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.

Mixed acinar-endocrine carcinoma of the pancreas: new clinical and pathological features in a contemporary series.

OBJECTIVE: The objective of this study was to characterize the novel clinical and pathological features of mixed acinar-endocrine carcinoma of the pancreas. METHODS: This was a retrospective review of medical records and surgical pathology specimens of patients with a diagnosis of mixed acinar-endocrine carcinoma of the pancreas at Cedars-Sinai Medical Center between 2005 and 2011. Additional immunohistochemistry was performed on the specimens of some patients. RESULTS: Five patients were identified. The median age at presentation was 74 years (range, 59-89 years), and all patients were male. The presenting symptoms were all related to tumor mass effects. The median size of the tumor was 10 cm (range, 3.9-16 cm). Preoperative clinical diagnosis aided by fine-needle aspiration biopsy was incorrect in all 5 cases. Most tumors (3/5) exhibited predominantly endocrine differentiation without hormonal production. Only 10% to 30% of cells were truly amphicrine, whereas most were differentiated into either endocrine or acinar phenotype. The clinical behavior ranged from moderate to aggressive with postoperative survival from 2.5 months to more than 3 years. Four patients received neoadjuvant or adjuvant chemotherapy with variable responses. CONCLUSIONS: Mixed acinar-endocrine carcinoma of the pancreas appears to be not uncommon in men, may harbor predominantly endocrine component, is often misdiagnosed by cytology, and exhibits variable clinical behavior. Mixed acinar-endocrine carcinoma of the pancreas should be considered in older patients with sizable pancreatic mass and may warrant aggressive surgical resection and chemotherapy.

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.

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.

Tumor size correlates with malignancy in nonfunctioning pancreatic endocrine tumor.

BACKGROUND: Tumor size is a criterion of staging in nonfunctioning pancreatic endocrine tumors as well as a predictor of outcome after curative resection. This study analyzes the correlation between tumor size and malignancy in patients with nonfunctioning pancreatic endocrine tumors. METHODS: All patients with nonfunctioning pancreatic endocrine tumors who underwent curative resection (R0) at our institution between 1990 and 2008 were considered. Their clinicopathologic characteristics were compared among 3 different groups according to tumor size. Univariate and multivariable analyses were performed. RESULTS: Over the study period, 177 patients were identified. Overall, 90 patients (51%) had a tumor size ≤2 cm (group 1), 46 (26%) had tumor size between >2 cm and ≤4 cm (group 2), and 41 (23%) had tumor size >4 cm (group 3). Tumors ≤2 cm were more frequently incidentally discovered (group 1, 57% vs group 2, 51% vs group 3, 32%; P = .014) and benign (group 1, 81% vs group 2, 65% vs group 3, 5%; P < .0001). The presence of a nonfunctioning pancreatic endocrine tumor >2 cm and a nonincidental diagnosis of the tumor were independent predictors of malignancy at multivariable analysis. None of the 51 patients (29%) with a pancreatic endocrine tumor ≤2 cm that was incidentally diagnosed died of disease. CONCLUSION: A strict correlation between tumor size and malignancy in nonfunctioning pancreatic endocrine tumors was demonstrated. A nonoperative management could be advocated for tumors ≤2 cm when discovered incidentally.

Nonfunctioning pancreatic endocrine tumor with extension into the main pancreatic duct: report of a case.

Pancreatic endocrine tumors (PETs) rarely involve the main pancreatic duct. We report a case of malignant nonfunctioning pancreatic endocrine tumor (NFPET) with prevalent intraductal growth. A 47-year-old woman was referred to us after ultrasonography at a routine health check showed diffuse swelling of the pancreas. Preoperative imaging showed a solid mass in the tail of the pancreas and a bulging intraductal mass in the main pancreatic duct. We performed total pancreatectomy because the tumor occupied almost the entire lumen of the main pancreatic duct. Histological examination confirmed well-differentiated endocrine carcinoma. We review reported cases of the intraductal growth of NFPETs and discuss the pathogenesis of these unusual tumors.

TNM stage and grade in predicting the prognosis of operated, non-functioning neuroendocrine carcinoma of the pancreas--a single-institution experience.

OBJECTIVE: To evaluate the prognostic significance of TNM and grading categories in curatively resected non-functioning neuroendocrine pancreatic carcinoma (nfnepC). METHOD: Eighteen nfnepC were retrospectively analyzed for differences in survival. RESULTS: (1) There was a correlation between pT (P = 0.026), respectively pM categories (P = 0.016) and survival. (2) G categories and length of survival were closely correlated (P = 0.0036). (3) Disease stages I-IV had a significant effect on survival (P = 0.051). (4) The WHO classification in well and poorly differentiated carcinomas proved to be the most conclusive predictive factor (P = 0.0009). (5) Subgroups with significantly different prognoses determined by histological grade were present within disease stage II. CONCLUSIONS: The retrospective analysis showed a good correlation between survival and pT, pM, tumor stage, G categories, and WHO classification in well and poorly differentiated carcinomas. Including histological differentiation in the staging system or carrying it out separately in well and poorly differentiated carcinomas, could enhance the predictive potential of TNM-based disease stages.

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.

Concurrent insulinoma and pancreatic adenocarcinoma: report of a rare case and review of the literature.

Pancreatic adenocarcinoma is the 5th leading cause of cancer-related death in Western countries and insulinomas are rare endocrine neoplasms of the pancreas. The concurrent appearance of pancreatic adenocarcinoma and insulinoma is very rare and to the best of our knowledge has never been reported again. Herein, we present such an occurrence in a 74-year-old man. Resection of a mass in the uncinate process of the pancreas revealed pancreatic adenocarcinoma with severe desmoplastic reaction. Two years later, due to symptomatology persistence the patient was re-examined and a new 2 cm mass in the uncinate process was found leading to surgery, which demonstrated a 2 cm endocrine islet-cell tumor. Establishing a diagnosis in patients with insulinoma is difficult and the imaging studies still have low sensitivity and specificity except for intra-operative ultrasonography, which is the most accurate method detecting 90% of these lesions.

Laparoscopic radiofrequency thermal ablation of neuroendocrine hepatic metastases: long-term follow-up.

BACKGROUND: Since our first report 13 years ago, laparoscopic radiofrequency ablation has been incorporated into the treatment algorithm of patients with neuroendocrine liver metastases. The aim of this study is to report long-term oncologic results. METHODS: Eighty-nine patients with neuroendocrine hepatic metastases underwent 119 laparoscopic radiofrequency ablation sessions within 13 years. Data were obtained from a prospective, Institutional Review Board approved database. Univariate Kaplan Meier and multivariate Cox proportional hazards model were used for statistical analyses. Data are expressed as mean ± standard error of the mean. RESULTS: Thirty-five women and 54 men with a mean age of 56 ± 1.4 years were included in this study. Tumor types included were carcinoid (n = 55), pancreatic islet cell (n = 23), and medullary thyroid cancer (n = 11). Mean tumor size was 3.6 ± 0.2 and the number of lesions was 6 ± 1. Perioperative morbidity was 6%, and 30-day mortality was 1%. Symptom relief was achieved in 97% of patients after radiofrequency ablation. Median follow-up was 30 ± 3 months. Twenty-two percent of patients developed local liver recurrence, 63% developed new liver lesions, and 59% developed extrahepatic disease in follow-up. Repeat radiofrequency ablation (27%) and chemoembolization (7%) were used to achieve additional local tumor control in follow up. Median disease-free survival was 1.3 years and the overall survival was 6 years after radiofrequency ablation. Liver tumor volume, symptoms, and extrahepatic disease were independent predictors of survival. CONCLUSION: To our knowledge, this is the largest prospective experience with radiofrequency ablation of neuroendocrine liver metastases. Effective symptom palliation and long-term local tumor control are possible in these patients with minimal morbidity.

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.

Hypoglycemia associated with the production of insulin-like growth factor II in a pancreatic islet cell tumor: a case report.

An insulinoma is characterized by endogenous hyperinsulinemia and hypoglycemia. However, it has been reported that insulinomas with normal levels of plasma insulin and a normal insulin to glucose ratio occur in patients with hypoglycemia. Although overproduction of Insulin-like growth factor II (IGF-II) by non-islet cell tumors such as large mesenchymal tumors, can cause hypoglycemia, no cases of circulating plasma IGF-II from an islet cell tumor contributing to hypoglycemia have been reported. We report here a rare case of a pancreatic islet tumor in a patient with hypoglycemia that was associated with increased plasma IGF-II, which returned to normal after tumor resection.

Wilms' tumor, pancreatic islet cell carcinoma, and pheochromocytoma in a child.

We present the first case of Wilms' tumor, pancreatic islet cell carcinoma, and pheochromocytoma affecting the same individual. This case underscores the importance of repeat biopsies in patients with multiple neoplasms to confirm the diagnosis and guide management.

Is laparoscopic resection adequate in patients with neuroendocrine pancreatic tumors?

Since the first reports with laparoscopic resection of islet cell tumors in 1996, the experience worldwide is still limited, with only short-term outcomes available. Some have suggested that a malignant tumor is a contraindication to laparoscopic resection. Aim The aim of this study was to evaluate the feasibility, safety, and long-term outcome of the laparoscopic approach in patients with functioning, nonfunctioning, or overt malignant pancreatic neuroendocrine tumor (PNT). To our knowledge this is the largest single-institution series on this subject to date. Patients and methods A total of 49 consecutive patients (43 women, 6 men; mean age 58 years, range 22-83 years) underwent laparoscopic pancreatic surgery (LPS) from April 1998 to June 2007. Preoperative localization was done by computed tomography, magnetic resonance imaging, endoscopic ultrasonography, and Octreoscan imaging. Other than 9 PNTs localized in the head of the pancreas, all tumors were located in the left pancreas. Malignancy was diagnosed based on the presence of lymph nodes or liver metastasis. There were 33 patients with functioning tumors: 4 with gastrinomas (mean size 1.2 cm), 1 with a glucagonoma (4 cm), 3 with vipomas (3.2 cm), 2 with carcinoids (5.2 cm), 20 with sporadic insulinomas (1.4 cm), 2 with insulinoma/multiple endocrine neoplasia type 1 (MEN-1) (4.4 cm), and 1 with a malignant insulinoma (13 cm). Sixteen patients had a nonfunctioning tumor (mean size 5 cm). The following techniques were performed: laparoscopic spleen-preserving distal pancreatectomy (Lap SPDP), laparoscopic distal pancreatectomy with splenectomy (Lap SxDP) and laparoscopic enucleation (Lap En)/laparoscopic excision (Lap E). Lymph node dissection was performed when malignancy was suspected (Strasberg s technique). Evaluation criteria included operative and postoperative factors, pathologic data including R0 or R1 resection (the pancreatic transection margin and all transection margins on the specimen were inked). Long-term outcomes were analyzed by tumor recurrence and patient survival. Results Four cases (8.2%) were converted to open surgery. Overall, Lap SPDP, Lap SxDP, and Lap En/Lap E were performed in 15 (33.3%), 8 (17.8%), and 22 (48.9%) patients, respectively. The operative time and blood loss was significantly lower in the Lap En group compared with the other laparoscopic techniques. The group of patients with malignant tumors undergoing Lap SxDP had a longer operating time and greater blood loss compared with the other distal pancreatectomy (Lap DP) techniques. Overall, the postoperative complications were significantly higher in the Lap En group (42.8%) than in the Lap DP (Lap SPDP+Lap SxDP) group (22%). These complications were mainly pancreatic fistula: 8.7% after Lap DP and 38% after Lap En. The overall morbidity was significantly higher after Lap SPDP (26.7%) than after Lap SxDP (12.5%) owing to the occurrence of splenic complications in the Lap SPDP group without splenic vessel preservation two of seven (28.5%). The means and ranges of hospital stay after Lap SPDP, Lap SxDP, and Lap En/Lap E were 5.9 (5-14), 7.5 (5-12), and 5.5 (5-7) days, respectively (NS). Pathology examination of the specimen showed R0 resection in all patients with malignant PNT. The mean time to resumption of previous activities for patients undergoing Lap DP or Lap En was 3 weeks. There were no postoperative (30 days) or hospital deaths. Conclusions This series demonstrates that LPS is feasible and safe in benign-appearing and malignant neuroendocrine pancreatic tumors (NEPTs). The benefits of minimally invasive surgery were manifest in the short hospital stay and acceptable pancreas-related complications in high-risk patients. LPS can achieve negative tangential margins in a high percentage of patients with malignant tumors. Although surgical cure is rare in malignant NEPTs, significant long-term palliation can be achieved in a large proportion of patients with an aggressive surgical approach.

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.