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CASE REPORT
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An Unusual Cause of Unilateral Pleural Effusion in the Setting of Aortic Stenosis: Acute Myeloid Leukemia Tufan Fatih, Yavuz Selim, Ayer Mesut, Yildirim Naciye Demirel and Pekcelen Yuksel
Abstract Pleural effusion has various causes. In the setting of aortic stenosis, new onset pleural effusion is generally considered as a consequence of heart failure. Here, we describe a 50-year-old male patient who had been followed with aortic stenosis for 30 years. During his admission he presented with exertional dyspnea and pleuritic chest pain. He had no other symptoms or findings of cardiac failure. Complete blood count revealed neutrophilic leukocytosis, a normal hemoglobin level and normal platelet count. Left sided pleural effusion was noted on the posteroanterior chest X-ray. Examination of the pleural fluid revealed myeloid blasts. Bone marrow aspiration smear and flow cytometric analysis of the bone marrow and pleural fluid were consistent with acute myeloid leukemia. Key words: aortic stenosis, pleural effusion, acute myeloid leukemia, unusual presentation, extramedullary (DOI: 10.2169/internalmedicine.46.6004)
Introduction Pleural effusion (PE) has many causes like heart failure, pneumonia, cirrhosis, cancer, nephrotic syndrome, pulmonary embolism, uremia, tuberculosis, connective tissue diseases and sarcoidosis (1). The most common causes of malignant pleural effusion are lung carcinoma, breast carcinoma, lymphoma and ovarian carcinoma (2). In Hodgkin’s and non-Hodgkin’s lymphomas, pleural effusion is a common finding, especially if mediastinal involvement is present (3). Acute myeloid leukemia (AML) presenting with unilateral pleural effusion is a very rare condition. Herein, we present a 50-year-old man known to have aortic stenosis for 30 years presenting with unilateral pleural effusion. Microscopic examination of pleural fluid revealed atypical mononuclear cells. Diagnosis of acute myeloid leukemia was done with further examinations.
Case Report A 50-year-old health worker presented with pleuritic chest pain, exertional dyspnea and subfebrile fever. He had been followed up for aortic stenosis for 30 years, without any complication. He was not born from a consanguineous mar-
riage. His family history was noncontributory. On physical examination there were signs of aortic stenosis and left sided pleural effusion. His physical examination revealed pulsus parvus et tardus and a 2/6 crescendodecrescendo systolic murmur accentuated in the aortic area was heard. He did not have any pathologic lymphadenopathy. Physical examination did not reveal organomegaly, sternal tenderness, gum hypertrophy nor any sign of heart failure. Automated complete blood count revealed neutrophilic leukocytosis (white blood cells: 19700/mm3, neutrophils: 17000/mm3, hemoglobin: 14.6 g/dl, hematocrit: 42%, platelets: 157000/mm3). Erythrocyte sedimentation rate was 92 mm/hour. His biochemical analysis was as follows: glucose, 99 mg/dl (Normal [N]: 70-110); blood urea nitrogen, 17 mg/ dl (N: 8-22); creatinine, 1.3 mg/dl (N: 0.7-1.4); uric acid, 6 mg/dl (N: 2.5-7); lactate dehydrogenase, 1001 U/L (N: 240480); aspartate aminotransferase, 43 U/L (N: 5-42); alanine aminotransferase, 65 U/L (N: 5-45); triglyceride, 229 mg/dl (N: 40-170); total cholesterol, 151 mg/dl (N: 130-200); total protein, 6.2 g/dl (N: 6-8); albumin, 3.6 g/dl (N: 3.2-5.5); gamma globulin, 1 g/dl (N: 0.8-1.7); thyroid stimulating hormone, 2.110 mIU/ml (N: 0.27-4.20). His prothrombin time was 13.2" (control: 13") and activated partial thromboplastin time was 23.3" (control: 2"-32"). Posteroanterior chest X-ray was consistent with severe left sided pleural ef-
Department of Internal Medicine, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey Received for publication April 16, 2006; Accepted for publication September 21, 2006 Correspondence to Dr. Tufan Fatih,
[email protected]
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fusion. There was no lesion on the rest of the lung parenchyma, nor mediastinal enlargement. Diagnostic thoracentesis revealed an exudative pleural fluid (pleural fluid total protein 4.6 g/dl, lactate dehydrogenase 780 U/L). On microscopic examination of the pleural fluid, atypical mononuclear cells were seen (Fig. 1). In the peripheral blood smear 90% of leukocytes were myeloid blasts. Bone marrow smear contained 94% myeloid blasts and peroxidase staining was positive in 3% of blasts (Fig. 2). Flow cytometric analysis of bone marrow aspirate was consistent with acute myeloid leukemia (AML M1 according to FAB classification) (CD 45: 100%, CD13: 41%, CD14: 15%, CD19: 82%, CD33: 59%, CD34: 82%, HLA-DR: 91%). Flow cytometric analysis of pleural fluid was also consistent with myeloid leukemic infiltration (CD45: 99%, CD13: 29%, CD19: 76%, CD 33: 49%). Cytogenetic analysis of the bone marrow revealed complex karyotype features (15 cells were examined, 7 of them were 45 XY, t(11;12), -17;5 and 5 of the remaining 8 cells with 46 XY karyotype had complex karyotype features with translocation between chromosomes 3,10,11 and 12). Because of dyspnea, therapeutic thoracentesis was done. He was given 3+7 AML protocol (100 mg/m2 cytosine arabinoside for 7 days and 12 mg/m2 idarubicin for 3 days). His pleural effusion disappeared after this treatment. He developed febrile neutropenia on the 8th day of this regimen and was given broad spectrum antibiotics. Because of persistent fever, he was empirically given liposomal preparation of amphotericin B (Ambisome 1 mg/kg/day). Ultrasonographic examination of the abdomen revealed round solid lesions on the liver consistent with invasive fungal infection. Because of severe hypokalemia, his antifungal treatment was replaced with caspofungin 50 mg/d. After this treatment, hypokalemia was resolved. Control bone marrow examination done on the 28th day of the treatment revealed no remission with 70% blasts. Given his age and cytogenetic abnormalities, FLAG-IDA protocol (50 mg/m2 fludarabin and 2 g/m2 cytosine arabinoside for 5 days, 10 mg/m2 idarubicin for 3 days and filgrastim 300 mcg subcutaneous injection starting on
the day prior to chemotherapy and continuing during postchemotherapy until a neutrophil count of 1000/mm3 was achieved) was started. Control bone marrow examination done on the 28th day of this regimen, revealed no remission with 90% blasts. He was given the FLAG-IDA regimen again, without achievement of remission. On control abdominal computed tomography there were no residual lesions in the liver. This was consistent with remission of invasive fungal liver infection. In the follow-up he never developed pleural effusion again. He was followed-up in outpatient setting with supportive measures. Three months after he was discharged from our clinic, he died.
Discussion Pleural effusion may be seen as a presentation of a hematological malignancy or as a complication. Among the possible suggested pathogenetic mechanisms are, an extramedullary proliferation of an occult leukemic clone with subsequent metastasis to the bone marrow or, a subclinical marrow relapse with consequent seeding to extramedullary sites (5). In leukemic patients, other causes which may be responsible for the presence of the pleural effusion such as infections, other disseminated solid tumors, or complications of treatment should be excluded (6-8). Immunocytologic examination of cells obtained from the pleural effusion, flow cytometry, as well as polymerase chain reaction can contribute to the differential diagnosis. The findings sometimes need to be confirmed by invasive procedures with surgical biopsy (8, 9). Acute myeloid leukemia generally presents with signs and symptoms of cytopenias like fatigue, hemorrhage and infections (10). Extramedullary involvement may accompany medullary involvement at the beginning. Hepatomegaly, splenomegaly, leukemia cutis, lymphadenopathy, bone pain, granulocytic sarcomas (isolated mass of leukemic blasts), gingival and central nervous system involvement may occur (10). When leukocyte count per cubic millimeter is above
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100,000, the findings of leukostasis may be seen (10). In Hodgkin’s and non-Hodgkin’s lymphomas, pleural effusion is a common finding seen in up to 20-30% of cases, especially if mediastinal involvement is present (3). Acute and chronic leukemias are rarely accompanied by pleural effusion (3). Acute myeloid leukemia presenting with pleural effusion is a very rare condition. One previously reported case presenting with pleural and pericardial effusion was related to granulocytic sarcoma (GS) (4). Another case presented with massive pleural effusion showing malignant cells whose bone marrow examination revealed CD7- and CD 19positive AML (12). Another case presented with cardiac tamponade and pleural effusion; his peripheral blood picture was normal and pericardial fluid examination revealed myeloblasts. Acute myeloid leukemia was diagnosed with bone marrow smear findings (13). Another one had myelodysplastic syndrome and developed anasarca showing GS in ascitic and pleural effusions while progressing to AML (14). Another case developed extramedullary relapse in the pleural fluid 3 years after allogeneic bone marrow transplantation for AML (15). The present case presented with symptoms and signs of pleural effusion rather than with classical symptoms and signs of acute myeloid leukemia. He also had aortic stenosis for 30 years, making us think cardiac causes of pleural effusion in the first place, but our patient did not have any symptom or sign of cardiac failure. Another etiol-
ogy to consider would be parapneumonic pleural effusion. Our patient did not have the typical symptoms of pneumonia like productive cough and fever. The findings of our case suggest that his leukemia was subclinical and it later seeded to pleura. We could not find any information in the literature regarding an association of aortic stenosis and pleural invasion of leukemia. In the Medical Research Council AML 10 trial, certain cytogenetic abnormalities are defined as poor prognostic signs. Patients having a complex karyotype, -5, del (5q), -7 or abnormalities of 3q were defined as a group of relatively poor prognosis (11). The present patient had complex karyotype features rendering him resistant to standard therapy. He did not respond to conventional therapy or to FLAG-IDA regimen which is used in resistant and relapsed cases. Eventually, he died while he was being followed-up with supportive measures in the outpatient setting. New treatment modalities should be found to achieve better results in such cases. Leukemia may present with unusual findings and thus delay the diagnosis and treatment. The diagnosis of leukemia which presented with extramedullary involvement was made straightforward with the examination of pleural fluid. This again demonstrates the importance of basic and simple procedures for the diagnosis of diseases including extremely rare cases like the present case.
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