Intimal Sarcoma Mimicking Acute Pulmonary Embolism

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1 台灣癌症醫誌 (J. Cancer Res. Pract.) 28(1),35-40, 2012 Case Report journal homepage: Intimal Sarcoma Mimicking Acute Pulmonary Embolism Shih-Feng Cho 1, Chao-Sung Chang 1,2, Sheng-Fung Lin 1,3 * 1 Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital 2 Graduate Institute of Healthcare Administration, Kaohsiung Medical University, Kaohsiung, Taiwan 3 Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Abstract. Intimal sarcoma is a very rare malignancy typically developing in adults, with male preponderance. It often arises from the pulmonary artery, especially the proximal pulmonary trunk. Its clinical manifestations are very similar to those of pulmonary embolism but imaging findings are not specific for proper diagnosis. Early surgical intervention for definitive diagnosis is critical for survival but prognosis is poor and the average survival is a few months. Complete tumor excision is the only curative intervention. This report is a case of intimal sarcoma in an adult female initially presenting with pulmonary embolism-like symptoms. Related articles are also reviewed. 病例報告 Keywords : intimal sarcoma, pulmonary embolism, immuno-histochemical study 血管內膜骨肉瘤以類似急性肺栓塞為初始表現 卓士峰 1 張肇松 1,2 林勝豐 1,3 * 1 高雄醫學大學附設中和紀念醫院血液腫瘤科 2 高雄醫學大學醫務管理研究所 3 高雄醫學大學醫學院內科學 中文摘要血管內膜骨肉瘤是一種十分罕見的惡性腫瘤, 文獻上以男性較多, 年齡自 14 歲至 71 歲皆有, 一般好發於肺動脈, 尤其是近端的肺動脈幹, 常以引起反覆的肺栓塞症狀來表現 因為在臨床上的表現難以和肺栓塞區分, 且影像學的表現缺乏專一性, 往往造成誤診及延遲診斷, 甚至導致錯誤的治療處置及病人死亡 本疾病的診斷有賴於臨床醫師之警覺性及盡早施行外科手術切片確立診斷, 免疫組織化學染色也是重要的診斷工具 本疾病的預後十分不好, 早期發現診斷合併完全腫瘤切除是唯一延長存活的機會 我們報告一位女性肺動脈血管內膜骨肉瘤之病人, 症狀上十分類似肺動脈栓塞, 經由內科治療後最後才進行手術達到確診, 此外我們也進行一些相關文獻的回顧 關鍵字 : 血管內膜骨肉瘤 肺動脈栓塞 免疫組織化學染色 INTRODUCTION Intimal sarcoma is a very rare malignancy which often arises from the pulmonary artery, especially in the proximal pulmonary trunk. Clinical manifestations

2 36 S. F. Cho et al./jcrp 28(2012) are dependent on tumor location and are very similar to pulmonary embolism if the vascular lumen is obstructed by the tumor. However, clinical presentations and imaging findings are insufficient to differentiate this tumor from embolism and delays in diagnosis are not uncommon. Early definite diagnosis by surgical intervention is very essential for patient survival. Immuno-histochemical study is also an important diagnostic tool. Nonetheless, prognosis is generally poor, with just a few months of survival. Complete tumor excision is the only way to prolong life span in some patients. CASE REPORT A 65-year-old female native Taiwanese consulted at the emergency department for progressive dyspnea of two weeks. Associated symptoms included rightsided non-radiating chest discomfort, intermittent cough with blood-tinged sputum, and general malaise. Her personal and medical histories were unremarkable except for hypertension. On physical examination, the patient had respiratory distress with increased respiratory rate (30~ 35/min) and heart rate (105~110/min), where as the blood pressure and body temperature were within normal range. However, there was systolic murmur (grade III to IV) and decreased breath sounds in the right lung field but no neck or axillary lymphadenopathy. Abdominal examination showed no hepatomegaly or splenomegaly. Results of initial laboratory examination showed increased white cell count and C-reactive protein level (12670/ul and 75.33mg/dl, respectively), and slightly elevated D-dimer level (1.14 mg/l). Chest x-ray (Fig- *Corresponding author: Sheng-Fung Lin M.D. * 通訊作者 : 林勝豐醫師 Tel: ext.6109 Fax: shlin@kmu.edu.tw ure 1A) showed right-sided pleural effusion and suspected atelectasis, while chest computed tomography with contrast (Figure 1B) showed diffuse embolism in the pulmonary trunk and the bilateral main pulmonary and more distal right pulmonary arteries. Because of unstable hemodynamic status, the patient was admitted to the intensive care unit. This patient received tissue plasminogen activator (t-pa) and heparin infusion as main therapy for pulmonary embolism. Two weeks later, the patient received technetium-99m macro-aggregated albumin (Tc-99m MAA) pulmonary perfusion/aerosol ventilation scintigraphy (Figure 2A, 2B), which revealed a high probability of pulmonary embolism with mismatch of ventilation/perfusion ratio. The patient s condition was gradually stabilized and she was discharged and followed-up at the out-patient department. However, the patient presented to the emergency department two months later with severe dyspnea with respiratory distress. The chest radiograph (Figure 1C) showed cardiomegaly with water-bottle appearance and worsened pleural effusion of the right lung. Chest computed tomography (Figure 1D) showed obvious pulmonary artery thrombosis and pericardial effusion. Lung tumor with thrombus formation was the impression but pericardiocentesis results were negative for malignancy. The patient underwent biopsy of the lung tumor by bronchoscopy. Microscopically, the benign bronchial epithelium had underlying submucosal tissue and smooth muscle infiltration by pleomorphic or spindle cells with high nucleo-cytoplasmic ratio (Figure 3A, 3B). The tumor cells were immuno-histochemically positive for vimentin but not for cytokeratin (CK), leukocyte common antigen (LCA), CD34, CD31, factor 8, smooth muscle actin (SMA), desmin, and S100. Intimal sarcoma of the pulmonary artery with lung metastasis was diagnosed. The patient s condition deteriorated rapidly after diagnosis and she subsequently expired due to multiple organ failure.

3 S. F. Cho et al./jcrp 28(2012) Figure 1. (A-B) Imaging studies on initial presentation. (A) Chest radiography showed right-sided pleural effusion with suspected atelectasis. (B) Computed tomography with contrast revealed diffuse filling defect in the pulmonary trunk and in the bilateral main and distal right pulmonary arteries, with note of a large bullae. (C-D) Imaging studies after two months. (C) Chest radiography showed worsening of the right-sided pleural effusion and cardiomegaly with water-bottle appearance. There was also a suspicious mass lesion in right lung field. (D) Computed tomography revealed a suspected lung mass with thrombus formation and pericardial effusion DISCUSSION have more aggressive growth pattern and are differen- Pulmonary artery sarcoma, firstly documented by tiated poorly compared with sarcoma of inferior vena Mandelstamm in 1923 [1], is a rare mesenchymal ma- cava. Most of pulmonary sarcomas were derived from lignancy. The patients of this disease are between 14 intimal cells with myofibroblastic differentiation [2]. to 71 year of age with male sex predominance [2,3]. Intimal sarcoma of the pulmonary artery tends to grow Primary sarcoma developed from aorta and pulmonary locally, with slight ability for distant metastasis [4].

4 38 S. F. Cho et al./jcrp 28(2012) Figure 2. From the anterior view of (A) ventilation and (B) perfusion scan via Tc-99m MAA pulmonary perfusion/aerosol ventilation scintigraphy, there were bilateral lung field lesions with obvious V/Q mismatch, predominantly in the right middle, right lower, and left lower lobes Lung metastasis was most common, and metastasis to other organs like the brain, pancreas and adrenal glands were also documented [2,3]. Grossly, pulmonary artery sarcoma affects the intimal layer of the arteries with appearance of a gelatinous or mucinous clot filling the arterial lumen. Microscopically, intimal sarcoma is often an a poorly differentiated tumor consisting of atypical and pleomorphic spindle or epithelioid cells along the intima [2,3,5]. Immunohistochemically, most pulmonary intimal sarcomas and leiomyosarcomas were positive for actin. Vimentin was positive in most intimal sarcoma. In intimal sarcoma, muscle-specific actin was only focally positive for the spindle-shaped cells. And the desmin positivity was obvious lower in intimal sarcoma compared with leomyosarcoma [2,3]. Other markers, such as CD31, CD 34 or cytokeratin were negative or rarely positive in pulmonary intimal sarcoma [3]. The proliferation index Ki-67 was between 5% and 80%. Genetically, Gains of 12q13 14 and overexpression of mdm2 were noted in about 75% of patients, expression of mdm2 is associated with degradation of tumor suppressor gene p53 [3,5]. Another study for tumorigenesis of pulmonary artery intimal sarcomas had demonstrated that amplifications of SAS/CDK4, MDM2, GLI, and PDGFRA are strongly associated with the development of tumor [6]. The course and mortality is determined by tumor location and by thrombus formation. As the disease progresses, symptoms similar to those of pulmonary embolism develop gradually, including cough, pleuritic pain, hemoptysis, dyspnea, and even sudden cardiopulmonary collapse due to acute right ventricular failure [3]. Early diagnosis of pulmonary artery sarcoma remains a challenge for clinician. The most important differential diagnosis is chronic pulmonary thromboembolic disease, because misdiagnosis often leads to inappropriate therapeutic intervention that has an adverse impact on survival. From literature review, 60% of reported cases have been identified by autopsy [7]. Clinically, pulmonary sarcoma tends to grow and occlude the vessel gradually. The patient s symptoms such as dyspnea tend to developed more slowly compare with pulmonary embolism. Some parameter to predict possibility of embolism such as Well s score

5 S. F. Cho et al./jcrp 28(2012) Figure 3. (A-B) Microscopically, H&E staining revealed benign bronchial epithelia with underlying sub-mucosal tissue and smooth muscle infiltrated by pleomorphic or spindle-shaped cells with hyperchromasia, prominent eosinophilic nucleoli, and high nucleo-cytoplasmic ratio (200X). (H&E stain, hematoxylin and eosin stain) may indicate low probability. In addition, the patient ossification compared with pulmonary thrombosis of pulmonary artery sarcoma may be free from any [10]. Gadolinium-enhanced magnetic resonance im- risk factor of thromboembolism. And the result of aging may be useful because gadolinium can reveal D-dimer levels may reveal normal or mild elevation in the tumor lesion rather than thrombosis [11]. Pulmo- sarcoma patient. nary artery sarcoma should be considered if imagine Several imaging techniques are also utilized for study found such an obvious mass lesion in pulmo- differential diagnosis. Chest x-rays may show pulmo- nary artery but other parameter didn t support the di- nary nodule or mass, pulmonary artery dilation, re- agnosis of thrombosis, such as normal or mild eleva- duced pulmonary vasculature, and cardiomegaly, but tion of D-dimer level, relatively indolent clinical all of these are non-specific. Echocardiogram may course, or low Well s score. Definitive diagnosis is reveal a mass lesion in the proximal pulmonary trunk based on pathology study results by invasive interven- or signs of right ventricular obstruction, such as a di- tions. lated right ventricle with severely elevated right ven- Due to its rarity, there are no guidelines regarding tricular systolic pressure [8]. Angiography reveals re- treatment of pulmonary intimal sarcoma. The progno- pletion in the pulmonary artery lumen, while con- sis is dismal, with median survival of 2-10 months [4]. trast-enhanced computed tomography can facilitate Surgical excision of the tumor seems to offer the best more accurate diagnosis by detecting a lobulated mass way to prolong survival and afford an opportunity of that originates from the pulmonary main trunk or main cure. Mattoo et al. and Mayer E et al [12,13] propose pulmonary artery and expands to the peripheral artery surgical treatment if the disease is diagnosed early, [9]. And sarcomas tend to have a more heterogeneous and if it has no metastasis or involvement of adjacent appearance from areas of necrosis, hemorrhage, and structures. Post-operative chemotherapy and radio-

6 40 S. F. Cho et al./jcrp 28(2012) therapy have also been used in some cases, with notable effectiveness. However, the role of these treatment modalities are not well defined [14,15]. In conclusion, this report is a fatal case of intimal sarcoma with presentation mimicking pulmonary embolism. This disease has very poor prognosis due to difficulty in diagnosis and involvement of vital organs. Early and correct diagnosis for definitive treatment is critical for patient survival. REFERENCES 1. Mandelstamm M. Über primäre Neubildungen des Herzens. Virchows Archiv 245: 43-47, Burke AP, Virmani R. Sarcomas of the great vessels. A clinicopathologic study. Cancer 71: , Gaumann A, Bode-Lesniewska B, Zimmermann DR, et al. Exploration of the APC/beta-catenin (WNT) pathway and a histologic classification system for pulmonary artery intimal sarcoma. A study of 18 cases. Virchows Archiv 453: , Furest I, Marin M, Escribano P, et al. Intimal sarcoma of the pulmonary artery: a rare cause of pulmonary hypertension. Arch Bronconeumol 42: , Bode-Lesniewska B, Zhao J, Speel EJ, et al. Gains of 12q13-14 and overexpression of mdm2 are frequent findings in intimal sarcomas of the pulmonary artery. Virchows Archiv 438: 57-65, Zhao J, Roth J, Bode-Lesniewska B, et al. Combined comparative genomic hybridization and genomic microarray for detection of gene amplifications in pulmonary artery intimal sarcomas and adrenocortical tumors. Genes Chromosomes and Cancer 34: 48-57, Ramp U, Gerharz CD, Iversen S, et al. Sarcoma of the pulmonary artery: report of two cases and a review of the literature. J Cancer Res Clin Oncol 118: , Zurick AO 3rd, Lenge De Rosen V, Tan CD, et al. Pulmonary artery intimal sarcoma masquerading as pulmonary embolism. Circulation 124: , Hou Y, Shen Z, Gao W, et al. Pulmonary artery intimal sarcoma: case report. J Card Surg 25: 29-31, Yamasaki M, Sumi Y, Sakakibara Y, et al. Pulmonary Artery Leiomyosarcoma Diagnosed without Delay. Case Rep Oncol 4: , Rafal RB, Nichols JN, Markisz JA. Pulmonary artery sarcoma: diagnosis and post-operative follow-up with gadolinium-diethylenetriamine penta-acetic acid-enhanced magnetic resonance imaging. Mayo Clin Proc 70: , Mattoo A, Fedullo PF, Kapelanski D, et al. Pulmonary artery sarcoma: a case report of surgical cure and 5-year follow-up. Chest 122: , Mayer E, Kriegsmann J, Gaumann A, et al. Surgical treatment of pulmonary artery sarcoma. J Thorac Cardiovasc Surg 121: 77-82, Uchida A, Tabata M, Kiura K, et al. Successful treatment of pulmonary artery sarcoma by a two-drug combination chemotherapy consisting of ifosfamide and epirubicin. Jpn J Clin Oncol 35: , Nonomura A, Kurumaya H, Kono N, et al. Primary pulmonary artery sarcoma. Report of two autopsy cases studied by immuno-histochemistry and electron microscopy, and review of 110 cases reported in the literature. Acta Pathol Jpn 38: , 1988.