A 78-year-old man developed dizziness, and head magnetic resonance imaging (MRI) revealed multiple infarcted areas in the left parietal lobe (Fig. 1a) at another hospital. His medical history included gastric ulcer at 45 years old and hypertension under treatment. He was diagnosed with cerebral embolism of the left parietal lobe, and treatment with the direct oral anticoagulant (DOAC) dabigatran was started.
Five days after the onset of the cerebral infarction, the dizziness completely recovered. Cardiogenic cerebral embolism was suspected based on the presence of transient atrial fibrillation, but the definite cause of the stroke was unknown. Contrast-enhanced abdominal computed tomography (CT) revealed an ill-defined mass in uncinate process of the pancreas. Fifty days after the onset of cerebral infarction, he presented to our hospital without neurologic findings, and his Eastern Cooperative Oncology Group performance status was 0. He lost weight with 4 kg in the past month. Serum total bilirubin and biliary enzymes, such as aspartate transaminase, alanine transaminase, alkaline phosphatase, and γ-glutamyl transpeptidase were not elevated. Blood coagulation test such as d-dimer, prothrombin time, and activated partial thromboplastin time were all within normal limits.
Contrast-enhanced abdominal CT at our hospital revealed a 24-mm hypodense mass at the pancreas head invading the superior mesenteric vein (SMV) and superior mesenteric artery (SMA) with abutment ≤ 180º (Fig. 2a). The tumor did not invade common bile duct. There was no evidence of lymph node involvement or visceral metastatic spread. Tumor markers (CEA, CA19-9, DUPAN-2, and Span-1) were within their respective normal ranges. Adenocarcinoma was detected in the pancreatic head mass by endoscopic ultrasound-guided fine-needle aspiration. Based on these findings, the diagnosis was borderline resectable pancreatic adenocarcinoma [9]. Because the clinical course of the cerebral infarction was good with no residual symptoms, we considered the patient likely to tolerate curative treatment including chemotherapy and surgery. Therefore, radical resection after neoadjuvant chemotherapy (NAC; two courses of gemcitabine plus nab-paclitaxel [10]) was planned.
During the second course of NAC, the patient complained of hematochezia, and upper gastrointestinal endoscopy revealed hemorrhagic multiple gastric ulcers. NAC was discontinued, and radical resection was planned at this point. In addition, 5 days later, he developed left hemiplegia and was diagnosed with multiple cerebral infarctions by MRI (Fig. 1b). Serum d-dimer was 3.9 µg/mL, slightly elevated from normal range. Ultrasonography of the carotid arteries, transthoracic echocardiology, and Holter electrocardiogram did not reveal the source of the embolism. Therefore, the patient was diagnosed with Trousseau’s syndrome related to pancreatic adenocarcinoma and we considered that both the first and the second strokes were caused by Trousseau’s syndrome. The anticoagulant was changed from oral dabigatran to intravenous heparin. Continuous intravenous infusion of unfractionated heparin was started in order to maintain an activated partial thromboplastin time (APTT) of 40–50 s.
To re-determine the treatment strategy for pancreatic cancer, contrast-enhanced abdominal CT and [18F]-2-fluoro-2-deoxy-d-glucose (FDG)-positron emission tomography (PET)/CT were conducted. CT revealed that the tumor had shrunk from 24 to 21 mm in size, while the tumor abutment to the SMA and SMV was unchanged (Fig. 2b). PET/CT revealed the accumulation of FDG in the tumor and no findings of new distant metastasis. The tumor response to NAC was classified as a stable disease [11]. Tumor markers, including CEA and CA19-9, were still within normal limits. It was difficult to decide on the best treatment for the patient. We discussed our options with the gastroenterologist and neurologist. Finally, after informing the patient and his family of the risks and benefits of radical resection, we obtained their consent and planned the operation.
Pancreatoduodenectomy was performed with combined resection of the SMV on the 176th day after the initial cerebral infarction. Dissection of the right half of the SMA nerve plexus was performed at the point of invasion. The operation time was 403 min, and intraoperative blood loss was 229 g. The resected tumor was 25 × 20 mm in size, and the pathological diagnosis was moderately differentiated pancreatic ductal adenocarcinoma without mucinous component. Although the tumor invaded portal vein, duodenum, posterior peripancreatic tissue, and pancreatic head nerve plexus, the resection margin was free of tumor cells. Microscopic lymphovascular invasion was observed but lymph node metastasis was not detected (pT2pN0M0 pStage IB, UICC 8th). About 10–50% of the tumor cells changed to fibrous tissue, which was defined as grade IIa in the Evans classification [12]. Continuous intravenous heparin was administered until nine hours before the start of surgery and was resumed on postoperative day 2. When heparin resumed, serum d-dimer level was 24.1 µg/mL.
On postoperative day 9, the patient had an elevated d-dimer value (76 μg/mL) and decreased APTT values from therapeutic to normal range (29.5 s) without any symptoms, and contrast-enhanced CT revealed a pulmonary embolism. However, the patient remained asymptomatic with only a heparin dosage adjustment. He was discharged on day 19 after surgery. The administration of heparin was switched from continuous intravenous infusion at the hospital to subcutaneous injection (10,000 U/day) at the patient’s home and has continued to the present. At the time of discharge, serum d-dimer level was improved to 15.4 µg/mL.
As the patient’s general condition was good and subcutaneous heparin injections were safely administered, adjuvant chemotherapy (S-1 80 mg/day) was started 46 days after surgery. However, it was discontinued after one course due to anorexia (Common Terminology Criteria for Adverse Events grade 1 [13]) and poor compliance. The patient is alive at more than 21 months after surgery without recurrence of thrombosis or cancer. The clinical course of the patient is summarized in Fig. 3.