Familial Intraductal Papillary Mucinous Neoplasm Associated With the Germline MSH6 Missense Variant and Progression of Pancreatic cancer.

OBJECTIVES: Intraductal papillary mucinous neoplasm (IPMN) in individuals with at least one first-degree relative with IPMN is defined as familial IPMN. However, few studies have reported on familial IPMN, its clinical characteristics, or the associated genetic factors. MATERIALS AND METHODS: We report the case of a 58-year-old woman with multifocal IPMN and a mural nodule in the pancreatic body. The patient underwent a distal pancreatectomy and developed pancreatic head cancer 1 year and 6 months postoperatively. The patient had a family history of multifocal IPMN in her father. Therefore, a genetic predisposition to IPMN and pancreatic cancer was suspected. The patient was analyzed for germline variants, and the resected IPMN was subjected to immunohistochemical and somatic variant analyses. RESULTS: Next-generation sequencing revealed a heterozygous germline missense variant in exon 5 of MSH6 (c.3197A>G; Tyr1066Cys). The pathogenicity of this variant of uncertain significance was suspected based on multiple in silico analyses, and the same MSH6 variant was identified in the patient's father's colonic adenoma. The mural nodule in the pancreatic body was pathologically diagnosed as a high-grade IPMN with ossification and somatic KRAS and PIK3CA variants. CONCLUSIONS: This case revealed a possible genetic factor for familial IPMN development and presented interesting clinicopathological findings.

Phase I/II study of streptozocin monotherapy in Japanese patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumors.

BACKGROUND: This phase I/II study was conducted to evaluate the efficacy, safety and pharmacokinetics of streptozocin (STZ) in Japanese patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumors. METHODS: Twenty-two patients received up to 4 cycles of intravenous STZ at either 500 mg/m2 once daily for 5 consecutive days every 6 weeks (daily regimen) or at 1000-1500 mg/m2 once weekly for 6 weeks (weekly regimen). Tumor response was evaluated using the modified RECIST criteria ver. 1.1, and adverse events were assessed by grade according to the National Cancer Institute CTCAE (ver. 4.0). RESULTS: Fourteen (63.6%) patients completed the study protocol. No patients had complete response; partial response in 2 (9.1%), stable disease in 17 (77.3%), non-complete response/non-progressive disease in 2 (9.1%) and only 1 (4.5%) had non-evaluable disease. Excluding the latter, the response rate in the daily and weekly regimens was 6.7% (1/15) and 16.7% (1/6), respectively, with an overall response rate of 9.5% (2/21). However, the best overall response in each patient showed that the disease control rate was 100%.Adverse events occurred in all 22 patients, including 17 grade 3 adverse events in 11 patients; however, no grade 4 or 5 adverse events were reported. Prophylactic hydration and antiemetic treatment reduced the severity and incidence of nephrotoxicity, nausea and vomiting. Plasma STZ concentrations decreased rapidly after termination of infusion, with a half-life of 32-40 min. Neither repeated administration nor dose increases affected pharmacokinetic parameters. CONCLUSIONS: STZ may be a useful option for Japanese patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumors.

S-1 induced discoid lupus erythematosus-like lesions and long-term complete response for para-aortic lymph node recurrence of pancreatic ductal adenocarcinoma: a case report.

BACKGROUND: Metastatic recurrence after resection of pancreatic cancer is considered to be an incurable disease, and discoid lupus erythematosus (DLE)-like lesions are known as a side effect of fluorouracil agents. We report a very rare case of metastatic recurrence of pancreatic cancer in a Japanese man with DLE-like lesions in which long-term complete response was achieved through S-1 monotherapy. CASE PRESENTATION: A 65-year-old man who had undergone distal pancreatectomy with splenectomy for pancreatic body cancer and had received adjuvant gemcitabine developed postoperative para-aortic lymph node recurrence 17 months after surgery. S-1 monotherapy was started. About 2 weeks after starting this treatment, he developed an erythematous rash on the face and scalp. DLE was diagnosed by skin biopsy. The eruptions were aggravated by the administration of S-1 and improved during periods of respite from S-1. Yet as CA19-9 was reduced by almost half 1 month after starting S-1 chemotherapy, S-1 chemotherapy was continued at a reduced dose. CA19-9 decreased to within a normal range within 6 months after starting S-1 chemotherapy, and a reduction in lymph node metastasis was detected through imaging. The patient is still alive without recurrence or metastasis 113 months after surgery. CONCLUSIONS: Even in patients with S-1-induced DLE-like lesions, continuation of S-1 is possible if the dose and duration of S-1 are appropriately regulated and medical therapy is administered for the skin lesions. Further investigation into the possible correlation between skin rash and clinical benefit in connection with S-1 is strongly warranted.

A case of mucinous cystic neoplasm of the gallbladder.

The patient was a 70-year-old woman in whom examination revealed a high level of carbohydrate antigen 19-9. Abdominal ultrasonography and computed tomography (CT) revealed a multilocular cystic lesion compressing the gallbladder. CT indicated the presence of a multilocular cystic tumor (67 × 68 × 72 mm) in contact with the right hepatic lobe. Intraoperative findings indicated that the cyst diameter was 8.5 × 6.0 cm, and the cyst was continuous with the gallbladder. The gallbladder was resected along with the cyst. The cyst was multilocular and originated from the cystic duct and gallbladder wall. The cyst wall contained cuboidal to columnar mucin-producing epithelial cells and ovarian-like stroma (OS). The final diagnosis was mucinous cystic neoplasm (MCN) of the gallbladder with low-grade dysplasia. In the 2010 WHO classification of tumors of the digestive system, MCN have been newly defined as a type of hepatobiliary tract epithelial neoplasms. MCN of the gallbladder with OS is extremely rare. Only three cases have been published in the literature. The presence of OS is necessary for diagnosis of MCN.

Validation of the 2012 Fukuoka Consensus Guideline for Intraductal Papillary Mucinous Neoplasm of the Pancreas From a Single Institution Experience.

OBJECTIVES: The 2012 Fukuoka consensus guideline has stratified the risks of malignant intraductal papillary mucinous neoplasm (IPMN) of the pancreas into "high-risk stigmata" (HRS) and "worrisome feature" (WF). This study aimed to evaluate its clinical validity based on a single institution experience. METHODS: Eighty-nine patients who underwent surgical resection with pathological diagnosis of IPMN were retrospectively studied. RESULTS: High-risk stigmata was significantly correlated with the prevalence of malignant IPMN as compared with WF. The positive predictive values of HRS and WF were 66.7% and 35.7% for branch duct IPMN and 80% and 38.1% for main duct IPMN, respectively. Univariate analysis indicated that all the factors in HRS and WF had statistical significance. Whereas multivariate analysis revealed only enhanced solid component (odds ratio [OR], 50.01; P = 0.008), presence of mural nodule (OR, 73.83; P < 0.001) and lymphadenopathy (OR, 20.85; P = 0.03) were independent predictors. Scoring HRS and WF by different numbers of positive factors resulted in improved predictive value. The area under the curve of HRS score was significantly lower than that of WF or HRS + WF score (0.680 vs 0.900 or 0.902, respectively; P < 0.001). CONCLUSIONS: As supplementary to the 2012 Fukuoka guideline, we suggest that calculating scores of WF and HRS may have superior diagnostic accuracy in predicting malignant IPMN.

Pancreatic volume is one of the independent prognostic factors for resectable pancreatic ductal adenocarcinomas.

BACKGROUND: It is well known that pancreatic ductal adenocarcinoma (PDAC) is accompanied with pancreatic atrophy and fibrosis. We previously reported the correlation between pancreatic volume and body surface area (BSA) and significant reduction of BSA-adjusted pancreatic volume in pancreatic cancer patients. We evaluated potential correlation between BSA-adjusted pancreatic volume and PDAC prognosis. METHODS: The study subjects were 48 pancreatic cancer patients received pancreatectomy at our department from June 2006 to September 2012. Pancreatic volumetry was retrospectively performed using the images obtained from multidetector computed tomography before the surgery. BSA-adjusted pancreatic volumes were calculated and analyzed for potential correlation with the prognosis. RESULTS: Average BSA-adjusted pancreatic volume among 48 cases was 35.4 ± 11.9 ml/m(2) . Types of surgery included 24 cases with pancreaticoduodenectomy and 24 cases with distal pancreatectomy. The cases with BSA-adjusted pancreatic volume less than 40 ml/m(2) had significantly poorer prognosis compared to the cases of 40 ml/m(2) and greater (3-year survival rate: 32.4% vs. 64.3%). Statistical analysis identified four prognosis factors, i.e. BSA-adjusted pancreatic volume less than 40 ml/m(2) , postoperative adjuvant chemotherapy, lymph node metastasis and lymphatic invasion. CONCLUSIONS: This study demonstrated BSA-adjusted pancreatic volume as a prognosis factor for PDAC and the volume of 40 ml/m(2) is considered to be the cutoff value.

A pancreaticoduodenectomy risk model derived from 8575 cases from a national single-race population (Japanese) using a web-based data entry system: the 30-day and in-hospital mortality rates for pancreaticoduodenectomy.

OBJECTIVE: To create a mortality risk model after pancreaticoduodenectomy (PD) using a Web-based national database system. BACKGROUND: PD is a major gastroenterological surgery with relatively high mortality. Many studies have reported factors to analyze short-term outcomes. SUBJECTS AND METHODS: After initiation of National Clinical Database, approximately 1.2 million surgical cases from more than 3500 Japanese hospitals were collected through a Web-based data entry system. After data cleanup, 8575 PD patients (mean age, 68.2 years) recorded in 2011 from 1167 hospitals were analyzed using variables and definitions almost identical to those of American College of Surgeons-National Surgical Quality Improvement Program. RESULTS: The 30-day postoperative and in-hospital mortality rates were 1.2% and 2.8% (103 and 239 patients), respectively. Thirteen significant risk factors for in-hospital mortality were identified: age, respiratory distress, activities of daily living within 30 days before surgery, angina, weight loss of more than 10%, American Society of Anesthesiologists class of greater than 3, Brinkman index of more than 400, body mass index of more than 25 kg/m, white blood cell count of more than 11,000 cells per microliter, platelet count of less than 120,000 per microliter, prothrombin time/international normalized ratio of more than 1.1, activated partial thromboplastin time of more than 40 seconds, and serum creatinine levels of more than 3.0 mg/dL. Five variables, including male sex, emergency surgery, chronic obstructive pulmonary disease, bleeding disorders, and serum urea nitrogen levels of less than 8.0 mg/dL, were independent variables in the 30-day mortality group. The overall PD complication rate was 40.0%. Grade B and C pancreatic fistulas in the International Study Group on Pancreatic Fistula occurred in 13.2% cases. The 30-day and in-hospital mortality rates for pancreatic cancer were significantly lower than those for nonpancreatic cancer. CONCLUSIONS: We conducted the reported risk stratification study for PD using a nationwide surgical database. PD outcomes in the national population were satisfactory, and the risk model could help improve surgical practice quality.

Histotopographical characterization of the para-aortic lymph nodes in the area near the origin of the thoracic duct, and its relationship to nodal cancer metastasis.

Using 10 elderly cadavers without macroscopically evident tumors, we histologically examined 115 para-aortic lymph nodes located near the origin of the thoracic duct after preparation of en bloc specimens using a clearance method. The afferent and efferent sides of these nodes were usually not discriminated clearly because i) the superficial cortex (B-lymphocyte area) and deep cortex (T-lymphocyte area) were not clearly differentiated due to lack of a typical hilus, and both cortices were intermingled to form "nodular masses"; ii) each nodule with a lining of macrophages was surrounded by dilated intermediate and subcapsular sinuses; iii) the nodes were often surrounded by multiple tributaries of the thoracic duct. Moreover, the nodes sometimes involved these tributaries inside. Therefore, the nodal architecture seemed to accelerate intranodal shunt flow without filtration through the cortex. Valves of the lymphatic vessel tended to be restricted to an area immediately before drainage into the thoracic duct. Thus, lymph flow was likely to change along a network of tributaries around a node. These morphologies suggested very limited barrier function of the para-aortic node against cancer metastasis. However, we hypothesized that "better" or "worse" types of nodes are histologically identifiable when they are picked up surgically along with the surrounding tissues.

Postoperative hematological changes after spleen-preserving distal pancreatectomy with preservation of the splenic artery and vein.

BACKGROUND: The aim of this study was to determine the early postoperative hematological changes after spleen-preserving distal pancreatectomy (SpDP) with preservation of the splenic artery and vein (PSAV). METHODS: We reviewed 53 patients who underwent SpDP with PSAV (n = 21) or distal pancreatectomy with splenectomy (DPS; n = 32) for benign or low-grade malignant lesions between July 1998 and June 2010. Red and white blood cell (WBC) count, platelet count, serum hemoglobin, hematocrit, C-reactive protein, albumin level, and clinical factors were compared between the SpDP with PSAV and DPS. RESULTS: There were no significant differences in the patient characteristics between the two groups. Platelet count on postoperative day (POD) 5 and WBC count on POD 3 were significantly higher in the DPS group, and these differences continued to be significant until the 3rd month after surgery. Serum hemoglobin and hematocrit in the 1st month after surgery were also significantly higher in the SpDP with PSAV group. CONCLUSION: The hematological benefits of SpDP with PSAV include reduction of postoperative hematological abnormalities in the early postoperative phase and recovery of the serum hemoglobin and hematocrit levels in the early postoperative phase.

Pancreatic schwannoma: Case report and an updated 30-year review of the literature yielding 47 cases.

Pancreatic schwannomas are rare neoplasms. Authors briefly describe a 64-year-old female patient with cystic pancreatic schwannoma mimicking other cystic tumors and review the literature. Databases for PubMed were searched for English-language articles from 1980 to 2010 using a list of keywords, as well as references from review articles. Only 41 articles, including 47 cases, have been reported in the English literature. The mean age was 55.7 years (range 20-87 years), with 45% of patients being male. Mean tumor size was 6.2 cm (range 1-20 cm). Tumor location was the head (40%), head and body (6%), body (21%), body and tail (15%), tail (4%), and uncinate process (13%). Thirty-four percent of patients exhibited solid tumors and 60% of patients exhibited cystic tumors. Treatment included pancreaticoduodenectomy (32%), distal pancreatectomy (21%), enucleation (15%), unresectable (4%), refused operation (2%) and the detail of resection was not specified in 26% of patients. No patients died of disease with a mean follow-up of 15.7 mo (range 3-65 mo), although 5 (11%) patients had a malignancy. The tumor size was significantly related to malignant tumor (13.8 ± 6.2 cm for malignancy vs 5.5 ± 4.4 cm for benign, P = 0.001) and cystic formation (7.9 ± 5.9 cm for cystic tumor vs 3.9 ± 2.4 cm for solid tumor, P = 0.005). The preoperative diagnosis of pancreatic schwannoma remains difficult. Cystic pancreatic schwannomas should be considered in the differential diagnosis of cystic neoplasms and pseudocysts. In our case, intraoperative frozen section confirmed the diagnosis of a schwannoma. Simple enucleation may be adequate, if this is possible.

Multicenter study of serous cystic neoplasm of the Japan pancreas society.

OBJECTIVES: There have been only a few reports on follow-up results of serous cystic neoplasm (SCN) of the pancreas. The frequency of malignancy and surgical indication of SCN are not determined yet. METHODS: In this multi-institutional study of the Japan Pancreas Society, a total of 172 patients with SCN were enrolled. The mean follow-up period was 4.5 years. Surgical resection was performed in 90 patients, whereas the remaining 82 were simply observed. RESULTS: Of all patients, 20% were symptomatic. The tumor was located in the pancreatic head (39%), body (35%), and tail (22%). The mean diameter of the tumor was 4.1 cm. None of the patients showed distant or lymph node metastasis except for liver metastasis found in 2 patients (1.2%). No patient died during the follow-up. The preoperative diagnosis did not correctly identify SCN in 57 (63%) of 90 resected cases. A honeycomb appearance, which is one of the most characteristic findings of SCN, could be diagnosed better by endoscopic ultrasonography than by other imaging diagnostic modalities. CONCLUSIONS: Surgical resection should be considered only when clear distinction from other surgical diseases is difficult, when symptoms or mass effects are present, and when the tumor size is large.

Clinicopathologic study of the MIB-1 labeling index (Ki67) and postoperative prognosis for intraductal papillary mucinous neoplasms and ordinary ductal adenocarcinoma.

OBJECTIVES: Intraductal papillary mucinous neoplasms (IPMNs) are pathologically classified as IPMN with low- or intermediate-grade dysplasia, IPMN with high-grade dysplasia, and IPMN with an associated invasive carcinoma. A stepwise carcinogenic pathway has been considered for IPMN. However, it is not obvious when surgical resection should be performed for IPMN. METHODS: We studied the MIB-1 labeling index in cases of IPMN and ordinary ductal adenocarcinoma (ODA). Moreover, IPMN with an associated invasive carcinoma was divided into 2, namely, carcinoma in situ and invasive components, and the respective MIB-1 labeling indexes were examined. RESULTS: The MIB-1 labeling index for IPMN with low- or intermediate-grade dysplasia (1.8%) was significantly lower than those for IPMN with high-grade dysplasia (14.2%), both the carcinoma in situ components (23.1%) and invasive components (19.2%) within the IPMN with an associated invasive carcinoma, and ODA (19.5%; P < 0.0001).The 5-year survival rates after resection were 100% for IPMN with low- or intermediate-grade dysplasia, 83.3% for IPMN with high-grade dysplasia, 53.8% for IPMN with an associated invasive carcinoma, and 10.3% for ODA. CONCLUSIONS: MIB-1 might be useful for the classification of malignant potential in IPMN. Intraductal papillary mucinous neoplasm should be surgically resected when the tumor is diagnosed as IPMN with high-grade dysplasia.

Surgical management of pancreatic neuroendocrine tumors.

This study outlines the surgical management and clinicopathological findings of pancreatic neuroendocrine tumors (P-NETs). There are various surgical options, such as enucleation of the tumor, spleen-preserving distal pancreatectomy, distal pancreatectomy with splenectomy, pancreatoduodenectomy, and duodenum-preserving pancreas head resection. Lymph node dissection is performed for malignant cases. New guidelines and classifications have been proposed and are now being used in clinical practice. However, there are still no clear indications for organ-preserving pancreatic resection or lymph node dissection. Hepatectomy is the first choice for liver metastases of well-differentiated neuroendocrine carcinoma without extrahepatic metastases. On the other hand, cisplatin-based combination therapy is performed as first-line chemotherapy for metastatic poorly differentiated neuroendocrine carcinoma. Other treatment options are radiofrequency ablation, transarterial chemoembolization/embolization, and liver transplantation. Systematic chemotherapy and biotherapy, such as that with somatostatin analogue and interferon-α, are used for recurrence after surgery. The precise surgical techniques for enucleation of the tumor and spleen-preserving distal pancreatectomy are described.

Volumetric and morphological analysis of intraductal papillary mucinous neoplasm of the pancreas using computed tomography and magnetic resonance imaging.

OBJECTIVE: The purpose of this study was to predict the malignancy of intraductal papillary mucinous neoplasm (IPMN) based on data obtained by computed tomography and magnetic resonance imaging. METHODS: Sixty-nine patients with IPMN underwent computed tomography, magnetic resonance imaging, and surgery. The tumors were classified pathologically as IPMN (adenoma), IPMN (in situ carcinoma), and invasive carcinoma derived from IPMN, and analyzed morphologically for the following characteristics: tumor size, main pancreatic duct (MPD) diameter, tumor area, MPD area, tumor volume, MPD volume, and intraductal volume (tumors volume + MPD volume). RESULTS: Main pancreatic duct diameter (P = 0.017) and intraductal volume (P = 0.0013) showed significant differences among IPMN (adenoma), IPMN (in situ carcinoma), and invasive carcinoma derived from IPMN. When IPMN (in situ carcinoma) and invasive carcinoma derived from IPMN were classified as malignant IPMN, an MPD diameter of 6 mm or more and an intraductal volume of 10 cm or more were set as cutoff levels predictive of malignancy using receiver operating characteristic curve analysis. On the basis of these criteria, the sensitivity and specificity for identifying malignancy in MPD were 83% and 59%, and those for intraductal volume were 70% and 73%, respectively. CONCLUSION: Intraductal volume (≥10 cm) determined by volumetric analysis is useful for diagnosis of malignant IPMN.

Expression of MUC1 and MUC2 in ampullary cancer.

BACKGROUND: Mucins are high-molecular-weight glycoproteins that play important roles in carcinogenesis or tumor invasion. The authors investigated the expression of mucins in ampullary cancer. METHODS: MUC1 and MUC2 expressions were examined using immunohistochemistry. Tissue samples were obtained from 32 patients with ampullary cancer who underwent resection at Yamagata University Hospital, Japan. The authors classified the cases with ampullary cancer into 2 subtypes--pancreatobiliary type (PB type) and intestinal type (I type)--using H&E, MUC1, and MUC2 staining. Then, the authors made a comparison of the clinicopathologic data of the 2 subtypes. RESULTS: Fourteen patients (44%) were classified as PB type and 18 patients (56%) as I type. The PB-type group had significantly worse histopathologic characteristics than the I-type group in nodal involvement (PB type 57% vs I type 22%; P = .04), perineural invasion (PB type 50% vs I type 17%; P = .04), duodenal invasion (PB type 100% vs I type 33%; P = .01), and pancreatic invasion (PB type 71% vs I type 33%; P = .03). The PB-type group had significantly worse outcome than the I-type group (5-year survival: PB type 40% vs I type 72%; P = .03). CONCLUSION: PB-type ampullary cancers were more aggressive than I-type carcinomas. MUC1 and MUC2 expression was useful for classification as PB or I type.

Topographical anatomy of Spiegel's lobe and its adjacent organs in mid-term fetuses: Its implication on the development of the lesser sac and adult morphology of the upper abdomen.

At 8-16 weeks of gestation, Spiegel's lobe of the caudate lobe appears as a sac-like herniation of the liver parenchyma between the inferior vena cava and ductus venosus or Arantius' duct. In 5 of 11 fetuses at 20-30 weeks of gestation, we found that an external notch was formed into the posterior aspect of the caudate lobe by a peritoneal fold containing the left gastric artery. This notch appeared to correspond to that observed in adults, which is usually seen at the antero-inferior margin of the lobe after rotation of the lobe along the horizontal or transverse axis. However, the notch did not accompany two of the three fetuses in which the left hepatic artery originated from the left gastric artery. Notably, until 9-10 weeks of gestation, the inferior and left part of Spiegel's lobe rode over the hepatoduodenal ligament and protruded medially into the lesser sac (bursa omentalis) behind the stomach. Thus, the fetal Winslow's foramen was located at the "superior" side of the ligament. However, as seen in adults, the protruding Spiegel's lobe was located at the posterior side of the lesser omentum. Therefore, a hypothetical rotation along the transverse axis in the later stages of development seems necessary to explain this repositioning. Considering that Spiegel's lobe develops faster than surrounding structures, it is likely that the lesser sac resulting from the rotation of the gastrointestinal tract, which actively contributes to facilitate the growth of the Spiegel lobe.

Groove pancreatitis.

Groove pancreatitis is a segmental chronic pancreatitis that affects the anatomical area between the pancreatic head, the duodenum, and the common bile duct, referred to as the groove area. Most patients with groove pancreatitis are males aged 40-50 years with a history of alcohol abuse. In about 20% of patients undergoing pancreaticoduodenectomy to treat chronic pancreatitis, groove pancreatitis is detected. The clinical symptoms are weight loss, upper abdominal pain, postprandial vomiting, and nausea due to duodenal stenosis. The pathogenesis of groove pancreatitis is thought to be anatomical or functional obstruction of the minor papilla. The viscosity of pancreatic juice increases due to excessive alcohol consumption and/or smoking, leading to calcification of the pancreatic duct. According to these conditions, pancreatitis in the groove area might arise due to impaired pancreatic juice outflow. The descending part of the duodenum is usually stenotic. Severe fibrosis and scarring are evident in the groove area. Characteristic pathological findings are cystic lesions in the duodenal wall, Brunner gland hyperplasia, dilation of Santorini's duct and protein plaques in the pancreatic duct. A differential diagnosis of groove pancreatitis from peripancreatic cancer is clinically important. Cystic lesions in the duodenal wall and smooth stenosis of the bile duct are important findings of groove pancreatitis revealed by endoscopic ultrasonography, computed tomography and magnetic resonance imaging. Biopsy through the duodenum is also useful for diagnosis. Conservative treatment options include endoscopic stenting of the minor papilla, but long-term outcomes remain unclear. Pancreatoduodenectomy is a rational treatment for symptomatic groove pancreatitis.