A previously healthy 45-year-old woman presented with a 2-week history of tenderness in both lower legs and dizziness. She was suspected to have a cerebellar stroke, pulmonary emboli, and bilateral deep venous thrombosis on enhanced computed tomography at previous hospital. In addition, undiagnosed malignancy was suspected on the findings of abdominal computed tomography, which revealed a 4-cm enhanced irregular mass in sigmoid colon adjacent to the left ovary with poor demarcation. Then, she was transferred to our hospital for further evaluation and treatment. On presentation, her body temperature was 38.1 °C and did not have a heart murmur. Laboratory findings revealed elevated white blood cells counts, anemia, and markedly elevated CA 19-9. C-reactive protein was within normal range. There were no immunologic findings associated with lupus erythematosus, antiphospholipid syndrome, other collagen diseases, or hematologic disorders. The coagulation panel was within normal limits except for elevated D-dimer levels at 19.6 μg/ml. She was started on apixaban, which is a direct factor Xa inhibitor. Initially, general surgery team tried to perform colonoscopy; however, she had severe abdominal pain and fever soon after taking premedication for colonoscopy. Abdominal computed tomography showed occlusive ileus. Transverse colostomy was performed on the same day emergently for decompression. Then, she was referred to cardiology department to evaluate preoperative cardiac function before additional surgery for treatment and diagnosis. Preoperative transthoracic echocardiography (TTE) revealed mobile vegetations on the mitral and aortic valves. Transesophageal echocardiography (TEE) also showed that all three coronary cusps of the aortic valve had 7–8 mm vegetations. Mild aortic insufficiency was seen around the vegetations. Similarly, both anterior and posterior mitral leaflets were thickened and had vegetations. The anterior mitral leaflet also had a 15-mm mobile mass and a few string-like bodies. Mild mitral regurgitation was observed from the center of the valve orifice (Fig. ).\nGiven the echocardiographic findings, infectious endocarditis was suspected. Although three separate blood cultures were negative, meropenem were started empirically. Head magnetic resonance imaging showed no infarction, bleeding, or infected arterial aneurysm. She underwent an emergent operation to prevent recurrent thrombotic emboli 4 weeks after chief complaint was initiated.\nA median sternotomy was performed, and cardiopulmonary bypass was instituted via ascending aortic and bicaval cannulation. After aortic cross-clamping, myocardial protection was achieved by the retrograde administration of cold blood cardioplegia. Then, aortotomy was performed, and antegrade blood cardioplegia was selectively administered into the coronary ostia. Vegetations were observed on all three cusps of the aortic valve. Both left and right coronary cusps had been destroyed structurally, and valve replacement using a biological valve (Carpentier-Edwards PERIMOUNT Magna Ease, 21 mm) was required. Since we could not rule out infectious endocarditis at that time, we chose a biological valve instead of a mechanical valve to minimize the postoperative bleeding risk due to anticoagulation. Next, right-sided left atriotomy was performed. Similar to the aortic valve, vegetations were attached to the anterior and posterior leaflets of the mitral valve. We successfully performed valve repair by careful debridement and ring annuloplasty. Remaining of surface of mitral valve was ablated with electric cautery. Weaning from cardiopulmonary bypass was possible with inotropic support.\nAfter the operation, anticoagulation therapy with warfarin was initiated. Follow-up TTE revealed no residual mitral regurgitation or vegetations on either the prosthetic aortic valve or native mitral valve. The pathology report revealed a few large brown-colored vegetations on both aortic and mitral valves that histopathologically consisted of eosinophilic fibrin. No bacterial organisms were detected microscopically (Fig. ).\nBased on these results, we suspected that the valve lesions were NBTE associated with occult malignancy. Three weeks after the cardiac operation, the general surgery team performed sigmoid colectomy and left salpingo-oophorectomy to remove the underlying malignancy causing thrombotic emboli. No mesenteric or hepatic metastases were observed. Histopathological examination revealed endometrioid adenocarcinoma in pelvic cavity and direct invasion in sigmoid colon. After 1-year follow-up, she has not experienced recurrent thromboembolic events on anticoagulation of warfarin and adjuvant chemotherapy for endometrioid adenocarcinoma.\nNBTE was originally described by Ziegler in 1888 and has been reported to be associated with malignancy. Adenocarcinoma is the most common associated malignancy. Patients with adenocarcinoma reportedly have a fivefold higher risk of NBTE than patients with other histological types of malignant tumor []. Moreover, NBTE in the course of gynecological neoplasms (ovarian, cervical) is reported to have the highest risk of ischemic stroke [].\nHistological examination of the resected valve remains the gold standard for the diagnosis of NBTE. The vegetations of NBTE are friable, white or tan masses, usually situated along the lines of the valve closure, on the leaflets, which may be normal or previously damaged. They vary greatly in size from tiny lesions to large and exuberant masses. NBTE consists of degenerating platelets interwoven with strands of fibrin and forming a bland, featureless eosinophilic mass except for a few trapped leukocytes []. Differential diagnosis between NBTE and infectious blood culture-negative endocarditis can only be made histologically by identifying valvular inflammation, vegetation, and the organisms or other changes consistent with endocarditis.\nTreatment of NBTE consists of systemic anticoagulation and therapy directed at treating the underlying malignancy or associated condition. Heparin is more effective than warfarin for hypercoagulability associated with malignancy [–]. However, Borowski et al. reported a case of recurrent embolism in the course of NBTE in spite of anticoagulation therapy [], and other authors also have reported that treatment with heparin alone does not prevent further emboli []. This implies that anticoagulation therapy alone may not be sufficient to control hypercoagulability due to underlying malignancy. We cannot prevent recurrent embolization without removing the cancer in patients with NBTE associated with malignancy, because malignancy can still create a hypercoagulable state in spite of anticoagulation therapy. Eventually, this would result in recurrence of NBTE and thrombotic emboli.\nSurgical indications and appropriate timing for surgery for NBTE have not been formally studied. In general, surgical indications for NBTE are the same as for infectious endocarditis and include uncontrollable heart failure or infection and mobile vegetations. In the present case, patient was relatively stable and TEE showed mobile vegetations which could cause stroke; emergent open-heart surgery was warranted. Although open-heart surgery might be waved because of systemic condition related to the malignancy, open-heart surgery should be performed as soon as possible when they are stable enough to underwent surgery and meet one of surgical indications listed above. Preservation of the valve might be possible in more cases of NBTE in which the valve is structurally and functionally normal after the vegetation is removed than that of bacterial infectious endocarditis.\nAppropriate timing of surgery for underlying malignancy after the cardiac operation in NBTE has also not been reported. Our patient underwent surgery for underlying malignancy soon after histopathological examination confirmed a diagnosis of NBTE. We believe that surgical intervention should be performed as soon as possible once the diagnosis of NBTE is made after cardiac surgery to prevent recurrent vegetations and embolization.
A 59-year-old female visited an emergency room with the chief complaints of abdominal pain and dizziness and was diagnosed with gastroenteritis and vertigo. Three days later, she was readmitted to the emergency room because of worsening abdominal pain and difficulty in movement due to headache and nausea. Plain whole-body computed tomography (CT) showed suspicious cerebral infarction and a low-density mass lesion in right liver lobe. Subsequent head magnetic resonance imaging (MRI) confirmed infarcted areas in multiple blood vessels defined as an embolic shower. Contrast-enhanced CT revealed about 9 × 6 × 4 cm-sized and ill-defined mass with several daughter nodules in the posterior segment of the right hepatic lobe, splenic infarction, and bilateral renal infarctions (Fig. ). The liver hypodense mass had a peripheral rim-like enhancement during the arterial phase and contacted with diaphragm, retroperitoneum, and inferior vena cava. The tumor in the liver was diagnosed as intrahepatic mass-forming cholangiocarcinoma. There was no suspicion of other gastrointestinal or gynecological malignancies. At that time of diagnosis, the level of carbohydrate antigen 19-9 (CA19-9) was > 120,000 U/mL, above the detectable range, and the level of carcinoembryonic antigen (CEA) was 211.7 ng/mL. The coagulation profile of the patient was as follows: platelet count, 8.7 × 104/μL; D-dimer, 36.6 μg/mL; prothrombin time-international normalized ratio, 1.16; and activated partial thromboplastin time, 28.1 s. Ultrasonography of the carotid arteries and lower limbs, transthoracic echocardiography, and Holter electrocardiogram did not reveal the source of embolism. Therefore, the patient was diagnosed with Trousseau’s syndrome due to intrahepatic cholangiocarcinoma.\nContinuous intravenous infusion of unfractionated heparin at a dose of 10,000 U per day was started immediately. However, she developed left hemiplegia 1 week later, and head MRI revealed thrombosis of the right middle cerebral artery. Activated partial thromboplastin time value was 23.4 s at that time in spite of continuous administration of heparin. She was transferred to a hospital where endovascular treatment was possible, and thrombectomy was performed. Although left paralysis remained after thrombectomy, she returned to our hospital for the treatment of intrahepatic cholangiocarcinoma. In the meantime, she was treated with continuous infusion of unfractionated heparin at a dose of 15,000 U per day. After the thrombectomy, activated partial thromboplastin time value was kept nearly 40.0 s with administration of heparin.\nPreoperative examination did not show any issues with cardiopulmonary function. Abdominal enhanced CT and MRI showed a tumor in the posterior segment of the right hepatic lobe (Fig. ). Hepatic reserve after right hepatectomy was confirmed with indocyanine green clearance test and technetium-99m diethylenetriamine penta-acetic acid-galactosyl human serum albumin (99mTc-GSA) liver scintigraphy (data not shown). Although the preoperative serum levels of CA19-9 and CEA were extremely high, the preoperative D-dimer, fibrin degradation product (FDP), and fibrinogen levels were slightly higher than the normal limits (Table ). Protein C level was 154% (normal 70–150), protein S level was 164% (normal 65–135), and cardiolipin antibodies were normal (IgG, < 8; IgM, 5).\nDuring the surgery, anticoagulation was performed with subcutaneous injection of low-molecular-weight heparin at a dose of 5000 U per 12 h. In surgery, the tumor was exposed on the liver surface and partially adhered to the diaphragm and retroperitoneum. Right hepatectomy was performed with combined resection of the invading tumor.\nThe resected tumor was 9 × 6 × 6 cm in size, and the pathological diagnosis was moderately differentiated intrahepatic cholangiocarcinoma (pT4pN0M0 pStage IVA, vp1, vv2, b1, UICC8th) (Fig. ). Intraoperative irrigation cytology was negative, and lymph nodes of no.12 did not show metastasis. Tumor invasion to the resected diaphragm was pathologically confirmed, but there was no invasion to the retroperitoneum.\nImmunohistochemistry was performed for cancer antigen 125 (CA125; clone M3519; Dako, Glostrup, Denmark), CEA (clone M7072; Dako), cell surface-associated mucin 1 recognized by the cancer antigen 15-3 (CA15-3) epitope (MUC-1; clone MA552; Leica Biosystems, Nussloch, Germany), and CA19-9 (M3517; Dako). As seen in Fig. , strong expression levels of CA19-9, CEA, and MUC-1 were observed in the cytoplasm and membrane of cholangiocarcinoma cells.\nAfter the surgery, the patient’s general condition was good and no neurological changes were observed. The perioperative changes in serum tumor maker levels are shown in Fig. . Serum CA19-9 remained above detectable levels until 4 days after surgery and decreased to 43,068 U/mL on postoperative day 4. By imaging, the splenic and renal infarcts were slightly enlarged and a new subacute subcortical hemorrhage in the right occipital lobe was observed on postoperative day 7. Starting at 1 week after surgery, anticoagulant therapy was resumed by continuous intravenous infusion of unfractionated heparin at a dose of 15,000 U per day. At 1-month postoperative evaluation, no new neurological changes were observed and there were no exacerbations in the infarcts and hemorrhagic lesions. The serum levels of CA19-9 started to increase, reaching 9459.4 and 80,256.2 U/mL at 4 and 8 weeks after the surgery, respectively. Although enhanced CT did not show recurrence, positron emission tomography suggested intrahepatic recurrence, hilar lymph node metastasis, and peritoneal dissemination at 7 weeks after the surgery (Fig. ). Therefore, the patient was initiated on combination chemotherapy with gemcitabine and cisplatin at 8 weeks after the surgery. The chemotherapy regimen comprised cisplatin (25 mg/m2 body surface area) followed by gemcitabine (1000 mg/m2 body surface area) [], both administered on days 1 and 8, every 3 weeks. This treatment was effective in stabilizing CA19-9 levels (Fig. ) but did not cure the tumor recurrence.\nContinuous intravenous heparin administration was changed to subcutaneous injection of low-molecular-weight heparin at a dose of 5000 U per 12 h, and she was discharged 12 weeks after the surgery. She has been subsequently followed in our outpatient clinic without further thrombosis during the last 6 months after surgery, and there has been no tumor progression.