Acute Respiratory Failure Due to Extramedullary Hematopoiesis

Acute Respiratory Failure Due to Extramedullary Hematopoiesis* Roger D. Yusen, MD; and Marin H. Kollef, MD, FCCP

Extramedullary hematopoiesis (EMH) associated with myelofibrosis uncommonly occurs within the thorax. We describe the first rep orted case of acute and rapidly fatal respira tory failure du e t o pulmon ary interstitial E MH associated with myelofibrosis. I nter stitial EMH should b e conside red in the differential diagnosis of p atients with interstitial p ulmonary infiltrates and respiratory failure accomp anying a disease process known to predisp ose to the development of EMH. (CHES T 1995; 108:1170-72) EMH=extramedullary hematopoiesis

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Key words: hematopoiesis; myeloid metaplasia; myeloproliferative disorder; respiratory distress syndrome

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xtramedullary hematopoiesis (EMH) or myeloid metaplasia associated with idiopathic (agnogenic) myelofibrosis is part of the spectrum of illnesses classified as the myeloproliferative syndromes, though it may also be associated with other illnesses such as thalassemia. 1 EMH most often occurs in the reticuloendothelial system, including the spleen, liver, and lymph nodes. 2 EMH has been described to occur less commonly in many other anatomic locations including the chest. 1-11 There are case reports and small case series of pleural-based tumors and paraspinous masses secondary to EMH. 1·2·4 In nonautopsy series, intrathoracic EMH has been almost entirely associated with thalassemia, 1·6 erythroblastosis fetalis, 1 or hereditary spherocytosis9·12 and uncommonly associated with idiopathic myelofibrosis. Pulmonary interstitial EMH associated with myelofibrosis rare% has been described in the English language literature. 2 ·8·13 We report a case of acute and rapidly fatal hypoxic respiratory failure (ie, acute respiratory distress syndrome) due to pulmonary EMH in a patient with idiopathic myelofibrosis.

eventually underwent splenectomy, which demonstrated the presence of extramedullary hematopoiesis. The patient then remained clinically stable until 2 to 3 weeks prior to her hospital admission when she developed asymptomatic thrombocytopenia with a platelet count of85x1

CASE REPORT

A 67-year-old white woman with a history of myelofibrosis and myeloid metaplasia was hospitalized with a 10-day history of dyspnea, dry cough, fevers, and sweats. The patient was initially diagnosed 5 years earlier with a myeloproliferative disorder in the setting of leukocytosis, thrombocytosis, and a hypercellular bone marrow. The chromosomal karyotype was normal, and the leukocyte alkaline phosphatase score was at the higher end of normal. The patient received chemotherapeutic treatment with busulfan for approximately 2 months, which led to relative quiescence of her disease. Two years later, leukocytosis with immature forms and progressive anemia led to a repeat bone marrow biopsy which showed myelofibrosis. Because of her enlarging spleen, therapy with hydroxyurea was started, and another 2 years later, the patient *From Washington University Medical School, St. Louis. !Wprint requests: Dr. Kollef, Campus Box 8052, 660 S. Euclid, St. Louis, MO 63110-1093 1170

FIGUHE l. Pulmonary EMH. The chest radiograph at the time of hospital admission shows bilateral interstitial inflltrates. Selected Reports

FIGURE 2. Top left: pulmonary EMH. A histologic section of transbronchiallung biopsies reveals an interstitial pneumonitis with atypical cells of megakaryocyte, erythroid, and myeloid lineages (hematoxylin and eosin). Top right: transbronchiallung biopsies with immunohistochemical staining (dark areas) for factor VIII confirm the presence of megakaryocytes. Bottom left: glycophorin A staining (dark areas) confirms the presence of erythroid cells. Bottom right: myeloperoxidase staining (dark areas ) confirms the presence of myeloid cells (original magnification x 100). anterior segment of the right upper lobe showed an interstitial pneumonitis with atypical cells of megakaryocyte, erythroid, and myeloid lineages (Fig 2, top left). Findings of relatively normal pneumocytes were not suggestive of drug-induced lung disease (busulfan). Immunohistochemical stains for factor VIII, glycophorin A, and myeloperoxidase, respectively, confirmed the presence of megakaryocytes, erythroid cells, and myeloid cells (Fig 2, top right, bottom left and right). A diagnosis of pulmonary interstitial extramedullary hematopoiesis was made. All fluid and tissue stains and cultures were negative for bacteria, acid-fast organisms, fungi, and viruses. The patient had a progressively downhill course for the remaining days of her 3-week hospitalization, requiring continued mechanical ventilatory support. Her alveolar-arterial oxygen gradient was elevated, and lung compliance was diminished. An inspired oxygen concentration of 60% with 5 em H20 positive end-expiratory pressure was necessary for adequate oxygenation. During the following 2 days, the patient received palliative therapy with interferon a, but her condition continued to deteriorate. Given the patient's previous wishes and the progression of her disease, ventilatory support was withdrawn and the patient died from the progressive respiratory failure . An autopsy was not performed. DISCUSSION

EMH associated with idiopathic myelofibrosis is one of the four commonly described myeloproliferative syndromes, including polycythemia vera, essential thrombocytosis, and chronic myelogenous leukemia.

EMH is a disorder related to clonal abnormalities in pleuripotent stem cells. 15 The relationship between EMH and marrow myelofibrosis has not been completely clarified, and they may or may not occur together. 2·15 The average age of EMH onset is during the 6th or 7th decade. Splenomegaly is the most common sign, seen in 95% of patients. 2 The classic peripheral blood smear reveals a leukoerythroblastic picture with immature WBC and RBCs, along with circulating megakaryocytes. The bone marrow is often fibrotic but may have a cellular phase with myelofibrosis. The typical clinical course consists of slow progression with complications of hematologic abnormalities including bleeding, cardiovascular illnesses, infection, or leukemic transformation. Treatment options are limited, and the prognosis is poor. The median survival is 4 to 5 years, but 25% of patients may live 15 years.l 6 EMH has been described in almost every area of the body including the thyroid, dura, and prostate. 2·11 Thoracic EMH is uncommon but well described. There are case reports and small series of EMH manifested as pleural based tumors and paraspinous masses.1·2.4 Pulmonary interstitial EMH associated with idiopathic myelofibrosis has not been commonly deCHEST I 108 I 4 I OCTOBER, 1995

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scribed but is a known entity. 2 ·4 •8.1 3 Most cases of pulmonary EMH have been associated with an antecedent hematologic disorder, but rarely may present de novo. Gowitt and Zaatari3 described a patient with a right lower lobe stenotic bronchus with no definite endobronchial lesion seen on bronchoscopy, but surgical resection confirmed that the area of stenosis was secondary to EMH. This patient had no known underlying hematologic disorder, but within 1 year was diagnosed with chronic myelogenous leukemia. Also of interest, nonhematologic malignancies of the lung have been associated with EMH. Lara and Rosen 5 described acase of bronchial carcinoid tumor with foci of EMH in a patient with a history of EMH and myelofibrosis. Pitcock and coworkers 2 reviewed the pathology records ofWashington University in St. Louis where 70 cases of myelofibrosis were histologically confirmed. Pulmonary EMH was seen in 2 out of 17 complete autopsies. Lieberman et al4 described one patient with symptomatic peribronchial EMH and another patient with EMH of the "lung" noted in the case records labeled as "myelofibrosis and myelosclerosis with myeloid metaplasia" in the Memorial-Sloan Kettering Cancer Center autopsy files. Clew etal8 reviewed over 100 cases ofEMH associated with myelofibrosis at the Johns Hopkins Hospital over an 18-year period (1952 to 1970) and found 4 cases with "aggressive infiltrations and tumefactions " of the lung due to EMH. Three of these patients had symptomatic pulmonary disease, and EMH of the lung likely contributed to two of these patients' deaths. Asakura and Colb/3 also recently described two cases of fatal pulmonary EMH vvithin the lung, but the patients' clinical courses w erechronic and progressive. The present case is unique in that it describes the first reported case of acute and rapidly fatal hypoxic respiratory failure secondary to EMH . The pathologic findings of EMH are relatively the same in all organs. The precursor cells of RBC, WBC, and platelets are located within organs either focally or diffusely.2 In the lungs, hematol~phoid infiltrates typically follow lymphatic routes. 7 The diagnosis of pulmonary EMH probably is most often made at autopsy, but may also be made by open-lung biopsy.8,l3 Our case and one previous reported case 1 have demonstrated that a transbronchial lung biopsy also may provide adequate tissue to make a diagnosis. However, immunohistochemical staining for erythroid, myeloid, and megakaryocyte precursors needs to be performed on lung biopsy specimens when EMH is suspected to help confirm the diagnosis. In summary, idiopathic myelofibrosis often is associated with EMH in the reticuloendothelial organs, but less commonly EMH has been described in the chest and lungs. vVe report a rare case of pulmonary interstitial EMH, and this case is unique in that it is the first 1172

description of pulmonary interstitial EMH where the initial presentation was acute with rapidly fatal respiratory failure suggesting a scenario consistent with ARDS.14 This case also represents one of two reports in the English-language literature where the diagnosis was made before death via transbronchial lung biopsy. EMH of the lung interstitium should be considered in the differential diagnosis of patients with interstitial pulmonary infiltrates and an accompanying disease process known to predispose to the development of EMH. Early confirmation of this diagnosis could allow directed therapy at the underlying cause in attempts to reverse the disorder. ACKNOWLE D GME NTS: The authors a re grate ful to Drs. John A. Wood and Robert E. Kraetsch f or providing clinical information and to Drs. Mark R. Wick and Louis P. Dehner for their pathology expertise.

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