Population-level analysis of pancreatic neuroendocrine tumors 2 cm or less in size.

BACKGROUND: There is a paucity of evidence regarding incidence and predictors of survival in pancreatic neuroendocrine tumors (PNETs)≤2 cm in size. METHODS: Patients having undergone resection for nonfunctioning PNETs were selected from the SEER database (1988-2009) and an institutional pathology database (1996-2012). PNETs≤2 cm were compared with PNETs>2 cm. Data were analyzed with χ2 tests, ANOVA, the Kaplan-Meier method, log rank tests, and Cox proportional hazard, and binary logistic regression. RESULTS: The incidence of PNETs≤2 cm in the United States has increased by 710.4% over the last 22 years. Rates of extrapancreatic extension, nodal metastasis, and distant metastasis in PNETs≤2 cm in the SEER database were 17.9, 27.3, and 9.1%, respectively. The rate of nodal metastasis in our institutional series was 5.7%. Disease-specific survival at 5, 10, and 15 years for PNETs≤2 cm was 91.5, 84.0, and 76.8%. Decreased disease-specific survival was not associated with nodal metastasis, but rather with high grade [moderately differentiated, hazard ratio (HR) 37.2, 95% confidence interval (CI) 2.7-518.8; poorly differentiated, HR 94.2, 95% CI 4.9-1,794.4; reference, well differentiated], and minority race (Asian, HR 30.2, 95% CI 3.1-291.7; Black, HR 60.1, 95% CI 2.1-1,027.9; reference, White). CONCLUSIONS: Pancreatic neuroendocrine tumors≤2 cm are increasingly common, and the most significant predictors of disease-specific survival are grade and race. The SEER database excludes PNETs considered to be benign, and rates of extrapancreatic extension, nodal metastasis, and distant metastasis are overestimated. Small size, however, does not preclude malignant behavior.

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.

Incidence rates of exocrine and endocrine pancreatic cancers in the United States.

Descriptive studies of pancreatic cancer incidence have been sparse particularly in terms of tumor histology and stage. The purpose of this study was to examine the incidence rate trends of exocrine and endocrine pancreatic cancers by demographic and tumor characteristics using data from the Surveillance, Epidemiology, and End Results (SEER) program from 1977 to 2005. During this period, the incidence of exocrine pancreatic cancer generally decreased whereas the incidence of endocrine pancreatic cancer increased. This difference in trends by histology was evident across age, gender, and racial groups. It was also evident among different racial/ethnic groups using data from 1992 to 2005. Variation in trends was observed by stage. The incidence of exocrine cancers declined for all stages except regional. Endocrine cancer incidence increased for all tumor stages, and the increase was most prominent for localized tumors. When exocrine tumors were stratified by tumor subsite, the incidence of cancers in the tail and body regions increased while the incidence in other regions decreased. While better detection and classification of tumors through improved diagnostic procedures may be related to these changing trends, etiologic factors warrant study.

Population-based study of islet cell carcinoma.

BACKGROUND: We examine the epidemiology, natural history, and prognostic factors that affect the duration of survival for islet cell carcinoma by using population-based registries. METHODS: The Surveillance, Epidemiology, and End Results (SEER) Program database (1973-2003 release, April 2006) was used to identify cases of islet cell carcinoma by histology codes and tumor site. RESULTS: A total of 1310 (619 women and 691 men) cases with a median age of 59 years were identified. The annual age-adjusted incidence in the periods covered by SEER 9 (1973-1991), SEER 13 (1992-1999), and SEER 17 (2000-2003) were .16, .14, and .12 per 100,000, respectively. The estimated 28-year limited duration prevalence on January 1, 2003, in the United States was 2705 cases. Classified by SEER stage, localized, regional, and distant stages corresponded to 14%, 23%, and 54% of cases. The median survival was 38 months. By stage, median survival for patients with localized, regional, and distant disease were 124 (95% CI, 80-168) months, 70 (95% CI, 54-86) months, and 23 (95% CI, 20-26) months, respectively. By multivariate Cox proportional modeling, stage (P < .001), primary tumor location (P = .04), and age at diagnosis (P < .001) were found to be significant predictors of survival. CONCLUSIONS: Islet cell carcinomas account for approximately 1.3% of cancers arising in the pancreas. Most patients have advanced disease at the time of diagnosis. Despite the disease's reputation of being indolent, survival of patients with advanced disease remains only 2 years. Development of novel therapeutic approaches is needed.

[Endocrine tumors of the pancreas (EPTs) in multiple endocrine neoplasia (MEN1): up-date on prognostic factors, diagnostic procedures and treatment]. / Les tumeurs endocrines du pancréas lors de la néoplasie endocrinienne multiple type 1 (NEM1): actualités sur les facteurs pronostiques, l'imagerie et le traitement.

Endocrine pancreatic tumors (EPTs) are uncommon tumors, representing 1-2% of all pancreatic neoplasms. They are categorized on the basis of their clinical features into functioning and non-functioning tumors. EPTs may be part of the multiple endocrine neoplasia type 1 (MEN 1), an autosomal dominant syndrome due to inactivating germline mutation of the menin gene. Somatic mutations of menin are present in about 20% of sporadic neoplasms, particularly gastrinomas and insulinomas. 30-75% of patients with MEN1 have EPTs. The most prevalent are the gastrinomas (20-60%), then the insulinomas (5-10%), the glucagonamas and VIPomas (6-10%), whereas the nonfunctioning EPTs are present in 20-40% of patients. The most important biochemical screening marker for EPTs is chromogranin A, as it increases in 50-80% of patients. The most important negative prognostic factors are the presence of metastases, the gross invasion of adjacent organs, the angioinvasion, the perineural invasion and an immunopositivity for Ki-67 > 2%. Among the different imaging techniques, echoendoscopy, computed tomography (CT) and magnetic resonance imaging (MRI) are indicated for the detection of the primary tumor, but (III)In-octreotide scintigraphy has the highest sensitivity for detecting metastases. The choice of treatment is still debated and is different when the tumor occurs as a part of the MEN syndrome. The surgical treatment is the first choice for insulinomas and is more controversial for gastrinomas. The medical treatment includes somatostatin analogues (SA), chemotherapy and interferon-alpha (IFN-alpha). SA seem to improve the symptoms and have an antiproliferative effect, the most striking effect being seen in patients with VIPomas. Chemotherapy, which is generally proposed as a combination of streptozotocin (STZ) and 5-fluorouracil (5-FU) or doxorubicin, is indicated when the tumors tend to grow. Interferon-alpha (IFN-alpha) stimulates the immune system, blocks the tumor cells in the G1/S-phase of the cell cycle, inhibits protein and hormone synthesis and inhibits angionenesis. Treatment with IFN has been shown to produce symptomatic response in 40-60% of patients, a biochemical response in 30-60% and tumor shrinkage in 10-15%.

Endocrine tumors of the pancreas.

PURPOSE OF REVIEW: Neoplasms of the endocrine pancreas, commonly referenced as pancreatic islet cell tumors, are rare, often well differentiated endocrine neoplasms, whose biology remains poorly characterized. This article reviews the current clinical management of pancreatic islet cell tumors and describes the molecular events that have been studied to guide future therapies of these peculiar neoplasms. RECENT FINDINGS: While some islet cell tumors arise in association with the MEN-1 syndrome, the majority of these neoplasms are sporadic lesions whose underlying genetic and molecular events remain largely unknown. Recent work has identified changes in gene expression occurring in metastatic and non-metastatic islet cell tumors, which appear to correlate with the occurrence of lymph node and liver metastases. Epigenetic alterations of select tumor suppressor genes may influence patient survival, and the presence of gene promoter methylation may be used as a prognostic marker system. In addition, multiple molecular alterations, including changes in expression of cellular proteins with migratory, cell cycle or angiogenic functions, have been demonstrated to influence islet cell tumor growth, invasion and metastatic spread. SUMMARY: Understanding the molecular events underlying the biology of pancreatic islet cell tumors will aid the development of accurate prognostic markers and will guide improved therapeutic modalities in the future.

Two cases of pancreatic neoplasia in British ferrets (Mustela putorius furo).

Two six-year-old male neutered polecat ferrets (Mustela putorius furo) were presented for the investigation of acute collapse or periodic weakness and weight loss. While blood biochemistry revealed hypoglycaemia in both cases, diagnosis of an insulin-secreting neoplasia was confirmed by exploratory surgery in one case and supported by the use of an insulin assay in the other. Subsequent histopathological examination showed the former to be a pancreatic islet cell carcinoma and the latter to be a pancreatic islet cell adenoma. While neoplasia of the pancreas commonly affects ferrets in the USA, there appears to be only one previous report from the UK.

Ductulo-insular pancreatic endocrine neoplasms: clinicopathologic analysis of a unique subtype of pancreatic endocrine neoplasms.

Pancreatic neoplasms with mixed ductal and endocrine components are a heterogeneous group of tumors. The least recognized of these are pancreatic endocrine tumors (PETs) displaying benign-appearing tumor-associated ductules. To characterize these ductulo-insular pancreatic endocrine tumors (DI-PETs), we reviewed a series of 92 resected PETs. To be considered as a DI-PET we required the presence and tight intermingling of ductules with the dominant endocrine component (including the presence of ductulo-insular units). A total of 15 PETs fulfilled our criteria (16.3%). The average age of the DI-PET patients was similar to typical PETs (54 years vs 56 years). These tumors were smaller and more often insulin positive than typical PETs (p <0.05). Diffuse stromal fibrosis was more frequent in DI-PETs (11 of 15; 73.3.7%) compared with PETs (8 of 72; 11.1%) (p <0.05). The tumor-associated ductules were composed of cuboidal cells with dense eosinophilic cytoplasm and round nuclei without atypia or mitoses. They were positive for cytokeratin 7 and cytokeratin 19 and lacked any neuroendocrine markers. Reversibly, the endocrine component was negative for cytokeratin 7 and cytokeratin 19 and positive for neuroendocrine markers. Ultrastructural examination of ductulo-insular units confirmed a dual ductal and endocrine differentiation with amphicrine differentiation in one case. Follow-up was available in 12 cases with an average follow-up of 70.1 months (range 25-203 months). Ten patients are currently alive, and two patients died 81 and 158 months after surgery. We conclude that DI-PETs are not uncommon and that they are biologically similar to other PETs. We also hypothesize that the ductal cells develop by transdifferentiation of the endocrine cells.

[Non-functional islet-cell tumor: analysis of 237 cases].

OBJECTIVE: To summarize the clinical aspects of nonfunctional islet-cell tumor (NIT) reported in Chinese periodicals. METHODS: Articles in Chinese on NIT were screened from the Chinese Bio-Medical Database (1981.1 - 1999.10). Data of epidemiology, clinical manifestations, diagnosis, defferential diagnosis, and treatment of NIT were analyzed. RESULTS: 60 articles and 237 cases of NIT were selected. The female to male ratio was 2.9:1. Abdominal mass was the most common clinical symptom. It was difficult for the pre-operative diagnosis of NIT and differentiation from pancreatic tumor or retroperitoneal mass. The malignant rate of NIT was 35%. The five-year survival rate of malignant NIT was 53.1%. CONCLUSION: NIT is rare. It occurs more often in female than in male. The preoperative diagnostic rate is rather low. The prognosis of malignant NIT is favorable. Active treatment is strongly recommended.

Nonmucinous cystic pancreatic neoplasms.

This article discusses serous cystadenomas, the most common of the nonmucinous cystic lesions of the pancreas. These microcystic lesions were previously known as "glycogen-rich" cystadenomas because of the presence of glycogen within the cyst epithelium. A small percentage of these lesions are macrocystic, and it may be difficult to differentiate them from mucinous lesions; however, endoscopic ultrasound guided fine needle aspiration can provide diagnostic material from the cyst fluid. The second most common nonmucinous cyst, the islet cell tumor, is also discussed. These rare cystic tumors may or may not be accompanied by excess hormone production. The prognosis for the rare cystic tumors is good if they are resected successfully.

Studies of the incidence of spontaneous pancreatic tumours in ageing CD rats.

A survey of the incidence of spontaneous pancreatic tumours in CD rats was carried out. The survey revealed islet cell adenomas to be the most common of pancreatic tumours with a higher incidence in untreated males (11.7% in comparison to in females 5.5%). 9040 untreated and 24578 treated rats were included in this survey. These rats were from two year carcinogenicity studies over a 15 year period. The sex difference appeared also in the incidence of islet cell carcinoma (males 2.4% vs females 1%). The third type of tumour was exocrine adenoma with an incidence of 2% in males, 0.1% in females. The last type, which was very rare in this strain, was exocrine carcinoma (0.08% in males, 0.02% in females). The tumour incidences were more in rats killed at termination than in those died or killed earlier during the study suggesting a late onset of these tumours. Exocrine carcinoma was rarest of all pancreatic tumours. In contrast to man, rat pancreatic tumours were not life-threatening in rats, except for exocrine carcinoma. Pancreatic tumours are somewhat age-related as they were very rare in young rats and appeared mainly in rats over 70 weeks of age. Cystic exocrine adenoma, cystic or duct exocrine adenocarcinoma reported in man, were not seen in rats. Exocrine tumours are fatal tumours in man with very poor prognosis. Pancreatic carcinomas in rats mostly showed only local invasion. On very rare occasions they showed metastasis in to liver, lung and bone marrow. Ductal/cystic exocrine carcinoma of man showed metastasis to liver, peripancreatic lymph nodes, lymphatics, skeletal muscle and the lung. Exocrine adenocarcinoma in man was twice as common in males as in females, comparable to the general incidence of pancreatic tumours in rats. Islet cell tumours in man show no clear difference between males and females which is in contrast to rats. Both in man and in rats pancreatic tumours appear to occur in the latter half of life span.

Thin-section contrast-enhanced computed tomography accurately predicts the resectability of malignant pancreatic neoplasms.

A prospective diagnostic study was designed to determine the ability of thin-section contrast-enhanced computed tomography (CT) to predict the resectability of malignant neoplasms of the pancreatic head. Patients with a presumed resectable pancreatic neoplasm referred during a 21-month period were studied with abdominal CT performed at 1.5-mm section thickness and 5-mm slice interval during the bolus phase of intravenous contrast enhancement. CT criteria for resectability included the absence of extrapancreatic disease, no evidence of arterial encasement, and a patent superior mesenteric-portal venous confluence. Of 145 patients evaluated, 42 were considered to have resectable tumors by CT criteria, and 37 (88%) underwent potentially curative pancreaticoduodenectomy. Six patients were found to have a microscopically positive retroperitoneal resection margin; no patient had a grossly positive resection margin. Five (12%) of 42 patients were found at laparotomy to have unresectable, locally advanced or metastatic tumors. Thin-section contrast-enhanced CT is an essential component of the preoperative evaluation for pancreaticoduodenectomy and can prevent needles laparotomy in most patients with locally advanced or metastatic disease.