Case 1
A 69-year-old woman with a past medical history of hyperlipidemia, endometriosis (hysterectomy when she was 39 years old), and cholelithiasis reported to her family doctor with a chief complaint of epigastric pain. Laboratory evaluation revealed elevated inflammatory markers and serum amylase levels, and computed tomography (CT) scan findings revealed gallstone pancreatitis. Endoscopic sphincterotomy and retrograde biliary drainage were immediately performed, and upon examination, an ulcerative lesion was unexpectedly identified in the ampulla of Vater (Fig. 1a). Mucosal biopsy results indicated the pathological diagnosis as adenocarcinoma, and the clinical staging was evaluated after an improvement in pancreatitis was observed. Contrast-enhanced CT revealed a 1.5-cm enhancing nodule around the papilla of Vater (Fig. 1b) with no obvious distant metastases or swollen lymph nodes. Endoscopic ultrasound (EUS) showed a possible tumor invasion of the pancreatic parenchyma beyond the duodenal muscle layer (Fig. 1c, d). Endoscopic retrograde cholangiopancreatography (ERCP) revealed no findings suggestive of obvious invasion of the main pancreatic duct and common bile duct. Laboratory data were as follows: white blood count, 4380 cells/μL; hemoglobin level, 14.0 g/dL; platelet count, 25.7 × 104 cells/μL; aspartate transaminase (AST), 17 IU/L; alanine aminotransferase (ALT), 13 IU/L; total bilirubin, 0.81 mg/dL; albumin, 4.4 g/dL; and creatinine, 0.65 mg/dL. The serum tumor markers, human carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA19-9), were within the normal range (1.02 ng/mL and 6.1 U/mL, respectively). Based on these results, the patient was diagnosed with clinical stage Ia (cT1bN0M0, Japanese Society of Hepato-Biliary-Pancreatic Surgery 7th edition) ampulla of Vater carcinoma. Subtotal stomach-preserving pancreatoduodenectomy (SSPPD) with modified Child's reconstruction and regional lymphadenectomy was performed. The surgical specimen showed a mixed-type tumor (12 × 6 mm, ulcerative-dominant type) (Fig. 2a). Histopathological examination revealed atypical cells with oval nuclei and increased chromatin that formed irregularly shaped ducts, indicating the existence of an adenocarcinoma component. In addition, atypical cells with salt-and-pepper chromatin with numerous mitoses (mitoses/10 high-power field > 20) showing solid-nest growth were also observed (Fig. 2b). Immunohistochemical examination of these cells showed that the tumor cells were positive for synaptophysin and partially positive for CD56, and negative for chromogranin A and CAM5.2. The cells had a Ki-67 index > 20% (Fig. 2c–f). These findings indicate the coexistence of poorly differentiated NEC components. Both components accounted for more than 30% of the tumor, which was consistent with the diagnostic criterion of MINEN. Lymph node metastasis was found in one of the lymph nodes on the dorsal side of the pancreas with the metastatic component being adenocarcinoma. The final pathological diagnosis was as follows: Adc, ulcerative predominant type, 12 × 6 mm, MINEN (large cell NEC > well), pT1b, int, INFb, ly2, v1, ne0, pN1 (1/16), pHM0, pPM0, pEM0, pPVX, pAX, R0 and pathological stage IA (T1N0M0, AJCC/UICC 8th edition). The postoperative course was uneventful, and the patient was discharged on the 17th postoperative day. Adjuvant chemotherapy with etoposide and cisplatin was administered for 6 months, and the patient is alive without recurrence 64 months after surgery.
Case 2
A 79-year-old man with a medical history of hyperlipidemia, hypertension, type II diabetes, benign prostatic hyperplasia, and stroke (he was on an anticoagulant therapy) reported to his family doctor with a chief complaint of anorexia. He was found to have elevated hepatobiliary enzyme levels: aspartate aminotransferase (AST), 594 IU/L; alanine aminotransferase (ALT), 355 IU/L; and gamma-glutamyl transpeptidase (γ-GTP),1900 IU/L. Ultrasonography revealed dilatation of the common bile duct and enlargement of the gallbladder. He underwent endoscopic retrograde biliary drainage and subsequently developed post-ERCP pancreatitis with extremely high levels of CRP (44.0 mg/L) which led to hospitalization for approximately 1 month. After an improvement in pancreatitis was observed, he was referred to our hospital and the cause of bile duct stenosis was investigated. Cholangiography showed severe stenosis of the distal bile duct and biliary cytology revealed adenocarcinoma (Fig. 3a). EUS findings showed a hypoechoic mass of 14 × 10 mm in the intrapancreatic bile duct and suggested no invasion to the pancreas and the duodenum (Fig. 3b). Contrast-enhanced CT showed circumferential wall thickening in the intrapancreatic bile duct (Fig. 3c–e) with no obvious distant metastasis. Laboratory data were as follows: white blood count, 4770 cells/μL; hemoglobin level, 14.3 g/dL; platelet count, 19.9 × 104 cells/μL; AST, 19 IU/L; ALT, 21 IU/L; total bilirubin, 0.47 mg/dL; γ-GTP, 79 IU/L; albumin, 3.9 g/dL; and creatinine, 1.17 mg/dL. CEA and CA19-9 levels were 1.92 ng/ml and 43.8 U/ml, respectively. Laboratory findings indicated mild renal dysfunction and a slight elevation in CA19-9 serum levels. Based on these results, the patient was diagnosed with clinical stage IIa (cT2N0M0, Japanese Society of Hepato-Biliary-Pancreatic Surgery 7th edition) distal bile duct carcinoma. Left cervical and supraclavicular fossa lymph node swelling was detected by CT, and biopsy revealed a low-grade follicular lymphoma. Considering the degree of malignancy, the treatment of bile duct cancer was prioritized and SSPPD with modified Child’s reconstruction and regional lymphadenectomy was performed. Macroscopic examination of the resected specimen showed a nodular-infiltrating type tumor (20 × 12 mm) in the distal bile duct (Fig. 4a). Histopathological examination revealed that atypical cells with tubular formation and solid-nest growth were coexisting, and both components accounted for more than 30% of the tumor. Immunohistochemical examination of the section indicating solid-nest growth revealed the tumor cells to test positive for synaptophysin, CD56, and partially positive for chromogranin A. The growth had Ki-67 index > 20%, indicating the existence of the NEC component. Lymph node metastasis was found in one of the lymph nodes around the common hepatic artery, and its metastatic component was NEC (Fig. 4b–g). The final pathological diagnosis was as follows: Bd, circ, nodular-infiltrating type, 20 × 12 mm, MINEN (SCNEC > well), pT2(SI), pPV0, pA0, INFb, Ly0, V0, Pn1c, pN1 (1/9), pHM0, pPM0, pEM0, R0, and pathological stage IB (T2N0M0, AJCC/UICC 8th edition). The patients required a relatively long hospital stay because of his poor oral intake; however, he was discharged on the 33rd postoperative day. The patient is alive and being monitored without adjuvant chemotherapy in an outpatient setting; 7 months after surgery, the patient was found to have a liver metastasis.