A 36-year-old male football player with no significant past medical history recently diagnosed with unprovoked deep venous thrombosis of the lower limb, presented with acute right-sided hemiplegia, hemi-sensory loss, facial upper motor neuron lesion and expressive aphasia. Prior to the presentation, the patient had a history of undocumented fever, but no reported history of chest pain, shortness of breath, weight loss, night sweating, drug abuse, alcohol consumption or family history of similar presentation. With the aid of the above information, the computed tomography (CT) of the brain showed multiple bilateral occipital and frontoparietal areas of hypodensities more on the left cerebral hemisphere. The transthoracic echocardiogram revealed left ventricular ejection fraction of 60%, the presence of masses attached to mitral and aortic valves needed to be evaluated further by tranesophageal echocardiogram (TEE). The TEE showed multiple highly mobile, irregular shape masses attached to right and left coronary cusps of the aortic valve, largest mass measuring 20 × 18 mm2 with eccentric severe aortic regurgitation, no associated abscess or fistula, similar echogenicity mass attached to anterior mitral valve measures 7 × 4 mm2, and posterior mitral valve mass measures 5 × 3 mm2, and there was mild mitral regurgitation and no intracardiac shunt ( and ()). Magnetic resonance imaging (MRI) of the brain ( and ()) revealed multifocal diffusion restrictions involving bilateral high frontal and left thalamus, bilateral occipital lobes, and bilateral cerebellar hemispheres, with no significant mass effect. Forty-eight hours of follow-up CT of the brain confirmed the presence of hemorrhagic transformation. Clinically, the patient showed improvement in the expressive aphasia and the right-sided hemiplegia during the first week of admission. The patient was clinically stable throughout his hospitalization course. The follow-up investigations of all the tests performed on the patient leads to the following conclusions: (1) all blood cultures were negative; (2) Brucella titer and serology for Q fever were negative; (3) markers for tumors came back positive (CA-125 102 U/mL, CA19-9 5247 U/mL, CEA 13.6 U/mL); (4) thrombophilic evaluation, including anti-nuclear antibody (ANA), anti-neutrophil cytoplasmic antibody (ANCA), antiphospholipid antibodies (cardiolipin IgG and IgM), Factor-V Leiden mutation, homocysteine, Protein-S, Protein-C and Antithrombin-III levels, was unremarkable; and (5) CT scan of chest, abdomen and pelvis unveiled the presence of hypovascular hepatic mass having dimensions of 7.8 × 5.7 × 6.4 cm3, which invaded the right portal vein as well as the right hepatic duct with multiple porta hepatis and retroperitoneal lymphadenopathies, thereby leading to an alarming stage of cholangiocarcinoma (). On a similar note, the peripheral right lung showed lesion with central cavitation probably infarction or metastasis, in addition to the presence of bilateral hypodense renal cervical lesions. The patient underwent ultrasound-guided liver biopsy showed well-differentiated adeno-carcinoma, consistent with the diagnosis of cholangiocarcinoma ( and ()).\nThe follow-up transthoracic echocardiogram after 10 days of admission showed the presence of a small calcified aortic valve mass, which measures 6 × 4 mm2, mild aortic and mitral regurgitation and no evidence of mitral valve mass ( and ()). At this stage, upon his and his family request, the patient was transferred to an oncology center in the United States, where he was recommended for palliative treatment. Unfortunately, 6 months later, the patient died.
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.