Attainment of a Long-term Favorable Outcome by Sunitinib Treatment for Pancreatic Neuroendocrine Tumor and Renal Cell Carcinoma Associated with von Hippel-Lindau Disease.

von Hippel-Lindau (VHL) disease, caused by germline mutations in the VHL gene, is a hereditary autosomal-dominant disorder which predisposes the individual to various malignant and benign tumors. VHL acts as a tumor suppressor, mainly through the negative regulation of hypoxia-inducible factors. Molecular-targeted drugs against vascular endothelial growth factor-signaling pathways, a target of hypoxia-inducible factors, have recently been introduced into clinical practice for the treatment of patients with sporadic renal cell carcinoma and pancreatic neuroendocrine tumors. However, whether such treatments are effective in patients with VHL disease remains to be elucidated. We herein report a Japanese patient with VHL disease who was successfully treated with sunitinib for approximately 5 years.

Management of Islet Cell Tumours: A Single Hospital Experience.

BACKGROUND/AIMS: Islet cell tumours (ICTs) are uncommon tumours in clinical practice. Surgical resection is the treatment of choice for ICTs, but localisation of these lesions can be challenging. The aim of this study was to analyse the clinical diagnosis and treatment for ICTs. METHODOLOGY: Thirty-one patients with ICTs who were diagnosed and who underwent surgical treatment in the affiliate hospital of Luzhou Medical College from 1 January 2000 to 31 July 2013 were enrolled. The clinical data of these patients were retrospectively reviewed. RESULTS: Among 31 patients (6 males, 25 females), 15 cases (48.39%) had non-functional ICTs and 16 (51.61%) cases were insulinoma: The mean age of patients with non-functional ICTs was 42.73 ± 12.34 years and of those with insulinoma was 48.88 ± 13 years. Non-functional ICTs had a non-specific presentation. Insulinoma makes different clinical presentations mostly with symptoms of hypoglycaemia. CONCLUSIONS: Preoperative and/or intra-operative localisation is needed for ICTs; CT scan or MRI is used routinely as the first choice. If the lesion is very small, DSA is also good for localisation before operation. IOUS is a reliable technique in exactly localising insulinoma. ICTs are considered to be cured with successful surgical removal.

Management of Islet Cell Tumours: A Single Hospital Experience.

BACKGROUND/AIMS: Islet cell tumours (ICTs) are uncommon tumours in clinical practice. Surgical resection is the treatment of choice for ICTs, but localisation of these lesions can be challenging. The aim of this study was to analyse the clinical diagnosis and treatment for ICTs. METHODS: Thirty-one patients with ICTs who were diagnosed and who underwent surgical treatment in the affiliate hospital of Luzhou Medical College from 1 January 2000 to 31 July 2013 were enrolled. The clinical data of these patients were retrospectively reviewed. RESULTS: Among 31 patients (6 males, 25 females), 15 cases (48.39%) had non-functional ICTs and 16 (51.61%) cases were insulinoma. The mean age of patients with non-functional ICTs was 42.73 ± 12.34 years and of those with insulinoma was 48.88 ± 13 years. Non-functional ICTs had a non-specific presentation. Insulinoma makes different clinical presentations mostly with symptoms of hypoglycaemia. CONCLUSIONS: Preoperative and/or intra-operative localisation is needed for ICTs; CT scan or MRI is used routinely as the first choice. If the lesion is very small, DSA is also good for localisation before operation. IOUS is a reliable technique in exactly localising insulinoma. ICTs are considered to be cured with successful surgical removal.

[Diagnosis and treatment of 51 patients with pancreatic islet cell tumors].

OBJECTIVE: To investigate the diagnosis and treatment of pancreatic islet cell tumors. METHODS: Fifty-one patients with islet cell tumors treated in our department from January 1991 to April 2011 were included in this study. The data of clinical features, diagnosis and treatment were retrospectively analyzed. RESULTS: Among the 51 cases, 38 cases showed typical Whipple's triad, and the other 13 cases were non-functional islet cell tumors. In these 13 cases, 5 patients had no specific clinical symptoms, and 8 patients had abdominal distending pain. The positive rates of imaging were: B-ultrasound 43.1%, multi-slice spiral CT 69.8%; MRI 62.5%, endoscopic ultrasonography (EUS) 64.7% (11/17), and intraoperative ultrasound (IOUS) 96.3%, the differences among them were statistically significant (P<0.05). All patients underwent surgical treatment. Postoperative pancreatic leakage happened in 6 cases. Finally all the patients recovered after effective external drainage, anti-infection treatment and nutritional support. CONCLUSIONS: Intraoperative ultrasonography (IOUS) has a higher accuracy in the diagnosis of pancreatic islet cell tumors, compared with preoperative B-ultrasonography, CT, MRI, and endoscopic ultrasound (EUS). The most effective treatment of this disease is surgery.

Pancreatic endocrine tumors: radiologic-clinicopathologic correlation.

Pancreatic endocrine tumors (PETs) are primarily well-differentiated tumors composed of cells that resemble normal islet cells but that arise from pancreatic ductal cells. They are classified as functioning or nonfunctioning according to their associated clinical symptoms; insulinoma, gastrinoma, and glucagonoma are the most common functioning PETs. They also are classified according to their biologic behavior, although all PETs have malignant potential. Most are sporadic, but some are associated with familial syndromes such as multiple endocrine neoplasia type 1, von Hippel-Lindau syndrome, and neurofibromatosis type 1. At imaging, PETs typically appear as well-defined hypervascular masses, a finding indicative of their rich capillary network. Cystic change, calcification, and necrosis are common in large tumors, which are associated with a poorer prognosis and a higher prevalence of local and vascular invasion and metastases than are smaller tumors. Even when metastases are present, many well-differentiated PETs have an indolent course. Poorly differentiated PETs are rare and have an infiltrative appearance; patients with such tumors have a poor prognosis. Knowledge of the characteristic clinical, pathologic, and radiologic features of PETs is important in the evaluation and management of patients with a suspected clinical syndrome or a pancreatic mass.

Metastatic pancreatic polypeptide-secreting islet cell tumor in a dog.

A 14-year-old female spayed Golden Retriever was presented to the University of Florida's Veterinary Medical Center with history of lymphoplasmacytic gastroenteritis, intermittent vomiting, watery diarrhea, and weight loss for over a year. CBC, biochemical profile, and urinalysis were within reference intervals. Abdominal ultrasonographic examination revealed mesenteric and jejunal lymphadenopathy and hyperechoic hepatic nodules. Cytologic examination of the enlarged lymph nodes revealed loosely cohesive cells with moderate nuclear pleomorphism and rare punctate eosinophilic cytoplasmic granules. The cytologic interpretation was metastatic neuroendocrine neoplasia. On surgical exploration, a mass was detected in the right lobe of the pancreas. Histologic evaluation determined the mass to be an islet cell tumor. Approximately 98% of cells were positive by immunolabeling for pancreatic polypeptide (PP), and only rare cells were positive for insulin or somatostatin. All cells were negative for glucagon, gastrin, vasoactive intestinal polypeptide, protein gene product 9.5, synaptophysin, and chromogranins A and B. Pancreatic tumors that primarily produce PP are rare in dogs, and this is the first report of both the cytologic and histologic features of an islet cell tumor predominantly secreting PP. Clinical signs for these tumors are typically absent or nonspecific; signs may include watery diarrhea, as noted in this dog, although the diarrhea may have resulted from lymphoplasmacytic gastroenteritis. Additional case studies are needed to further characterize the cytomorphologic features and clinical presentation of PP-secreting islet cell tumor, or polypeptidoma, in dogs.

Gastric and pancreatoduodenal resection for malignant lesions after previous gastric bypass--diagnosis and methods of reconstruction.

BACKGROUND: The diagnosis and treatment of gastric and pancreatoduodenal neoplasms after previous gastric bypass has been limited. Experience should increase in the future owing to the number of bariatric procedures being performed. The diagnosis and resection of these neoplasms and restoration of biliopancreatic intestinal continuity pose challenges. We present a 2-institutional experience of diagnosis and reconstruction after resection of gastric and pancreatoduodenal neoplasms and discuss the technical options for reconstruction. METHODS: The medical records were reviewed retrospectively from 2003 to 2009 for patients with previous gastric bypass who developed a gastric or pancreatoduodenal neoplasm. RESULTS: Of the available patients, 7 were identified with 2 remnant gastric cancers (2 signet ring cell adenocarcinomas), 4 pancreatic neoplasms (2 adenocarcinomas and 2 neuroendocrine cancers), and 1 ampullary cancer. The gastric neoplasms required complete remnant gastrectomy but did not require additional gastrointestinal reconstruction. The pancreatic and duodenal neoplasms required pancreatoduodenectomy, with 4 of 5 patients also undergoing remnant gastrectomy. The patients after pancreatoduodenectomy required biliary and pancreatic reconstruction with the pancreaticobiliary limb, Roux limb, or proximal common channel, depending on the limb length. Operative mortality was nil, and the morbidity rate was 28%. CONCLUSION: Gastric and pancreatoduodenal neoplasms after previous gastric bypass, although rare, will most likely increase as the number of bariatric operations increases. A high index of suspicion and focused diagnostic testing are key in identifying these lesions. Resection is feasible and safe but could require complex gastric and pancreatobiliary reconstruction.

Islet cell tumours.

Pancreatic endocrine tumours can cause hormonal symptoms by over-secretion of hormones. They are less aggressive than exocrine pancreatic cancer, but carry a variable prognosis. The tumours are either sporadic or hereditary, as part of the multiple endocrine neoplasia type 1 syndrome. Despite the rarity of these tumours, they evoke significant interest in the research community and important advances have been made over the past years. This chapter provides an overview of the tumours and recent advances in the field. Hereditary forms of pancreatic endocrine tumours are caused by mutations in the MEN1 gene. Menin, the protein encoded by this gene, has been shown to interact with numerous transcription factors and proteins involved in cell-cycle control, shedding some light on the importance of the protein. Several genes have been shown to be up- or down-regulated, suggesting candidates to be further evaluated for a role in tumourigenesis. Several advances have been made in prognostication; a tumour-node-metastasis system has been evaluated and seems to have prognostic value, and several new molecular prognostic markers are under evaluation. It is hoped that the tumour-node-metastasis system and other prognostic markers will be adopted in clinical routine and improve prognostication and treatment choices. Surgery is still the only cure, but several new palliative drugs and interventions are in use or under investigation. Radiofrequency ablation is increasingly used for liver metastases, and a number of new chemotherapy drugs are being tested. Despite improvements in treatment, no clear improvement in survival has been demonstrated.

[Diagnosis and surgical treatment for non-functional islet cell tumor: a retrospective analysis of 44 cases].

OBJECTIVE: To evaluate the methods of diagnosis and surgical treatment for nonfunctional islet cell tumor (NICT). METHODS: Forty-four patients with non-functional islet cell tumor treated at the First Affiliated Hospital of Nanjing Medical University during January 1968 to June 2008 were analyzed retrospectively. There were 9 males and 35 females, aged from 7- to 70-years-old. Clinical manifestation: 15 cases (34.1%) of abdominal masses, 17 patients (38.6%) with epigastric or back pain, 5 cases of jaundice, 5 cases (11.4%) for upper abdominal fullness or vomiting, 10 cases (22.7%) of pancreatic tumor noticed by routine health checkups or imaging examinations. Imaging examination: CT scan, sonography, ERCP, MRI, upper GI series were performed in 33 (75.0%), 16 (36.4%), 6 (13.6%), 2 (4.5%), and 10 cases (22.7%) respectively. Operation methods: 39 patients (88.6%) underwent surgical resection and the other 5 patients did not. COMPLICATIONS: pancreatic fistula in 7 patients (15.9%), intra-abdominal bleeding in 4 (9.1%), gastrojejunal anastomosis outlet obstruction in 1 (2.3%), biliary fistula in 2 (4.5%) and incisional infection in 3 (6.8%). Surgery related mortality happened in 2 patients (4.5%), both treated before 1999. Twenty-five patients underwent operation between January 1999 and June 2008 were followed up for 6 to 108 months. All survive except one died 75 months after the surgery for unknown reason. CONCLUSIONS: No specific clinical manifestation is recognized for non-functional islet cell tumor. Spiral CT is an optimal diagnostic method, while surgery is the first choice for treatment. Middle segmental pancreatectomy has become an alternative surgical protocol for NICT.

Improved histologic and clinicopathologic criteria for prognostic evaluation of pancreatic endocrine tumors.

Currently used histopathologic criteria for the diagnosis of pancreatic endocrine tumors are still under discussion as far as to their capacity to identify prognostically different tumor subsets, which are potentially helpful for patient management. A recently developed TNM staging system and a variety of proposed histologic and clinicopathologic parameters still need to be fully validated. One hundred fifty-five pancreatic endocrine tumors encompassing all the main histologic types and stages, operated with intention to cure and then followed up for a median 126 months, were carefully investigated histologically to identify prognostically informative parameters at univariable, bivariable, and multivariable analysis. Ki67 index, mitotic rate, neuroinvasion with or without vascular, peritumoral or stromal infiltrative patterns, as well as tumor size, and association with endocrine syndromes other than insulinoma proved effective in predicting recurrence and disease-specific death among well-differentiated tumors. Poorly differentiated histologic features, more than 10 mitoses/10 high power fields, and necrosis were helpful in the identification of high-grade cancers with an invariably poor prognosis. The TNM system proved to be highly predictive of patient outcome and easy to combine with histologic and clinicopathologic parameters to classify pancreatic endocrine tumors into groups of increasing malignant potential.

[Pancreatic endocrine tumors: clinical manifestations and predictive factors associated with survival].

BACKGROUND/AIMS: Since pancreatic endocrine tumors (PET) are rare and heterogeneous diseases, their survival and prognosis are not well known. Due to recent advances in CT/MRI technology, incidentalomas of the pancreas are detected with increasing frequency. This study presents results of clinical manifestations of PET and predictive factors associated with survival. METHODS: From year 1990 through 2006, medical records of 98 patients (56 men, 42 women) who were diagnosed as PET pathologically at Seoul National University Hospital were reviewed retrospectively. RESULTS: Ages ranged from 17 to 76 years (mean 51.6+/-1.3 years) with a mean follow-up of 3.6+/-0.4 years (range 0-10.1 years). Overall 5-year survival rate was 68.1%, and 5-year survival rate of the patients who had distant metastases at initial diagnosis was 43.9%. Functioning tumors [hazard ratio (HR) 0.229, 95% confidence interval (CI) 0.056-0.943, p=0.041] and lymph node or liver metastases (HR 5.537, 95% CI 2.106-14.555, p<0.001) were the significant prognostic factors associated with survival rate. However, tumor size and pathology showed no significant association with survival. CONCLUSIONS: Because small and pathologically benign nature do not predict good prognosis in PET, aggressive treatment such as curative resection would be considered initially even in the case of incidental PET.

Small islet cell tumour in the pancreas: diagnostic value of diffusion-weighted MRI.

We present a case of a small islet cell tumour that was clearly depicted on diffusion-weighted imaging using a free breathing approach and discuss the diagnostic value of this sequence.

Spontaneous pancreatic islet cell tumor in a black and white colobus monkey (Colobus guereza kikuyuensis).

A 12-year-old, male black and white colobus monkey (Colobus guereza kikuyuensis) from a small community zoo presented with a 6-month history of mild, slowly progressive ataxia and paresis culminating in an acute episode of recumbency, depression, and seizures. The animal was humanely euthanatized. Gross post-mortem examination revealed significant abnormalities including diffuse pallor of the carcass and a firm, pale, 8-cm diameter mass, adherent to the serosa of the proximal duodenum and colon, and embedded within the pancreas and mesenteric root. Histologically, the mass had characteristics of a neuroendocrine or endocrine tumor. Immunohistochemical stains for chromogranin, synaptophysin, insulin, and glucagon were positive, confirming the diagnosis of a mixed pancreatic islet cell tumor. These tumors are rare in all species except ferrets and unreported previously in colobus monkeys.

Molecular genetics of gastroenteropancreatic neuroendocrine tumors.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are usually sporadic; however, familial (inherited) syndromes, such as the multiple endocrine neoplasia 1 (MEN-1) syndrome, von Hippel-Lindau (VHL) syndrome, neurofibromatosis (NF-1), as well as tuberous sclerosis, may be associated with proximal intestinal and pancreatic NETs. For example, 25% of gastrinoma patients have MEN-1 syndrome. Over the last two decades, the genetic basis of tumorigenesis for these familial syndromes has been clearly identified, providing clinicians with useful screening tools for affected families. Also, over the last few years, advanced molecular genetic techniques, such as comparative genomic hybridization (CGH) and loss of heterozygosity (LOH) analyses, have detected some differences in genomic aberrations among various types of NETs. Whether these chromosomic alterations have implications in the treatment of patients and the outcome of the disease is still unclear.

Islet cell tumor of the pancreas: increasing diagnosis after instituting ultrasonography-guided fine needle aspiration.

OBJECTIVE: To review the clinical and cytomorphologic features of pancreatic islet cell tumors (ICT). STUDY DESIGN: Computer search identified patients with pancreatic ICT diagnosed by fine needle aspiration biopsy (FNAB) between January 1995 and December 2003. Clinical, radiographic, and cytomorphologic findings were reviewed. RESULTS: Thirty-eight patients (19 men, 19 women; median age 60 years, range 30-82) with ICT were identified; 30 were diagnosed through endoscopic ultrasonography (EUS)-FNAB and 8 through computed tomography (CT)-guided FNAB. Smears of 37 specimens had adequate cellularity. Most were highly cellular with bloody backgrounds. No major differences were observed between specimens obtained by EUS-FNAB or CT-FNAB. Radiographically, 20 tumors measured 1-5 cm, 7 were > 5 cm and 4 < 1 cm. Twenty-two patients underwent tumor resection. CONCLUSION: Newer radiography and biopsy techniques to detect and examine smaller pancreatic masses have increased the number of pancreatic ICT diagnoses at our institution. The distinctive cytomorphologic features of pancreatic ICT make it reliably diagnosable by FNAB.

Usefulness of S100P in diagnosis of adenocarcinoma of pancreas on fine-needle aspiration biopsy specimens.

Even though the cytologic criteria for pancreatic ductal adenocarcinoma (PDA) on fine-needle aspiration biopsy (FNAB) specimens have been well defined, a diagnostic challenge is still present. We immunohistochemically evaluated the diagnostic value of S100P on cell-block and/or smear preparations in 58 cases of FNAB specimens of the pancreas. The 58 cases were divided into 4 groups: 1, 32 cases of PDA; 2, 6 cases with an atypical or "suspicious" diagnosis; 3, 14 cases of benign or reactive ductal epithelium; and 4, 6 cases of endocrine tumor. Positive immunoreactivity for S100P was observed in all cases in groups 1 and 2, whereas only 1 of 14 cases in group 3 was positive for S100P. All cases in group 4 were negative for S100P. S100P is a sensitive and specific marker for the detection of PDA on FNAB specimens on cell-block and smear preparations.

[Management of nonfunctioning islet cell tumors of the pancreas].

OBJECTIVE: To analyze the clinical and pathological features in order to investigate appropriate way of diagnosis and treatment for non-functional islet cell tumors of the pancreas (NFICT). METHODS: The data and experience of surgically treated 43 patients with pathologically confirmed NFICT over the last 30 years were retrospectively reviewed. The survival rate was estimated using Kaplan-Meier method and the potential risk factors affecting survival were compared with Log rank test. RESULTS: There were 7 males and 36 females in this series with a mean age of 31.6 years ranged from 8 to 67 years. Twenty-eight patients were diagnosed as having non-functional islet cell carcinomas of the pancreas (NFICC) and 15 patients benign islet cell tumors. The most common symptoms in NFICT were abdominal pain 55.8%, nausea and/or vomiting (32.6%), fatigue (25.6%) and abdominal mass (23.3%). Preoperatively, all of those were found to have a mass in their pancrease by ultrasonic and computed tomography examination, with 21 in the head, 10 in the body and 6 in the tail of the pancreas. Multicemtric tumor were found in one patient. Thirty-nine of these 43 patients (90.7%) underwent surgical resection, with a curative resection in 30 (69.8%) and palliative in 9 (20.9%). The resectability and curative resection rate in 28 patients with nonfunctioning islet cell carcinomas of the pancreas was 78.6% and 60.7%, respectively. None of the 15 patients with benign nonfunctioning islet cell tumor of the pancreas died of this disease. While the overall cumulative 5- and 10-year survival rate in 28 patients with non-functional islet cell carcinomas of the pancreas was only 58.1% and 29.0%, respectively. Curative resection, female, younger than 30 years old and mass diameter < 10 cm were found to be positive prognostic factors. But multivariate Cox regression analysis indicated that radical resection was the only independent prognostic factor (P = 0.007). CONCLUSION: Nonfunctioning islet cell tumor of the pancreas is frequently found in young female. Surgical resection, especially curative resection can achieve satisfactory long-term survival.