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.

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.

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.

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.

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.

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.

Hepatoid carcinoma of the pancreas: a case report and literature review of a heterogeneous group of tumors.

Hepatoid carcinomas are tumors that display, at least focally, cytologic and/or architectural features of hepatocellular carcinoma. They have been described in several organs, most notably in the stomach and ovary. We report a case of hepatoid carcinoma of the pancreas that developed in a 41-year-old woman in association with a pancreatic endocrine carcinoma. The fine needle aspiration material was characterized by the presence of monotonous, small-to-medium sized tumor cells with round nuclei and finely granular chromatin, intermixed with more atypical tumor cells displaying larger nuclei with coarse clumped chromatin, prominent nucleoli, and moderate amounts of foamy cytoplasm. The excised specimen displayed a poorly differentiated pancreatic endocrine carcinoma associated with well-defined islands of larger tumor cells growing in a perisinusoidal pattern which, based on their immunohistochemical profile and the demonstration of bile, proved to represent a hepatoid component. This case and prior examples in the literature suggest that hepatoid carcinomas of the pancreas appear to be a heterogeneous group of tumors (pure or associated with another histologic component) that are often associated with early liver metastasis and a short survival, although those arising as a component of endocrine tumors seem to fare slightly better. Hepatoid carcinoma of the pancreas should be included in the differential diagnosis of pancreatic tumors composed of large eosinophilic cells.

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.

Successful pancreatectomy with en-bloc resection of the celiac artery and portal vein for pancreatic endocrine carcinoma.

Invasion to the celiac axis and portal vein is one reason for the unresectability of pancreatic carcinoma of the body and tail. Some authors advocate a radical distal pancreatectomy with en-bloc resection of the celiac artery and portal vein. However, long-term survival is still rare. We report here on a very rare, long-term survivor of a locally-advanced endocrine carcinoma of the body of the pancreas that was treated by distal pancreatectomy with en-bloc resection of the celiac artery and portal vein. The patient recovered well postoperatively, and has survived for 55 months without evidence of recurrence. The experience gained in the present case suggests that radical pancreatectomy with en-bloc resection of the celiac artery and portal vein is a potential approach that might increase tumor resectability and improve the prognosis of patients with locally-advanced endocrine carcinomas of the pancreas.

The predictive value of CK19 and CD99 in pancreatic endocrine tumors.

Prediction of behavior in pancreatic endocrine tumors (PETs) is reliant on clinicopathologic features. However, there remains a cohort of PETs that behave aggressively despite showing indolent pathologic features. Recently, it has been suggested that CK19 and CD99 are sensitive ancillary markers that predict outcome in PETs. An analysis of 54 PETs and 2 resected liver metastases was undertaken to examine the relationship of CK19 and CD99 and the pathologic criteria in the WHO classification of PETs. CK19 was found to correlate with mitotic count (>5/50 high-power fields), an MIB-1 labeling index of > or =2%, lymphovascular/perineural permeation, lymph node involvement, and liver spread. Although not statistically significant, CK19-negative tumors tended to be smaller than the average tumor size in the series (2.5 vs. 3.6 cm). CD99 did not show any significant correlation with any of the WHO criteria. Tumors that are confined to the pancreas with low mitotic count and MIB-1 labeling index, tended to be CD99-positive. Both CK 19 (negative) and CD99 (positive) correlated with insulin-positive PETs. In conclusion, CK 19 may prove to be a useful ancillary diagnostic test in the routine work-up of PETs. CD99 does not appear to be as useful. There is no compelling evidence, from our study, to suggest that both these markers may be used in concert to predict the behavior of PETs.

Intraductal spread by metastatic islet cell tumor (well-differentiated pancreatic endocrine neoplasm) involving the breast of a child, mimicking a primary mammary carcinoma.

Metastases to the breast are rare, accounting for an estimated 1% to 2% of malignant breast neoplasms. The key histopathologic features supporting a metastasis to the breast have been stated to be the absence of elastosis, presence of a pushing border (circumscribed lesion), multiple satellite foci, lymphatic emboli, and, most importantly, the absence of an in situ carcinoma component. We report a unique case of a pancreatic islet cell tumor metastatic to the breast of an 18-year-old girl. Clinically, the patient was thought to have a mammary primary because on her initial biopsy, the metastasis grew within mammary ducts and colonized a complex sclerosing lesion, simulating an in situ component. However, review of slides from the prior pancreatic neoplasm, review of slides from the subsequent mastectomy, and use of immunohistochemistry allowed recognition of the lesion as a metastasis, which proved to be the first clinical manifestation of a systemic relapse. To our knowledge, this is the second case of islet cell tumor reported to metastasize to the breast, and the first report of a metastasis proven to have grown within existing ducts of the breast by immunohistochemistry.

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.

Differences in survival for patients with resectable versus unresectable metastases from pancreatic islet cell cancer.

Well-differentiated islet cell tumors can be associated with aggressive biology, resulting in early metastases to the liver. This study was carried out to determine whether survival for patients with malignant islet cell tumors and synchronous liver metastases is affected by complete surgical resection. Thirty-one patients with synchronous liver metastases from islet cell cancer underwent surgical exploration with the intent for complete tumor resection, and all patients underwent resection of the pancreatic primary. The patients were divided into two groups, those with resectable versus unresectable liver metastases. Twenty-six of 31 (84%) patients underwent complete resection of both the primary tumor and all liver metastases, and 5 (16%) patients underwent only complete resection of the pancreatic primary without liver resection. To extirpate the primary tumor, a pancreaticoduodenectomy was performed in 11 of the 26 (42%) completely resected patients and in 4 of the 5 (80%) incompletely resected patients, P = NS. The remainder of the patients underwent distal pancreatectomy. There were no statistical differences in primary tumor size, lymph node metastases, or adjuvant treatments between patients with resected and unresected liver metastases. The median overall survival for the completely resected group was 78 months, longer than the 17 months for the group with unresectable liver metastases (P = 0.06). Complete tumor resection (or the tumor biology that allows such complete resection) affords a survival advantage to patients with metastatic islet cell tumors of the pancreas. Patterns of liver metastases from islet cell tumors, specifically multiple bilobar metastases that are not amenable to resection and/or ablation, predict a poor outcome despite resection of the primary pancreatic tumor.

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.

The clinical value of serum CEA, CA19-9, and CA242 in the diagnosis and prognosis of pancreatic cancer.

AIM: Serum tumour markers carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9) and CA242 were investigated to evaluate the values of single and combined test in the diagnosis and prognosis of pancreatic cancer. METHODS: Pre-operative serum CEA, CA19-9 and CA242 were measured in 105 pancreatic cancers, 70 non-pancreatic malignancies and 30 benign pancreatic diseases. RESULTS: The sensitivity of CA19-9 alone was the highest in pancreatic cancer patients (80%), but the specificity was significantly lower than that of CEA and CA242 (P<0.01). The combination of CEA and CA242 could increase the specificity to 92%. In serum CA242 positive patients, the survival time was remarkably shorter than that of patients with negative result (P<0.01). The survival time in patients with more than two markers positive expression of CEA, CA19-9 and CA242 was obviously shorter than that of only one or no marker positive expression (P<0.05). CONCLUSION: The diagnostic rate of CA19-9 in pancreatic cancer is better than that of CEA and CA242. Combined detection of CEA and CA242 can improve the diagnostic specificity obviously. High levels of serum markers are associated with advanced stage of the disease. Patients with two or three markers positive expression of CEA, CA19-9, and CA242 simultaneously had a shorter survival time.

[Surgical treatment of gastric, enteric, and pancreatic endocrine tumors Part 1. Treatment of primary endocrine tumors]. / Traitement chirurgical des tumeurs endocrines gastro-entéro-pancréatiques.

Endocrine tumors (ET) of the digestive tract (formerly called neuroendocrine tumors) are rare. They are classified into two principal types: gastrointestinal ET's (formerly called carcinoid tumors) which are the most common, and pancreaticoduodenal ET's. Functioning ET's secrete polypeptide hormones which cause characteristic hormonal syndromes. The management of ET is multidisciplinary. Poorly-differentiated ET's have a poor prognosis and are treated by chemotherapy. Surgical excision is the only curative treatment of well-differentiated ET's. The surgical goals are to: 1. prolong survival by resecting the primary tumor and any nodal or hepatic metastases, 2. control the symptoms related to hormonal secretion, 3. prevent or treat local complications. The most common sites of gastrointestinal ET's ( carcinoids) are the appendix and the rectum; these are often small (<1 cm), benign, and discovered fortuitously at the time of appendectomy or colonoscopic removal. Ileal ET's, even if small, are malignant, frequently multiple, and complicated in 30-50% of cases by bowel obstruction, mesenteric invasion, or bleeding. The carcinoid syndrome (consisting of abdominal pain, flushing, diarrhea, hypertension, bronchospasm, and right sided cardiac vegetations) is caused by the hypersecretion of serotonin into the systemic circulation; it occurs in 10% of cases and is usually associated with hepatic metastases. More than half of the cases of pancreatic ET are non-functional. They are usually malignant and of advanced stage at diagnosis presenting as a palpable or obstructing mass or as liver metastases. Insulinoma and gastrinoma (cause of the Zollinger-Ellison syndrome) are the most common functional ET's. 80% are sporadic; in these cases, tumor size, location, and malignant potential determine the type of resection which may vary from a simple enucleation to a formal pancreatectomy. In 10-20% of cases, pancreaticoduodenal ET presents in the setting of multiple endocrine neoplasia (NEM type I), an autosomal-dominant genetic disease with multifocal endocrine involvement of the pituitary, parathyroid, pancreas, and adrenal glands. For insulinoma with NEM-I, enucleation of lesions in the pancreatic head plus a caudal pancreatectomy is the most appropriate procedure. For gastrinoma with NEM-I, the benefit of surgical resection for tumors less than 2-3 cm in size is not clear. The lesions are frequently small, multiple, and widespread and recurrence is frequent after excision. The long-term prognosis is nevertheless fairly good. But the eventual development of liver metastases which are the most common cause of mortality still argues for an aggressive surgical approach in the early stages of the disease.

Neuroendocrine carcinomas of the pancreas with 'Rhabdoid' features.

Neuroendocrine carcinomas of the pancreas are rare neoplasms whose morphologic features generally mirror those seen in neuroendocrine tumors in other organs. Rarely, however, they may display unusual morphologic appearances that can introduce difficulties for diagnosis. We report four cases of primary neuroendocrine carcinomas of the pancreas (islet cell tumors) that were characterized by prominent "rhabdoid" features of the tumor cells. The lesions occurred in two men and two women 37-79 years of age who presented with symptoms of biliary obstruction and epigastric pain; one patient had recurrent gastric ulcers and an elevated gastrin level. The tumors were located in the head and tail of the pancreas and measured 2.5-4.5 cm in greatest diameter. Histologic examination revealed sheets of monotonous tumor cells with uniform round nuclei showing dispersed chromatin and containing abundant densely eosinophilic cytoplasmic inclusions that displaced the nuclei toward the periphery. In all cases, the rhabdoid elements appeared to merge with areas showing a more conventional neuroendocrine morphology. Immunohistochemical studies in all cases showed strong cytoplasmic positivity of the rhabdoid tumor cells for chromogranin, synaptophysin, and cytokeratin. Recognition of this unusual morphologic appearance is of importance to avoid mistaking these lesions for other types of malignant neoplasm.

Nonfunctioning islet cell carcinoma of the pancreas.

BACKGROUND: Nonfunctioning islet cell carcinoma of the pancreas has a variable and often indolent natural history, which has resulted in a wide range of treatment recommendations. To more clearly define the natural history and appropriate treatment of this disease, we reviewed our institutional experience over the last 39 years. METHODS: The records of all patients confirmed to have a nonfunctioning islet cell carcinoma of the pancreas were retrospectively reviewed. Kaplan-Meier life tables were constructed and log-rank comparisons were performed. RESULTS: The 73 patients studied had an overall 5-year actuarial survival rate of 50%. Patients with localized disease at presentation (n = 39) had a significantly higher survival rate (p = 0.03) compared with patients with metastatic disease (n = 34). The 19 patients who underwent a potentially curative resection of the primary tumor had a significantly higher survival rate (p = 0.03) compared with the 20 patients with locally advanced, unresectable, nonmetastatic disease. Nine of these 20 patients died of complications of the primary tumor. In contrast, only 2 of 22 cancer-related deaths in the 34 patients with metastatic disease at diagnosis were due to the primary tumor. CONCLUSIONS: (1) Surgical resection should be performed in patients with resectable nonmetastatic disease. (2) Resection of the primary tumor in the presence of metastatic disease is rarely indicated. (3) Innovative treatment strategies are needed for patients with locally advanced, unresectable, nonmetastatic tumors of the pancreatic head.