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.
A 73-year-old Japanese woman experienced light-headedness and dementia of unknown cause for 6 months. She had had diabetes for 20 years and had a history of surgical excision of breast cancer and laparoscopic cholecystectomy 10 and 20 years before, respectively. Her neurological disturbance had advanced, and she sought treatment at Kansai Medical University Kori Hospital.\nAt the first medical examination, no abnormalities were detected by brain computed tomography (CT) scan. However, 1 month after the consultation, the patient experienced general hypotonia with progressive dementia and was hospitalized. At the time of admission, her blood coagulation tests were as follows (normal range in parentheses): platelets 6.8 × 104/μl (14–34 × 104/μl), fibrinogen 74.0 mg/dl (180–355 mg/dl), D-dimer 101.6 μg/ml (0–0.9 μg/ml), prothrombin time 81.2% (75–130%) and activated partial thromboplastin time 27.9 s (23–35 s). Her serum albumin had decreased to 1.8 g/dl (3.8–5.0 mg/dl), and γ-GTP had increased to 172 U/l (8–45 U/l). The serum CA19-9 level was 376,100 U/ml (<37 U/ml), and the CA15-3 level was 124 U/ml (<27 U/ml), both of which were significantly increased. Upper abdominal CT scan revealed a large ill-defined mass in the periphery of the right liver lobe and multiple ischemic lesions in the spleen. Because of her poor condition, further examination of the liver mass was impossible. Cerebral magnetic resonance imaging showed multi-regional hypointense areas in the hemisphere of her right cortex, which were compatible with acute cerebral infarction. Cardiac ultrasound showed abnormal movements in the mitral and aortic valves.\nDespite continuous anticoagulant therapy, her consciousness deteriorated and she died 3 months after the hospitalization due to multiple organ failure. The postmortem examination was performed 8 h after her death. The main object of the autopsy was to elucidate the pathological cause of the cerebral infarction.