Case Report

Multiple Ischemic Strokes Caused by Nonbacterial Thrombotic Endocarditis Because of Gallbladder Cancer: A Case Report Akiko Yamane, MD,* Hirokazu Sadahiro, MD, PhD,* Hisaharu Goto, MD, PhD,* Akinori Inamura, MD,* Hideyuki Ishihara, MD, PhD,* Fumiaki Oka, MD, PhD,* Takayuki Oku, MD, PhD,* Tomoko Kondo, MD, PhD,† and Michiyasu Suzuki, MD, PhD*

We report a case of a 62-year-old woman with multiple ischemic strokes caused by nonbacterial thrombotic endocarditis (NBTE) because of gallbladder cancer. Transesophageal echocardiography showed NBTE on the mitral valve. The NBTE disappeared with anticoagulation treatment for 2 weeks. Abdominal computed tomography showed a gallbladder tumor that was surgically resected. Histopathologic studies showed poorly differentiated tumor cells and the production of mucin. Trousseau syndrome with gallbladder cancer is very rare. We suggest that the development of NBTE is related to the production of mucin. Key Words: Nonbacterial thrombotic endocarditis—Trousseau syndrome—gallbladder cancer—transesophageal echocardiography—anticoagulation. Ó 2014 by National Stroke Association

Introduction Trousseau syndrome is well known as thromboembolism caused by malignancy.1 Some patients with pancreatic, ovarian, and lung cancer experience ischemic stroke because of nonbacterial thrombotic endocarditis (NBTE)2,3; however, this rarely occurs with gallbladder cancer.4 We report a rare case of multiple ischemic strokes caused by NBTE because of gallbladder cancer.

Case Report A 62-year-old woman with no cardiovascular risk factors exhibited the sudden onset of transient left

From the *Department of Neurosurgery, Yamaguchi University Hospital, Yamaguchi; and †Department of Pathology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan. Received October 21, 2013; revision received December 3, 2013; accepted December 18, 2013. Address correspondence to Hirokazu Sadahiro, MD, PhD, Department of Neurosurgery and Clinical Neuroscience, Yamaguchi University School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, Japan. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.12.031

upper and lower limb weakness. In a previous hospital, diffusion-weighted image and magnetic resonance angiography revealed no findings. One week later, repeated diffusion-weighted imaging revealed multiple cerebral and cerebellar infarctions and magnetic resonance angiography showed right internal carotid artery occlusion (Fig 1). The patient was transferred to our hospital for further examination and treatment. On arrival, she exhibited left hemispatial neglect and left sensory disturbance, and the National Institutes of Health Stroke Scale score was 6 points. Holter electrocardiogram showed no signs of atrial fibrillation, and laboratory examinations showed high levels of carcinoembryonic antigen (50.6 ng/mL) and D-dimer (10.8 mg/mL), although other coagulation studies were within the normal range: prothrombin time international ratio (1.17), activated partial thromboplastin time (26.5 seconds), fibrinogen (230 mg/dL), and antithrombin III (102.7%). Transesophageal echocardiography (TEE) showed an adhesion of the vegetation on both the anterior and posterior mitral leaflets, suggesting NBTE (Fig 2, A). TEE did not show any causes of embolic stroke, such as patent foramen ovale, dysfunction of the left atrial appendage, and atherosclerotic changes of the aortic arch. Carotid duplex ultrasonography showed distal occlusion of the right internal carotid

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Figure 1. Magnetic resonance imaging. (A) Diffusion-weighted imaging showed multiple infarcts in the bilateral cerebrum and cerebellum. (B) Magnetic resonance angiography showed right internal carotid artery occlusion; however, the right middle cerebral artery was patent via a posterior communicating artery.

artery with distal thrombus and no other atherosclerotic lesion of the visible artery. Abdominal computed tomography scan showed a 24-mm diameter mass at the gallbladder. Anticoagulation therapy with heparin was initiated, with a targeted controlled activated partial thromboplastin time up to twice of the pretreatment score. Subsequently, there was no recurrence of the ischemic stroke, and TEE performed 2 weeks later showed disappearance of the vegetation (Fig 2, B). The mass on the gallbladder was surgically resected, and histopathologic examination showed poorly differentiated tumor cells and the production of mucin (Fig 3).

Discussion Trousseau syndrome often occurs in patients with carcinoma of the pancreas, ovary, and lung.2,3 However, it occurs rarely in carcinoma of the gallbladder, and to date, there have been only 3 cases reported.4,5 Recent studies suggest that there are multiple mechanisms and factors involved in the hypercoagulation in patients

with various cancers.1,6-9 The factors include tissue factor, cysteine protease, tumor hypoxia, tumor-induced inflammatory cytokines, and carcinoma mucin. Of these factors, carcinoma production of mucin is thought to play an important role in the onset of this syndrome.6,9 The frequencies of the mucin production by tumors are 30% in pancreatic,10 10% in ovarian,11 and 10% in lung carcinoma.12 Dursun et al13 analyzed 606 cases with carcinoma of the gallbladder, and they reported that only 15 cases (2.5%) involved mucinous carcinoma. In our case, histopathologic examination revealed adenocarcinoma of the gallbladder with mucin production, in which NBTE might lead to the production of multiple emboli. We suggest that the development of NBTE is related to the production of mucin. In this case, the patient exhibited vegetations on the cardiac valves and was diagnosed as having NBTE. NBTE is a disease that is characterized by the formation of aseptic vegetations consisting of fibrin and platelets on cardiac valves.2,3,14 Nguyen and DeAngelis15 reported that the prevalence of NBTE was more than 60% in ischemic

Figure 2. Transesophageal echocardiography. Transesophageal echocardiography showed the vegetation adhering to the mitral valves (A). The vegetation disappeared after 2 weeks of anticoagulation (B).

MULTIPLE ISCHEMIC STROKES CAUSED BY NONBACTERIAL THROMBOTIC ENDOCARDITIS

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Figure 3. Pathological findings. Histopathologic study of the gallbladder with hematoxylin–eosin (A and B) and Alcian blue stains (C). The poorly differentiated tumor cells proliferated densely (A) and were surrounded by mucin ‘‘floating islands’’ (B). Alcian blue stain confirmed the production of mucin-7 (C). Hematoxylin–eosin stain: original magnification 1003 (A) and 2003 (B). Alcian blue stain 2003 (C).

stroke patients with cancer. Multiple infarctions could be caused from NBTE, and TEE has a higher sensitivity than transthoracic echocardiography in detecting valvular vegetations.2,3 Treatment of Trousseau syndrome is to immediately approach the underlying malignancy and provide systemic anticoagulation. Heparin appears to be more effective than vitamin K antagonists.1,3 In addition to activation of antithrombin, heparin cofactor II, and protein C inhibitor, heparin also blocks the binding of Pselectins and L-selectins. This may play an important role in the interruption of tumor–mucin interactions mediated by these selectins.1 Although there is no established evidence of anticoagulant treatment for Trousseau syndrome, heparin was very effective in our case.

Conclusion We report a rare case of Trousseau syndrome because of NBTE in a patient with gallbladder carcinoma that produced mucin. TEE revealed NBTE that was immediately treated with heparin, and there was no recurrence.

References 1. Varki A. Trousseau’s syndrome: multiple definitions and multiple mechanisms. Blood 2007;110:1723-1729. 2. Asopa S, Patel A, Khan OA, et al. Non-bacterial thrombotic endocarditis. Eur J Cardiothorac Surg 2007;32:696-701. 3. el-Shami K, Griffiths E, Streiff M. Nonbacterial thrombotic endocarditis in cancer patients: pathogenesis, diagnosis, and treatment. Oncologist 2007;12:518-523. 4. Kawahara M, Ueno S. Ischemic stroke in cancer patients. J Nara Med Assoc 2009;60:123-135.

5. Diggory P, Jacyma MR, Booth MR, et al. Gallbladder cancer presenting with trousseau’s sign in a 31-year-old man with occupational exposure to aromatic hydrocarbons. J R Soc Med 1989;82:631-632. 6. Wahrenbrock M, Borsig L, Le D, et al. Selectin-mucin interactions as a probable molecular explanation for the association of trousseau syndrome with mucinous adenocarcinomas. J Clin Invest 2003;112:853-862. 7. Falanga A, Panova-Noeva M, Russo L. Procoagulant mechanisms in tumour cells. Best Pract Res Clin Haematol 2009;22:49-60. 8. Falanga A, Russo L, Verzeroli C. Mechanisms of thrombosis in cancer. Thromb Res 2013;131:S59-S62. 9. Shao B, Wahrenbrock MG, Yao L, et al. Carcinoma mucins trigger reciprocal activation of platelets and neutrophils in a murine model of trousseau syndrome. Blood 2011; 118:4015-4023. 10. Crippa S, Fernandez-Del Castillo C, Salvia R, et al. Mucin-producing neoplasms of the pancreas: an analysis of distinguishing clinical and epidemiologic characteristics. Clin Gastroenterol Hepatol 2010;8:213-219. 11. Jung ES, Bae JH, Lee A, et al. Mucinous adenocarcinoma involving the ovary: comparative evaluation of the classification algorithms using tumor size and laterality. J Korean Med Sci 2010;25:220-225. 12. Kakegawa S, Shimizu K, Sugano M, et al. Clinicopathological features of lung adenocarcinoma with KRAS mutations. Cancer 2011;117:4257-4266. 13. Dursun N, Escalona OT, Roa JC, et al. Mucinous carcinomas of the gallbladder: clinicopathologic analysis of 15 cases identified in 606 carcinomas. Arch Pathol Lab Med 2012;136:1347-1358. 14. Dutta T, Karas MG, Segal AZ, et al. Yield of transesophageal echocardiography for nonbacterial thrombotic endocarditis and other cardiac sources of embolism in cancer patients with cerebral ischemia. Am J Cardiol 2006; 97:894-898. 15. Nguyen T, DeAngelis LM. Stroke in cancer patients. Curr Neurol Neurosci Rep 2006;6:187-192.

Multiple ischemic strokes caused by nonbacterial thrombotic endocarditis because of gallbladder cancer: a case report.

We report a case of a 62-year-old woman with multiple ischemic strokes caused by nonbacterial thrombotic endocarditis (NBTE) because of gallbladder ca...
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