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Systemic Mast Cell Disease Associated With the Hypereosinophilic Syndrome

      Systemic mast cell disease (SMCD) is an uncommon disorder characterized by a proliferation of mast cells involving the bone marrow, spleen, liver, skin, and lymph nodes. Although rare, the association of SMCD and other hematologic disorders is well established. To our knowledge, however, no previously published reports have described SMCD associated with the hypereosinophilic syndrome (HES). Herein we describe two patients who had SMCD in association with HES. Both patients had evidence of cardiac eosinophilic involvement, and both responded to systemic therapy. SMCD is often associated with eosinophilia and may be associated with HES more frequently than is commonly appreciated. Because congestive heart failure is a major cause of morbidity in patients with HES, cardiac assessment in patients with eosinophilia and SMCD is important in order to identify those with eosinophilic organ involvement and treat them aggressively.
      AST (aspartate aminotransferase), HES (hypereosinophilic syndrome), SMCD (systemic mast cell disease)
      Systemic mast cell disease (SMCD) is a rare disorder characterized by an abnormal proliferation of mast cells that infiltrate the bone marrow, spleen, liver, skin, and lymph nodes. Numerous hematologic abnormalities including eosinophilia have been reported in association with SMCD.
      • Travis WD
      • Li CY
      • Bergstralh EJ
      • Yam LT
      • Swee RG
      Systemic mast cell disease: analysis of 58 cases and literature review [published erratum appears in Medicine 1990;69:34].
      • Lawrence JB
      • Friedman BS
      • Travis WD
      • Chinchilli VM
      • Metcalfe DD
      • Gralmck HR
      Hematologic manifestations of systemic mast cell disease: a prospective study of laboratory and morphologic features and their relation to prognosis.
      • Wong KF
      • Chan JK
      • Chan JC
      • Kwong YL
      • Ma SK
      • Chow TC
      Concurrent acute myeloid leukemia and systemic mastocytosis.
      • Le Tourneau A
      • Gaulard P
      • D'Agay MF
      • Vainchencker W
      • Cadiou M
      • Dévidas A
      • et al.
      Primary thrombocythaemia associated with systemic mastocytosis: a report of five cases.
      • Travis WD
      • Li CY
      • Yam LT
      • Bergstralh EJ
      • Swee RG
      Significance of systemic mast cell disease with associated hematologic disorders.
      • Hutchinson RM
      Mastocytosis and co-existent non-Hodgkin's lymphoma and myeloproliferative disorders.
      • Yam LT
      • Yam CF
      • Li CY
      Eosinophilia in systemic mastocytosis.
      • Miranda RN
      • Esparza AR
      • Sambandam S
      • Medeiros LJ
      Systemic mast cell disease presenting with peripheral blood eosinophilia.
      In fact, eosinophils commonly accompany mast cell aggregates in involved tissues, and peripheral eosinophilia has been noted in 2 to 40% of patients with SMCD.
      • Travis WD
      • Li CY
      • Bergstralh EJ
      • Yam LT
      • Swee RG
      Systemic mast cell disease: analysis of 58 cases and literature review [published erratum appears in Medicine 1990;69:34].
      Occasionally, pronounced eosinophilia has been described in such patients, but no previous reports have described an adverse effect from the eosinophilia.
      Hypereosinophilic syndrome (HES), also a rare disorder, has three defining features: sustained blood eosinophilia of greater than 1,500 uL, signs and symptoms of organ involvement by eosinophils, and no underlying infectious or allergic cause to explain the eosinophilia.
      • Weller PF
      • Bubley GJ
      The idiopathic hypereosinophilic syndrome.
      Of these criteria, organ involvement by eosinophils is the most important; thus, most patients with clinically benign eosinophilia do not have HES. The diagnosis, prognosis, and treatment of patients with HES have been well described.
      • Weller PF
      • Bubley GJ
      The idiopathic hypereosinophilic syndrome.
      • Schooley RT
      • Flaum MA
      • Gralnick HR
      • Fauci AS
      A clinico-pathologic correlation of the idiopathic hypereosinophilic syndrome. II. Clinical manifestations.
      Although several published articles have reported substantially increased peripheral eosinophil counts in association with SMCD, to our knowledge, no reports have previously described eosinophilic organ involvement, or HES, associated with SMCD. Herein we describe two patients with SMCD who had hypereosinophilia and evidence of eosinophilic organ involvement.-

      REPORT OF CASES

      Case 1.—In January 1993, a previously healthy 26-year-old man had development of a nonproductive cough, myalgias, rhinorrhea, and low-grade fever. Throughout the next month, most of the symptoms gradually resolved, but the nonproductive cough and low-grade fever persisted. In November 1993, the cough worsened, and the patient began to have dyspnea on exertion associated with dependent edema. He also began to experience occasional posttussive syncopal episodes. In December 1993, he was admitted to his local hospital; leukocytosis and eosinophilia were noted on laboratory evaluation. He had lost 27.2 kg in the previous year but had been dieting. An echocardiogram revealed right ventricular dilatation, severe tricuspid regurgitation, and apical cavity obliteration. Computed tomography of the abdomen and pelvis revealed ascites and hepatosplenomegaly.
      The patient was referred to Mayo Clinic Rochester. On physical examination, his blood pressure was 105/80 mm Hg, and his heart rate was 105 beats/min. Decreased breath sounds were detected in the posterior lung fields bilaterally with associated dullness to percussion over the bases. Cardiovascular examination was remarkable for a laterally displaced and double apical impulse. A summation gallop was audible at the lower left sternal border, and a grade 2 (on the basis of 1 to 6) holosystolic murmur was detected at the cardiac apex. Jugular venous distention was present to the angle of the jaw, and pitting edema was noted bilaterally in the lower extremities. Laboratory studies yielded the following results: a hematocrit of 43% (normal, 38.8 to 50.0), a leukocyte count of 12.2 × 109/L (normal, 3.5 to 10.5) with an absolute eosinophil count of 4.56 × 109/L (normal, 0.05 to 0.50), and a platelet count of 178 × 109/L (normal, 150 to 450). The prothrombin time was 1.4 (international normalized ratio), and the activated partial thromboplastin time was 46.1 seconds (normal, 23 to 37). The serum alkaline phosphatase level was 486 U/L (normal, 98 to 251), and the aspartate aminotransferase (AST) level was 20 U/L (normal, 12 to 31). The total bilirubin level was 1.5 mg/dL (normal, 0.1 to 1.1), direct bilirubin was 0.6 mg/dL (normal, 0.0 to 0.3), and the creatinine was 1.4 mg/dL (normal, 0.8 to 1.2).
      An electrocardiogram showed sinus tachycardia with low anterior forces and a nonspecific T-wave abnormality in the lateral leads. Echocardiographic findings were typical of hypereosinophilic involvement of the heart with a biapical thrombus present. The tricuspid leaflets also appeared to have hypereosinophilic involvement. Right-sided cardiac chambers were enlarged. The left ventricle was normal in size, and the ejection fraction was 35%. Mild mitral regurgitation and a small pericardial effusion were also present. A bone marrow aspirate and biopsy specimen were obtained in order to evaluate the peripheral eosinophilia. The bone marrow examination revealed perivascular aggregates of atypical mast cells (tryptase positive) surrounded by eosinophils (Fig. 1 and 2), findings consistent with a diagnosis of SMCD. No ringed sideroblasts were present. Analysis of a liver biopsy specimen, which had been obtained in December 1993, revealed portal inflammation composed of focal aggregates of eosinophils and scattered cells (thought to be mast cells), findings consistent with hepatic involvement by SMCD. Results of chromosomal studies of the bone marrow samples were normal.
      Figure thumbnail gr1
      Fig. 1Bone marrow biopsy specimen, demonstrating perivascular mast cells surrounded by intense eosinophilic reaction.(Hematoxylin-eosin; original magnification, × 80.)
      Figure thumbnail gr2
      Fig. 2Immunoperoxidase stain for tryptase highlighting large aggregates of atypical mast cells in bone marrow biopsy specimen.(Original magnification, × 80.)
      The patient was hospitalized and treated initially with diuretics. On Jan. 12, 1994, cardiomyectomy of the right atrium, removal of an endocardial scar and thrombus from the right and left ventricle, and a tricuspid valve replacement with a St. Jude valve were performed. On histologic examination, the myocardium was infiltrated with eosinophils, and only a few, scattered, normal-appearing mast cells were evident. The ventricular endocardial and thrombus specimens had extensive endocardial fibrosis, ranging from dense fibrosis to looser myxoid-proliferative granulation tissue. Increased numbers of tissue eosinophils were present in the interstitium, inside the vessels, and in the thrombus itself.
      Despite treatment with anticoagulants, the patientapos;s postoperative course was complicated by thrombotic fixation of the prosthetic valve leaflets 2 weeks later. He was given tissue plasminogen activator to relieve the valve fixation, and the previously instituted anticoagulant therapy was resumed. In an effort to prevent further cardiac damage from hypereosinophilia, the patient was given interferon alfa-2a (Roferon-A), 4 million U per day, and prednisone, 60 mg per day. During the subsequent 10 days, the patientapos;s eosinophil count decreased from 9.16 × 109/L to 2.18. The patient was then transferred to his local hospital. He tolerated the medications well except he had daily fevers associated with the interferon injections. The dose of prednisone was tapered, and the interferon dose was increased to 5 million U per day at his local hospital. Thirteen months postoperatively, the eosinophil count was 0.31 × 109/L, and the interferon dose had been reduced to 9 million U three times per week. His symptoms of congestive heart failure were completely relieved.
      Case 2.—On Mar. 23,1992, a 72-year-old man was transferred to our institution for evaluation and treatment of leukocytosis and constitutional symptoms of arthralgias, myalgias, fevers, fatigue, and nausea. The patientapos;s symptoms of fatigue, nausea, fever (up to 37.8°C), myalgias, and a sore throat began on Mar. 11, 1992. His local physician prescribed cephalexin for presumed pharyngitis. After one dose, a pruritic rash developed on the patientapos;s extremities, and his fever increased. He was hospitalized, and his antibiotic therapy was changed to ciprofloxacin by intravenous infusion. The patient had had a pituitary adenoma resected in 1990 and had no evidence of recurrence. He was receiving maintenance thyroid hormone and cortisone replacement therapy. Because initial cultures of blood and urine were negative, the prednisone dose was increased to 20 mg twice per day in an attempt to relieve the patientapos;s now severe arthralgias. Subsequent blood and urine cultures were also negative.
      Despite antibiotic treatment, the patient still had fevers, worsening arthralgias, and an increasing leukocytosis; he was transferred to our institution. On arrival, his temperature was 37.5°C, blood pressure was 110/70 mm Hg, and heart rate was 90 beats/min (regular). Physical examination revealed erythema in the oropharynx, bilateral wrist swelling, bilateral wrist erythema and tenderness to movement and palpation, and a fading papular rash on his extremities. No adenopathy or hepatosplenomegaly was evident. Initial laboratory evaluation revealed a hematocrit of 45%; a leukocyte count of 29.6 × 10 with neutrophils of 23.7 × 109 (normal, 1.7 to 7.0), lymphocytes of 2.4 × 109/L (normal, 0.9 to 2.9), monocytes of 0.9 × 109/L (normal, 0.3 to 0.9), and eosinophils of 2.7 × 109/L; and a platelet count of 365 × 109/ L. The AST level was 20 U/L, the alkaline phosphatase was 224 U/L, and the creatinine was 1.4 mg/dL. The rheumatoid factor was less than 30 IU/mL (normal, 0 to 39), and an antinuclear antibody test was negative. Complement levels, serum immunoglobulins, and a serum protein electrophoresis were within normal limits. Repeated blood and urine cultures were negative. The dose of prednisone was increased because of presumed serum sickness. The patient was dismissed when he had symptomatic improvement. His local physician gradually tapered the dose of prednisone until his maintenance dose was achieved.
      The patient did well until November 1994, when knee pain developed. A routine laboratory evaluation again showed a peripheral eosinophilia, leukocyte count of 22.3 × 109/L with eosinophil count of 9.4 × 109/L, hematocrit of 43%, and platelet count of 286 × 109/L. He was again referred to our institution. Analysis of a previously obtained bone marrow biopsy specimen, which had been obtained to evaluate his persistent eosinophilia, revealed SMCD. Pronounced eosinophilia and focal paratrabecular aggregates of atypical mast cells with fibrosis were noted on tryptase staining, findings consistent with the diagnosis of SMCD. No ringed sideroblasts were seen. Chromosomal analysis of a direct preparation of the bone marrow sample revealed that 5 of 20 metaphases lacked a Y chromosome. The rest of the metaphases were normal.
      In January 1995, assessment of the patient at our institution disclosed no recent weight loss, fever, chills, night sweats, bone pain, diarrhea, or flushing episodes. Findings on physical examination were unremarkable except for cataracts, decreased hearing, scattered keratosis on the skin, and degenerative joint changes of the extremities. Results of a radiographic bone scan were normal. An electrocardiogram revealed a normal sinus rhythm. Laboratory studies yielded a leukocyte count of 25.2 × 109/L with neutrophils of 7.3 × 109/L, lymphocytes of 2.5 × 107L, monocytes of 0.5 × 107L, and eosinophils of 14.9 × 109/L; hematocrit of 44%; and platelet count of 289 × 109/L. The AST, alkaline phosphatase, serum electrolytes, and creatinine levels were all within normal limits. The lactate dehydrogenase value was 222 U/L (normal, 112 to 257). Results of urinalysis were unremarkable. Serum protein electrophoresis was within normal limits. Twenty-four-hour urine levels of methylimidazoleacetic acid and histamine were both within normal limits.
      An echocardiogram revealed increased thickness of the left ventricular wall with a normal ejection fraction of 60%. Trivial to mild regurgitation of both atrioventricular valves was noted. Increased wall thickness in the ventricular apex was present, consistent with an eosinophilic cardiomyopathic deposit.
      In an effort to prevent further cardiac deposits, hydroxyurea was instituted (the initial dose of 500 mg per day was gradually increased to 1,500 mg per day). On Jun. 12, 1995, the patient was tolerating the therapy well. His leukocyte count had decreased to 9.2 × 109/L with eosinophils of0.12 × 109/L.

      DISCUSSION

      Our two patients with SMCD had peripheral blood eosinophilia and cardiac involvement, findings consistent with a concurrent diagnosis of HES. Both peripheral blood and bone marrow eosinophilia in the setting of SMCD have been well described previously,
      • Travis WD
      • Li CY
      • Bergstralh EJ
      • Yam LT
      • Swee RG
      Systemic mast cell disease: analysis of 58 cases and literature review [published erratum appears in Medicine 1990;69:34].
      • Yam LT
      • Yam CF
      • Li CY
      Eosinophilia in systemic mastocytosis.
      • Miranda RN
      • Esparza AR
      • Sambandam S
      • Medeiros LJ
      Systemic mast cell disease presenting with peripheral blood eosinophilia.
      • Brunning RD
      • McKenna RW
      • Rosai J
      • Parkin JL
      • Risdall R
      Systemic mastocytosis: extracutaneous manifestations.
      • Meggs WJ
      • Macher AM
      • Friedman MM
      • Kramer N
      • Metcalfe DD
      Lymphadenopathic mastocytosis with eosinophilia [abstract].
      • Frieri M
      • Linn N
      • Schweitzer M
      • Angadi C
      • Pardanani B
      Lymphadenopathic mastocytosis with eosinophilia and bidonai gam-mopathy.
      • Webb TA
      • Li CY
      • Yam LT
      Systemic mast cell disease: a clinical and hematopathologic study of 26 cases.
      • Horny HP
      • Parwaresch MR
      • Lennert K
      Bone marrow findings in systemic mastocytosis.
      but, to our knowledge, ours is the first report of cardiac involvement by eosinophils in patients with SMCD. One of our patients (case 2) was asymptomatic, but an echocardiogram clearly demonstrated the typical echocardiographic features of cardiac involvement by eosinophils. Because congestive heart failure is a major cause of morbidity and mortality in patients who have HES,
      • Weller PF
      • Bubley GJ
      The idiopathic hypereosinophilic syndrome.
      a thorough baseline cardiac evaluation in this patient with SMCD and peripheral eosinophilia was important in order to initiate therapy before asymptomatic cardiac involvement.
      Many patients with SMCD are treated symptomatically with histamine antagonists, prostaglandin inhibitors, disodium cromoglycate, ketotifen, and psoralens and ultraviolet A. More aggressive, systemic treatment of SMCD has been traditionally accomplished with agents similar to those used in the treatment of HES. The most common initial therapy is prednisone. More recently, interferon has been used successfully in patients with SMCD and in those with HES.
      • Bockenstedt PL
      • Santinga JT
      • Boiling SF
      Alpha-interferon treatment for idiopathic hypereosinophilic syndrome.
      • Butterfield JH
      • Gleich GJ
      Interferon-alpha treatment of six patients with the idiopathic hypereosinophilic syndrome.
      • Kluin-Nelemans HC
      • Jansen JH
      • Breukelman H
      • Wolthers BG
      • Kluin PM
      • Kroon HM
      • et al.
      Response to interferon alfa-2b in a patient with systemic mastocytosis.
      • Petit A
      • Pulik M
      • Gaulier A
      • Lionnet F
      • Mahe A
      • Sigal M
      Systemic mastocytosis associated with chronic myelomonocytic leukemia: clinical features and response to interferon alfa therapy.
      • Pulik M
      • Lionnet F
      • Petit A
      • Genet P
      • Gaulier A
      Long-term response to interferon-alpha in a patient with systemic mastocytosis and chronic myelomonocytic leukemia [letter].
      • Harrison BD
      • Ashford RA
      • Hatton CS
      Systemic mastocytosis–a case treated with interferon alpha and radiotherapy.
      In the past, cytotoxic chemotherapy for patients with SMCD was reserved for those with an associated overt hematologic malignancy.
      • Tharp MD
      The spectrum of mastocytosis.
      • Horan RF
      • Austen KF
      Systemic mastocytosis: retrospective review of a decade's clinical experience at the Brigham and Women's Hospital.
      • Metcalfe DD
      The treatment of mastocytosis: an overview.
      • Parker RI
      Hematologic aspects of mastocytosis. II. Management of hematologic disorders in association with systemic mast cell disease.
      Numerous chemotherapeutic agents such as hydroxyurea, vinca alkaloids, etoposide, and alkylating agents have also been used in the treatment of both these diseases; success has varied.
      • Wong KF
      • Chan JK
      • Chan JC
      • Kwong YL
      • Ma SK
      • Chow TC
      Concurrent acute myeloid leukemia and systemic mastocytosis.
      • Weller PF
      • Bubley GJ
      The idiopathic hypereosinophilic syndrome.
      • Schooley RT
      • Flaum MA
      • Gralnick HR
      • Fauci AS
      A clinico-pathologic correlation of the idiopathic hypereosinophilic syndrome. II. Clinical manifestations.
      • Webb TA
      • Li CY
      • Yam LT
      Systemic mast cell disease: a clinical and hematopathologic study of 26 cases.
      • Metcalfe DD
      The treatment of mastocytosis: an overview.
      • Parker RI
      Hematologic aspects of mastocytosis. II. Management of hematologic disorders in association with systemic mast cell disease.
      Regardless of the initial therapy, close monitoring of the eosinophil level and periodic cardiac assessment seem to be important in patients with SMCD and peripheral eosinophilia. In patients with HES, the degree of cardiac involvement does not always correlate with the level of peripheral eosinophilia.
      • Weller PF
      • Bubley GJ
      The idiopathic hypereosinophilic syndrome.
      Eosinophils on peripheral blood smears or in bone marrow samples cannot be differentiated histopathologically between those that cause HES and those that do not. Patients who have evidence of early cardiac involvement by eosinophils warrant an aggressive treatment approach.
      Both surgical and medical treatments of cardiac involvement are clearly important and can provide a great deal of symptomatic relief, as demonstrated in one of our patients (case 1). Nevertheless, because of the vascular instability of some patients with SMCD, an operation should be undertaken only at a center with experienced anesthesia support.
      Thrombotic and thromboembolic events are well-known, frequent, and potentially serious complications of HES. Our first patient (case 1) had postoperative thrombosis of his St. Jude valve, and antithrombotic therapy was necessary. Whether prophylactic anticoagulation or antiplatelet agents are efficacious in patients with HES who have no indication for anticoagulation has not been clearly established.
      • Weller PF
      • Bubley GJ
      The idiopathic hypereosinophilic syndrome.

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