菅野 敦

OBJECTIVES: We examined the efficacy and limitations of acquiring large specimens by endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) for diagnosing type 1 autoimmune pancreatitis (AIP). METHODS: Patients from 12 institutions with non-neoplastic diseases or pancreatic ductal adenocarcinoma (PDAC) with large EUS-FNB specimens were investigated. Slides stained with hematoxylin-eosin, elastic, IgG4, and IgG stains were evaluated. The IgG4- and IgG-positive cell numbers were counted in three foci. The diagnoses were based on the Japan Pancreas Society 2011 (JPS 2011) criteria and the International Consensus Diagnostic Criteria (ICDC). RESULTS: We analyzed 85 non-neoplastic (definite type 1 AIP in 73/85 based on the ICDC) cases and 64 PDAC cases. IgG4-positive cells were numerous (>10 in 85.9%), and the IgG4/IgG ratios were high (>40% in 81.2%). Plasma cell crushing by an artifact caused unsuccessful immunostaining, notably in smaller samples. Tissue lengths were an important factor for the presence of storiform fibrosis and obliterative phlebitis, but storiform fibrosis was equivocal even in large tissues. A definite or possible histological diagnosis was achieved in 45.9% (39/85) and 41.2% (35/85), respectively, and contributed to the definite final diagnosis of type 1 AIP in 33.3% (ICDC) and 55.6% (JPS 2011) in cases with segmental/focal lesions. In the PDAC group, >10 IgG4-positive cells was rare (2/58), but elastic stains revealed fibrous venous occlusions in 10.3% (6/58). CONCLUSIONS: EUS-FNB with large tissue amounts was useful for diagnosing type 1 AIP, notably by facilitating successful IgG4 immunostaining, but definite diagnosis may not be achieved even in cases with large specimens.

A 58-year-old man was referred for obstructive jaundice. Imaging modalities revealed the presence of multiple pancreatic tumors and the stenosis of the middle common bile duct due to a hypoenhanced localized tumor. The multiple pancreatic tumors were histopathologically diagnosed as autoimmune pancreatitis by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). To differentiate between IgG4-related sclerosing cholangitis (IgG4-SC) and cholangiocarcinoma, we diagnosed the biliary tumor as IgG4-SC by EUS-FNA because of insufficient pathological materials obtained in a transpapillary manner. We herein report a case of IgG4-SC diagnosed by EUS-FNA.

Mixed adenoneuroendocrine carcinoma (MANEC) is defined as a tumor composed of both adenocarcinoma and neuroendocrine components. Here, we report the case of a 75-year-old woman with ampullary MANEC. She visited a physician with the chief complaint of dark urine and was diagnosed with advanced jaundice. Subsequently, she was referred to our hospital. Contrast-enhanced computed tomography scan revealed a neoplastic lesion measuring approximately 2 cm with a contrast effect at the duodenal papilla. Upper endoscopy showed a non-exposed tumor at the duodenal papilla. After biliary drainage, a subtotal stomach-preserving pancreaticoduodenectomy was performed. Histopathological examination revealed that the tumor components were composed of circular-to-oval atypical cells admixed with tubular adenocarcinoma tissue. These atypical cells were immunohistochemically positive for synaptophysin and diagnosed as neuroendocrine carcinoma with a Ki-67 labeling index of 63%. The patient was diagnosed with MANEC with a neuroendocrine carcinoma component of approximately 40%. The neuroendocrine carcinoma component had metastasized to the posterior pancreatic lymph nodes. Despite starting adjuvant chemotherapy with S-1, computed tomography revealed the presence of multiple liver metastases within 4 months after surgery. MANEC with neuroendocrine carcinoma is well known to have an extremely poor prognosis. Therefore, establishing a multidisciplinary therapy including chemotherapy is crucial.

BACKGROUND: In patients with malignant perihilar biliary strictures, preoperative biliary drainage (PBD) of the hepatic lobe to be resected may decrease the liver volume of the future liver remnant (FLR) after percutaneous transhepatic portal vein embolization (PVE). However, evidence of its application is insufficient. This study aimed to clarify the effects of PBD on liver hypertrophy after PVE. METHODS: Between January 2008 and December 2017, 169 patients with malignant perihilar biliary strictures underwent major hepatectomy or palliative surgery at our hospital. Of these, 76 patients who underwent PVE were categorized into two groups: group A (n = 29) who received unilateral PBD of the FLR and group B (n = 47) who received bilateral PBD, including that of the hepatic lobe to be resected. FLR ratios after PVE and liver hypertrophy ratios were retrospectively compared in both groups. RESULTS: Group B exhibited significantly severe biliary stenosis (p = 0.0038) and high serum bilirubin before biliary drainage (p = 0.0037). After PVE, the total liver volumes were 1287 ± 260 ml and 1340 ± 257 ml (p = 0.39), respectively. FLR volumes were 555 ± 135 and 577 ± 113 ml (p = 0.45), respectively. FLR ratios were 43.4 ± 8.2% and 43.4 ± 6.4%, respectively (p = 0.98). Liver hypertrophy ratios were 124.2 ± 17.7% and 129.2 ± 20.9%, respectively (p = 0.28). In addition, an examination which excluded patients with Bismuth type I obtained similar result. CONCLUSIONS: PBD of the hepatic lobe to be resected did not decrease the FLR ratios and hypertrophy ratios. Thus, in patients with poor biliary drainage, additional PBD of the target lobe is acceptable.

BACKGROUND: Although there are numerous reports focusing on surgical indication for intraductal papillary mucinous neoplasm (IPMN), the recurrence patterns following surgery are less widely reported. To ascertain optimal treatment and postoperative surveillance for IPMN patients, we analyzed patterns and risk factors for recurrence after surgery for IPMN. METHODS: This study is a retrospective, multi-institutional, observational study, including 1074 patients undergoing surgery for IPMN at 11 academic institutions. We analyzed the risk factors for recurrence after classifying postoperative recurrences into metachronous high-risk lesions (malignant progression of IPMN and/or metachronous pancreatic ductal adenocarcinoma) in the remnant pancreas and extra-pancreatic recurrence. RESULTS: Of 1074 patients undergoing surgery for IPMN, 155 patients (14.4%) developed postoperative recurrence. We found that 34.3% of 70 high-risk lesions in the remnant pancreas occurred over 5 years after surgery, and survival of 36 patients undergoing second operation for high-risk lesions was better than that of 34 patients who did not (P = 0.04). We found four independent risk factors for metachronous high-risk lesions in remnant pancreas: symptoms [P = 0.005, hazard ratio (HR) 1.988], location of pancreatic body/tail (P < 0.001, HR 3.876), main duct size ≥ 10 mm (P = 0.021, HR 1.900), and high-grade dysplasia/invasive intraductal papillary mucinous carcinoma (IPMC) (P < 0.001, HR 3.204). Although six patients (0.7%) with low- or high-grade dysplasia IPMN developed extra-pancreatic recurrence, invasive IPMC was the strongest risk factor for extra-pancreatic recurrence (P < 0.001, HR 39.667). CONCLUSION: We suggest that life-time continuous surveillance might be necessary for IPMN patients. Second surgery for metachronous high-risk lesions in remnant pancreas should be considered to improve survival.

BACKGROUND: Chronic pancreatitis (CP) is a fibro-inflammatory disease of the pancreas. Early diagnosis and intervention, before CP becomes established and irreversible, are essential to improve the long-term outcomes. The world's first diagnostic criteria for early CP were proposed in Japan in 2009, but their clinical utility remains elusive. This study aimed to clarify whether patients with early CP progress to definite CP. METHODS: This is a multicenter, prospective study. Patients diagnosed as having early CP according to the Japanese diagnostic criteria were prospectively followed for 2 years. Clinical profiles including symptoms, drinking and smoking status, laboratory data, imaging findings and treatments were analyzed. RESULTS: Among the 83 patients who completed the 2-year follow-up period, four (4.8%) patients progressed to definite CP. The diagnosis of 48 (57.8%) patients was unchanged, and that of 31 (37.3%) patients was downgraded. All the four progressive patients were male, alcohol-related, smokers (3 current and 1 ever), and continued drinking. Comparison of the clinical profiles between the progression group (n = 4) and non-progression group (n = 79) revealed that etiology (alcohol-related), smoking status and presence of acute pancreatitis episodes were associated with the progression to definite CP. CONCLUSIONS: The Japanese diagnostic criteria could identify some patients before the progression to definite CP, while the majority of the patients did not progress. TRIAL REGISTRATION NUMBER: UMIN000015992.

長年の研究と多数例の経験から自己免疫性膵炎（autoimmune pancreatitis；AIP）の診断能が向上した．特に，画像診断における進歩はめざましく，腹部超音波検査，CT，MRI，FDG-PET，超音波内視鏡（endoscopic ultrasonography；EUS），内視鏡的逆行性胆管膵管造影（endoscopic retrograde cholangio-pancreatography；ERCP）などを用いたAIPの診断に関する報告が多数認められる．超音波内視鏡下穿刺吸引法（EUS-fine needle aspiration；EUS-FNA）による病理組織学的診断の精度も向上しつつある．これらの進歩を踏まえ，わが国のAIP臨床診断基準が2018年に改訂され，さらなる診断能の向上が期待される．

IgG4-related sclerosing cholangitis (IgG4-SC) is a distinct type of cholangitis frequently associated with autoimmune pancreatitis and currently recognized as a biliary manifestation of IgG4-related disease. Although clinical diagnostic criteria of IgG4-SC were established in 2012, differential diagnosis from primary sclerosing cholangitis and cholangiocarcinoma is sometimes difficult. Furthermore, no practical guidelines for IgG4-SC are available. Because the evidence level of most articles retrieved through searching the PubMed, Cochrane Library, and Igaku Chuo Zasshi databases was below C based on the systematic review evaluation system of clinical practice guidelines MINDS 2014, we developed consensus guidelines using the modified Delphi approach. Three committees (a guideline creating committee, an expert panelist committee for rating statements according to the modified Delphi method, and an evaluating committee) were organized. Eighteen clinical questions (CQs) with clinical statements were developed regarding diagnosis (14 CQs) and treatment (4 CQs). Recommendation levels for clinical statements were set using the modified Delphi approach. The guidelines explain methods for accurate diagnosis, and safe and appropriate treatment of IgG4-SC.

OBJECTIVES: The aim of this study was to evaluate the diagnostic and prognostic impact of systemic inflammatory markers for IPMN with high-grade dysplasia (HGD)/invasive carcinoma. METHODS: Neutrophil-to-lymphocyte ratio (NLR), derived NLR, platelet-to-lymphocyte ratio, and C-reactive protein-to-albumin ratio were compared across the different histological grades of 205 IPMN cases. We also tested the diagnostic performance for IPMN with HGD/invasive carcinoma. RESULTS: The median (interquartile range) preoperative NLR was higher in IPMN with HGD/invasive carcinoma (2.03 [1.48-2.93]) than IPMN with low-grade dysplasia (1.74 [1.42-2.24], P = 0.0137). The C-reactive protein-to-albumin ratio and derived NLR values were also significant higher in cases with HGD/invasive carcinoma. A combination assay of NLR, carcinoembryonic antigen, and carbohydrate antigen 19-9 revealed a 58.8% sensitivity and 76.8% specificity. Among the cases with worrisome features, the high NLR values increased the positive predictive value (68.8%) compared with low values (31.8%). In IPMN cases with the associated invasive carcinoma, high NLR values showed association with the deeper vertical invasion and shorter survival periods. CONCLUSIONS: Preoperative NLR, combined with tumor markers and image findings, can be a useful predictive marker for the presence of HGD/invasive carcinoma in IPMNs. Preoperative NLR also predicts the long-term outcomes in IPMN cases with invasive carcinoma.

BACKGROUND: Primary sclerosing cholangitis (PSC) is relatively rare disease and pathogenesis and methods of treatments were still not established. Then, we had conducted the making clinical guidelines to manage patients with PSC based on the literature review and expert opinions. These clinical guidelines were made for the medical doctors on the management of PSC, except child case of PSC. METHODS: We had employed modified Delphi method. The production committee decided guidelines, strength of recommendations and evidence level after reviewed literatures systematically, and The Expert panel evaluated those. The Scientific Committee of the Japan Biliary Association (JBA) evaluated revised guidelines, and the Public comments were collected on web site of JBA. RESULTS: We had made 16 guidelines about epidemiology/pathophysiology, diagnostics, therapy and prognosis. Also, we had made both diagnostic and therapeutic flow chart. CONCLUSIONS: We hope that these guidelines will contribute to the improvement and development of the medical care of PSC.

We report a case of the pancreas head cancer with peritoneal metastasis, which was resected curatively after chemotherapy. A6 6-year-old male was referred to our hospital for the treatment of biliary stenosis. The serum CA19-9 level was elevated and abdominal CT scan showed stenosis of distal bile duct. By laparotomy, we noticed mass in the head of the pancreas with 8mm of the seeding nodule in a diameter at jejunal mesentery which was diagnosed as adenocarcinoma by intraoperative frozen sections. Therefore, the patient was diagnosed as pancreas head cancer with peritoneal metastasis. After hepaticojejunostomy, we started chemotherapy planning adjuvant surgery if the clinical response was observed. Systemic chemotherapy with gemcitabine and nab-paclitaxel was administrated on days 1, 8 and 15 every 4 weeks. After 5 courses, therapeutic effect was stable disease(SD)in response evaluation criteria in solid tumor(RECIST). All of tumor markers were normalized. Subtotal stomach-preserving pancreatoduodenectomy(SSPPD)was performed 6 months after the initial surgery. Histopathologically, most cancer cells showed degeneration and eliminated in the head of the pancreas. R0 resection was achieved with diagnosis of ypT3, ypN1, pM1(PER), Stage IV . Histological therapeutic effect was Grade III according to the Evans classification. The patient is alive, with no sign of recurrence 8 months after surgery. Adjuvant surgery was suggested to be one of the therapeutic options for pancreatic cancer with peritoneal metastasis.

自己免疫性膵炎（AIP）は，びまん性の膵腫大と主膵管の不整狭細像を特徴とする．AIPにしばしば合併するIgG4関連硬化性胆管炎（IgG4-SC）は，胆管の狭窄を呈する．したがって，AIPは膵癌と，IgG4-SCは胆管癌や原発性硬化性胆管炎と鑑別することが重要である．内視鏡検査は，主膵管の狭細像や胆管の狭窄像を描出し，病理組織学的診断における組織標本を採取できるため，AIPとIgG4-SCの診断における中心的な役割を担っている．内視鏡的逆行性胆管膵管造影（ERCP）による膵管のびまん性不整狭細像は，AIPに特徴的であり診断も比較的容易であるが，限局的な主膵管狭細像を呈するAIPと主膵管の途絶像を呈する膵癌を鑑別することは難しい．尾側の膵管拡張を伴わない主膵管全長の1/3より長い狭細像がERCPにおけるAIPの膵管像の特徴である．限局的な狭窄や下部胆管の狭窄，狭窄より肝側の拡張を伴う長い狭窄といった胆管像の所見は，胆管癌よりIgG4-SCに認められることが多い．ERCPに引き続いて行われる管腔内超音波検査による胆管壁の所見は，IgG4-SCと胆管癌の鑑別に有用である．超音波内視鏡検査（EUS）では，膵臓はびまん性の低エコー腫大を示す．また，Elastographyや造影EUSなど近年開発された新規診断法による診断能の向上が期待されている．さらに，EUSガイド下穿刺吸引法を用いたAIPの組織学的診断の有用性が報告されている．内視鏡検査と機器のさらなる発展により，AIPおよびIgG4-SCの診断能の向上が期待される．