Pancreatic endocrine neoplasms: epidemiology and prognosis of pancreatic endocrine tumors

in Endocrine-Related Cancer

Pancreatic endocrine tumors (PETs) are uncommon tumors with an annual incidence <1 per 100 000 person-years in the general population. The PETs that produce hormones resulting in symptoms are designated as functional. The majority of PETs are non-functional. Of the functional tumors, insulinomas are the most common, followed by gastrinomas. The clinical course of patients with PETs is variable and depends on the extent of the disease and the treatment rendered. Patients with completely resected tumors generally have a good prognosis, and aggressive surgical therapy in patients with advanced disease may also prolong survival. The epidemiology, prognosis, and established and novel prognostic markers of PETs are reviewed.

Abstract

Pancreatic endocrine tumors (PETs) are uncommon tumors with an annual incidence <1 per 100 000 person-years in the general population. The PETs that produce hormones resulting in symptoms are designated as functional. The majority of PETs are non-functional. Of the functional tumors, insulinomas are the most common, followed by gastrinomas. The clinical course of patients with PETs is variable and depends on the extent of the disease and the treatment rendered. Patients with completely resected tumors generally have a good prognosis, and aggressive surgical therapy in patients with advanced disease may also prolong survival. The epidemiology, prognosis, and established and novel prognostic markers of PETs are reviewed.

Introduction

Pancreatic endocrine tumors (PETs) are uncommon neoplasms with an incidence of <1 per 100 000 person-years in population studies (Moldow & Connelly 1968, Buchanan et al. 1986, Eriksson et al. 1989, Watson et al. 1989, Carriaga & Henson 1995, Lam & Lo 1997, Halfdanarson et al. 2007). The incidence is higher in autopsy studies, ranging from 0.8 to 10% suggesting that these tumors frequently go unnoticed (Grimelius et al. 1975, Kimura et al. 1991). PETs comprise <3% of all pancreatic neoplasms (Cubilla & Hajdu 1975, Carriaga & Henson 1995, Fesinmeyer et al. 2005, Öberg & Eriksson 2005). Pancreatic endocrine tumors are generally more indolent than adenocarcinoma of the pancreas and have a better prognosis (Carriaga & Henson 1995, Fesinmeyer et al. 2005). The origin of these tumors is not fully known, but they may arise from pluripotent cells within the exocrine pancreas (Vortmeyer et al. 2004). PETs are frequently divided into two groups based on their functional status, but unfortunately there is no uniformly accepted definition of a functional PET. Patients with ‘functional’ PETs commonly manifest symptoms resulting from hormone production of the tumor, although these tumors may also produce hormones without the patient having any symptoms secondary to the overproduced hormones. For the purpose of this review, we consider patients without symptoms of hormone production to have non-functional tumors even though elevated levels of hormones are detected in the blood, but we acknowledge the limitations of that definition. Multiple studies have addressed the epidemiology and prognosis of PETs but there are few large population studies available. A substantial proportion of the literature regarding these tumors stems from case reports and case series, often involving highly selected groups of patients, limiting the generalizability of the results. The purpose of this article is to review the epidemiology and prognosis of PETs and the commonly used prognostic predictors. We briefly discuss the role of novel prognostic markers.

Pathology and classification of PETs

Pancreatic endocrine tumors are frequently graded and classified according to the WHO classification of endocrine tumors (Table 1; Solcia et al. 2000, Heitz et al. 2004, Klöppel et al. 2004). The diagnosis of PETs rests upon confirming the neuroendocrine nature of the malignant cells. These tumors can have heterogeneous microscopic findings, and immunohistochemical staining with markers, such as chromogranin A, synaptophysin, and neuron-specific enolase, can usually confirm the neuroendocrine origin. It can be difficult to accurately assess the degree of malignancy of pancreatic endocrine tumors but the current WHO classification provides guidance in that respect. Other features of the tumors, including local invasion and metastases to lymph nodes and distant organs, have also been helpful in defining their malignant nature. The European Neuroendocrine Tumor Society has recently published guidelines on the management of PETs (Falconi et al. 2006, de Herder et al. 2006, O'Toole et al. 2006).

Table 1

WHO classification of pancreatic endocrine tumors (Heitz et al. 2004)

1. Well-differentiated endocrine tumor
 1.1. Benign behavior
    Confined to the pancreas, <2 cm in diameter, ≤2 mitoses per 10 HPF, ≤2% Ki-67-positive cells, no angioinvasion, or perineural invasion
 1.2. Uncertain behavior
    Confined to the pancreas and one or more of the following features: ≥2 cm in diameter, >2 mitoses per 10 HPF, >2% Ki-67-positive cells, angioinvasion, perineural invasion
2. Well-differentiated endocrine carcinoma
    Low-grade malignant
    Gross local invasion and/or metastases
3. Poorly differentiated carcinoma
    High-grade malignant
    >10 mitoses per HPF

HPF, high-power field.

Epidemiology of PETs

Our knowledge of the epidemiology and risk factors for PETs is limited. While multiple studies have evaluated prognosis after diagnosis and therapy, few studies have focused on the epidemiology of PETs in defined populations. Not all studies separated PETs from other gastroenteropancreatic (GEP) neuroendocrine tumors, and thus provided limited information on tumors located in the pancreas. Other studies did not separate tumors with more indolent clinical behavior, such as insulinomas, from tumors showing more malignant behavior. Studies from large referral centers are common but may not represent the general population of patients with PETs. Furthermore, definitions of PETs have varied over the years, and until recently there was no consensus among pathologists regarding the diagnostic criteria or the criteria for malignant behavior.

The diverse nature of pancreatic tumors has been known for more than a century. It is of historical interest to review earlier reports on pancreatic tumors other than adenocarcinoma (Table 2). These studies have to be interpreted with caution as PETs were not well-defined entities at the time they were conducted, and there likely are substantial inaccuracies regarding the diagnoses. An autopsy study from the early twentieth century by Nicholls reports a case of pancreatic adenoma arising in the islet of Langerhans among 1514 patients (Nicholls 1902). Korpássy (1939) found four cases (0.8%) of macroscopic islet cell adenomas in 500 autopsies in 1938. Twenty-four cases (0.3%) of ‘benign islet cell neoplasms’ were observed in a series of 9158 consecutive autopsies reported by Frantz (1959). Warren et al. reported 24 islet cell tumors among 2708 autopsies of patients without diabetes and 18 tumors in 1858 diabetic patients, corresponding to a prevalence of 0.9% (Warren et al. 1966). Similar prevalence of 1.4% was reported by Becker where 62 ‘islet cell adenomas’ were found in 4280 autopsies (Becker 1971).

Table 2

Published autopsy series of islet cell tumors

Author, yearNumber of autopsiesNumber of islet cell tumorsPercent
Nicholls 1902 (Nicholls 1902)151410.07
Korpássy 1939 (Korpássy 1939)50040.8
Frantz 1959 (Frantz 1959)9158240.3
Warren 1966 (Warren et al. 1966)4566420.9
Becker 1971 (Becker 1971)4280621.4
Grimelius 1975 (Grimelius et al. 1975)1366110.8
Kimura 1991 (Kimura et al. 1991)
 Overall800202.5
 5 mm sectionsa60610
Lam 1997 (Lam & Lo 1997)11 472130.1

Sixty patients of the 800 were randomly selected for a thorough pathological examination with 5 mm sections of the pancreas.

More recent studies have used more accurate diagnostic criteria for PETs providing better information on the prevalence of PETs in patients undergoing autopsy (Table 2). Eleven ‘endocrine adenomas’ were found among 1366 Swedish autopsy cases (0.8%; Grimelius et al. 1975). No patients carried the diagnosis of pancreatic tumor in life or had evidence of hormone overproduction. Twenty PETs were found among 800 consecutive patients (2.5%) undergoing autopsy in a Japanese geriatric hospital (Kimura et al. 1991). None of these patients had symptoms of excessive hormone secretion prior to their death but one patient had a prior history of resected gastrinoma. A randomly selected subset of 60 patients had 5 mm thick sections of the pancreas examined thoroughly and 6 (10%) were found to have an occult PET (Kimura et al. 1991). This study suggests that PETs may be much more common than previously thought the patients are frequently asymptomatic. Another study described 53 Chinese patients with PETs and estimated the annual incidence of symptomatic PETs to be 0.2/100 000. Furthermore, 11 472 autopsies were reviewed yielding 13 PETs (0.11%) where only 4 patients were symptomatic antemortem. The autopsy prevalence of asymptomatic PETs was thus 0.08% and the annual incidence of symptomatic PETs 0.2/100 000 (Lam & Lo 1997).

Several studies on the incidence of PETs in defined populations have been performed (Table 3; Moldow & Connelly 1968, Buchanan et al. 1986, Eriksson et al. 1989, Watson et al. 1989, Carriaga & Henson 1995, Lam & Lo 1997, Lepage et al. 2004, Halfdanarson et al. 2007). Moldow & Connelly reported on all patients diagnosed with pancreatic tumors in Connecticut during 1957–1963 (Moldow & Connelly 1968). Out of the 856 pancreatic tumors, islet cell tumors accounted for <5%. In this study, no effort was made to distinguish between islet cell tumors and other rare pancreatic tumors. These tumor types in addition to PETs comprised 5% of all pancreatic tumors and the incidence was <1/100 000 (Moldow & Connelly 1968). A Swedish study reported an annual incidence of 0.4/100 000 (Eriksson et al. 1989) and a study from Northern Ireland found an annual incidence of 0.18/100 000 (Buchanan et al. 1986). The latter study was later updated reporting the incidence to be 0.23/100 000 (Watson et al. 1989).

Table 3

Population studies of pancreatic endocrine tumors

Author, yearNumber of PET cases in the populationAnnual incidence (all types)Comments
Moldow 1968 (Moldow & Connelly 1968)NR<1/100 000aAll cases in Connecticut, USA over a given period; PETs grouped with other rare tumors of the pancreas
Eriksson 1989 (Eriksson et al. 1989)840.4/100 000Well-defined region in Sweden; single referral hospital
Watson 1989 (Watson et al. 1989)940.23/100 000Well-defined Northern Irish population; same series as Buchanan et al. (1986)
Carriaga 1995 (Carriaga & Henson 1995)402<0.6/100 000aSEER data 1973–1987; exact incidence of PETs not provided
Lam 1997 (Lam & Lo 1997)530.2/100 000Referral to a single hospital in Hong Kong
Lepage 2004 (Lepage et al. 2004)47♀: 0.12/100 000Well-defined geographic region in France
♂: 0.19/100 000
Halfdanarson 2007 (Halfdanarson et al. 2007)1488♀: 0.2/100 000SEER data 1973–2000; all (neuro)endocrine tumors of the pancreas
♂: 0.3/100 000

NR, not reported; SEER, surveillance, epidemiology, and end results.

Accurate figure not provided for pancreatic endocrine tumors.

A recent French study using a population-based cancer registry found the overall annual crude incidence of malignant digestive endocrine tumors to be 1.15/100 000 for men and 0.91/100 000 for women. Pancreatic tumors accounted for 20.5% of all tumors in this cohort. The age-standardized incidence rates of PETs were 0.19/100 000 and 0.12/100 000 for men and women respectively, with a male-to-female ratio of 1.6 (Lepage et al. 2004). The incidence rates were low in persons under 40 years of age but increased steadily with age, reaching a peak at the age of 75 for men and 65 for women. A study using the Surveillance, Epidemiology, and End Results (SEER) registry data from 1973 to 1987 found the annual incidence of <0.6/100 000 for all age groups (Carriaga & Henson 1995). We have recently presented our data on all PETs in the SEER registry from 1973 to 2000. The overall annual incidence of PETs was 0.2/100 000 with the highest incidence (0.7–0.8/100 000) in the sixth and seventh decades with a slight male predominance (Halfdanarson et al. 2007). The incidence has increased over time, possibly related to increased awareness of these tumors among clinicians.

The frequency of the various subtypes of functional PETs has been described in several studies (Tables 4 and 5; Jacobsen et al. 1986, Cullen & Ong 1987, Eriksson et al. 1989, 1990, Watson et al. 1989, Service et al. 1991, Stamm et al. 1991). Insulinoma is the most frequently encountered functional PET and is usually a benign tumor and almost always located in the pancreas (Soga & Yakuwa 1994, Öberg & Eriksson 2005). The incidence of insulinoma in a well-defined population in Olmsted County in southeastern Minnesota was found to be 0.4 per 100 000 person-years (Service et al. 1991). Other investigators have reported annual incidence rates ranging from 0.07 to 0.12/100 000 in populations less well defined than in Olmsted County (Kavlie & White 1972, Cullen & Ong 1987, Eriksson et al. 1989, Watson et al. 1989). The annual incidence of malignant insulinoma in the SEER registry is 0.1/million (Halfdanarson et al. 2008). Gastrinoma is the second most commonly encountered functional PET but gastrinomas are also frequently found outside the pancreas (Soga & Yakuwa 1998a, Norton et al. 1999, Roy et al. 2000, Öberg & Eriksson 2005). Pancreatic gastrinomas may be more aggressive and frequently associated with liver metastases (Weber et al. 1995). Up to 30% of gastrinomas are associated with multiple endocrine neoplasia type 1 (MEN-1; Soga & Yakuwa 1998a, Roy et al. 2000). Gastrinoma is the most common functional PET seen in patients with MEN-1 and the prognosis may be worse than that in sporadic gastrinoma (Norton et al. 1999, Gibril et al. 2001, Norton 2005). Investigators in Denmark estimated the incidence of gastrinoma to be 0.5 per million per year (Jacobsen et al. 1986). A higher incidence of 2–4 per million has been found in Switzerland (Stamm et al. 1991). Other studies have reported an annual incidence of 0.5–1.2 cases per million (Eriksson et al. 1989, Watson et al. 1989). Our recent study using the SEER registry suggested an annual incidence of 0.1/million, but this may be a substantial underestimate given the way that SEER registers these tumors (Halfdanarson et al. 2008).

Table 4

Annual incidence (cases per million) of functional pancreatic endocrine neoplasms (PETs)

Author, yearCountryAnnual incidence of all PETsInsulinomaGastrinomaVIPomaGlucagonoma
Eriksson 1989 (Eriksson et al. 1989)Sweden41.11.20.640.04
Watson 1989 (Watson et al. 1989)Northern Ireland2.31.20.50.120.12
Service 1991 (Service et al. 1991)USA4
Cullen 1987 (Cullen & Ong 1987)New Zealand0.67
Jacobsen 1986 (Jacobsen et al. 1986)Denmark0.5
Stamm 1991 (Stamm et al. 1991)Switzerland2–4
Table 5

Subtypes of pancreatic endocrine tumors

Tumor typeAnnual incidence (cases per million)Percentage of all PETsAge (years)Percent malignantaPercent located in the pancreasPercent associated with MEN-1
Insulinoma0.7–4.030–4530–605–10>954–8
Gastrinoma0.5–4.016–3020–7040–9025–7012–22
VIPoma0.1–0.6<1020–80>5075–906–11
Glucagonoma≤0.1<1040–60>50>955–13
Somatostatinoma<0.1<530–80>6040–702–7
Other hormonesbRare<1Unknown
Non-functioningc (clinically silent)≤125–100d50–60>501000–21
0.1–10% in autopsy series

Data compiled from original articles and reviews (Grimelius et al. 1975, Creutzfeldt 1980, Weil 1985, Harris et al. 1987, Klöppel & Heitz 1988, Eriksson et al. 1989, Watson et al. 1989, Demeure et al. 1991, Kimura et al. 1991, Service et al. 1991, Soga & Yakuwa 1994, 1998b, 1999, Wermers et al. 1996, Lam & Lo 1997, Solcia et al. 1997, Smith et al. 1998, Jensen 1999, Roy et al. 2000, Tomassetti et al. 2001, Lepage et al. 2004, Mansour & Chen 2004, Öberg & Eriksson 2005, Warner 2005, Halfdanarson et al. 2007).

Malignant behavior based on the presence of invasion and metastases.

Data on these tumors are insufficient for further analysis.

Includes tumors that produce pancreatic polypeptide (PP).

The higher percentage comes from autopsy studies.

Epidemiological data on functioning PETs other than insulinoma and gastrinoma is sparse. Pancreatic endocrine tumors secreting vasoactive intestinal peptide (VIPoma) comprise <10% of all PETs and appear to be slightly more common in females according to some but not all reports (Klöppel & Heitz 1988, Solcia et al. 1997, Smith et al. 1998, Soga & Yakuwa 1998c, Peng et al. 2004). VIPomas are found in extrapancreatic locations in up to 25% of cases (Soga & Yakuwa 1998c). Two studies have reported the annual incidence of VIPoma to be 0.1–0.6 per million but the incidence of pancreatic VIPoma is not well known (Eriksson et al. 1989, Watson et al. 1989). Glucagon-secreting tumors (glucagonomas) represent <10% of PETs and are almost exclusively found within the pancreas (Klöppel & Heitz 1988, Solcia et al. 1997). Glucagonomas are very rare and their annual incidence has been estimated to be around or <0.1 per million (Eriksson et al. 1989, Watson et al. 1989). Glucagonomas may be slightly more common among females and patients are usually in their fifth decade at the time of diagnosis (Wermers et al. 1996, Soga & Yakuwa 1998b). PETs secreting somatostatin (somatostatinoma) are rare and account for <5% of all PETs and the true incidence of these tumors is unknown. Somatostatinomas typically present in the fifth and sixth decades of life with a slight female preponderance. Up to 50% of somatostatinomas arise outside the pancreas (Harris et al. 1987, Konomi et al. 1990, Soga & Yakuwa 1999). Pancreatic tumors secreting other hormones such as cholecystokinin, gastric inhibitory peptide, gastrin-releasing peptide (GRP), adrenocorticotrophin (ACTH), growth hormone-releasing hormone, PTHrP, and ghrelin are extremely rare and their incidence is unknown.

Non-functioning tumors comprise a substantial proportion of all PETs and have been reported to comprise 25–100% of all PETs. The annual incidence of symptomatic non-functional PETs has been estimated to be 0.07–0.1/100 000 (Eriksson et al. 1989, Watson et al. 1989). Autopsy studies have shown much higher incidence than that reported in clinical series (Kimura et al. 1991).

PETs associated with hereditary syndromes

Pancreatic endocrine tumors are commonly observed in MEN-1 and less frequently in von Hippel–Lindau disease (VHL). Cases of PET in association with the tuberous sclerosis complex and type 1 neurofibromatosis have also been reported but are rare (Tan et al. 1996, Verhoef et al. 1999, Fujisawa et al. 2002, Francalanci et al. 2003).

The MEN-1 syndrome is an autosomal dominant inherited disorder characterized by multiple endocrine and non-endocrine tumors (Brandi et al. 2001, Doherty 2005, Lakhani et al. 2007). The endocrine tumors most frequently described in patients with MEN-1 include parathyroid adenomas, pituitary adenomas, and PETs. Multiple other tumors of varying penetrance have been reported in association with MEN and include tumors of the adrenal glands, carcinoid tumors, angiofibroma, collagenoma, and lipoma. The penetrance of PETs in MEN-1 patients ranges from 30 to 75% and these tumors are frequently multifocal and metastatic at the time of diagnosis (Vasen et al. 1989, Skogseid et al. 1991, Le Bodic et al. 1996, Burgess et al. 1998a,b). Gastrinomas are the most commonly encountered PETs, followed by non-functioning tumors and insulinomas (Brandi et al. 2001, Gibril & Jensen 2004, Triponez et al. 2006). A recent study suggested that non-functioning tumors were more common than gastrinomas in MEN-1 patients (Triponez et al. 2006). PETs are a major cause of morbidity and mortality in patients with MEN-1, but discussion of screening and treatment of these patients is outside the scope of this review (Wilkinson et al. 1993, Doherty et al. 1998, Dean et al. 2000). VHL disease is an autosomal dominant tumor predisposition syndrome caused by a germ line mutation in the VHL gene (Lonser et al. 2003). The typical features of VHL disease include retinal and brain hemangioblastoma, renal cell carcinoma, renal cysts, pheochromocytoma, and pancreatic tumors and cysts (Lonser et al. 2003). Pancreatic endocrine tumors are found in 9.5–17% of patients with VHL disease (Binkovitz et al. 1990, Libutti et al. 1998, Hammel et al. 2000, Blansfield et al. 2007). The PETs associated with VHL disease are virtually always non-functional (Blansfield et al. 2007).

Prognosis following resection

Functional and non-functional tumors

Patients with PETs generally have a much better prognosis than those with pancreatic adenocarcinoma. Recent studies using the SEER database have reported improved survival after resection or a median overall survival of 58–97 months compared with 15–21 months in patients not undergoing surgery, although the number of patients with information regarding the surgery was small (Fesinmeyer et al. 2005, Halfdanarson et al. 2007). Numerous retrospective reports on PETs have been published, which provide valuable information about the mode of presentation and the prognosis of patients with these tumors, but there is marked heterogeneity among the patient populations studied as well as a large potential for referral bias, decreasing the generalizability of the results (Tables 6–8; Cubilla & Hajdu 1975, Kent et al. 1981, Broughan et al. 1986, Eckhauser et al. 1986, Legaspi & Brennan 1988, Thompson et al. 1988, Venkatesh et al. 1990, Service et al. 1991, Grama et al. 1992, Cheslyn-Curtis et al. 1993, Evans et al. 1993, White et al. 1994, Closset et al. 1996, Lo et al. 1996, La Rosa et al. 1996, Madura et al. 1997, Phan et al. 1997, 1998, Furukawa et al. 1998, Madeira et al. 1998, Bartsch et al. 2000, Hellman et al. 2000, Matthews et al. 2000, Yang et al. 2000, Corleto et al. 2001, Solorzano et al. 2001, Chu et al. 2002, Hochwald et al. 2002, Sarmiento et al. 2002, Gullo et al. 2003, Norton et al. 2003, Dralle et al. 2004, Guo et al. 2004, Lepage et al. 2004, Liang et al. 2004, Pape et al. 2004, Jarufe et al. 2005, Kang et al. 2005, Kouvaraki et al. 2005, Panzuto et al. 2005, Tomassetti et al. 2005, House et al. 2006, Kazanjian et al. 2006, Schurr et al. 2007).

Table 6 lists the studies of patients with both functional and non-functional tumors, who have undergone resection. The extent of the disease and the completeness of resection were major predictors of survival in most of these series (Legaspi & Brennan 1988, Thompson et al. 1988, Lo et al. 1996, Phan et al. 1997, Madeira et al. 1998, Chu et al. 2002, Hochwald et al. 2002, Lepage et al. 2004, Pape et al. 2004, Panzuto et al. 2005, Tomassetti et al. 2005, House et al. 2006). Several studies have suggested that the functional status of the tumors may affect prognosis. Functional tumors have been reported to have a better prognosis than non-functional tumors (Thompson et al. 1988, Phan et al. 1998, Sarmiento et al. 2002). Other studies have either reported worse prognosis of functional tumors or no effect of functional status on prognosis (Cubilla & Hajdu 1975, White et al. 1994). We have recently reported our analysis of the SEER data on PETs where functional tumors had a better prognosis after adjusting for other predictors such as age and stage. We also found that prognosis has improved with time and the improvement does not seem to be explained by stage migration. It is possible that more aggressive surgical therapy or improved medical care has resulted in better prognosis (Halfdanarson et al. 2007).

Table 6

Selected studies of both functional and non-functional pancreatic endocrine tumors

Study (author, year)Number of patientsNumber (%) of functioning tumorsNumber (%) insulinomasNumber of patients with metastases at diagnosis (%)SurvivalFactors adversely affecting overall survival or disease-free survival
Cubilla et al. 1975 (Cubilla & Hajdu 1975)3012 (34)4 (13)LN: 19 (63)5-OS: 57%Functional tumor
Liver: 21 (70)MS: 4.3 (N) and 2.8 (F) years
Broughan et al. 1986 (Broughan et al. 1986)8463 (75)41 (49)Liver and/or LN: 39 (46%)5-OS: 63.1% (N), 68.4% (G), 96.9 (I)Non-insulinoma or non-functionala
Phan et al. 1998 (Phan et al. 1998)125b (including 86 PETs)64 of all tumors (52)35 (28)NR5-OS: 65% (all), 77% (F), 52% (N)Non-functional tumors, positive margins, malignant tumorsa
Sarmiento et al. 2002 (Sarmiento et al. 2002)299 (31)3 (10)LN: 16 (55) Liver: 1 (3)5-OS: 81% (all), 100% (F), 70% (N)Non-functional, positive lymph nodesa
White et al. 1994 (White et al. 1994)2819 (68)3 (11)44% (N) 53% (NF)DFS at 2 years: 67% (N) and 40% (F)No difference between functioning and non-functioning tumorsa
Jarufe et al. 2005 (Jarufe et al. 2005)4424 (55)16 (36)22 (50)5-OS: 74.4%Metastases (multivariate analysis)
Thompson et al. 1988 (Thompson et al. 1988)5831 (54)8 (14)LN: 25 (43) Liver: 19 (33)5-OS: 42%Liver metastases, non-functional tumor (versus gastrinoma)a
Panzuto et al. 2005 (Panzuto et al. 2005)156b (including 67 PETs)26 (39)1 (1.5)LN: 6 (9) Liver: 28 (42) Extra-hepatic: 11 (16)5-OS: 62%Poorly differentiated tumors, distant metastases (multivariate analysis)
Legaspi et al. 1988 (Legaspi & Brennan 1988)3311 (33)0Distant metastases: 16 (48)3-year survival 76%Incomplete resection or residual tumora
Lepage et al. 2004 (Lepage et al. 2004)47NRNRNR5-OS: 42%Metastatic disease and advanced age (multivariate analysis)
Venkatesh et al. 1990 (Venkatesh et al. 1990)9855 (56)7 (7)47 (48)Mean survival 42.7±49 monthsNon-functional tumorsa metastatic disease and advanced age (multivariate analysis)
Tomassetti et al. 2005 (Tomassetti et al. 2005)8331 (37)7 (8)LN: 47 (60) Liver: 27 (33)MS: 90 months 5-OS: 55.3%Liver and lymph node metastases at diagnosis and incomplete resection, MEN-1a
Chu et al. 2002 (Chu et al. 2002)5021 (42)6 (12)Liver: 29 (58) Synchronous liver metastasesMS 40 months 5-OS: 36%Incomplete resection and liver metastases, less aggressive treatment of liver metastasesa
Lo et al. 1996 (Lo et al. 1996)6430 (47)4 (6)LN: 38 (59) Liver: 39 (61)3-year survival: curative resection: 80%, non-curative resection 62%Liver metastases, non-curative resectiona
Madeira et al. 1998 (Madeira et al. 1998)82b (including 62 PETs)38 (46)3 (4)LN: 52 (83) Liver: 49 (60) (among all 82 patients)5-OS: No liver metastases 100% Liver metastases 40%Liver metastases, poor differentiation and incomplete resection (multivariate analysis)
Pape et al. 2004 (Pape et al. 2004)254b (including 73 PETs)53 (32)6 (8)53 (73)MS: 47 months 5-OS: 42.9%Metastases at diagnosis and incomplete resectiona
Hochwald et al. 2002 (Hochwald et al. 2002)13647 (35)21 (15)NRDFS after curative resection: 110 months (N) and 152 months (F)High mitotic rate (DSS), presence of tumor necrosis, LN or liver metastases (DFS) (multivariate analysis)
House et al. 2006 (House et al. 2006)318 (26)1 (3)100MS: resection of primary tumor and liver metastases: 78 months (5-OS: 65%)Incomplete resection
Resection of primary tumor only: 17 months
Kazanjian et al. 2006 (Kazanjian et al. 2006)7020 (29)16 (23)LN: 21 (57)c Liver: 9 (24)c5-OS: 89%Malignant tumors (neuroendocrine carcinoma)
Norton et al. 2003 (Norton et al. 2003)2011 (55)d1 (5)LN: 14 (70)5-OS: 80%NR
Liver: 8 (40)
Hellman et al. 2000 (Hellman et al. 2000)317 (23)NRLN: 10 (32) Liver: 10 (32)5-OS: 75%NR
Corleto et al. 2001 (Corleto et al. 2001)98a (including 41 PETs)18 (44)5 (12)NRNRNR
Schurr et al. 2007 (Schurr et al. 2007)6219 (31) Liver: 16 (26)

DFS, disease-free survival; DSS, disease-specific survival; F, functional PET; G, gastrinoma; I, insulinoma; LN, lymph nodes; MS, median survival; 5-OS, 5-year overall survival; N, non-functional PET; NR, not reported; NS, not significant.

Univariate analysis (results of univariate analyses are not reported where results of multivariate analyses are provided).

The study included both pancreatic and extrapancreatic tumors.

The number patients with metastatic lesions relates to the 37 patients with neuroendocrine carcinoma.

Out of 11 functional tumors, 10 were gastrinomas.

Taken together, these studies of heterogeneous cohorts of patients with both functional and non-functional tumors have not consistently shown functional status to be a prognostic factor in terms of survival when the benign insulinomas have been excluded. The heterogeneity of the studies makes all comparisons difficult. Ninety percent of insulinomas are benign and have excellent prognosis after resection (Service et al. 1991). Patients with gastrinoma seem to have a better survival than those with other malignant and functional PETs, especially after surgery with curative intent (Norton et al. 1999). As expected, patients with more advanced and metastatic diseases as well as those with residual disease following resection had shorter survival.

Non-functional tumors

Several studies have been limited to non-functional PETs (Table 7; Kent et al. 1981, Eckhauser et al. 1986, Cheslyn-Curtis et al. 1993, Evans et al. 1993, Closset et al. 1996, La Rosa et al. 1996, Madura et al. 1997, Furukawa et al. 1998, Bartsch et al. 2000, Matthews et al. 2000, Yang et al. 2000, Solorzano et al. 2001, Gullo et al. 2003, 2004, Liang et al. 2004, Kang et al. 2005). Similar to the studies combining functional and non-functional tumors, the presence of distant metastases and incomplete resection predict worse survival. The 5-year overall survival ranges from 26 to 58% and appears lower than those in the series combining both functional and non-functional tumors. However, the heterogeneity among the studies and the potential for selection bias make any comparison problematic (Dralle et al. 2004, Kouvaraki et al. 2005). Non-functional PETs seem to have inferior prognosis when compared with functional PETs, even after adjusting known prognostic factors such as age, stage, and grade (Halfdanarson et al. 2007).

Table 7

Selected studies of non-functional pancreatic endocrine tumors

Study (author, year)Number of patientsMetastasis at diagnosis (%)SurvivalFactors adversely affecting survival
Kent et al. 1981 (Kent et al. 1981)2518 (72)3- and 5-year OS: 60 and 44%NR
Liver 11 (44)
Eckhauser et al. 1986 (Eckhauser et al. 1986)119 (82)Mean survival: 23 months (4–72 months)No predictors identified
Liver: 5 (45)
LN: 7 (64)
Evans et al. 1993 (Evans et al. 1993)7337 (51)5-year OS: 50%Metastatic disease and incomplete resectiona
Cheslyn-Curtis et al. 1993 (Cheslyn-Curtis et al. 1993)20Liver: 5 (25)Median survival: Curative resection: 42 months
LN: 5 (25)No curative resection: 32 months
La Rosa et al. 1996 (La Rosa et al. 1996)6134 (56)Mean survival (months): Increased risk: 50.7 Well differentiated: 44.2 Poorly differentiated: 3.7Capsular penetration, distant metastases, vascular microinvasion, and high Ki-67 proliferative indexa
Matthews et al. 2000 (Matthews et al. 2000)286 (21)2-year survival: node negative 77.8%, node positive 71.4 and metastatic 36.4Liver metastasesa
Bartsch et al. 2000 (Bartsch et al. 2000)17LN: 15 (83) Distant: 6 (33)5- and 10-year OS: 65.4% and 49.1%. 5-year OS 100% in the completely resected patients versus 14.3% in patients treated with palliative intentIncomplete resectiona
Solorzano et al. 2001 (Solorzano et al. 2001)163101 (62)5-year OS: 43% (77% in patients with localized and resected disease, 16% in patients with metastatic disease and no resection)Incomplete resection, no anti-cancer therapy and age >65 years (multivariate analysis)
Gullo et al. 2003 (Gullo et al. 2003)18469 (38)5-year OS: resected 76.9%, not resected 28.6%Metastatic disease, incomplete resection, symptomatic at diagnosis and tumor >3 cma
Liang et al. 2004 (Liang et al. 2004)436 (14)5- and 10-year OS: 58 and 29%Incomplete resection (multivariate analysis)
Kang et al. 2005 (Kang et al. 2005)197 (37)5-year OS: 32% (curative resection 90%)Metastases, unresectable disease, macroscopic invasiona
Guo et al. 2004 (Guo et al. 2004)41 (all patients had resection)4 (10)NRNR
Only LN metastasesTumors recurred in three patients following enucleation
Furukawa et al. 1998 (Furukawa et al. 1998)164 (25) LN: 2 (13) Liver: 2 (13)5-year OS: 83%Both patients with liver metastasis died secondary to their malignancy
Yang et al. 2000 (Yang et al. 2000)16LN: 8 (50) Liver: 2 (13)All patients alive after a mean follow-up time of 5.3 years (one with recurrent disease)NR
Madura et al. 1997 (Madura et al. 1997)14LN: 7 (50)Median survival 31.2 monthsLN metastases

LN, lymph nodes; NR, not reported; OS, overall survival.

Univariate analysis.

La Rosa et al. (1996) studied 61 patients with non-functional PETs. The tumors were considered malignant if there was a direct invasion into adjacent tissues or organs or if distant metastases were present. Multiple tumor characteristics predicted malignant behavior in a univariate analysis, including tumor diameter, vascular and perineural invasion, the presence of mitoses, nuclear atypia, and high proliferative index (>2%) as evaluated by Ki-67 immunohistochemical staining. The tumors were classified according to the histological features and Ki-67 proliferative index (Ki-67 PI) into four groups. Malignant tumors were also classified as poorly differentiated based on the appearance of the tumor cells and the presence of mitoses and areas of necrosis. All other PETs were classified into limited risk tumors (LRT) and increased risk tumors (IRT) based on the presence of either high Ki-67 PI (>2%) or vascular and/or perineural invasion. These subtypes were found to predict survival in a univariate analysis. LRT had better prognosis than IRT, which in turn had better prognosis than well-differentiated carcinomas. The poorly differentiated carcinomas had the worst prognosis. Even though capsular penetration, the presence of distant metastases, vascular microinvasion, and high Ki-67 PI all were found to adversely affect prognosis in a univariate analysis, the predictive value disappeared on a multivariate analysis (La Rosa et al. 1996).

Functional tumors

Several studies have focused solely on therapy and outcome of functional PETs (Table 8; Harrison et al. 1973, Lundstam et al. 1979, Danforth et al. 1984, Zeng et al. 1988, Service et al. 1991, Grama et al. 1992, Weber et al. 1995, Boukhman et al. 1998, Norton et al. 1999, Chen et al. 2002, Feng et al. 2002, Matthews et al. 2002, Grant 2005, Hirshberg et al. 2005, Starke et al. 2005, Kang et al. 2006). The largest study of insulinomas is a retrospective review by Service et al. from the Mayo Clinic in Rochester, spanning a 60-year period from 1927 to 1986 (Service et al. 1991). The study included 244 patients with insulinoma, including eight patients who were residents of Olmsted County in southeastern Minnesota. Thirteen patients (5.8%) had malignant insulinoma and 17 patients (7.6%) had MEN-1 in addition. As expected, the survival of patients with benign insulinoma was long following therapy and did not differ from expected survival of this population. The 10-year survival of patients with benign insulinoma was 78%. The factors adversely affecting the prognosis were malignant phenotype, advanced age, and patients diagnosed early in the study period. Patients with MEN-1 had shorter survival but the difference was not statistically significant. A more recent report from the same institution reported 225 patients with benign insulinoma, who underwent resection from 1982 to 2004 (Grant 2005). The outcome for this cohort of patients was excellent, with 98% of patients being cured with resection. The general good outcome of patients with insulinoma may thus skew the outcome results in a series where patients with insulinomas are grouped with patients having other functional or non-functional tumors.

Table 8

Selected studies of functional pancreatic endocrine tumors

Study (author, year)Number of patientsMedian age (years)Type of tumor (hormone produced)Malignant PET (%) number of patients with metastasesSurvivalFactors adversely affecting survival
Service et al. 1991 (Service et al. 1991)24447Insulinoma5.810-year OS: 78% for benign and 29% for malignant insulinomaMalignant insulinoma, advanced age
Grant 2005 (Grant 2005)225NRInsulinoma098% cure rateNR
Grama et al. 1992 (Grama et al. 1992)85NRInsulinoma 56%4710 OS: insulinoma 50%, malignant PET 28%Liver metastases, tumor >4 cm, complete resection
Norton et al. 1999 (Norton et al. 1999)151 (36 with pancreatic gastrinoma)48 (mean age)GastrinomaaNR5-year OS: 100% for sporadic gastrinoma, 42% free of disease at 5 yearsMEN-1 (lower disease-free survival)
Danforth et al. 1984 (Danforth et al. 1984)17Insulinoma17 (100) LN: 8 (47) Liver: 12 (70)NRNR
Hirshberg et al. 2005 (Hirshberg et al. 2005)10Insulinoma100Survival ranged from 4 months to 30 yearsNR
Matthews et al. 2002 (Matthews et al. 2002)20Gastrinoma: 8 (40) Insulinoma: 7 (35)Metastases: 5 (20)63% survival at a mean follow-up of 47 monthsNR
Glucagonoma: 4 (20)
VIPoma: 1 (5)
MEN: 3 (15)
Harrison et al. 1973 (Harrison et al. 1973)35InsulinomaMetastases: 3 (9%)NRMetastatic disease (two out of three patients died shortly after referral
Starke et al. 2005 (Starke et al. 2005)77InsulinomaMetastases 10 (13)2-year survival (metastatic only): 2.6 yearsNR
Chen et al. 2002 (Chen et al. 2002)74InsulinomaMalignant insulinoma: 2 (3%)All patients with benign insulinoma were cured. One patient with malignant insulinoma survived 18 yearsNR
Feng et al. 2002 (Feng et al. 2002)105InsulinomaMalignant insulinoma: 4 (4%)All patients with benign insulinoma were cured; three out of four patients with malignant insulinoma had relief of their symptoms and one diedNR
Boukhman et al. 1998 (Boukhman et al. 1998)67InsulinomaMalignant insulinoma: 10 (15%)89% underwent a successful operation (no survival data reported)NR
Kang et al. 2006 (Kang et al. 2006)14Insulinoma: 12 (86%) Gastrinoma: 2 (14%)Two malignant tumors (one insulinoma and one gastrinoma)10 year survival: 81% (one patient died of unrelated causes)NR
Lundstam et al. 1979 (Lundstam et al. 1979)12Insulinoma1 (8)All patients with benign insulinoma survivedNR
Zeng et al. 1988 (Zeng et al. 1988)110Insulinoma3 (3)Four cases with recurrent hypoglycemia; no information on the metastatic casesNR

LN, lymph nodes; NR, not reported; OS, overall survival.

Pancreatic and non-pancreatic gastrinoma.

Norton et al. 1999 reported their experience with 151 patients with gastrinoma undergoing surgery. Their cohort of patients included 36 (24%) patients with pancreatic gastrinoma, of which 19 had MEN-1. Gastrinoma was localized to the pancreas in 17 out of 123 (14%) patients with sporadic tumors. The 5- and 10-year disease-specific survival of all patients with sporadic gastrinoma was 100 and 95% respectively and 40% of the patients were free of disease at 5 years postoperatively. A previous study by the same investigators showed that survival was primarily determined by the presence of liver metastases (Weber et al. 1995). Gastrinomas associated with the Cushing syndrome seem to have a particularly poor prognosis (Maton et al. 1986, Ilias et al. 2005).

Other prognostic factors

Several investigators have attempted to evaluate previously established and novel prognostic factors in PETs. The WHO classification of PETs has been shown to be useful in predicting the clinical behavior of these tumors Heymann et al. (2000). Histological findings such as grade and the number of mitotic figures have been found to predict survival in a few studies. Hochwald et al. (2002) retrospectively evaluated 136 patients with low-grade or intermediate-grade PETs who had undergone tumor resection. After adjusting for other prognostic factors including the presence of distal metastases, tumor necrosis was found to be associated with shorter disease-free survival (DFS). Higher tumor mitotic rate (>2 per 50 high-power fields (HPFs)) was associated with shorter disease-specific survival (DSS). There was no difference in DFS or DSS between functional and non-functional tumors. The authors proposed a simple system for grading these tumors based on the presence of necrosis and the number of mitoses where patients with a low-grade tumor (<2 mitoses per 50 HPFs and no necrosis) had a significantly longer DFS and DSS (Hochwald et al. 2002). Other authors have suggested a prognostic model for well-differentiated gastroenteropathic neuroendocrine tumors (GEP-NET) using abnormal liver chemistries and urinary excretion of 5-HIAA, but the model has not been validated in patients with tumors limited to the pancreas (Formica et al. 2006). Proliferation markers such as Ki-67 immunohistochemistry have been found to predict prognosis in patients with PETs (Lloyd 1998). However, the results have not uniformly supported the prognostic value of increased Ki-67 expression, especially after adjusting for other known prognostic variables such as stage (La Rosa et al. 1996, Pelosi et al. 1996, 1997, Clarke et al. 1997, Gentil Perret et al. 1998, Lloyd 1998, Jorda et al. 2003, Goto et al. 2004, Böhmig et al. 2005, Panzuto et al. 2005, Couvelard et al. 2006). Recent studies have identified additional markers that may be of prognostic value. Positive staining for CK19 was shown to be a powerful prognostic factor predicting shorter survival, even after controlling for variables such as the number of mitoses, tumor necrosis, and Ki-67 expression (Deshpande et al. 2004). CK19 may not be predictive of survival in patients with non-functional PETs (La Rosa et al. 2007). Expression of CD10 has also been shown to predict worse survival, and a correlation was found between CD10 expression and the WHO classification where the more malignant tumors were more likely to express CD10 (Deschamps et al. 2006). There was also a correlation between positive CD10 staining and higher proliferative index, larger tumor size, and the presence of hepatic metastases. Loss of expression of CD99 has been suggested to predict worse outcome by some authors but not others (Goto et al. 2004, Ali et al. 2006) and expression of CD44 isoforms v6 and v9 may be indicative of more benign behavior and better prognosis in patients with PET (Imam et al. 2000).

With advances in genetic and molecular biology, multiple potential prognostic markers have been identified. These markers have not yet been validated in large cohorts of patients and have not found their way into routine clinical use. The molecular genetics of GEP tumors have been reviewed in detail elsewhere (Zikusoka et al. 2005). Certain chromosomal aberrations have been found more frequently in patients with metastatic PETs when compared with non-metastatic tumors. These aberrations involve multiple chromosomes, including 1,3,5,6,7,14,22 and the X chromosome (Speel et al. 1999, Barghorn et al. 2001a,b, Zhao et al. 2001, Guo et al. 2002a,b, Wild et al. 2002, Chen et al. 2003, 2004). Chromosomal instability as manifested by the number of aberrations per tumor has been shown to be an indicator for the development of metastases in patients with sporadic insulinoma, and loss of sex chromosomes may predict shorter survival in patients with functional and non-functional PETs (Missiaglia et al. 2002, Jonkers et al. 2005).

Methylation of tumor suppressor genes has been implicated as an important factor in the etiology of various tumors. House et al. have shown that silencing of multiple tumor suppressor genes by promoter hypermethylation is frequent in PETs and may be associated with more advanced tumor stage and shorter survival (House et al. 2003b). The most frequently silenced genes were RASSF1A, p16/INK4A, O6-MGMT, RAR-β, and hMLH1 (House et al. 2003b). The association between RASSF1A and p16/INK4A methylation and more advanced stage was confirmed by other authors (Liu et al. 2005). Methylation of hMLH1 has also been shown to result in microsatellite instability in patients with PETs and may be associated with a favorable prognosis (House et al. 2003a). Telomerase activity has also been suggested as being useful in the diagnosis of PETs, and it has been suggested that the presence of telomerase activity may predict an unfavorable outcome (Lam et al. 2000, Tang et al. 2002, Vezzosi et al. 2006).

Studies using gene expression analysis can be powerful tools for prognostication of various tumors. Several investigators have used gene expression analysis in tumor tissue from patients with PET using microarray methods (Maitra et al. 2003, Bloomston et al. 2004, Durkin et al. 2004, Hansel et al. 2004, Capurso et al. 2006, Couvelard et al. 2006). Numerous genes have been found to be either over- or underexpressed, and these findings have been validated with immunohistochemical studies and PCR studies for several of the overexpressed genes. Genes found to be overexpressed in metastatic PETs when compared with non-metastatic PETs include Met proto-oncogene, IGF-binding protein 3 gene (IGFBP-3) as well as various genes involved in angiogenesis, signal transduction, cell cycle control, and ion transport (Hansel et al. 2004, Couvelard et al. 2006). Other investigators using a different set of overexpressed genes did not show a significant difference in gene expression between primary and metastatic lesions (Capurso et al. 2006).

Angiogenesis is important for tumor growth and formation of metastases, and several studies have evaluated the prognostic role of angiogenesis markers and mediators. Expression of Vascular endothelial growth factor (VEGF) has been associated with more aggressive tumor growth, the presence of metastases, and shorter progression-free survival in patients with low-grade neuroendocrine tumors when compared with tumors not expressing VEGF (Hansel et al. 2003, Phan et al. 2006). Microvessel density (MVD) in PETs has also received attention recently and decreased MVD may be an adverse prognostic factor according to some studies but not others (Marion-Audibert et al. 2003, La Rosa et al. 2003, Tan et al. 2004, Couvelard et al. 2005, 2006, Takahashi et al. 2007).

Conclusions

Pancreatic endocrine tumors (PETs) are uncommon tumors thought to originate from pluripotent cells in the exocrine pancreas. PETs account for only 1–3% of all neoplasms of the pancreas and their clinical behavior is much more indolent than that of adenocarcinoma of the pancreas. PETs are uncommon tumors with an annual incidence of <0.4 cases per 100 000. Asymptomatic PETs appear to be much more common according to large autopsy studies and frequently are undiagnosed in life. Functioning PETs are rare except for insulinomas and gastrinomas. The prognosis of PET is much better than that of pancreatic adenocarcinoma, even though patients are frequently diagnosed with metastatic disease. Multiple studies have shown that metastatic tumor and incomplete resection portend worse prognosis. Aggressive resection of the primary tumor as well as metastatic lesions may improve survival. Functional tumors may have a better prognosis in some studies, which may partly be explained by the much more benign nature and the favorable prognosis of the hormonally active insulinomas. Patients with functional tumors may also be diagnosed at an earlier stage, especially if they present with classical symptoms of hormone overproduction. Other prognostic factors include higher proliferative rate as manifested by increased number of mitoses as well as tumor necroses but those histological features are not universally reported by pathologists. Novel prognostic factors include increased expression of Ki-67, overexpression of angiogenesis markers, chromosomal aberrations, and overexpression of various genes as identified on microarray studies. Given the heterogeneous nature of PETs, it is unlikely that there will be a prognostic model applicable to all subtypes of these uncommon tumors.

Acknowledgements

We thank Ricardo V Lloyd MD, PhD for reviewing the manuscript. Research support: Mayo Clinic SPORE in Pancreatic Cancer (P50 CA 102701). The authors declare that there is no conflict of interest that would prejudice the impartiality of this scientific work.

References

  • AliASerraSAsaSLChettyR2006The predictive value of CK19 and CD99 in pancreatic endocrine tumors. American Journal of Surgical Pathology3015881594.

  • BarghornAKomminothPBachmannDRutimannKSaremaslaniPMuletta-FeurerSPerrenARothJHeitzPUSpeelEJ2001aDeletion at 3p25.3–p23 is frequently encountered in endocrine pancreatic tumours and is associated with metastatic progression. Journal of Pathology194451458.

  • BarghornASpeelEJFarspourBSaremaslaniPSchmidSPerrenARothJHeitzPUKomminothP2001bPutative tumor suppressor loci at 6q22 and 6q23–q24 are involved in the malignant progression of sporadic endocrine pancreatic tumors. American Journal of Pathology15819031911.

  • BartschDKSchillingTRamaswamyAGerdesBCelikIWagnerHJSimonBRothmundM2000Management of nonfunctioning islet cell carcinomas. World Journal of Surgery2414181424.

  • BeckerV1971Pathologicoanatomical aspects of tumors with endocrine activity. Langenbecks Archiv für Chirurgie329426437.

  • BinkovitzLAJohnsonCDStephensDH1990Islet cell tumors in von Hippel–Lindau disease: increased prevalence and relationship to the multiple endocrine neoplasias. American Journal of Roentgenology155501505.

  • et alPresented at the 28th Annual Meeting of the American Association of Endocrine Surgeons

  • BloomstonMDurkinAYangIRojianiMRosemurgyASEnkmannSYeatmanTJZervosEE2004Identification of molecular markers specific for pancreatic neuroendocrine tumors by genetic profiling of core biopsies. Annals of Surgical Oncology11413419.

  • Le BodicMFHeymannMFLecomteMBergerNBergerFLouvelADe MiccoCPateyMDe MascarelABurtinF1996Immunohistochemical study of 100 pancreatic tumors in 28 patients with multiple endocrine neoplasia, type I. American Journal of Surgical Pathology2013781384.

  • BöhmigMPapeUFTilingNBerndtUMüller-NordhornJWillichSNWiedenmannB2005Prognostic factors in gastroenteropancreatic neuroendocrine tumors – a retrospective multivariate analysis. 23(Abstract 4086)

  • BoukhmanMPKaramJHShaverJSipersteinAEDuhQYClarkOH1998Insulinoma – experience from 1950 to 1995. Western Journal of Medicine16998104.

  • BrandiMLGagelRFAngeliABilezikianJPBeck-PeccozPBordiCConte-DevolxBFalchettiAGheriRGLibroiaA2001Guidelines for diagnosis and therapy of MEN type 1 and type 2. Journal of Clinical Endocrinology8656585671.

  • BroughanTALeslieJDSotoJMHermannRE1986Pancreatic islet cell tumors. Surgery99671678.

  • BuchananKDJohnstonCFO'HareMMArdillJEShawCCollinsJSWatsonRGAtkinsonABHaddenDRKennedyTL1986Neuroendocrine tumors. A European view. American Journal of Medicine811422.

  • BurgessJRGreenawayTMParameswaranVChallisDRDavidRShepherdJJ1998aEnteropancreatic malignancy associated with multiple endocrine neoplasia type 1: risk factors and pathogenesis. Cancer83428434.

  • BurgessJRGreenawayTMShepherdJJ1998bExpression of the MEN-1 gene in a large kindred with multiple endocrine neoplasia type 1. Journal of Internal Medicine243465470.

  • CapursoGLattimoreSCrnogorac-JurcevicTPanzutoFMilioneMBhaktaVCampaniniNSwiftSMBordiCDelle FaveG2006Gene expression profiles of progressive pancreatic endocrine tumours and their liver metastases reveal potential novel markers and therapeutic targets. Endocrine-Related Cancer13541558.

  • CarriagaMTHensonDE1995Liver, gallbladder, extrahepatic bile ducts, and pancreas. Cancer75171190.

  • ChenXCaiWYYangWPLiHW2002Pancreatic insulinomas: diagnosis and surgical treatment of 74 patients. Hepatobiliary & Pancreatic Diseases International1458461.

  • ChenYJVortmeyerAZhuangZHuangSJensenRT2003Loss of heterozygosity of chromosome 1q in gastrinomas: occurrence and prognostic significance. Cancer Research63817823.

  • ChenYJVortmeyerAZhuangZGibrilFJensenRT2004X-chromosome loss of heterozygosity frequently occurs in gastrinomas and is correlated with aggressive tumor growth. Cancer10013791387.

  • Cheslyn-CurtisSSitaramVWilliamsonRC1993Management of non-functioning neuroendocrine tumours of the pancreas. British Journal of Surgery80625627.

  • ChuQDHillHCDouglassHOJrDriscollDSmithJLNavaHRGibbsJF2002Predictive factors associated with long-term survival in patients with neuroendocrine tumors of the pancreas. Annals of Surgical Oncology9855862.

  • ClarkeMRBakerEEWeyantRJHillLCartySE1997Proliferative activity in pancreatic endocrine tumors: association with function, metastases, and survival. Endocrine Pathology8181187.

  • ClossetJDelhayeMSperdutoNRickaertFGelinM1996Nonfunctioning neuroendocrine tumors of the pancreas: clinical presentation of 7 patients. Hepatogastroenterology4316401644.

  • CorletoVDPanzutoFFalconiMCannizzaroRAngelettiSMorettiADelle FaveGFarinatiF2001Digestive neuroendocrine tumours: diagnosis and treatment in Italy. A survey by the Oncology Study Section of the Italian Society of Gastroenterology (SIGE). Digestive and Liver Disease33217221.

  • CouvelardAO'TooleDTurleyHLeekRSauvanetADegottCRuszniewskiPBelghitiJHarrisALGatterK2005Microvascular density and hypoxia-inducible factor pathway in pancreatic endocrine tumours: negative correlation of microvascular density and VEGF expression with tumour progression. British Journal of Cancer9294101.

  • CouvelardAHuJSteersGO'TooleDSauvanetABelghitiJBedossaPGatterKRuszniewskiPPezzellaF2006Identification of potential therapeutic targets by gene-expression profiling in pancreatic endocrine tumors. Gastroenterology13115971610.

  • CreutzfeldtW1980Endocrine tumors of the pancreas: clinical, chemical and morphological findings. Monographs in Pathology21208230.

  • CubillaALHajduSI1975Islet cell carcinoma of the pancreas. Archives of Pathology99204207.

  • CullenRMOngCE1987Insulinoma in Auckland 1970–1985. New Zealand Medical Journal100560562.

  • DanforthDNJrGordenPBrennanMF1984Metastatic insulin-secreting carcinoma of the pancreas: clinical course and the role of surgery. Surgery9610271037.

  • DeanPGvan HeerdenJAFarleyDRThompsonGBGrantCSHarmsenWSIlstrupDM2000Are patients with multiple endocrine neoplasia type I prone to premature death?World Journal of Surgery2414371441.

  • DemeureMJKlonoffDCKaramJHDuhQYClarkOH1991Insulinomas associated with multiple endocrine neoplasia type I: the need for a different surgical approach. Surgery1109981005.

  • DeschampsLHandra-LucaAO'TooleDSauvanetARuszniewskiPBelghitiJBedossaPCouvelardA2006CD10 expression in pancreatic endocrine tumors: correlation with prognostic factors and survival. Human Pathology37802808.

  • DeshpandeVFernandez-del CastilloCMuzikanskyADeshpandeAZukerbergLWarshawALLauwersGY2004Cytokeratin 19 is a powerful predictor of survival in pancreatic endocrine tumors. American Journal of Surgical Pathology2811451153.

  • DohertyGM2005Multiple endocrine neoplasia type 1. Journal of Surgical Oncology89143150.

  • DohertyGMOlsonJAFrisellaMMLairmoreTCWellsSAJrNortonJA1998Lethality of multiple endocrine neoplasia type I. World Journal of Surgery22581587.

  • DralleHKrohnSLKargesWBoehmBOBrauckhoffMGimmO2004Surgery of resectable nonfunctioning neuroendocrine pancreatic tumors. World Journal of Surgery2812481260.

  • DurkinAJBloomstonMYeatmanTJGilbert-BarnessECojitaDRosemurgyASZervosEE2004Differential expression of the Tie-2 receptor and its ligands in human pancreatic tumors. Journal of the American College of Surgeons199724731.

  • EckhauserFECheungPSVinikAIStrodelWELloydRVThompsonNW1986Nonfunctioning malignant neuroendocrine tumors of the pancreas. Surgery100978988.

  • ErikssonBÖbergKSkogseidB1989Neuroendocrine pancreatic tumors. Clinical findings in a prospective study of 84 patients. Acta Oncologica28373377.

  • ErikssonBSkogseidBLundqvistGWideLWilanderEÖbergK1990Medical treatment and long-term survival in a prospective study of 84 patients with endocrine pancreatic tumors. Cancer6518831890.

  • EvansDBSkibberJMLeeJEClearyKRAjaniJAGagelRFSellinRVFenoglioCJMerrellRCHickeyRC1993Nonfunctioning islet cell carcinoma of the pancreas. Surgery11411751182.

  • FalconiMPlockingerUKwekkeboomDJManfrediRKornerMKvolsLPapeUFRickeJGoretzkiPEWildiS2006Well-differentiated pancreatic nonfunctioning tumors/carcinoma. Neuroendocrinology84196211.

  • FengLSMaXXTangZZhaoYFYeXXXuPQ2002Diagnosis and treatment of insulinoma: report of 105 cases. Hepatobiliary & Pancreatic Diseases International1137139.

  • FesinmeyerMDAustinMALiCIDe RoosAJBowenDJ2005Differences in survival by histologic type of pancreatic cancer. 1417661773.

  • FormicaVNormanARCunninghamDWotherspoonASirohiBOatesJChongG2006The prognostic role of the WHO classification, urinary 5-hydroxyindoleacetic acid (u5HIAA) and liver function tests (LFTs) in metastatic neuroendocrine carcinomas (NECs) of the gastroenteropancreatic (GEP) tract. Journal of Clinical Oncology244092

  • FrancalanciPDiomedi-CamasseiFPurificatoCSantorelliFMGiannottiADominiciCInserraABoldriniR2003Malignant pancreatic endocrine tumor in a child with tuberous sclerosis. American Journal of Surgical Pathology2713861389.

  • Frantz VK 1959 Tumors of the pancreas. In Atlas of Tumor Pathology

  • FujisawaTOsugaTMaedaMSakamotoNMaedaTSakaguchiKOnishiYToyodaMMaedaHMiyamotoK2002Malignant endocrine tumor of the pancreas associated with von Recklinghausen's disease. Journal of Gastroenterology375967.

  • FurukawaHMukaiKKosugeTKanaiYShimadaKYamamotoJMizuguchiYUshioK1998Nonfunctioning islet cell tumors of the pancreas: clinical, imaging and pathological aspects in 16 patients. Japanese Journal of Clinical Oncology28255261.

  • Gentil PerretAMosnierJFBuonoJPBerthelotPChipponiJBaliqueJGCuilleretJDechelottePBoucheronS1998The relationship between MIB-1 proliferation index and outcome in pancreatic neuroendocrine tumors. American Journal of Clinical Pathology109286293.

  • GibrilFJensenRT2004Zollinger–Ellison syndrome revisited: diagnosis, biologic markers, associated inherited disorders, and acid hypersecretion. Current Gastroenterology Reports6454463.

  • GibrilFVenzonDJOjeaburuJVBashirSJensenRT2001Prospective study of the natural history of gastrinoma in patients with MEN1: definition of an aggressive and a nonaggressive form. Journal of Clinical Endocrinology8652825293.

  • GotoANikiTTeradoYFukushimaJFukayamaM2004Prevalence of CD99 protein expression in pancreatic endocrine tumours (PETs). Histopathology45384392.

  • GramaDErikssonBMartenssonHCedermarkBAhrenBKristofferssonARastadJObergKAkerstromG1992Clinical characteristics, treatment and survival in patients with pancreatic tumors causing hormonal syndromes. World Journal of Surgery16632639.

  • GrantCS2005Insulinoma. Best Practice & Research. Clinical Gastroenterology19783798.

  • GrimeliusLHultquistGTStenkvistB1975Cytological differentiation of asymptomatic pancreatic islet cell tumours in autopsy material. 365275288.

  • GulloLMiglioriMFalconiMPederzoliPBettiniRCasadeiRDelle FaveGCorletoVDCeccarelliCSantiniD2003Nonfunctioning pancreatic endocrine tumors: a multicenter clinical study. American Journal of Gastroenterology9824352439.

  • GuoSSAroraCShimoideATSawickiMP2002aFrequent deletion of chromosome 3 in malignant sporadic pancreatic endocrine tumors. Molecular and Cellular Endocrinology190109114.

  • GuoSSWuAYSawickiMP2002bDeletion of chromosome 1, but not mutation of MEN-1, predicts prognosis in sporadic pancreatic endocrine tumors. World Journal of Surgery26843847.

  • GuoKJLiaoHHTianYLGuoRXHeSGShenK2004Surgical treatment of nonfunctioning islet cell tumor: report of 41 cases. Hepatobiliary and Pancreatic Diseases International3469472.

  • .

  • HalfdanarsonTRabeKGRubinJPetersenGM2008Pancreatic Neuroendocrine Tumors (PNETS): Incidence, prognosis and recent trend toward improved survival. Annals of Oncology[in press]

  • HammelPRVilgrainVTerrisBPenfornisASauvanetACorreasJMChauveauDBalianABeigelmanCO'TooleD2000Pancreatic involvement in von Hippel–Lindau disease. The Groupe Francophone d'Etude de la Maladie de von Hippel–Lindau. Gastroenterology11910871095.

  • HanselDERahmanAHermansJde KrijgerRRAshfaqRYeoCJCameronJLMaitraA2003Liver metastases arising from well-differentiated pancreatic endocrine neoplasms demonstrate increased VEGF-C expression. Modern Pathology16652659.

  • HanselDERahmanAHouseMAshfaqRBergKYeoCJMaitraA2004Met proto-oncogene and insulin-like growth factor binding protein 3 overexpression correlates with metastatic ability in well-differentiated pancreatic endocrine neoplasms. Clinical Cancer Research1061526158.

  • HarrisGJTioFCruzABJr1987Somatostatinoma: a case report and review of the literature. Journal of Surgical Oncology36816.

  • HarrisonTSChildCGFryWJFloydJCJrFajansSS1973Current surgical management of functioning islet cell tumors of the pancreas. Annals of Surgery178485495.

  • HeitzPUKomminothPPerrenAKlimstraDSDayalYBordiCLechagoJCentenoBAKlöppelGPancreatic endocrine tumors: introductionDeLellisDALloydRVHeitzPUEngCPathology and Genetics of Tumours of Endocrine Organs. WHO Classification of Tumours2004IARC PressLyon, France:177182.

  • HellmanPAnderssonMRastadJJuhlinCKaracagilSErikssonBSkogseidBAkerstromG2000Surgical strategy for large or malignant endocrine pancreatic tumors. World Journal of Surgery2413531360.

  • de HerderWWNiederleBScoazecJYPauwelsSKloppelGFalconiMKwekkeboomDJObergKErikssonBWiedenmannB2006Well-differentiated pancreatic tumor/carcinoma: insulinoma. Neuroendocrinology84183188.

  • HeymannMFJoubertMNemethJFrancBVissetJHamyAle BorgneJle NeelJCMuratACordelS2000Prognostic and immunohistochemical validation of the Capella classification of pancreatic neuroendocrine tumours: an analysis of 82 sporadic cases. Histopathology36421432.

  • HirshbergBCochranCSkarulisMCLibuttiSKAlexanderHRWoodBJChangRKleinerDEGordenP2005Malignant insulinoma: spectrum of unusual clinical features. Cancer104264272.

  • HochwaldSNZeeSConlonKCColleoniRLouieOBrennanMFKlimstraDS2002Prognostic factors in pancreatic endocrine neoplasms: an analysis of 136 cases with a proposal for low-grade and intermediate-grade groups. Journal of Clinical Oncology2026332642.

  • HouseMGHermanJGGuoMZHookerCMSchulickRDCameronJLHrubanRHMaitraAYeoCJ2003aPrognostic value of hMLH1 methylation and microsatellite instability in pancreatic endocrine neoplasms. Surgery134902909.

  • HouseMGHermanJGGuoMZHookerCMSchulickRDLillemoeKDCameronJLHrubanRHMaitraAYeoCJ2003bAberrant hypermethylation of tumor suppressor genes in pancreatic endocrine neoplasms. Annals of Surgery238423431.

  • HouseMGCameronJLLillemoeKDSchulickRDChotiMAHanselDEHrubanRHMaitraAYeoCJ2006Differences in survival for patients with resectable versus unresectable metastases from pancreatic islet cell cancer. Journal of Gastrointestinal Surgery10138145.

  • IliasITorpyDJPacakKMullenNWesleyRANiemanLK2005Cushing's syndrome due to ectopic corticotropin secretion: twenty years' experience at the National Institutes of Health. Journal of Clinical Endocrinology9049554962.

  • ImamHErikssonBÖbergK2000Expression of CD44 variant isoforms and association to the benign form of endocrine pancreatic tumours. Annals of Oncology11295300.

  • JacobsenOBardramLRehfeldJF1986The requirement for gastrin measurements. Scandinavian Journal of Clinical and Laboratory Investigation46423426.

  • JarufeNPColdhamCOrugTMayerADMirzaDFBuckelsJABramhallSR2005Neuroendocrine tumours of the pancreas: predictors of survival after surgical treatment. Digestive Surgery22157162.

  • JensenRT1999Pancreatic endocrine tumors: recent advances. Annals of Oncology10170176.

  • JonkersYMHClaessenSMHPerrenASchmidSKomminothPVerhofstadAAHoflandLJde KrijgerRRSlootwegPJRamaekersFCS2005Chromosomal instability predicts metastatic disease in patients with insulinomas. Endocrine-Related Cancer12435447.

  • JordaMGhorabZFernandezGNassiriMHanlyANadjiM2003Low nuclear proliferative activity is associated with nonmetastatic islet cell tumors. Archives of Pathology and Laboratory Medicine127196199.

  • KangCMKimKSChoiJSLeeWJKimBR2005Experiences with nonfunctioning neuroendocrine neoplasms of the pancreas. Digestive Surgery22453458.

  • KangCMParkSHKimKSChoiJSLeeWJKimBR2006Surgical experiences of functioning neuroendocrine neoplasm of the pancreas. Yonsei Medical Journal47833839.

  • KavlieHWhiteTT1972Pancreatic islet beta cell tumors and hyperplasia: experience in 14 Seattle hospitals. Annals of Surgery175326335.

  • KazanjianKKReberHAHinesOJ2006Resection of pancreatic neuroendocrine tumors: results of 70 cases. Archives of Surgery141765770.

  • KentRBIIIvan HeerdenJAWeilandLH1981Nonfunctioning islet cell tumors. Annals of Surgery193185190.

  • KimuraWKurodaAMoriokaY1991Clinical pathology of endocrine tumors of the pancreas. Analysis of autopsy cases. Digestive Diseases and Sciences36933942.

  • KlöppelGHeitzPU1988Pancreatic endocrine tumors. 183155168.

  • KlöppelGPerrenAHeitzPU2004The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification. Annals of the New York Academy of Sciences10141327.

  • KonomiKChijiiwaKKatsutaTYamaguchiK1990Pancreatic somatostatinoma: a case report and review of the literature. Journal of Surgical Oncology43259265.

  • KorpássyB1939Die Basalzellenmetaplasie des Ausführungsgänge des Pankreas. Virchows Archiv. A: Pathology. Pathologische Anatomie303359373.

  • KouvarakiMASolorzanoCCShapiroSEYaoJCPerrierNDLeeJEEvansDB2005Surgical treatment of non-functioning pancreatic islet cell tumors. Journal of Surgical Oncology89170185.

  • LakhaniVTYouYNWellsSA2007The multiple endocrine neoplasia syndromes. Annual Review of Medicine58253265.

  • LamKYLoCY1997Pancreatic endocrine tumour: a 22-year clinico-pathological experience with morphological, immunohistochemical observation and a review of the literature. European Journal of Surgical Oncology233642.

  • LamKYLoCYFanSTLukJM2000Telomerase activity in pancreatic endocrine tumours: a potential marker for malignancy. Molecular Pathology53133136.

  • LegaspiABrennanMF1988Management of islet cell carcinoma. Surgery10410181023.

  • LepageCBouvierAMPhelipJMHatemCVernetCFaivreJ2004Incidence and management of malignant digestive endocrine tumours in a well defined French population. Gut53549553.

  • LiangHWangPWangXNWangJCHaoXS2004Management of nonfunctioning islet cell tumors. World Journal of Gastroenterology1018061809.

  • LibuttiSKChoykePLBartlettDLVargasHWaltherMLubenskyIGlennGLinehanWMAlexanderHR1998Pancreatic neuroendocrine tumors associated with von Hippel–Lindau disease: diagnostic and management recommendations. Surgery12411531159.

  • LiuLBroaddusRRYaoJCXieSWhiteJAWuTTHamiltonSRRashidA2005Epigenetic alterations in neuroendocrine tumors: methylation of RAS-association domain family 1, isoform A and p16 genes are associated with metastasis. Modern Pathology1816321640.

  • LloydRV1998Utility of Ki-67 as a prognostic marker in pancreatic endocrine neoplasms. American Journal of Clinical Pathology109245247.

  • LoCYvan HeerdenJAThompsonGBGrantCSSoreideJAHarmsenWS1996Islet cell carcinoma of the pancreas. World Journal of Surgery20878884.

  • LonserRRGlennGMWaltherMChewEYLibuttiSKLinehanWMOldfieldEH2003von Hippel–Lindau disease. Lancet36120592067.

  • LundstamSLundholmKScherstenT1979A ten-year material of insulinoma: diagnosis and surgical treatment. Scandinavian Journal of Gasteroenterology14653656.

  • MadeiraITerrisBVossMDenysASauvanetAFlejouJFVilgrainVBelghitiJBernadesPRuszniewskiP1998Prognostic factors in patients with endocrine tumours of the duodenopancreatic area. Gut43422427.

  • MaduraJACummingsOWWiebkeEABroadieTAGouletRLJrHowardTJ1997Nonfunctioning islet cell tumors of the pancreas: a difficult diagnosis but one worth the effort. American Surgeon63573578.

  • MaitraAHanselDEArganiPAshfaqRRahmanANajiADengSGeradtsJHawthorneLHouseMG2003Global expression analysis of well-differentiated pancreatic endocrine neoplasms using oligonucleotide microarrays. Clinical Cancer Research959885995.

  • MansourJCChenH2004Pancreatic endocrine tumors. Journal of Surgical Research120139161.

  • Marion-AudibertAMBarelCGouysseGDumortierJPilleulFPourreyronCHervieuVPoncetGLombard-BohasCChayvialleJA2003Low microvessel density is an unfavorable histoprognostic factor in pancreatic endocrine tumors. Gastroenterology12510941104.

  • MatonPNGardnerJDJensenRT1986Cushing's syndrome in patients with the Zollinger–Ellison syndrome. New England Journal of Medicine31515.

  • MatthewsBDHenifordBTReardonPRBrunicardiFCGreeneFL2000Surgical experience with nonfunctioning neuroendocrine tumors of the pancreas. American Surgeon6611161122.

  • MatthewsBDSmithTIKercherKWHolderWDJrHenifordBT2002Surgical experience with functioning pancreatic neuroendocrine tumors. American Surgeon68660666.

  • MissiagliaEMoorePSWilliamsonJLemoineNRFalconiMZamboniGScarpaA2002Sex chromosome anomalies in pancreatic endocrine tumors. International Journal of Cancer98532538.

  • MoldowREConnellyRR1968Epidemiology of pancreatic cancer in Connecticut. Gastroenterology55677686.

  • NichollsAG1902Simple adenoma of the pancreas arising from an island of Langerhans. Journal of Medical Research8385395.

  • NortonJA2005Surgical treatment and prognosis of gastrinoma. Best Practice & Research. Clinical Gastroenterology19799805.

  • NortonJAFrakerDLAlexanderHRVenzonDJDoppmanJLSerranoJGoebelSUPeghiniPLRoyPKGibrilF1999Surgery to cure the Zollinger-Ellison syndrome. New England Journal of Medicine341635644.

  • NortonJAKivlenMLiMSchneiderDChuterTJensenRT2003Morbidity and mortality of aggressive resection in patients with advanced neuroendocrine tumors. Archives of Surgery138859866.

  • ÖbergKErikssonB2005Endocrine tumours of the pancreas. Best Practice & Research. Clinical Gastroenterology19753781.

  • O'TooleDSalazarRFalconiMKaltsasGCouvelardAde HerderWWHyrdelRNikouGKrenningEVulliermeMP2006Rare functioning pancreatic endocrine tumors. Neuroendocrinology84189195.

  • PanzutoFNasoniSFalconiMCorletoVDCapursoGCassettaSDi FonzoMTornatoreVMilioneMAngelettiS2005Prognostic factors and survival in endocrine tumor patients: comparison between gastrointestinal and pancreatic localization. Endocrine-Related Cancer1210831092.

  • PapeU-FBöhmigMBerndtUTilingNWiedenmannBPlöckingerU2004Survival and clinical outcome of patients with neuroendocrine tumors of the gastroenteropancreatic tract in a German Referral Center. Annals of the New York Academy of Sciences1014222233.

  • PelosiGBresaolaEBoginaGPasiniFRodellaSCastelliPIaconoCSerioGZamboniG1996Endocrine tumors of the pancreas: Ki-67 immunoreactivity on paraffin sections is an independent predictor for malignancy: a comparative study with proliferating-cell nuclear antigen and progesterone receptor protein immunostaining, mitotic index, and other clinicopathologic variables. Human Pathology2711241134.

  • PelosiGPasiniFBresaolaEBoginaGPederzoliPBioloSMenardSZamboniG1997High-affinity monomeric 67-kD laminin receptors and prognosis in pancreatic endocrine tumours. Journal of Pathology1836269.

  • PengSYLiJTLiuYBFangHQWuYLPengCHWangXBQianHR2004Diagnosis and treatment of VIPoma in China: (case report and 31 cases review) diagnosis and treatment of VIPoma. Pancreas289397.

  • PhanGQYeoCJCameronJLMaherMMHrubanRHUdelsmanR1997Pancreaticoduodenectomy for selected periampullary neuroendocrine tumors: fifty patients. Surgery122989996.

  • PhanGQYeoCJHrubanRHLillemoeKDPittHACameronJL1998Surgical experience with pancreatic and peripancreatic neuroendocrine tumors: review of 125 patients. Journal of Gastrointestinal Surgery2472482.

  • PhanATWangLXieKZhangJRashidAEvansDVautheyJAbdallaEAbbruzzeseJLYaoJC2006Association of VEGF expression with poor prognosis among patients with low-grade neuroendocrine carcinoma. Journal of Clinical Oncology244091

  • La RosaSSessaFCapellaCRivaCLeoneBEKlersyCRindiGSolciaE1996Prognostic criteria in nonfunctioning pancreatic endocrine tumours. Virchows Archiv429323333.

  • La RosaSUccellaSFinziGAlbarelloLSessaFCapellaC2003Localization of vascular endothelial growth factor and its receptors in digestive endocrine tumors: correlation with microvessel density and clinicopathologic features. Human Pathology341827.

  • La RosaSRigoliEUccellaSNovarioRCapellaC2007Prognostic and biological significance of cytokeratin 19 in pancreatic endocrine tumours. Histopathology50597606.

  • RoyPKVenzonDJShojamaneshHAbou-SaifAPeghiniPDoppmanJLGibrilFJensenRT2000Zollinger-Ellison syndrome. Clinical presentation in 261 patients. Medicine79379411.

  • SarmientoJMFarnellMBQueFGNagorneyDM2002Pancreaticoduodenectomy for islet cell tumors of the head of the pancreas: long-term survival analysis. World Journal of Surgery2612671271.

  • SchurrPGStrateTReseKKaifiJTReicheltUPetriSKleinhansHYekebasEFIzbickiJR2007Aggressive surgery improves long-term survival in neuroendocrine pancreatic tumors: an institutional experience. Annals of Surgery245273281.

  • ServiceFJMcMahonMMO'BrienPCBallardDJ1991Functioning insulinoma – incidence, recurrence, and long-term survival of patients: a 60-year study. Mayo Clinic Proceedings66711719.

  • SkogseidBErikssonBLundqvistGLoreliusLERastadJWideLAkerstromGÖbergK1991Multiple endocrine neoplasia type 1: a 10-year prospective screening study in four kindreds. Journal of Clinical Endocrinology73281287.

  • SmithSLBrantonSAAvinoAJMartinJKKlinglerPJThompsonGBGrantCSvan HeerdenJA1998Vasoactive intestinal polypeptide secreting islet cell tumors: a 15-year experience and review of the literature. Surgery12410501055.

  • SogaJYakuwaY1994Pancreatic endocrinomas: a statistical analysis of 1857 cases. Journal of Hepato-Biliary-Pancreatic Surgery1522529.

  • SogaJYakuwaY1998aThe gastrinoma/Zollinger-Ellison syndrome: statistical evaluation of a Japanese series of 359 cases. Journal of Hepato-Biliary-Pancreatic Surgery57785.

  • SogaJYakuwaY1998bGlucagonomas/diabetico-dermatogenic syndrome (DDS): a statistical evaluation of 407 reported cases. Journal of Hepato-Biliary-Pancreatic Surgery5312319.

  • SogaJYakuwaY1998cVipoma/diarrheogenic syndrome: a statistical evaluation of 241 reported cases. Journal of Experimental and Clinical Cancer Research17389400.

  • SogaJYakuwaY1999Somatostatinoma/inhibitory syndrome: a statistical evaluation of 173 reported cases as compared to other pancreatic endocrinomas. Journal of Experimental and Clinical Cancer Research181322.

  • Atlas of Tumor Pathology

  • World Health Organization International Histological Classification of Tumours

  • SolorzanoCCLeeJEPistersPWVautheyJNAyersGDJeanMEGagelRFAjaniJAWolffRAEvansDB2001Nonfunctioning islet cell carcinoma of the pancreas: survival results in a contemporary series of 163 patients. Surgery13010781085.

  • SpeelEJRichterJMochHEgenterCSaremaslaniPRutimannKZhaoJBarghornARothJHeitzPU1999Genetic differences in endocrine pancreatic tumor subtypes detected by comparative genomic hybridization. American Journal of Pathology15517871794.

  • StammBHackiWHKlöppelGHeitzPUGastrin-producing tumors and the Zollinger-Ellison syndromeDayalYEndocrine Pathology of the Gut and Pancreas11991CRC PressBoca Raton, FL:155194.

  • StarkeASaddigCMansfeldLKoesterRTschaharganeCCzyganPGoretzkiP2005Malignant metastatic insulinoma-postoperative treatment and follow-up. World Journal of Surgery29789793.

  • TakahashiYAkishima-FukasawaYKobayashiNSanoTKosugeTNimuraYKanaiYHiraokaN2007Prognostic value of tumor architecture, tumor-associated vascular characteristics, and expression of angiogenic molecules in pancreatic endocrine tumors. Clinical Cancer Research13187196.

  • TanCCHallRISemeraroDIronsRPFreemanJG1996Ampullary somatostatinoma associated with von Recklinghausen's neurofibromatosis presenting as obstructive jaundice. European Journal of Surgical Oncology22298301.

  • TanGCiocAMPerez-MontielDEllisonECFrankelWL2004Microvascular density does not correlate with histopathology and outcome in neuroendocrine tumors of the pancreas. Applied Immunohistochemistry and Molecular Morphology123135.

  • TangSJDumotJAWangLMemmesheimerCConwellDLZuccaroGGoormasticMOrmsbyAHCowellJ2002Telomerase activity in pancreatic endocrine tumors. American Journal of Gastroenterology9710221030.

  • ThompsonGBvan HeerdenJAGrantCSCarneyJAIlstrupDM1988Islet cell carcinomas of the pancreas: a twenty-year experience. Surgery10410111017.

  • TomassettiPMiglioriMLalliSCampanaDTomassettiVCorinaldesiR2001Epidemiology, clinical features and diagnosis of gastroenteropancreatic endocrine tumours. Annals of Oncology12S95S99.

  • TomassettiPCampanaDPiscitelliLCasadeiRSantiniDNoriFMorselli-LabateAMPezzilliRCorinaldesiR2005Endocrine pancreatic tumors: factors correlated with survival. Annals of Oncology1618061810.

  • TriponezFDossehDGoudetPCougardPBautersCMuratACadiotGNiccoli-SirePChayvialleJACalenderA2006Epidemiology data on 108 MEN 1 patients from the GTE with isolated nonfunctioning tumors of the pancreas. Annals of Surgery243265272.

  • VasenHFLamersCBLipsCJ1989Screening for the multiple endocrine neoplasia syndrome type I. A study of 11 kindreds in The Netherlands. Archives of Internal Medicine14927172722.

  • VenkateshSOrdonezNGAjaniJSchultzPNHickeyRCJohnstonDASamaanNA1990Islet cell carcinoma of the pancreas. A study of 98 patients. Cancer65354357.

  • VerhoefSvan Diemen-SteenvoordeRAkkersdijkWLBaxNMAriyurekYHermansCJvan NieuwenhuizenONikkelsPGLindhoutDHalleyDJ1999Malignant pancreatic tumour within the spectrum of tuberous sclerosis complex in childhood. European Journal of Pediatrics158284287.

  • VezzosiDBouissonMEscourrouGLaurellHSelvesJSeguinPPradayrolLCaronPBuscailL2006Clinical utility of telomerase for the diagnosis of malignant well-differentiated endocrine tumours. Clinical Endocrinology646367.

  • VortmeyerAOHuangSLubenskyIZhuangZ2004Non-islet origin of pancreatic islet cell tumors. Journal of Clinical Endocrinology8919341938.

  • WarnerRR2005Enteroendocrine tumors other than carcinoid: a review of clinically significant advances. Gastroenterology12816681684.

  • WarrenSLeComptePMLeggMAThe Pathology of Diabetes Mellitus1966Lea & FebigerPhiladelphia:

  • WatsonRGJohnstonCFO'HareMMAndersonJRWilsonBGCollinsJSSloanJMBuchananKD1989The frequency of gastrointestinal endocrine tumours in a well-defined population – Northern Ireland 1970–1985. Quarterly Journal of Medicine72647657.

  • WeberHCVenzonDJLinJTFishbeinVAOrbuchMStraderDBGibrilFMetzDCFrakerDLNortonJA1995Determinants of metastatic rate and survival in patients with Zollinger-Ellison syndrome: a prospective long-term study. Gastroenterology10816371649.

  • WeilC1985Gastroenteropancreatic endocrine tumors. Klinische Wochenschrift63433459.

  • WermersRAFatourechiVWynneAGKvolsLKLloydRV1996The glucagonoma syndrome. Clinical and pathologic features in 21 patients. Medicine755363.

  • WhiteTJEdneyJAThompsonJSKarrerFWMoorBJ1994Is there a prognostic difference between functional and nonfunctional islet cell tumors?American Journal of Surgery168627630.

  • WildALangerPCelikIChaloupkaBBartschDK2002Chromosome 22q in pancreatic endocrine tumors: identification of a homozygous deletion and potential prognostic associations of allelic deletions. European Journal of Endocrinology147507513.

  • WilkinsonSTehBTDaveyKRMcArdleJPYoungMShepherdJJ1993Cause of death in multiple endocrine neoplasia type 1. Archives of Surgery128683690.

  • YangCSShyrYMChiuCTSuCHLinCPLinJT2000Non-functioning islet cell tumors of the pancreas – a multicentric clinical study in Taiwan. Hepatogastroenterology4717471749.

  • ZengXJZhongSXZhuYFeiLMWuWJCaiLX1988Insulinoma: 31 years of tumor localization and excision. Journal of Surgical Oncology39274278.

  • ZhaoJMochHScheidweilerAFBaerASchafferAASpeelEJRothJHeitzPUKomminothP2001Genomic imbalances in the progression of endocrine pancreatic tumors. 32364372.

  • ZikusokaMNKiddMEickGLatichIModlinIM2005The molecular genetics of gastroenteropancreatic neuroendocrine tumors. Cancer10422922309.

 

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References

AliASerraSAsaSLChettyR2006The predictive value of CK19 and CD99 in pancreatic endocrine tumors. American Journal of Surgical Pathology3015881594.

BarghornAKomminothPBachmannDRutimannKSaremaslaniPMuletta-FeurerSPerrenARothJHeitzPUSpeelEJ2001aDeletion at 3p25.3–p23 is frequently encountered in endocrine pancreatic tumours and is associated with metastatic progression. Journal of Pathology194451458.

BarghornASpeelEJFarspourBSaremaslaniPSchmidSPerrenARothJHeitzPUKomminothP2001bPutative tumor suppressor loci at 6q22 and 6q23–q24 are involved in the malignant progression of sporadic endocrine pancreatic tumors. American Journal of Pathology15819031911.

BartschDKSchillingTRamaswamyAGerdesBCelikIWagnerHJSimonBRothmundM2000Management of nonfunctioning islet cell carcinomas. World Journal of Surgery2414181424.

BeckerV1971Pathologicoanatomical aspects of tumors with endocrine activity. Langenbecks Archiv für Chirurgie329426437.

BinkovitzLAJohnsonCDStephensDH1990Islet cell tumors in von Hippel–Lindau disease: increased prevalence and relationship to the multiple endocrine neoplasias. American Journal of Roentgenology155501505.

et alPresented at the 28th Annual Meeting of the American Association of Endocrine Surgeons

BloomstonMDurkinAYangIRojianiMRosemurgyASEnkmannSYeatmanTJZervosEE2004Identification of molecular markers specific for pancreatic neuroendocrine tumors by genetic profiling of core biopsies. Annals of Surgical Oncology11413419.

Le BodicMFHeymannMFLecomteMBergerNBergerFLouvelADe MiccoCPateyMDe MascarelABurtinF1996Immunohistochemical study of 100 pancreatic tumors in 28 patients with multiple endocrine neoplasia, type I. American Journal of Surgical Pathology2013781384.

BöhmigMPapeUFTilingNBerndtUMüller-NordhornJWillichSNWiedenmannB2005Prognostic factors in gastroenteropancreatic neuroendocrine tumors – a retrospective multivariate analysis. 23(Abstract 4086)

BoukhmanMPKaramJHShaverJSipersteinAEDuhQYClarkOH1998Insulinoma – experience from 1950 to 1995. Western Journal of Medicine16998104.

BrandiMLGagelRFAngeliABilezikianJPBeck-PeccozPBordiCConte-DevolxBFalchettiAGheriRGLibroiaA2001Guidelines for diagnosis and therapy of MEN type 1 and type 2. Journal of Clinical Endocrinology8656585671.

BroughanTALeslieJDSotoJMHermannRE1986Pancreatic islet cell tumors. Surgery99671678.

BuchananKDJohnstonCFO'HareMMArdillJEShawCCollinsJSWatsonRGAtkinsonABHaddenDRKennedyTL1986Neuroendocrine tumors. A European view. American Journal of Medicine811422.

BurgessJRGreenawayTMParameswaranVChallisDRDavidRShepherdJJ1998aEnteropancreatic malignancy associated with multiple endocrine neoplasia type 1: risk factors and pathogenesis. Cancer83428434.

BurgessJRGreenawayTMShepherdJJ1998bExpression of the MEN-1 gene in a large kindred with multiple endocrine neoplasia type 1. Journal of Internal Medicine243465470.

CapursoGLattimoreSCrnogorac-JurcevicTPanzutoFMilioneMBhaktaVCampaniniNSwiftSMBordiCDelle FaveG2006Gene expression profiles of progressive pancreatic endocrine tumours and their liver metastases reveal potential novel markers and therapeutic targets. Endocrine-Related Cancer13541558.

CarriagaMTHensonDE1995Liver, gallbladder, extrahepatic bile ducts, and pancreas. Cancer75171190.

ChenXCaiWYYangWPLiHW2002Pancreatic insulinomas: diagnosis and surgical treatment of 74 patients. Hepatobiliary & Pancreatic Diseases International1458461.

ChenYJVortmeyerAZhuangZHuangSJensenRT2003Loss of heterozygosity of chromosome 1q in gastrinomas: occurrence and prognostic significance. Cancer Research63817823.

ChenYJVortmeyerAZhuangZGibrilFJensenRT2004X-chromosome loss of heterozygosity frequently occurs in gastrinomas and is correlated with aggressive tumor growth. Cancer10013791387.

Cheslyn-CurtisSSitaramVWilliamsonRC1993Management of non-functioning neuroendocrine tumours of the pancreas. British Journal of Surgery80625627.

ChuQDHillHCDouglassHOJrDriscollDSmithJLNavaHRGibbsJF2002Predictive factors associated with long-term survival in patients with neuroendocrine tumors of the pancreas. Annals of Surgical Oncology9855862.

ClarkeMRBakerEEWeyantRJHillLCartySE1997Proliferative activity in pancreatic endocrine tumors: association with function, metastases, and survival. Endocrine Pathology8181187.

ClossetJDelhayeMSperdutoNRickaertFGelinM1996Nonfunctioning neuroendocrine tumors of the pancreas: clinical presentation of 7 patients. Hepatogastroenterology4316401644.

CorletoVDPanzutoFFalconiMCannizzaroRAngelettiSMorettiADelle FaveGFarinatiF2001Digestive neuroendocrine tumours: diagnosis and treatment in Italy. A survey by the Oncology Study Section of the Italian Society of Gastroenterology (SIGE). Digestive and Liver Disease33217221.

CouvelardAO'TooleDTurleyHLeekRSauvanetADegottCRuszniewskiPBelghitiJHarrisALGatterK2005Microvascular density and hypoxia-inducible factor pathway in pancreatic endocrine tumours: negative correlation of microvascular density and VEGF expression with tumour progression. British Journal of Cancer9294101.

CouvelardAHuJSteersGO'TooleDSauvanetABelghitiJBedossaPGatterKRuszniewskiPPezzellaF2006Identification of potential therapeutic targets by gene-expression profiling in pancreatic endocrine tumors. Gastroenterology13115971610.

CreutzfeldtW1980Endocrine tumors of the pancreas: clinical, chemical and morphological findings. Monographs in Pathology21208230.

CubillaALHajduSI1975Islet cell carcinoma of the pancreas. Archives of Pathology99204207.

CullenRMOngCE1987Insulinoma in Auckland 1970–1985. New Zealand Medical Journal100560562.

DanforthDNJrGordenPBrennanMF1984Metastatic insulin-secreting carcinoma of the pancreas: clinical course and the role of surgery. Surgery9610271037.

DeanPGvan HeerdenJAFarleyDRThompsonGBGrantCSHarmsenWSIlstrupDM2000Are patients with multiple endocrine neoplasia type I prone to premature death?World Journal of Surgery2414371441.

DemeureMJKlonoffDCKaramJHDuhQYClarkOH1991Insulinomas associated with multiple endocrine neoplasia type I: the need for a different surgical approach. Surgery1109981005.

DeschampsLHandra-LucaAO'TooleDSauvanetARuszniewskiPBelghitiJBedossaPCouvelardA2006CD10 expression in pancreatic endocrine tumors: correlation with prognostic factors and survival. Human Pathology37802808.

DeshpandeVFernandez-del CastilloCMuzikanskyADeshpandeAZukerbergLWarshawALLauwersGY2004Cytokeratin 19 is a powerful predictor of survival in pancreatic endocrine tumors. American Journal of Surgical Pathology2811451153.

DohertyGM2005Multiple endocrine neoplasia type 1. Journal of Surgical Oncology89143150.

DohertyGMOlsonJAFrisellaMMLairmoreTCWellsSAJrNortonJA1998Lethality of multiple endocrine neoplasia type I. World Journal of Surgery22581587.

DralleHKrohnSLKargesWBoehmBOBrauckhoffMGimmO2004Surgery of resectable nonfunctioning neuroendocrine pancreatic tumors. World Journal of Surgery2812481260.

DurkinAJBloomstonMYeatmanTJGilbert-BarnessECojitaDRosemurgyASZervosEE2004Differential expression of the Tie-2 receptor and its ligands in human pancreatic tumors. Journal of the American College of Surgeons199724731.

EckhauserFECheungPSVinikAIStrodelWELloydRVThompsonNW1986Nonfunctioning malignant neuroendocrine tumors of the pancreas. Surgery100978988.

ErikssonBÖbergKSkogseidB1989Neuroendocrine pancreatic tumors. Clinical findings in a prospective study of 84 patients. Acta Oncologica28373377.

ErikssonBSkogseidBLundqvistGWideLWilanderEÖbergK1990Medical treatment and long-term survival in a prospective study of 84 patients with endocrine pancreatic tumors. Cancer6518831890.

EvansDBSkibberJMLeeJEClearyKRAjaniJAGagelRFSellinRVFenoglioCJMerrellRCHickeyRC1993Nonfunctioning islet cell carcinoma of the pancreas. Surgery11411751182.

FalconiMPlockingerUKwekkeboomDJManfrediRKornerMKvolsLPapeUFRickeJGoretzkiPEWildiS2006Well-differentiated pancreatic nonfunctioning tumors/carcinoma. Neuroendocrinology84196211.

FengLSMaXXTangZZhaoYFYeXXXuPQ2002Diagnosis and treatment of insulinoma: report of 105 cases. Hepatobiliary & Pancreatic Diseases International1137139.

FesinmeyerMDAustinMALiCIDe RoosAJBowenDJ2005Differences in survival by histologic type of pancreatic cancer. 1417661773.

FormicaVNormanARCunninghamDWotherspoonASirohiBOatesJChongG2006The prognostic role of the WHO classification, urinary 5-hydroxyindoleacetic acid (u5HIAA) and liver function tests (LFTs) in metastatic neuroendocrine carcinomas (NECs) of the gastroenteropancreatic (GEP) tract. Journal of Clinical Oncology244092

FrancalanciPDiomedi-CamasseiFPurificatoCSantorelliFMGiannottiADominiciCInserraABoldriniR2003Malignant pancreatic endocrine tumor in a child with tuberous sclerosis. American Journal of Surgical Pathology2713861389.

Frantz VK 1959 Tumors of the pancreas. In Atlas of Tumor Pathology

FujisawaTOsugaTMaedaMSakamotoNMaedaTSakaguchiKOnishiYToyodaMMaedaHMiyamotoK2002Malignant endocrine tumor of the pancreas associated with von Recklinghausen's disease. Journal of Gastroenterology375967.

FurukawaHMukaiKKosugeTKanaiYShimadaKYamamotoJMizuguchiYUshioK1998Nonfunctioning islet cell tumors of the pancreas: clinical, imaging and pathological aspects in 16 patients. Japanese Journal of Clinical Oncology28255261.

Gentil PerretAMosnierJFBuonoJPBerthelotPChipponiJBaliqueJGCuilleretJDechelottePBoucheronS1998The relationship between MIB-1 proliferation index and outcome in pancreatic neuroendocrine tumors. American Journal of Clinical Pathology109286293.

GibrilFJensenRT2004Zollinger–Ellison syndrome revisited: diagnosis, biologic markers, associated inherited disorders, and acid hypersecretion. Current Gastroenterology Reports6454463.

GibrilFVenzonDJOjeaburuJVBashirSJensenRT2001Prospective study of the natural history of gastrinoma in patients with MEN1: definition of an aggressive and a nonaggressive form. Journal of Clinical Endocrinology8652825293.

GotoANikiTTeradoYFukushimaJFukayamaM2004Prevalence of CD99 protein expression in pancreatic endocrine tumours (PETs). Histopathology45384392.

GramaDErikssonBMartenssonHCedermarkBAhrenBKristofferssonARastadJObergKAkerstromG1992Clinical characteristics, treatment and survival in patients with pancreatic tumors causing hormonal syndromes. World Journal of Surgery16632639.

GrantCS2005Insulinoma. Best Practice & Research. Clinical Gastroenterology19783798.

GrimeliusLHultquistGTStenkvistB1975Cytological differentiation of asymptomatic pancreatic islet cell tumours in autopsy material. 365275288.

GulloLMiglioriMFalconiMPederzoliPBettiniRCasadeiRDelle FaveGCorletoVDCeccarelliCSantiniD2003Nonfunctioning pancreatic endocrine tumors: a multicenter clinical study. American Journal of Gastroenterology9824352439.

GuoSSAroraCShimoideATSawickiMP2002aFrequent deletion of chromosome 3 in malignant sporadic pancreatic endocrine tumors. Molecular and Cellular Endocrinology190109114.

GuoSSWuAYSawickiMP2002bDeletion of chromosome 1, but not mutation of MEN-1, predicts prognosis in sporadic pancreatic endocrine tumors. World Journal of Surgery26843847.

GuoKJLiaoHHTianYLGuoRXHeSGShenK2004Surgical treatment of nonfunctioning islet cell tumor: report of 41 cases. Hepatobiliary and Pancreatic Diseases International3469472.

.

HalfdanarsonTRabeKGRubinJPetersenGM2008Pancreatic Neuroendocrine Tumors (PNETS): Incidence, prognosis and recent trend toward improved survival. Annals of Oncology[in press]

HammelPRVilgrainVTerrisBPenfornisASauvanetACorreasJMChauveauDBalianABeigelmanCO'TooleD2000Pancreatic involvement in von Hippel–Lindau disease. The Groupe Francophone d'Etude de la Maladie de von Hippel–Lindau. Gastroenterology11910871095.

HanselDERahmanAHermansJde KrijgerRRAshfaqRYeoCJCameronJLMaitraA2003Liver metastases arising from well-differentiated pancreatic endocrine neoplasms demonstrate increased VEGF-C expression. Modern Pathology16652659.

HanselDERahmanAHouseMAshfaqRBergKYeoCJMaitraA2004Met proto-oncogene and insulin-like growth factor binding protein 3 overexpression correlates with metastatic ability in well-differentiated pancreatic endocrine neoplasms. Clinical Cancer Research1061526158.

HarrisGJTioFCruzABJr1987Somatostatinoma: a case report and review of the literature. Journal of Surgical Oncology36816.

HarrisonTSChildCGFryWJFloydJCJrFajansSS1973Current surgical management of functioning islet cell tumors of the pancreas. Annals of Surgery178485495.

HeitzPUKomminothPPerrenAKlimstraDSDayalYBordiCLechagoJCentenoBAKlöppelGPancreatic endocrine tumors: introductionDeLellisDALloydRVHeitzPUEngCPathology and Genetics of Tumours of Endocrine Organs. WHO Classification of Tumours2004IARC PressLyon, France:177182.

HellmanPAnderssonMRastadJJuhlinCKaracagilSErikssonBSkogseidBAkerstromG2000Surgical strategy for large or malignant endocrine pancreatic tumors. World Journal of Surgery2413531360.

de HerderWWNiederleBScoazecJYPauwelsSKloppelGFalconiMKwekkeboomDJObergKErikssonBWiedenmannB2006Well-differentiated pancreatic tumor/carcinoma: insulinoma. Neuroendocrinology84183188.

HeymannMFJoubertMNemethJFrancBVissetJHamyAle BorgneJle NeelJCMuratACordelS2000Prognostic and immunohistochemical validation of the Capella classification of pancreatic neuroendocrine tumours: an analysis of 82 sporadic cases. Histopathology36421432.

HirshbergBCochranCSkarulisMCLibuttiSKAlexanderHRWoodBJChangRKleinerDEGordenP2005Malignant insulinoma: spectrum of unusual clinical features. Cancer104264272.

HochwaldSNZeeSConlonKCColleoniRLouieOBrennanMFKlimstraDS2002Prognostic factors in pancreatic endocrine neoplasms: an analysis of 136 cases with a proposal for low-grade and intermediate-grade groups. Journal of Clinical Oncology2026332642.

HouseMGHermanJGGuoMZHookerCMSchulickRDCameronJLHrubanRHMaitraAYeoCJ2003aPrognostic value of hMLH1 methylation and microsatellite instability in pancreatic endocrine neoplasms. Surgery134902909.

HouseMGHermanJGGuoMZHookerCMSchulickRDLillemoeKDCameronJLHrubanRHMaitraAYeoCJ2003bAberrant hypermethylation of tumor suppressor genes in pancreatic endocrine neoplasms. Annals of Surgery238423431.

HouseMGCameronJLLillemoeKDSchulickRDChotiMAHanselDEHrubanRHMaitraAYeoCJ2006Differences in survival for patients with resectable versus unresectable metastases from pancreatic islet cell cancer. Journal of Gastrointestinal Surgery10138145.

IliasITorpyDJPacakKMullenNWesleyRANiemanLK2005Cushing's syndrome due to ectopic corticotropin secretion: twenty years' experience at the National Institutes of Health. Journal of Clinical Endocrinology9049554962.

ImamHErikssonBÖbergK2000Expression of CD44 variant isoforms and association to the benign form of endocrine pancreatic tumours. Annals of Oncology11295300.

JacobsenOBardramLRehfeldJF1986The requirement for gastrin measurements. Scandinavian Journal of Clinical and Laboratory Investigation46423426.

JarufeNPColdhamCOrugTMayerADMirzaDFBuckelsJABramhallSR2005Neuroendocrine tumours of the pancreas: predictors of survival after surgical treatment. Digestive Surgery22157162.

JensenRT1999Pancreatic endocrine tumors: recent advances. Annals of Oncology10170176.

JonkersYMHClaessenSMHPerrenASchmidSKomminothPVerhofstadAAHoflandLJde KrijgerRRSlootwegPJRamaekersFCS2005Chromosomal instability predicts metastatic disease in patients with insulinomas. Endocrine-Related Cancer12435447.

JordaMGhorabZFernandezGNassiriMHanlyANadjiM2003Low nuclear proliferative activity is associated with nonmetastatic islet cell tumors. Archives of Pathology and Laboratory Medicine127196199.

KangCMKimKSChoiJSLeeWJKimBR2005Experiences with nonfunctioning neuroendocrine neoplasms of the pancreas. Digestive Surgery22453458.

KangCMParkSHKimKSChoiJSLeeWJKimBR2006Surgical experiences of functioning neuroendocrine neoplasm of the pancreas. Yonsei Medical Journal47833839.

KavlieHWhiteTT1972Pancreatic islet beta cell tumors and hyperplasia: experience in 14 Seattle hospitals. Annals of Surgery175326335.

KazanjianKKReberHAHinesOJ2006Resection of pancreatic neuroendocrine tumors: results of 70 cases. Archives of Surgery141765770.

KentRBIIIvan HeerdenJAWeilandLH1981Nonfunctioning islet cell tumors. Annals of Surgery193185190.

KimuraWKurodaAMoriokaY1991Clinical pathology of endocrine tumors of the pancreas. Analysis of autopsy cases. Digestive Diseases and Sciences36933942.

KlöppelGHeitzPU1988Pancreatic endocrine tumors. 183155168.

KlöppelGPerrenAHeitzPU2004The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification. Annals of the New York Academy of Sciences10141327.

KonomiKChijiiwaKKatsutaTYamaguchiK1990Pancreatic somatostatinoma: a case report and review of the literature. Journal of Surgical Oncology43259265.

KorpássyB1939Die Basalzellenmetaplasie des Ausführungsgänge des Pankreas. Virchows Archiv. A: Pathology. Pathologische Anatomie303359373.

KouvarakiMASolorzanoCCShapiroSEYaoJCPerrierNDLeeJEEvansDB2005Surgical treatment of non-functioning pancreatic islet cell tumors. Journal of Surgical Oncology89170185.

LakhaniVTYouYNWellsSA2007The multiple endocrine neoplasia syndromes. Annual Review of Medicine58253265.

LamKYLoCY1997Pancreatic endocrine tumour: a 22-year clinico-pathological experience with morphological, immunohistochemical observation and a review of the literature. European Journal of Surgical Oncology233642.

LamKYLoCYFanSTLukJM2000Telomerase activity in pancreatic endocrine tumours: a potential marker for malignancy. Molecular Pathology53133136.

LegaspiABrennanMF1988Management of islet cell carcinoma. Surgery10410181023.

LepageCBouvierAMPhelipJMHatemCVernetCFaivreJ2004Incidence and management of malignant digestive endocrine tumours in a well defined French population. Gut53549553.

LiangHWangPWangXNWangJCHaoXS2004Management of nonfunctioning islet cell tumors. World Journal of Gastroenterology1018061809.

LibuttiSKChoykePLBartlettDLVargasHWaltherMLubenskyIGlennGLinehanWMAlexanderHR1998Pancreatic neuroendocrine tumors associated with von Hippel–Lindau disease: diagnostic and management recommendations. Surgery12411531159.

LiuLBroaddusRRYaoJCXieSWhiteJAWuTTHamiltonSRRashidA2005Epigenetic alterations in neuroendocrine tumors: methylation of RAS-association domain family 1, isoform A and p16 genes are associated with metastasis. Modern Pathology1816321640.

LloydRV1998Utility of Ki-67 as a prognostic marker in pancreatic endocrine neoplasms. American Journal of Clinical Pathology109245247.

LoCYvan HeerdenJAThompsonGBGrantCSSoreideJAHarmsenWS1996Islet cell carcinoma of the pancreas. World Journal of Surgery20878884.

LonserRRGlennGMWaltherMChewEYLibuttiSKLinehanWMOldfieldEH2003von Hippel–Lindau disease. Lancet36120592067.

LundstamSLundholmKScherstenT1979A ten-year material of insulinoma: diagnosis and surgical treatment. Scandinavian Journal of Gasteroenterology14653656.

MadeiraITerrisBVossMDenysASauvanetAFlejouJFVilgrainVBelghitiJBernadesPRuszniewskiP1998Prognostic factors in patients with endocrine tumours of the duodenopancreatic area. Gut43422427.

MaduraJACummingsOWWiebkeEABroadieTAGouletRLJrHowardTJ1997Nonfunctioning islet cell tumors of the pancreas: a difficult diagnosis but one worth the effort. American Surgeon63573578.

MaitraAHanselDEArganiPAshfaqRRahmanANajiADengSGeradtsJHawthorneLHouseMG2003Global expression analysis of well-differentiated pancreatic endocrine neoplasms using oligonucleotide microarrays. Clinical Cancer Research959885995.

MansourJCChenH2004Pancreatic endocrine tumors. Journal of Surgical Research120139161.

Marion-AudibertAMBarelCGouysseGDumortierJPilleulFPourreyronCHervieuVPoncetGLombard-BohasCChayvialleJA2003Low microvessel density is an unfavorable histoprognostic factor in pancreatic endocrine tumors. Gastroenterology12510941104.

MatonPNGardnerJDJensenRT1986Cushing's syndrome in patients with the Zollinger–Ellison syndrome. New England Journal of Medicine31515.

MatthewsBDHenifordBTReardonPRBrunicardiFCGreeneFL2000Surgical experience with nonfunctioning neuroendocrine tumors of the pancreas. American Surgeon6611161122.

MatthewsBDSmithTIKercherKWHolderWDJrHenifordBT2002Surgical experience with functioning pancreatic neuroendocrine tumors. American Surgeon68660666.

MissiagliaEMoorePSWilliamsonJLemoineNRFalconiMZamboniGScarpaA2002Sex chromosome anomalies in pancreatic endocrine tumors. International Journal of Cancer98532538.

MoldowREConnellyRR1968Epidemiology of pancreatic cancer in Connecticut. Gastroenterology55677686.

NichollsAG1902Simple adenoma of the pancreas arising from an island of Langerhans. Journal of Medical Research8385395.

NortonJA2005Surgical treatment and prognosis of gastrinoma. Best Practice & Research. Clinical Gastroenterology19799805.

NortonJAFrakerDLAlexanderHRVenzonDJDoppmanJLSerranoJGoebelSUPeghiniPLRoyPKGibrilF1999Surgery to cure the Zollinger-Ellison syndrome. New England Journal of Medicine341635644.

NortonJAKivlenMLiMSchneiderDChuterTJensenRT2003Morbidity and mortality of aggressive resection in patients with advanced neuroendocrine tumors. Archives of Surgery138859866.

ÖbergKErikssonB2005Endocrine tumours of the pancreas. Best Practice & Research. Clinical Gastroenterology19753781.

O'TooleDSalazarRFalconiMKaltsasGCouvelardAde HerderWWHyrdelRNikouGKrenningEVulliermeMP2006Rare functioning pancreatic endocrine tumors. Neuroendocrinology84189195.

PanzutoFNasoniSFalconiMCorletoVDCapursoGCassettaSDi FonzoMTornatoreVMilioneMAngelettiS2005Prognostic factors and survival in endocrine tumor patients: comparison between gastrointestinal and pancreatic localization. Endocrine-Related Cancer1210831092.

PapeU-FBöhmigMBerndtUTilingNWiedenmannBPlöckingerU2004Survival and clinical outcome of patients with neuroendocrine tumors of the gastroenteropancreatic tract in a German Referral Center. Annals of the New York Academy of Sciences1014222233.

PelosiGBresaolaEBoginaGPasiniFRodellaSCastelliPIaconoCSerioGZamboniG1996Endocrine tumors of the pancreas: Ki-67 immunoreactivity on paraffin sections is an independent predictor for malignancy: a comparative study with proliferating-cell nuclear antigen and progesterone receptor protein immunostaining, mitotic index, and other clinicopathologic variables. Human Pathology2711241134.

PelosiGPasiniFBresaolaEBoginaGPederzoliPBioloSMenardSZamboniG1997High-affinity monomeric 67-kD laminin receptors and prognosis in pancreatic endocrine tumours. Journal of Pathology1836269.

PengSYLiJTLiuYBFangHQWuYLPengCHWangXBQianHR2004Diagnosis and treatment of VIPoma in China: (case report and 31 cases review) diagnosis and treatment of VIPoma. Pancreas289397.

PhanGQYeoCJCameronJLMaherMMHrubanRHUdelsmanR1997Pancreaticoduodenectomy for selected periampullary neuroendocrine tumors: fifty patients. Surgery122989996.

PhanGQYeoCJHrubanRHLillemoeKDPittHACameronJL1998Surgical experience with pancreatic and peripancreatic neuroendocrine tumors: review of 125 patients. Journal of Gastrointestinal Surgery2472482.

PhanATWangLXieKZhangJRashidAEvansDVautheyJAbdallaEAbbruzzeseJLYaoJC2006Association of VEGF expression with poor prognosis among patients with low-grade neuroendocrine carcinoma. Journal of Clinical Oncology244091

La RosaSSessaFCapellaCRivaCLeoneBEKlersyCRindiGSolciaE1996Prognostic criteria in nonfunctioning pancreatic endocrine tumours. Virchows Archiv429323333.

La RosaSUccellaSFinziGAlbarelloLSessaFCapellaC2003Localization of vascular endothelial growth factor and its receptors in digestive endocrine tumors: correlation with microvessel density and clinicopathologic features. Human Pathology341827.

La RosaSRigoliEUccellaSNovarioRCapellaC2007Prognostic and biological significance of cytokeratin 19 in pancreatic endocrine tumours. Histopathology50597606.

RoyPKVenzonDJShojamaneshHAbou-SaifAPeghiniPDoppmanJLGibrilFJensenRT2000Zollinger-Ellison syndrome. Clinical presentation in 261 patients. Medicine79379411.

SarmientoJMFarnellMBQueFGNagorneyDM2002Pancreaticoduodenectomy for islet cell tumors of the head of the pancreas: long-term survival analysis. World Journal of Surgery2612671271.

SchurrPGStrateTReseKKaifiJTReicheltUPetriSKleinhansHYekebasEFIzbickiJR2007Aggressive surgery improves long-term survival in neuroendocrine pancreatic tumors: an institutional experience. Annals of Surgery245273281.

ServiceFJMcMahonMMO'BrienPCBallardDJ1991Functioning insulinoma – incidence, recurrence, and long-term survival of patients: a 60-year study. Mayo Clinic Proceedings66711719.

SkogseidBErikssonBLundqvistGLoreliusLERastadJWideLAkerstromGÖbergK1991Multiple endocrine neoplasia type 1: a 10-year prospective screening study in four kindreds. Journal of Clinical Endocrinology73281287.

SmithSLBrantonSAAvinoAJMartinJKKlinglerPJThompsonGBGrantCSvan HeerdenJA1998Vasoactive intestinal polypeptide secreting islet cell tumors: a 15-year experience and review of the literature. Surgery12410501055.

SogaJYakuwaY1994Pancreatic endocrinomas: a statistical analysis of 1857 cases. Journal of Hepato-Biliary-Pancreatic Surgery1522529.

SogaJYakuwaY1998aThe gastrinoma/Zollinger-Ellison syndrome: statistical evaluation of a Japanese series of 359 cases. Journal of Hepato-Biliary-Pancreatic Surgery57785.

SogaJYakuwaY1998bGlucagonomas/diabetico-dermatogenic syndrome (DDS): a statistical evaluation of 407 reported cases. Journal of Hepato-Biliary-Pancreatic Surgery5312319.

SogaJYakuwaY1998cVipoma/diarrheogenic syndrome: a statistical evaluation of 241 reported cases. Journal of Experimental and Clinical Cancer Research17389400.

SogaJYakuwaY1999Somatostatinoma/inhibitory syndrome: a statistical evaluation of 173 reported cases as compared to other pancreatic endocrinomas. Journal of Experimental and Clinical Cancer Research181322.

Atlas of Tumor Pathology

World Health Organization International Histological Classification of Tumours

SolorzanoCCLeeJEPistersPWVautheyJNAyersGDJeanMEGagelRFAjaniJAWolffRAEvansDB2001Nonfunctioning islet cell carcinoma of the pancreas: survival results in a contemporary series of 163 patients. Surgery13010781085.

SpeelEJRichterJMochHEgenterCSaremaslaniPRutimannKZhaoJBarghornARothJHeitzPU1999Genetic differences in endocrine pancreatic tumor subtypes detected by comparative genomic hybridization. American Journal of Pathology15517871794.

StammBHackiWHKlöppelGHeitzPUGastrin-producing tumors and the Zollinger-Ellison syndromeDayalYEndocrine Pathology of the Gut and Pancreas11991CRC PressBoca Raton, FL:155194.

StarkeASaddigCMansfeldLKoesterRTschaharganeCCzyganPGoretzkiP2005Malignant metastatic insulinoma-postoperative treatment and follow-up. World Journal of Surgery29789793.

TakahashiYAkishima-FukasawaYKobayashiNSanoTKosugeTNimuraYKanaiYHiraokaN2007Prognostic value of tumor architecture, tumor-associated vascular characteristics, and expression of angiogenic molecules in pancreatic endocrine tumors. Clinical Cancer Research13187196.

TanCCHallRISemeraroDIronsRPFreemanJG1996Ampullary somatostatinoma associated with von Recklinghausen's neurofibromatosis presenting as obstructive jaundice. European Journal of Surgical Oncology22298301.

TanGCiocAMPerez-MontielDEllisonECFrankelWL2004Microvascular density does not correlate with histopathology and outcome in neuroendocrine tumors of the pancreas. Applied Immunohistochemistry and Molecular Morphology123135.

TangSJDumotJAWangLMemmesheimerCConwellDLZuccaroGGoormasticMOrmsbyAHCowellJ2002Telomerase activity in pancreatic endocrine tumors. American Journal of Gastroenterology9710221030.

ThompsonGBvan HeerdenJAGrantCSCarneyJAIlstrupDM1988Islet cell carcinomas of the pancreas: a twenty-year experience. Surgery10410111017.

TomassettiPMiglioriMLalliSCampanaDTomassettiVCorinaldesiR2001Epidemiology, clinical features and diagnosis of gastroenteropancreatic endocrine tumours. Annals of Oncology12S95S99.

TomassettiPCampanaDPiscitelliLCasadeiRSantiniDNoriFMorselli-LabateAMPezzilliRCorinaldesiR2005Endocrine pancreatic tumors: factors correlated with survival. Annals of Oncology1618061810.

TriponezFDossehDGoudetPCougardPBautersCMuratACadiotGNiccoli-SirePChayvialleJACalenderA2006Epidemiology data on 108 MEN 1 patients from the GTE with isolated nonfunctioning tumors of the pancreas. Annals of Surgery243265272.

VasenHFLamersCBLipsCJ1989Screening for the multiple endocrine neoplasia syndrome type I. A study of 11 kindreds in The Netherlands. Archives of Internal Medicine14927172722.

VenkateshSOrdonezNGAjaniJSchultzPNHickeyRCJohnstonDASamaanNA1990Islet cell carcinoma of the pancreas. A study of 98 patients. Cancer65354357.

VerhoefSvan Diemen-SteenvoordeRAkkersdijkWLBaxNMAriyurekYHermansCJvan NieuwenhuizenONikkelsPGLindhoutDHalleyDJ1999Malignant pancreatic tumour within the spectrum of tuberous sclerosis complex in childhood. European Journal of Pediatrics158284287.

VezzosiDBouissonMEscourrouGLaurellHSelvesJSeguinPPradayrolLCaronPBuscailL2006Clinical utility of telomerase for the diagnosis of malignant well-differentiated endocrine tumours. Clinical Endocrinology646367.

VortmeyerAOHuangSLubenskyIZhuangZ2004Non-islet origin of pancreatic islet cell tumors. Journal of Clinical Endocrinology8919341938.

WarnerRR2005Enteroendocrine tumors other than carcinoid: a review of clinically significant advances. Gastroenterology12816681684.

WarrenSLeComptePMLeggMAThe Pathology of Diabetes Mellitus1966Lea & FebigerPhiladelphia:

WatsonRGJohnstonCFO'HareMMAndersonJRWilsonBGCollinsJSSloanJMBuchananKD1989The frequency of gastrointestinal endocrine tumours in a well-defined population – Northern Ireland 1970–1985. Quarterly Journal of Medicine72647657.

WeberHCVenzonDJLinJTFishbeinVAOrbuchMStraderDBGibrilFMetzDCFrakerDLNortonJA1995Determinants of metastatic rate and survival in patients with Zollinger-Ellison syndrome: a prospective long-term study. Gastroenterology10816371649.

WeilC1985Gastroenteropancreatic endocrine tumors. Klinische Wochenschrift63433459.

WermersRAFatourechiVWynneAGKvolsLKLloydRV1996The glucagonoma syndrome. Clinical and pathologic features in 21 patients. Medicine755363.