Pediatric Hematology and Oncology): If the eosinophils are reactive, why do you think their morphologic features were abnormal?
Dr. Hasserjian: This degree of morphologic abnormality is unusual in reactive eosinophilia. Perhaps the intense stimulation mediated by interleukin-3 leads to the abnormal eosinophils that typically characterize this leukemia.
Discussion of Management
Dr. Harris: Dr. Huang, would you tell us about the management of this disease in this patient?
Dr. Huang: This patient has the most common and curable type of childhood cancer. Acute lymphoblastic leukemia accounts for 25 percent of cancers in childhood, and chemotherapy currently results in a cure in more than 75 percent of patients and nearly 85 percent of those in the most favorable prognostic group.31 A decision about therapy for this patient depended on an assessment of clinical and pathologic prognostic factors, including age, sex, white-cell count, and cytogenetic features. Children between the ages of one and nine years who have a white-cell count below 50,000 per cubic millimeter and a precursor B-cell phenotype are considered at "standard risk," and all others are considered at "high risk." Male sex and central nervous system and testicular involvement are adverse prognostic factors. Genetic markers that confer a relatively good risk are simultaneous trisomies of chromosomes 4, 10, and 17 as well as the t(12;21) translocation and hyperdiploidy (DNA index, 1.16 or greater). Molecular markers that confer an especially poor risk are hypodiploidy, with a DNA index of less than 0.81, and the Philadelphia chromosome (a t(9;22) translocation).31 There is no specific risk associated with the t(5;14) translocation.
The findings from a cerebrospinal fluid analysis in this patient were negative, but he was assigned to the high-risk category on the basis of his sex and age. According to criteria developed by the Children's Oncology Group,32 any boy 12 years of age or older is at high risk regardless of his white-cell count at presentation. Although his white-cell count was elevated, it was not due to an increase in the number of peripheral blasts and thus would not be considered an independent adverse risk factor. An echocardiogram showed no evidence of damage from his hypereosinophilia, but early changes are not always easily detected. He will have serial echocardiograms during his treatment, since he will be receiving potentially cardiotoxic chemotherapy.
Therapy for this patient with childhood precursor B-cell acute lymphoblastic leukemia will involve several phases over two and a half years. The initial induction therapy for standard-risk patients includes three drugs (vincristine, asparaginase, and a corticosteroid) and central nervous system prophylaxis with intrathecal methotrexate. In this patient, who was at high risk, we added a fourth agent (daunorubicin). A longer duration of intensive therapy than that used for patients with standard-risk disease has been shown to improve the outcome for patients with high-risk disease.33 Therefore, he received more intensive therapy during the first 10 months of treatment, which included consolidation with cytarabine, cyclophosphamide, mercaptopurine, vincristine, asparaginase and double-delayed intensification with doxorubicin, dexamethasone, vincristine, thioguanine, cytarabine, and asparaginase.
The patient tolerated his induction chemotherapy well, had no episodes of severe cytopenia, and required no transfusions. His peripheral eosinophilia cleared within 21 days after the start of therapy, and his disease was in remission on day 29 of treatment. A bone marrow aspirate confirmed continued remission six months after diagnosis, and findings from cytogenetic studies and fluorescence in situ hybridization showed no evidence of the translocation. Fifteen months after the diagnosis, his disease is still in remission, during the continuation phase of his treatment. He will receive mercaptopurine, dexamethasone, vincristine, and methotrexate as an outpatient until he has completed the balance of the two and a half years of therapy. With this treatment, we hope for about a 70 percent chance of long-term, event-free survival.
Anatomical Diagnosis
Precursor B-cell acute lymphoblastic leukemia with eosinophilia and the t(5;14)(q31;q32) translocation.
Source Information
From the Division of Pediatric Oncology (M.S.H.) and the Department of Pathology (R.P.H.), Massachusetts General Hospital; and the Departments of Pediatrics (M.S.H.) and Pathology (R.P.H.), Harvard Medical School.
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A 12-year-old boy was evaluated in the hematology clinic of this hospital because of fatigue and peripheral-blood eosinophilia. For one week, he had had fatigue that had caused him to miss school, and his appetite had decreased. He also had intermittent cramping, pain in his arms and legs, and anterior chest pain that was worse with movement, deep breathing, and coughing. The patient's mother noted that he had felt warm; the maximum documented temperature was 38.3°C. He had no nausea, vomiting, changes in stool or urinary habits, or night sweats. He took ibuprofen and acetaminophen, both of which resulted in limited improvement. He was seen by his family physician, and the results of a physical examination were normal. Laboratory tests were performed (Table 1 and Table 2). The result of a mononucleosis spot test was negative. The boy was referred to this hospital for further evaluation.
Table 1. Hematologic Laboratory Data.
Table 2. Blood Chemical Values.
He had previously been healthy. He had recovered spontaneously from a respiratory illness three weeks earlier, was doing well in school, and was physically active and did not have a history of hospitalizations, surgical procedures, or allergic reactions to drugs. There was no history of international travel. He was taking no medications at the time of the evaluation. He lived with his parents and siblings, and he had a dog, a lizard, and fish as pets. His mother had a history of ulcerative colitis, ascending cholangitis, and colon cancer that had been treated with a colectomy and that was in remission after treatment with chemotherapy. His father and siblings were healthy. His maternal grandfather had died of leukemia. Distant relatives had heart disease, melanoma, and ovarian cancer.
On physical examination, he appeared tired but not in acute distress. The weight was 33.9 kg, and the height was 146.2 cm. He was afebrile; the blood pressure was 102/50 mm Hg, the heart rate 120 beats per minute, and the respiratory rate 22 breaths per minute. His cheeks were flushed; the results of an examination of the head, ears, eyes, nose, and throat were otherwise normal. The neck was supple. A few lymph nodes, each less than 1.5 cm in diameter, were palpable in the inguinal regions. The lungs and heart were normal on auscultation. The abdomen was soft and nontender, with normal bowel sounds and no hepatosplenomegaly. Genitourinary, cutaneous, and neurologic examinations were normal, as was examination of his arms and legs.
Additional tests were ordered, including serologic tests for helminthic infections, quantitative immunoglobulin assays, and examination of a stool specimen for ova and parasites. A radiograph of the chest showed no abnormalities.
A diagnostic procedure was performed.
Differential Diagnosis
Dr. Mary S. Huang: This patient's clinical presentation was not immediately impressive. His symptoms were nonspecific, but his primary care physician recognized a marked contrast from the boy's baseline state and emphasized how uncharacteristic it was for this child to say he was not feeling well. For this reason, the physician ordered laboratory tests, which disclosed marked eosinophilia. As the consultant in hematology, I had to consider the differential diagnosis of eosinophilia. Normally, eosinophils constitute 1 to 3 percent of the peripheral-blood leukocytes, at a count of 350 to 650 per cubic millimeter. Eosinophilia can be categorized as mild (fewer than 1500 eosinophils per cubic millimeter), moderate (1500 to 5000 per cubic millimeter), or severe (more than 5000 per cubic millimeter).1,2 This patient had severe eosinophilia. The list of causes of eosinophilia shown in Table 3 is broad but not exhaustive.
Table 3. Causes of Eosinophilia.
Infectious Diseases
Worldwide, the most common cause of eosinophilia is infection.1 Severe eosinophilia is most commonly associated with helminthic infections.3,4 This patient had no history of international travel, but he was exposed to the household dog and he did eat meat. The most likely culprits in this setting would be Toxocara canis and trichinella.
T. canis, or dog roundworms, are generally transmitted by the oral–fecal route. Pica or close contact with a dog facilitates infection. A history of pica may not always be obvious, but as many as 10 to 30 percent of soil samples in public playgrounds and parks in the United States have been reported to be contaminated with toxocara eggs. The disease caused by this agent, visceral larva migrans, is associated with absolute eosinophil counts that are greater than 3000 per cubic millimeter and with hyperglobulinemia, fever, hepatosplenomegaly, pneumonitis, and pruritic rashes.4 This patient had malaise and fever but did not have hepatosplenomegaly, respiratory symptoms, or a rash. However, infection with toxocara or other helminths can be subtle or even asymptomatic, and the first sign can be eosinophilia that is discovered incidentally.
This patient had no history of eating undercooked or raw pork, but Trichinella spiralis must be considered as a possible causative agent. In addition to pork, beef — especially ground beef processed in the same facility as pork — can transmit the disease. Trichinosis can be a consideration in a patient with more than 7000 eosinophils per cubic millimeter who also has myalgias, periorbital edema, and fever. The eosinophilia is often preceded by diarrhea and abdominal pain. Approximately 100 cases of trichinosis are reported each year in the United States.4 Again, this patient's symptoms were not specific to this infection, but neither are they inconsistent.
This patient had no history of travel or contact with recent travelers. Occult exposures can occur, however, but this information may not be readily apparent during an interview with a patient or family. Infection remained a strong possibility in this patient. It is important to identify the specific infection, since some helminthic infections can cause late sequelae and specific therapy may be required to eradicate the infection.
Disorders of the Immune System
The second most common cause of eosinophilia in the United States is allergy or atopic disease. Discussion after the initial history taking revealed that the patient had food allergies, and in particular, that hives without respiratory symptoms developed after he ate cashews or pistachios. The illness in this case is not associated with specific symptoms suggestive of an allergic reaction. The patient had had no new exposures that might be implicated. Although allergic reactions can result in relatively high eosinophil counts, this severe degree of eosinophilia is sufficiently unusual that even if symptoms of allergy were present, other possible causes should be investigated.2
Lupus and rheumatoid arthritis can be associated with eosinophilia.5 The eosinophilia in this case was more severe than it usually is in patients with rheumatologic disease,6,7 however, and the boy had no signs or symptoms suggestive of this group of disorders.
He had a family history of ulcerative colitis, and eosinophilia to this degree has been reported in ulcerative colitis.8 His mother's diagnosis of ulcerative colitis was made only after her presentation with colon cancer, so she had been asymptomatic. The boy might also have had ulcerative colitis, but the diagnosis is relatively unlikely without gastrointestinal symptoms.
Toxins, Drugs, and Environmental Factors
Several drugs have been associated with a syndrome of drug reaction with eosinophilia and systemic symptoms (known as the DRESS syndrome). The most notorious are the anticonvulsant agents phenytoin, carbamazepine, and phenobarbital. Other drugs, including ranitidine and sulfonamide antibiotics, can also cause hypersensitivity syndromes with peripheral eosinophilia.9 Some drugs specifically promote the production of eosinophils, such as granulocyte colony-stimulating factor. It is worth mentioning both the eosinophilia–myalgia syndrome and the toxic-oil syndrome in this category. These syndromes have been associated, respectively, with the ingestion of tryptophan and cooking oil that contains aniline. The mechanism of this reaction is unclear, but it can be associated with severe eosinophilia, with an eosinophil count as high as 36,000 per cubic millimeter. This patient had no recent history of drug use or suspicious exposures and did not have associated clinical findings to support these causes of eosinophilia.
Endocrine Abnormalities
Endocrinologists cite idiopathic eosinophilia as a marker of adrenal insufficiency. It may be present in as many as 17 percent of patients,10 and although this diagnosis is unlikely in the case under discussion because of the severity of the eosinophilia, I mention it because of its clinical significance. In critically ill patients, the presence of eosinophilia may raise the possibility of adrenal insufficiency.11,12 Recognition of adrenal insufficiency in such patients directs the use of corticosteroid replacement therapy.
Inherited Disorders
Familial eosinophilia, which has an autosomal dominant mode of inheritance, was recognized in the early 1900s. No specific gene has been implicated, but in one kindred, linkage analysis targeted the region of 5q31-33, notably close to the genes for interleukin-3, interleukin-5, and granulocyte colony-stimulating factor, all of which are thought to be important in activating eosinophils.13 This patient had no family history of eosinophilia.
Hypereosinophilic Syndromes
Eosinophilia can be associated with disorders such as Churg–Strauss syndrome, Kimura's disease, Wells's syndrome, and Castleman disease, which are characterized by various combinations of specific skin findings, pulmonary symptoms, lymphadenopathy, and vasculitis.1,14,15,16 This patient had no findings consistent with these disorders.
Idiopathic hypereosinophilic syndrome was originally defined as the presence of an absolute eosinophil count above 1500 per cubic millimeter for more than six months (or death within six months after presentation — indicative of the potential severity of this entity), end-organ damage attributable to eosinophilia, and "no identifiable cause" of the eosinophilia. It was soon recognized that in some patients with idiopathic hypereosinophilic syndrome, leukemia subsequently developed. Within the past decade, many cases that would have fallen into the idiopathic category have been shown to have clonal cytogenetic abnormalities that are consistent with the presence of a malignant process, usually a myeloproliferative disorder or mast-cell disease.15,16,17 Some patients have an abnormal clonal population of T cells that secrete interleukin-5, which results in eosinophilia.18 A recent study found a fusion between the Fip1-like 1 gene and platelet-derived growth factor receptor in 9 of 16 patients with hypereosinophilic syndrome; the disease in these 9 patients responded to treatment with the tyrosine kinase inhibitor, imatinib.19
Cancer
Eosinophilia can be seen in association with many forms of cancer. It would be unusual for it to be this severe in a patient with Hodgkin's lymphoma or carcinomas. There are, however, some distinct hematopoietic cancers that occur in children that are associated with eosinophilia.
Acute lymphoblastic leukemia is the most common cancer in childhood, and in the majority of cases it is of the precursor B-cell type. Eosinophilia to the degree seen in the patient under discussion has been described in a small subset of cases of precursor B-cell acute lymphoblastic leukemia, associated with a translocation between chromosomes 5 and 14, which links the immunoglobulin heavy-chain locus on chromosome 14 with the interleukin-3 gene on chromosome 5. This translocation up-regulates the expression of interleukin-3, which stimulates eosinophilia.20,21 Because the eosinophilia is stimulated by cytokine production by the malignant cells, small numbers of leukemic cells can result in impressive eosinophilia. Patients who have this specific condition often do not have peripheral blasts or other cytopenias, and they have a relatively low percentage of blasts in the bone marrow.
Acute myeloid leukemia is classified into several subtypes on the basis of cytogenetic and other features. Acute myeloid leukemia with a pericentric inversion of chromosome 16 is associated with an increase in the number of eosinophils in the bone marrow, which are morphologically abnormal. There is no increase in the number of eosinophils in the peripheral blood.22
Finally, a recently described entity with severe peripheral-blood and bone marrow eosinophilia, precursor T-cell lymphoblastic lymphoma, and the subsequent development of myeloid leukemia is associated with the translocation t(8;13)(p11;q11).23 This breakpoint involves the fibroblast growth factor receptor 1 gene and ZNF198, a zinc finger protein gene. The pathophysiology of the eosinophilia in this disorder is unclear.
End-Organ Damage in Hypereosinophilic Syndromes
Multisystem organ damage can result from eosinophilia regardless of the underlying cause; the extent of the damage does not strictly correlate with the degree or duration of eosinophilia. The mechanism of injury is thought to be related to inflammatory mediators in the eosinophilic granules.14
L?ffler's endocarditis, the chief cause of illness and death associated with eosinophilia, has been described in children with acute lymphoblastic leukemia and other hypereosinophilic syndromes.24,25,26 Treatment of the underlying disease and resolution of the eosinophilia can arrest or reverse progressive heart damage14; therefore, it is critical to identify and appropriately treat the cause.
On the basis of the degree of eosinophilia and the history and physical examination of the patient under discussion, the two categories of disease I was most compelled to pursue were infection and leukemia. Of the leukemias to consider, I thought the most likely would be precursor B-cell acute lymphoblastic leukemia with the t(5;14) translocation. Serologic tests for the presence of several infections were ordered and an elective bone marrow aspirate and biopsy were scheduled.
Dr. Nancy Lee Harris (Pathology): Dr. D'Angelo, since you are the patient's family practitioner, please tell us what your thoughts were when you saw the patient.
Dr. Henry A. D'Angelo (Newton–Wellesley Family Practice): I know the boy well, and I am also his mother's doctor. The patient came into the office on a Monday, and what struck me most was that at church the day before the 30 minutes of standing up and sitting down had exhausted him to the extent that he had to lie in bed for the rest of the day. This apparent fatigue was so uncharacteristic of this normally energetic boy that I immediately ordered blood tests. His blood count had never previously been obtained. Shortly thereafter, I received a call from the laboratory at the hospital and was informed that he had a tremendously high eosinophil count. A couple of hours later, I spoke with Dr. Huang, and we arranged an appointment for the boy the next day.
Clinical Diagnosis
Acute lymphoblastic leukemia with eosinophilia or helminthic infection.
Pathological Discussion
Dr. Robert P. Hasserjian: Examination of the peripheral-blood smear revealed leukocytosis with marked eosinophilia (Figure 1). There was no monocytosis or basophilia, nor were blasts identified. The eosinophils had abnormal morphologic features, characterized by frequent forms with three nuclear lobes and uneven cytoplasmic granulation (Figure 1, inset).
Figure 1. Peripheral-Blood Smear.
There is leukocytosis with marked eosinophilia. The eosinophils include many abnormal forms with three nuclear lobes and uneven cytoplasmic granulation (Wright–Giemsa, x200; inset, x1000).
Smears of the bone marrow aspirate were markedly hypercellular. A differential count of 200 cells revealed 32 percent blasts, 52 percent eosinophils, 1 percent promyelocytes, 3 percent myeloid precursors, 1 percent basophils, 2 percent erythroid precursors, 8 percent lymphocytes, and 1 percent monocytes. The eosinophils were similar to those found in the peripheral-blood smear. The blasts were medium in size, with irregular nuclei, finely dispersed chromatin, small nucleoli, and scant, agranular cytoplasm (Figure 2A). Auer rods were not identified. Examination of the bone marrow biopsy specimens revealed a hypercellular marrow with markedly increased numbers of eosinophils and precursors along with some maturing erythroid elements and clusters of blasts (Figure 2B).
Figure 2. Bone Marrow Aspirate and Biopsy Specimen.
The bone marrow aspirate (Panel A) predominantly contains populations of maturing eosinophils and blasts with scant, agranular cytoplasm (Wright–Giemsa, x500; inset, x1000). The biopsy specimen (Panel B) is markedly hypercellular, with maturing eosinophils and erythroid elements amid clusters of medium-to-large blasts with irregular nuclei and distinct nucleoli (hematoxylin and eosin, x500).
Immunophenotyping of bone marrow cells by flow cytometry revealed a distinct population of cells expressing CD19, CD20, CD10, and terminal deoxynucleotidyl transferase and weakly expressing CD34 and CD33 — a pattern indicative of a precursor B-cell phenotype. It was a possibility that these cells represented benign normal bone marrow B-cell precursors (i.e., hematogones), but the uniform phenotype of this cell population and the lack of a maturation pattern typical of hematogones suggested that these cells could be characterized as malignant B-cell lymphoblasts (Figure 3).27 The weak expression of CD33, a marker usually associated with myeloid differentiation, would also be aberrant for hematogones.
Figure 3. Flow-Cytometric Analysis of Bone Marrow.
Immunophenotyping of bone marrow aspirate by flow cytometry shows a discrete population of CD10 and CD20 cells (circled, Panel A). The discrete nature of this cell population contrasts with the weaker intensity of CD10 expression and the continuous pattern of CD10 and CD20 expression in normal, maturing B-cell precursors (i.e., hematogones) seen on flow-cytometric analysis of bone marrow from a normal subject (Panel B).
Acute leukemias are broadly classified as acute myeloid leukemia, precursor B-cell acute lymphoblastic leukemia, and precursor T-cell acute lymphoblastic leukemia.28 Immunophenotyping is critical to definitive classification. In this case, the morphologic and immunophenotypic features confirmed a diagnosis of precursor B-cell lymphoblastic leukemia, associated with marked eosinophilia. Expression of a single myeloid marker (CD33) does not qualify this case as biphenotypic leukemia.
Cytogenetic studies are assuming an increasingly important role in the classification of leukemia; specific cytogenetic findings are the basis for the current classification of acute myeloid leukemia and provide critical prognostic information in precursor B-cell acute lymphoblastic leukemia and precursor T-cell acute lymphoblastic leukemia.29 Beyond providing prognostic information, cytogenetic abnormalities identify molecular lesions that underlie the pathogenesis of specific leukemia subtypes and that may be vulnerable to targeted therapy. Cytogenetic analysis of bone marrow from this patient revealed a 46,XY,t(5;14)(q31;q32),add(9) (p13) karyotype in 6 of 20 metaphases analyzed (Figure 4A). Fluorescence in situ hybridization studies using a dual-color probe confirmed that the t(5;14) translocation involved the immunoglobulin heavy-chain gene locus on chromosome 14 and was present in 10 percent of the bone marrow cells (Figure 4B).
Figure 4. Cytogenetic and Fluorescence in Situ Hybridization Analysis of the Bone Marrow.
Cytogenetic analysis of the patient's bone marrow revealed a 46,XY,t(5;14)(q31;q32),add(9)(p13) karyotype in 6 of 20 analyzed nuclei of cells in metaphase; the remaining nuclei of cells in metaphase were normal (46,XY). The arrows indicate the abnormal chromosomes 5 and 14 affected by the translocation of an abnormal chromosome 9, which contains additional material on its short arm (Panel A). Fluorescence in situ hybridization was performed on cells in interphase from the bone marrow aspirate with the use of dual-color probes flanking the breakpoint region of the immunoglobulin heavy-chain gene (Panel B); this site is affected by translocation in many B-cell neoplasms. The abnormal cell (lower cell) exhibits separation of the red and green signals, indicating a chromosomal rearrangement at this site in 10 of 100 nuclei of cells in interphase. One and two fused (yellow) signals are seen in the abnormal cell and the adjacent normal cell (upper cell), respectively, representing the normal, intact immunoglobulin heavy-chain gene (fluorescence microscopy, x500).
The t(5;14) translocation is a rare but recurrent mutation found in fewer than 1 percent of cases of B-cell acute lymphoblastic leukemia; in it, the interleukin-3 gene is joined to the immunoglobulin heavy-chain gene in a head-to-head fusion.21 The translocation leaves the interleukin-3 coding region intact and results in overproduction of interleukin-3 by the blasts, a change reflected by increased levels of serum interleukin-3.30 Interleukin-3 is a hematopoietic growth factor that stimulates the proliferation and differentiation of hematopoietic cells, including eosinophils. B-cell acute lymphoblastic leukemia with the t(5;14) translocation is typically characterized by marked eosinophilia, presumably a result of interleukin-3 overproduction by the blasts bearing the t(5;14) translocation.
The differential diagnosis in this case includes two other acute leukemias associated with eosinophilia, each of which has a characteristic cytogenetic translocation (Table 4). In T-cell lymphoblastic lymphoma with the t(8;13) translocation, the translocation is present in both the neoplastic T lymphoblasts and in the eosinophils of the associated myeloproliferative disorder.23 In a similar fashion, the eosinophils in acute myeloid leukemia with bone marrow eosinophilia are also neoplastic. It is not known whether the eosinophils also bear the t(5;14) translocation, but it is generally assumed that they are not part of the neoplastic clone and are reactive in nature. In this case, since the translocation was identified in only 10 percent of the bone marrow cells, whereas eosinophils comprised 52 percent of the cells in the bone marrow aspirate, it is likely that the translocation was limited to the blasts.
Table 4. Acute Leukemias Associated with Eosinophilia and Their Characteristic Cytogenetic Aberrations.
Dr. Howard Weinstein (Pediatric Hematology and Oncology): If the eosinophils are reactive, why do you think their morphologic features were abnormal?
Dr. Hasserjian: This degree of morphologic abnormality is unusual in reactive eosinophilia. Perhaps the intense stimulation mediated by interleukin-3 leads to the abnormal eosinophils that typically characterize this leukemia.
Discussion of Management
Dr. Harris: Dr. Huang, would you tell us about the management of this disease in this patient?
Dr. Huang: This patient has the most common and curable type of childhood cancer. Acute lymphoblastic leukemia accounts for 25 percent of cancers in childhood, and chemotherapy currently results in a cure in more than 75 percent of patients and nearly 85 percent of those in the most favorable prognostic group.31 A decision about therapy for this patient depended on an assessment of clinical and pathologic prognostic factors, including age, sex, white-cell count, and cytogenetic features. Children between the ages of one and nine years who have a white-cell count below 50,000 per cubic millimeter and a precursor B-cell phenotype are considered at "standard risk," and all others are considered at "high risk." Male sex and central nervous system and testicular involvement are adverse prognostic factors. Genetic markers that confer a relatively good risk are simultaneous trisomies of chromosomes 4, 10, and 17 as well as the t(12;21) translocation and hyperdiploidy (DNA index, 1.16 or greater). Molecular markers that confer an especially poor risk are hypodiploidy, with a DNA index of less than 0.81, and the Philadelphia chromosome (a t(9;22) translocation).31 There is no specific risk associated with the t(5;14) translocation.
The findings from a cerebrospinal fluid analysis in this patient were negative, but he was assigned to the high-risk category on the basis of his sex and age. According to criteria developed by the Children's Oncology Group,32 any boy 12 years of age or older is at high risk regardless of his white-cell count at presentation. Although his white-cell count was elevated, it was not due to an increase in the number of peripheral blasts and thus would not be considered an independent adverse risk factor. An echocardiogram showed no evidence of damage from his hypereosinophilia, but early changes are not always easily detected. He will have serial echocardiograms during his treatment, since he will be receiving potentially cardiotoxic chemotherapy.
Therapy for this patient with childhood precursor B-cell acute lymphoblastic leukemia will involve several phases over two and a half years. The initial induction therapy for standard-risk patients includes three drugs (vincristine, asparaginase, and a corticosteroid) and central nervous system prophylaxis with intrathecal methotrexate. In this patient, who was at high risk, we added a fourth agent (daunorubicin). A longer duration of intensive therapy than that used for patients with standard-risk disease has been shown to improve the outcome for patients with high-risk disease.33 Therefore, he received more intensive therapy during the first 10 months of treatment, which included consolidation with cytarabine, cyclophosphamide, mercaptopurine, vincristine, asparaginase and double-delayed intensification with doxorubicin, dexamethasone, vincristine, thioguanine, cytarabine, and asparaginase.
The patient tolerated his induction chemotherapy well, had no episodes of severe cytopenia, and required no transfusions. His peripheral eosinophilia cleared within 21 days after the start of therapy, and his disease was in remission on day 29 of treatment. A bone marrow aspirate confirmed continued remission six months after diagnosis, and findings from cytogenetic studies and fluorescence in situ hybridization showed no evidence of the translocation. Fifteen months after the diagnosis, his disease is still in remission, during the continuation phase of his treatment. He will receive mercaptopurine, dexamethasone, vincristine, and methotrexate as an outpatient until he has completed the balance of the two and a half years of therapy. With this treatment, we hope for about a 70 percent chance of long-term, event-free survival.
Anatomical Diagnosis
Precursor B-cell acute lymphoblastic leukemia with eosinophilia and the t(5;14)(q31;q32) translocation.
Source Information
From the Division of Pediatric Oncology (M.S.H.) and the Department of Pathology (R.P.H.), Massachusetts General Hospital; and the Departments of Pediatrics (M.S.H.) and Pathology (R.P.H.), Harvard Medical School.
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