Malignant-functioning neuroendocrine tumors of the pancreas: A survival analysis.

BACKGROUND: Malignant-functioning pancreatic neuroendocrine tumors (mFpNETs) are rare. Research analyzing the presentation, biological behavior, and patient outcomes of these tumors is limited. METHODS: We used the Surveillance, Epidemiology, and End Results database to identify patients with malignant insulinomas, gastrinomas, glucagonomas, vasoactive intestinal peptide secreting tumors (VIPomas), somastatinomas, and mixed islet cell tumors (MICTs). The primary endpoint of this study was to identify factors affecting survival. RESULTS: We identified 401 patients with mFpNETs. Between histologic subtypes, there were significant differences in sex and age, and in tumor size, grade, location, and stage. Median survival time for insulinomas was 12.7 years; gastrinomas, 10.2 years; glucagonomas, 7.7 years; VIPomas, 7.9 years; and MICTs, 3.4 years. Multivariable analysis showed that histology (insulinoma, gastrinoma, and VIPoma; P = .009), absence of distant metastases (P = .002), age < 50 years (P = .001), surgical intervention (P = .001), and stage I/II disease (P = .011) were independently associated with prolonged survival. Subgroup analysis demonstrated that removal of the primary tumor in stage IV mFpNETs was associated with significantly prolonged survival (P = .01). CONCLUSION: mFpNETs are rare tumors that commonly present at an advanced stage despite hormonal secretion. Primary tumor resection is associated with longer survival in stages I-III as well as stage IV tumors.

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

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

Survival impact of malignant pancreatic neuroendocrine and islet cell neoplasm phenotypes.

BACKGROUND: The low incidence of malignant "functional" (F) or "nonfunctional" (NF) neuroendocrine islet cell tumors (ICTs) of the pancreas represents a challenge to precise post-therapeutic survival prediction. This study examined the survival impact of malignant pancreatic ICT morphologic subtypes. METHODS: A pancreatic ICT data set was created from a US-based population database from 1980-2004. Prognostic factors with survival impact and relationships between surgical therapy and overall survival (OS) were analyzed. RESULTS: There were 2,350 individuals with malignant ICTs. Histologic subtypes included carcinoid tumors, islet cell carcinomas, neuroendocrine carcinomas, and malignant gastrinomas, insulinomas, glucagonomas, or VIPomas. There was no difference in resection rates between FICTs and NFICTs (23% vs. 20%, P = ns). Median OS was 30 months, with group differences ranging from NE carcinomas (21) to VIPomas (96; P < 0.0001). Median OS of resected versus unresected FICTs was 172 versus 37 months, while that of NFICTs was 113 versus 18 months (P < 0.0001). Compared to neuroendocrine carcinomas, hazard ratios were: VIPomas 0.48, gastrinomas 0.65, carcinoid tumors 0.76, insulinomas 0.84, glucagonomas 0.93, and islet cell carcinomas 1.0. CONCLUSIONS: When controlled for other established prognostic parameters, histopathologic subtype assignment of pancreatic ICTs affects survival prediction. Resection is associated with superior survival for all tumor types.

Prognostic relevance of survivin in pancreatic endocrine tumors.

BACKGROUND: Better prognostic markers are needed for pancreatic endocrine tumors. Survivin is an apoptosis inhibitor that is suggested to have a negative prognostic impact in several tumor types. Contradictory data exist, especially regarding the significance of a nuclear versus cytoplasmic location of survivin. The prognostic relevance of nuclear and cytoplasmic survivin expression in pancreatic endocrine tumors-controlled for the tumor Ki-67 index, World Health Organization classification, and TNM stage-was investigated. METHODS: A total of 111 patients treated at a tertiary referral center were retrospectively evaluated. Clinical data were gathered from medical records. Immunohistochemistry for survivin and Ki-67 was performed on paraffin-embedded tissue. Univariate and multivariate Cox analyses were performed. RESULTS: Patients with tumors that had <5% survivin-positive nuclei had a mean survival of 225 months [95% confidence interval (CI) 168-281]. The corresponding figure for patients with 5 to 50% survivin-positive tumor cell nuclei was 101 months [95% CI 61-140; hazard ratio (HR) 2.4; P < 0.01) and with >50% survivin-positive nuclei 47 months (95% CI 24-71; HR 4.9; P < 0.001). Nuclear survivin expression in >50% of the tumor cells was an independent marker of a poor prognosis (HR 5.7; P < 0.01). Cytoplasmic survivin was not a significant prognostic factor in the multivariate analysis (HR 0.94; P = 0.90). CONCLUSIONS: High expression of nuclear survivin is a significant marker of a poor prognosis in patients with a pancreatic endocrine tumor.

Extended surgery for advanced pancreatic endocrine tumours.

BACKGROUND: Pancreatic endocrine tumours are often diagnosed at an advanced stage with hepatic metastasis. This study investigated whether extended resections for advanced malignant pancreatic endocrine tumours influenced disease-free and disease-specific survival. METHODS: Patients who had curative resection of pancreatic endocrine tumours were analysed retrospectively for disease-free and disease-specific survival, with a focus on the role of extended surgical resection. RESULTS: Forty-one patients were included in the analysis, 13 of whom underwent extended surgical resection in addition to pancreatic resection. This included partial liver resection in nine patients, portal vein resection in three, partial gastric resection in five and liver transplantation in three patients. There were no deaths in hospital or within 30 days. Median follow-up was 40 (range 2-239) months. Thirty-five, 24 and 13 patients survived more than 1, 3 and 5 years respectively. Patients who underwent extended resection had similar disease-specific survival to those who had pancreatic resection alone (hazard ratio (HR) 1·50, 95 per cent confidence interval (c.i.) 0·35 to 6·35; P = 0·581) but with a higher frequency of complications (odds ratio (OR) 4·28, 95 per cent c.i. 1·04 to 17·62; P = 0·044). Among patients with liver metastases, the mortality rate was higher in those in whom liver resection was not possible than in patients who had liver resection (HR 9·24, 1·00 to 85·18; P = 0·049). Patients who had liver resection had similar disease-specific survival to those without liver metastases (HR 0·84, 0·09 to 7·57; P = 0·877). CONCLUSION: Extended surgical resection for locally advanced and metastatic pancreatic endocrine tumours is feasible with encouraging disease-specific survival.

Support for a postresection prognostic score for pancreatic endocrine tumors.

BACKGROUND: Prognostic scores predicting long-term survival of patients with pancreatic neuroendocrine tumors (PNETs) have been created. The purpose of this study was to validate a prognostic scoring scheme at a single institution. METHODS: We reviewed all resections for PNETs from 1996 to 2004. Prognostic scores based on patient age, tumor grade, and distant metastasis were calculated. Survival was compared with an established postresection prognostic score for PNETs. RESULTS: A total of 34 PNETs were identified. Predicted 5-year survival for prognostic scores of 1, 2, and 3 were 76.7%, 50.9%, and 35.7%, respectively. Final prognostic scores of 1, 2, and 3 were observed in 13 (38%), 18 (53%), and 3 (9%) patients, with observed actual 5-year survivals of 92.3%, 72.2%, and 66.7%, respectively. CONCLUSIONS: PNET prognostic scores were found to be inversely related to survival. PNET postresection prognostic score categories may be useful tools in predicting long-term survival.

First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas.

BACKGROUND: Temozolomide is an active agent in metastatic pancreatic endocrine carcinomas. In vitro data indicate that the combination of capecitabine and temozolomide is synergistic for induction of apoptosis in neuroendocrine tumor cell lines. The authors retrospectively evaluated the efficacy of capecitabine and temozolomide in 30 patients with metastatic pancreatic endocrine carcinomas to assess response rate, progression free survival (PFS), and overall survival (OS). METHODS: Patients with metastatic, well, or moderately differentiated pancreatic endocrine carcinomas who had not received prior systemic chemotherapy were treated with capecitabine (750 mg/m² twice daily, days 1-14) and temozolomide (200 mg/m² once daily, days 10-14) every 28 days. RESULTS: Among 30 patients treated, 21 (70%) patients achieved an objective radiographic response. Median progression-free survival was 18 months. The rate of survival at two years was 92%. Only 4 patients (12%) experienced grade 3 or 4 adverse events. CONCLUSIONS: The combination of capecitabine and temozolomide is associated with an exceptionally high and durable response rate in metastatic endocrine carcinomas of the pancreas. Clinical endpoints, including response rate, survival, and toxicity, are superior to those observed with streptozocin-based regimens.

Proposed histopathologic grading system derived from a study of KIT and CK19 expression in pancreatic endocrine neoplasm.

Predicting the biologic behavior of pancreatic endocrine neoplasm in the absence of local invasion or metastasis is difficult. We recently proposed an immunohistochemical classification system based on a combination of KIT and CK19 expression: low risk (KIT-/CK19-), intermediate risk (KIT-/CK19+), and high risk (KIT+/CK19+). In the current study, we sought histopathologic features that correlated with the immunohistochemical categories and that could be used in predicting tumor behavior. We assessed histologic findings of 97 pancreatic endocrine neoplasm that had been classified into 3 risk groups based on KIT/CK19 expression. Clinicopathologic associations with prognosis were evaluated using Cox proportional hazards regression models. Tumor size, mitoses, infiltrative border, extrapancreatic extension, perineural invasion, and presence of amyloid were significantly different among the 3 risk groups, and tumor necrosis approached statistical significance as well (P = .089). A scoring system using mitoses, necrosis, and tumor border was developed as follows: mitosis: 0 (0/50 high-power field), 1 (1-3/50 high-power field), and 2 (≥4/50 high-power field); necrosis: 0 (absent) and 1 (present); tumor border: 0 (noninfiltrating) and 1 (infiltrating), giving a possible histology score of 0 to 4. Although there was an overall difference in disease-specific survival among the 4 histology scores (P < .001), there was not a statistically significant difference between patients with scores of 0 and 1 or between patients with scores of 3 and 4. Therefore, a 3-tied grading system was developed by combining score 0 and 1 tumors as grade 1, score 2 tumors as grade 2, and score 3 and 4 tumors as grade 3. There was a significant difference in survival, tumor metastasis, tumor recurrence, and functioning status among the 3 grades. By analyzing histopathologic features in KIT/CK19 risk groups, we developed a 3-tiered histopathologic grading system using reproducible parameters (mitoses, tumor necrosis, and infiltrative border) that are easy to apply in practice.

Surgical resection and multidisciplinary care for primary and metastatic pancreatic islet cell carcinomas.

INTRODUCTION: The role of multidisciplinary management of islet cell cancers (ICC) has not been fully investigated in a population-based setting. METHODS: The Los Angeles County Cancer Surveillance Program was assessed for patients with ICC between the years 1982 to 2006. Patients were stratified by treatment received and clinicopathologic characteristics and survival were compared. RESULTS: We identified 236 patients with ICC; 86 patients underwent curative-intent surgery with median survival for local, regional, and distant disease of 17.3, 12.2, and 4.0 years, respectively. In comparison, 102 patients underwent medical management alone; survival was significantly shorter when compared to the surgical cohort for local, regional, and distant disease (p < 0.05). To determine whether adjuvant chemotherapy was associated with improved survival, we compared patients who underwent surgery alone compared to patients who underwent surgery followed by adjuvant chemotherapy. Although patients with metastatic disease had 3-year longer survival with adjuvant chemotherapy, these improvements in survival were not statistically significant. CONCLUSION: Surgical resection was associated with improved survival compared to medical management for any extent of disease in patients with ICC. Furthermore, adjuvant chemotherapy was not associated with survival but does warrant further examination in patients with metastatic disease.

Pancreatic acinar cell carcinomas with prominent ductal differentiation: Mixed acinar ductal carcinoma and mixed acinar endocrine ductal carcinoma.

BACKGROUND: Pancreatic acinar cell carcinomas (ACCs) are clinically and pathologically distinct from pancreatic ductal adenocarcinomas (PDAs). Whereas endocrine differentiation has been well shown in ACCs, significant ductal components are rare. This paper reviews the clinicopathologic features of a series of ACCs with prominent ductal differentiation. DESIGN: Cases of pancreatic ACCs with significant ductal differentiation were identified in the surgical pathology databases of 2 academic centers. Patient clinical information, gross and histologic features, and histochemical and immunohistochemical (IHC) results were recorded. Cases were tested for KRAS2 mutations. RESULTS: Eleven cases were identified (10 men and 1 woman; age range 52 to 79 y). Four patients presented with jaundice. At last follow-up, 7 patients died of disease and 2 others had recurrences. Tumors measured between 2 and 5.5 cm and were ill-defined, nodular, and multilobulated. Ten were located in the head of the pancreas. All but 2 exhibited extrapancreatic invasion. All cases showed significant evidence of both acinar and ductal differentiation, estimated to be at least 25% of the neoplastic cells, and 3 cases in addition had endocrine differentiation in more than 25% of cells. Five cases were predominately acinar with intracellular and sometimes extracellular mucin ("mucinous acinar cell carcinoma" pattern). Six cases seemed more mixed with areas recapitulating typical PDAs whereas the other portions of the tumors seemed akin to typical acinar cell carcinomas ("combined acinar and ductal" pattern). IHC positive staining results were as: trypsin (92%), chymotrypsin (92%), monoclonal carcinoembryonic antigen (100%), CK19 (100%), B72.3 (73%), CA19.9 (73%), CD56 (18%), synaptophysin (36%), and chromogranin (36%). One case showed p53 over-expression aznd none showed DPC4/Smad4 loss. Two cases had KRAS2 mutations. CONCLUSION: Despite the early embryologic divergence of acinar and ductal cell lineages, rare pancreatic tumors have both acinar and ductal differentiation, usually predominantly the former. The clinical course is highly aggressive.

EUS-FNA predicts 5-year survival in pancreatic endocrine tumors.

BACKGROUND: Pancreatic endocrine tumors (PETs) differ in clinical behavior and prognosis. Determination of malignant potential through specimens obtained by EUS-FNA can help in the management of these patients. OBJECTIVE: To determine the value of EUS-FNA for diagnosing PETs and for classifying their underlying malignant potential based on the World Health Organization (WHO) classification. DESIGN: Single-center, retrospective, cohort study. SETTING: Tertiary referral hospital. PATIENTS: This study involved 86 consecutive patients (44 men, mean age 58 +/- 14 years) who had been diagnosed with PETs and submitted to EUS-FNA from January 1999 to August 2008. INTERVENTION: EUS-FNA of a pancreatic mass and/or a metastasis site. Immunohistochemistry on microbiopsies or on monolayer cytology was routinely used. The lesions were classified as recommended by the WHO. MAIN OUTCOME MEASUREMENTS: EUS-FNA sensitivity and 5-year survival rate. RESULTS: Overall, in 90% (77 of 86) of patients in this study, PET was diagnosed with EUS-FNA. The sensitivity did not vary with tumor size, type, location, or the presence of hormonal secretion. Of 86 patients, 30 (35%) were submitted to surgical resection. The kappa correlation index between the WHO classification obtained by EUS-FNA and by surgery was 0.38 (P = .003). Major discrepancies were found in the group of patients diagnosed with endocrine tumor of uncertain behavior by EUS-FNA, because 72% turned out to have well-differentiated endocrine carcinoma. Sixteen patients (27%) died during a mean follow-up period of 34 +/- 27 months. The 5-year survival rates were 100% for endocrine tumors, 68% for well-differentiated endocrine carcinomas, and 30% for poorly differentiated endocrine carcinomas (P = .008, log-rank test). LIMITATIONS: Retrospective design, selection bias, and small sample size. CONCLUSIONS: This largest single-center experience to date demonstrated the accuracy of EUS-FNA in diagnosing and determining the malignant behavior of PETs. EUS-FNA findings predict 5-year survival in patients with PETs.

Pancreatic endocrine tumor EUS-guided FNA DNA microsatellite loss and mortality.

BACKGROUND: The clinical course of pancreatic endocrine tumors (PET) depends on tumor size, the presence of invasion or metastasis, the Ki-67 index, mitoses per high power field, and mutational damage. Most of this information is not available before surgery for clinical decision making or prognostication. OBJECTIVE: To evaluate PET EUS-guided FNA (EUS-FNA) microsatellite loss analysis in the context of PET-related mortality. DESIGN: A single institution retrospective cohort. PATIENTS: Patients with PET diagnosed by EUS-FNA who underwent DNA microsatellite loss analysis and at least 1 year of follow-up or subsequent death. INTERVENTION: PET microsatellite loss analysis results and current clinical status were compared. RESULTS: Twenty-nine patients were included in the final analysis; the mean age of the patients was 57 years, and 10 were women (35%). The mean follow-up was 33.7 months (median 30 months, range 2-66 months). Twelve patients had disease progression, and 8 died, all from disease-specific causes. Malignant PET contained multiple microsatellite losses, with a median fractional allelic loss (FAL) of 0.37 (range 0.12-0.69, interquartile range [IQR] 0.23-0.42), significantly different from benign PET, median FAL 0 (range 0-0.18, IQR 0-0.08, P < .0001). Survival analysis revealed a significant difference in disease recurrence or progression at 2 years (P < .0001) and in the 5-year survival between patients with FAL 0.2 (P < .0001). Logistic regression could not be performed because of the perfect association between an FAL >0.2 and disease status or mortality. LIMITATIONS: Retrospective design, referral bias, and DNA analysis availability. CONCLUSIONS: PET EUS-FNA microsatellite loss analysis provides preoperative prognostic information. An FAL >0.2 is not only associated with disease progression but also with mortality.

Functional MRI evaluation of tumor response in patients with neuroendocrine hepatic metastasis treated with transcatheter arterial chemoembolization.

OBJECTIVE: The purpose of this study was to evaluate contrast-enhanced and diffusion-weighted MRI changes in neuroendocrine tumors treated with transcatheter arterial chemoembolization (TACE). MATERIALS AND METHODS: Sixty-six targeted lesions in 26 patients (18 men, eight women; mean age, 57 years) with hepatic metastasis of neuroendocrine tumors treated with TACE were retrospectively analyzed. MRI studies were performed before and after TACE. Imaging features included tumor size, percentage of enhancement in the arterial and portal venous phases, and diffusion-weighted imaging apparent diffusion coefficients (ADCs) of the tumor, liver, and spleen. Tumor response to treatment was recorded according to World Health Organization criteria and Response Evaluation Criteria in Solid Tumors. Liver function tests were performed, and clinical performance was assessed before and after treatment. Statistical analysis included paired Student's t tests and Kaplan-Meier survival curves. RESULTS: Mean tumor size and percentage enhancement in the arterial and portal venous phases decreased significantly after treatment (p < 0.0001). The tumor ADC increased from 1.51 x 10(-3) mm2/s before treatment to 1.79 x 10(-3) mm2/s after treatment (p < 0.0001), but the ADCs for the liver and spleen remained unchanged. Despite the change in tumor size, no patient in this cohort achieved complete response according to World Health Organization criteria and Response Evaluation Criteria in Solid Tumors. Partial response was achieved in only 27% and 23% of the patients according to the respective criteria. Results of liver function tests and performance status also remained unchanged. The mean survival period for all patients was 78 months. CONCLUSION: Contrast-enhanced and diffusion-weighted imaging showed significant changes after TACE of neuroendocrine tumors and can be used to assess response of targeted tumors.

WHO 2004 criteria and CK19 are reliable prognostic markers in pancreatic endocrine tumors.

BACKGROUND: It is difficult to predict the biologic behavior of pancreatic endocrine tumors in absence of metastases or invasion into adjacent organs. The World Health Organization (WHO) has proposed in 2004 size, angioinvasion, mitotic activity, and MIB1 proliferation index as prognostic criteria. Our aim was to test retrospectively the predictive value of these 2004 WHO criteria and of CK19, CD99, COX2, and p27 immunohistochemistry in a large series of patients with long-term follow-up. DESIGN: The histology of 216 pancreatic endocrine tumor specimens was reviewed and the tumors were reclassified according to the 2004 WHO classification. The prognostic value of the WHO classification and the histopathologic criteria necrosis and nodular fibrosis was tested in 113 patients. A tissue microarray was constructed for immunohistochemical staining. The staining results were scored quantitatively for MIB1 and semiquantitatively for CK19, COX2, p27, and CD99. The prognostic value of these markers was tested in 93 patients. RESULTS: The stratification of the patients into 4 risk groups according to the 2004 WHO classification was reliable with regard to both time span to relapse and tumor-specific death. In a multivariate analysis, the CK19 status was shown to be independent of the WHO criteria. By contrast, the prognostic significance of COX2, p27, and CD99 could not be confirmed. CONCLUSIONS: The 2004 WHO classification with 4 risk groups is very reliable for predicting both disease-free survival and the time span until tumor-specific death. CK19 staining is a potential additional prognostic marker independent from the WHO criteria for pancreatic endocrine tumors.

Prognostic and biological significance of cytokeratin 19 in pancreatic endocrine tumours.

AIM: The prognosis of well-differentiated pancreatic endocrine tumours (PETs) is difficult to establish on a histological basis. The expression of cytokeratin (CK19) has recently been proposed as an indicator of unfavourable outcome. However, this finding still needs to be verified and to be compared with more frequently used prognosticators such as proliferative indices, vascular and/or perineural invasion. The aim of this study was to evaluate the prognostic value of CK19 expression in PETs. METHODS AND RESULTS: One hundred and forty-five PETs were studied using two different anti-CK19 monoclonal antibodies (BA17 and RCK108). The results were statistically compared with proliferation markers, vascular and perineural invasion and the presence of metastases. On univariate analysis, CK19 immunoreactivity correlated with prognosis only when it was detected with the RCK108 antibody and only in the whole group of PETs and in insulinomas. Conversely, it did not predict survival in non-functioning neoplasms. Ki67 index, mitotic count, vascular and perineural invasion were all statistically correlated with prognosis. On multivariate analysis, only the Ki67 index and metastases were independent prognosticators. CONCLUSIONS: CK19 expression correlates with patient survival only when detected with the RCK108 antibody and mainly in insulinomas. Ki67 index and metastases represent the only two independent predictors of survival.

Cytoreduction results in high perioperative mortality and decreased survival in patients undergoing pancreatectomy for neuroendocrine tumors of the pancreas.

We reviewed our experience with pancreatectomy for neuroendocrine tumors (NE) to determine outcomes after R0/R1 or R2 resection and compare them to patients in whom resection was not attempted. Data were reviewed for all patients presenting with NE tumors of the pancreas between 1990 and 2005. Kaplan-Meier survival curves were compared by log-rank analysis. Multivariate analysis was completed using Cox proportional hazards to identify risk factors for poor survival after resection. Of 120 patients, 65 (54%) had functional tumors. Resection was undertaken in 83: distal pancreatectomy in 41, pancreaticoduodenectomy in 27, enucleation in 14, and central pancreatectomy in 1. Survival was significantly longer after resection (91 months versus 24, P<0.001). R0/R1 resection was accomplished in 64 (77%) and resulted in lower perioperative mortality (2% versus 21%, P<0.01) and longer survival (112 months versus 24, P<0.001) compared to R2 resection. Survival after R2 resection was no better than after no resection. Factors predictive of decreased survival were moderate/poor differentiation, R2 resection, and high-risk features. Long-term survival is possible following complete resection for NE tumors of the pancreas. However, cytoreduction resulting in incomplete tumor removal carries significant perioperative mortality without long-term survival benefit and should be discouraged.

Hepatic arterial embolization and chemoembolization for the treatment of patients with metastatic neuroendocrine tumors: variables affecting response rates and survival.

BACKGROUND: The objective of this study was to determine the prognostic variables that influence response and survival in patients with metastatic neuroendocrine tumors who are treated with hepatic arterial embolization (HAE) or chemoembolization (HACE). METHODS: Patients with metastatic neuroendocrine tumors who underwent HAE or HACE were included in this retrospective study. Follow-up imaging studies were compared with baseline imaging to determine the radiologic response. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Univariate and multivariate analyses were performed to assess the prognostic variables that affected response and survival. RESULTS: The study included 69 patients with carcinoid tumors and 54 patients with pancreatic islet cell carcinomas. Patients who had carcinoid tumors had a higher response rate (66.7% vs. 35.2%; P = 0.0001) and had longer PFS (22.7 mos vs. 16.1 mos; P = 0.046) and OS (33.8 mos vs. 23.2 mos; P = 0.012) compared with patients who had islet cell carcinomas. For patients with carcinoid tumors, multivariate analysis identified male gender as the only independent risk factor for poor survival (P = 0.05). Octreotide was predictive marginally for PFS (P = 0.06). Patients who were treated with HAE had a higher response rate than patients who were treated with HACE (P = 0.004). For patients with islet cell carcinoma, an intact primary tumor, > or = 75% liver involvement, and extrahepatic metastases were associated with reduced OS in the univariate analysis; the presence of bone metastases was the only risk factor (P = 0.031) in the multivariate analysis. Patients who were treated with HACE had a prolonged OS (31.5 mos vs. 18.2 mos) and improved response (50% vs. 25%) compared with patients who were treated with HAE, although the differences did not reach statistical significance. CONCLUSIONS: Patients with carcinoid tumors had better outcomes than patients with islet cell carcinomas. The addition of intraarterial chemotherapy to HAE did not improve the outcome of patients with carcinoid tumors, but it seemed to benefit patients with islet cell carcinomas. In patients who had carcinoid tumors, male gender predicted a poor outcome, and a trend toward prolonged PFS was observed in patients who received concomitant octreotide. An intact primary tumor, extensive liver disease, and bone metastases were associated with reduced survival in patients with islet cell carcinomas.

Experiences with nonfunctioning neuroendocrine neoplasms of the pancreas.

AIM: We present our experiences in the treatment of nonfunctioning neuroendocrine neoplasms of the pancreas to define the natural history and to suggest proper management. METHOD: From August 1993 to June 2005, the medical records of 19 patients with the diagnosis of nonfunctioning neuroendocrine (islet cell) neoplasms of the pancreas were retrospectively reviewed with respect to patient characteristics, characteristics of neoplasms, surgical procedures, and long-term outcomes in the Yonsei University Medical Center, Seoul, Korea. RESULTS: The median age of the patients (10 males and 9 females) was 51 years. Abdominal pain and discomfort (58%) were the most frequent symptoms. Tumors with a median size of 3.5 cm were noted in the head of the pancreas in 9 patients and in the body or in the tail of the pancreas in 10 patients. Thirteen patients (68%) had neoplasms with malignant features. Twelve patients (63%) underwent surgical resection, and curative resection was performed in 10 patients (53%). Unresectable neoplasms (p=0.0055), distant metastases (p=0.0124), and macroinvasion to adjacent organs (p=0.024) had significantly adverse effects on the mean survival. Neither palliative surgery nor adjuvant chemoradiation therapy seemed to be effective. CONCLUSIONS: Early detection of nonfunctioning neuroendocrine neoplasms of the pancreas is important, and curative resection should be attempted for a good prognosis.

Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas.

PURPOSE: The role of systemic chemotherapy in the management of pancreatic endocrine carcinoma (islet cell carcinoma; PEC) is an area of considerable controversy. Response rates ranging from 6% to 69% have been reported for streptozocin-based chemotherapy. We retrospectively studied 84 patients with locally advanced or metastatic PEC who had been treated with fluorouracil, doxorubicin, and streptozocin (FAS) to determine the objective response rate, duration of progression-free survival (PFS), and duration of overall survival (OS). PATIENTS AND METHODS: Eligible patients had histologic or cytologic confirmation of their tumor and measurable disease on computed tomography or magnetic resonance imaging scans. Response to treatment was evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors Committee. RESULTS: Sixty-one of the patients were male and 23 were female, with a median age of 54 years (range, 24 to 78 years). The response rate (RR) to FAS was 39%, with a median response duration of 9.3 months. The 2-year PFS rate was 41%, and the 2-year OS rate was 74%. The extent of liver metastatic disease correlated with a worse PFS (P = .01 by log-rank test) and a worse OS (P < .0001 by log-rank test). Analyses showed that metastatic replacement of more than 75% of the liver and prior chemotherapy were independently associated with inferior PFS. CONCLUSION: Patients with locally advanced or metastatic PEC who are treated with FAS may have a reasonable RR, and responders may experience longer PFS and OS. The volume of metastases in the liver is the most important predictor of outcome.