2. Case report
A 70-year-old male patient who was referred to our hospital, for the treatment of obstructive jaundice was diagnosed with pancreatic head cancer. He was 168 cm tall, weighed 71.6 kg, had a body mass index of 25.4 kg/m2, did not smoke or drink alcohol, and had no history of chronic pancreatitis or diabetes. His blood test results were as follows: total bilirubin, 15.0 mg/dL (0.3–1.2); direct bilirubin, 11.4 mg/dL (<0.4); aspartate aminotransferase, 125 U/L (10–40); alanine aminotransferase, 218 U/L (5–40); carbohydrate antigen 19–9 (CA19-9), 38.2 U/mL (<37.0); carcinoembryonic antigen (CEA), 4.4 ng/mL (5.0); duke pancreatic monoclonal antigen type 2 (DUPAN-2), >1600 U/mL (<150); and s-pancreas-1 antigen (SPan1), 240 U/mL (<30). Computed tomography (CT) revealed a low-density mass (27 mm in diameter) with no major vessel involvement in the pancreatic head (Fig. 1) and no distant metastases. Endoscopic retrograde cholangiopancreatography was performed for biliary drainage, and the pancreatic tumor was pathologically diagnosed as a PDAC. The clinical stage was T3N1M0, stage IIB, according to the eighth edition of the TNM classification of the American Joint Committee on Cancer (AJCC) /Union for International Cancer Control (UICC). The tumor was considered resectable and the patient underwent PpPD. Because tumor invasion was observed in the superior mesenteric vein (SMV), combined resection and reconstruction of the SMV was performed. No postoperative complications were observed and the patient was discharged on the 21st postoperative day.
Macroscopic examination revealed a whitish solid mass, 50×40×30 mm in size, located in the pancreatic head (Fig. 2A and 2B ). The mass was histologically diagnosed as a well-differentiated adenocarcinoma, T3 N1(7/38) M0, stage IIB, according to the eighth edition of the TNM classification of the AJCC/UICC (Fig. 2C ). The lymphatic invasion was severe, vascular invasion was moderate, and neural invasion was severe. Biliary, duodenal, anterior tissue, retoroperitoneal tissue, superior mesenteric vein, and extrapancreatic nerve plexus invasions were observed.
One month after surgery, the patient received gemcitabine and S-1 (GS: gemcitabine at a dose of 800 mg/m2 on days 1 and 8 plus S-1 at a dose of 100 mg/body twice daily on days 1–14 of a 21-day cycle) as postoperative adjuvant chemotherapy. At the time, only gemcitabine was recommended for adjuvant chemotherapy after PDAC surgery in Japan, and S1 was not yet recommended7. In addition, since there have been some reports that GS therapy is effective as adjuvant chemotherapy89, GS therapy was not standard clinical treatment at that time, but selected after providing sufficient explanation to the patient and obtaining informed consent. Eleven months post-PpPD, multiple microscopic bilateral pulmonary metastases were suspected on CT. Since the lesions suspected to be multiple lung metastases remained almost unchanged in size and only gemcitabine was the chemotherapy medication recommended for unresectable PDAC in Japan at that time 7, GS therapy was continued with sufficient informed consent for an extended period, even after lung metastasis recurrence.
At 4 years and 6 months post-PpPD, only one lesion in the right lower lung grew rapidly (Fig. 3A ), and bronchoscopy revealed class V cytopathology (Fig. 3B ). Whole-body dynamic CT showed no metastasis except in the lung, and since the possibility of primary lung cancer could not be ruled out, the bottom portion of the right lung was thoracoscopically resected 5 years and 5 months post-PpPD. Other pulmonary lesions showed almost no change in size; therefore, we concluded that chemotherapy was effective. In addition, they were not resected because they were numerous and complete resection was impossible.
The lesion was pathologically diagnosed as an adenocarcinoma, similar to the primary lesion (Fig. 4A ). Immunostaining was positive for CK7 (Fig. 4B ), and negative for CK20 (Fig. 4C ) and TTF-1 (Fig. 4D ). This indicated a low likelihood of primary lung cancer. Based on these findings, metastatic PDAC was diagnosed. In addition, multiple lung lesions were obscured, and after obtaining sufficient informed consent from the patient, he was followed up without chemotherapy. However, 6 months after the second surgery (5 years and 10 months after PpPD), CT revealed a nodule in the upper lobe of the right lung. Although GS was resumed, the number of lung metastases increased. Seven years and five months post-PpPD, the treatment regimen was switched to a combination therapy of gemcitabine plus nab-paclitaxel (GEM + nab-PTX: gemcitabine at a dose of 450 mg/m2 and nab-PTX at a dose of 115 mg/m2 on days 1 and 8 of a 21-day cycle). Eleven years and one month post-PpPD, FOLFIRINOX (a combination of folinic acid, fluorouracil, irinotecan hydrochloride, and oxaliplatin) was required to stem the growth of the lung metastases. However, the resulting adverse effects compelled the physicians to discontinue the treatment after only one course, and the patient was subsequently treated with S-1 alone (at a dose of 80 mg/body twice daily on days 1–14 of a 21-day cycle).
11 years and 2 months post-PpPD, the patient was readmitted because of dizziness and left hemiplegia. Contrast-enhanced magnetic resonance imaging (MRI) revealed a 23×22×20-mm neoplasm in the right inferior parietal lobule. A strong contrast effect was evident at the edges and center, and mulberry-like papillary structures were observed within the lesion (Fig. 5A ). A 5-mm ring-shaped contrast effect was also observed in the right cingulate gyrus. Metastatic brain tumors were suspected in the right inferior parietal lobule and right cingulate gyrus. Only the right inferior parietal lobe lesion was resected to relieve symptoms at 11 years and 4 months post-PpPD.
Histopathological analysis revealed metastatic PDAC in the brain (Fig. 5B ). Six weeks after the third surgery, S-1 treatment was resumed (at a dose of 100 mg/body twice daily on days 1–14 of a 21-day cycle).
MRI performed at this time demonstrated numerous small lesions in the brain, and a tumor appeared in the meninges at the site of the previous surgery. Subsequently, the patient underwent whole-brain irradiation, and his condition improved to the point where he was able to walk without assistance. However, the patient died of PDAC recurrence 6 months after the craniotomy (11 years and 8 months after the first surgery).
The CA19-9, CEA, SPan1, and DUPAN-2 levels were measured monthly. CA19-9 was slightly elevated only at the first visit but remained low throughout the observation period, and CEA only spiked just before death. SPan1 and DUPAN-2 levels increased as metastasis increased and decreased as the chemotherapy regimen was changed (Fig. 6 ).