Malignant Pancreatic Endocrine Tumors Research Articles

A novel deletion of theMEN1gene in a large family of multiple endocrine neoplasia type 1 (MEN1) with aggressive phenotype

The MEN1 syndrome is associated with parathyroid, pancreatic and pituitary tumours and is caused by mutations in the MEN1 gene. In general, there is no genotype-phenotype correlation. To characterize a large family with MEN1 with aggressive tumour behaviour: malignant pancreatic endocrine tumours were present in five affected subjects and were the presenting features in three subjects. The coding region of MEN1 was sequenced. Gene copy number analysis was performed by multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (aCGH). Loss of heterozygosity (LOH) in tumour tissue was studied by microsatellite analysis. Insulin-like growth factor II (IGF-II) and CDKN1C/p57KIP2 expression were investigated by immunohistochemistry. Mutation screening by conventional PCR sequence analysis of patients' peripheral blood DNA did not reveal any mutation in the MEN1 or CDKN1B gene. Gene copy number analysis by MLPA and aCGH demonstrated a novel monoallelic deletion of 5 kb genomic DNA involving the MEN1 promoter and exons 1 and 2. LOH analysis indicated somatic deletion of maternal chromosome 11, including MEN1 locus (11q13) and 11p15 imprinting control regions (ICR). Methylation analysis of ICR demonstrated ICR1 hypermethylation and ICR2 hypomethylation in the tumour specimens. ICR1 and ICR2 control the expression of IGF-2 and CDKN1C/p57KIP2, respectively. Immunohistochemistry showed that expression of paternally expressed IGF-2 was up-regulated and the maternally expressed CDKN1C/p57KIP2 was lost in the pancreatic endocrine tumours. Gene copy number analysis by MLPA should be considered in patients with negative conventional mutation screening. Although large MEN1 deletion causes MEN1, disruption of imprinted CDKN1C/p57KIP2 and IGF-2 gene expression may contribute to tumour progression and aggressive phenotype.

Extended surgery for advanced pancreatic endocrine tumours

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. 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. 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). Extended surgical resection for locally advanced and metastatic pancreatic endocrine tumours is feasible with encouraging disease-specific survival.

Curative resection of a huge malignant pancreatic endocrine tumor by pancreatoduodenectomy with portal and superior mesenteric vein resection and reconstruction using the right ovarian vein: Report of a case

Nonfunctioning pancreatic endocrine tumors (PETs) are rare and generally asymptomatic. A 68-year-old woman who had refused treatment for a pancreatic mass, revealed by ultrasonography to be 55 mm in diameter, was referred to us again 29 months later with jaundice. Investigations showed an 82-mm tumor in the head of pancreas, exposed from the papilla of Vater to the duodenal lumen. After biliary decompression and drainage, we performed pancreatoduodenectomy with resection of the portal vein and superior mesenteric vein, followed by reconstruction using a cylindrically customized autologous graft harvested from the right ovarian vein. The tumor was resected curatively. Microscopically, it consisted of trabecular and ribbon-like arrangement of neoplastic cells. Immunohistochemical staining was positive for chromogranin A and synaptophysin and negative for insulin, gastrin, glucagons, somatostatin, and pancreatic peptide. Although metastasis was detected in a lymph node along the superior mesenteric vein with perineural invasion, the portal and superior mesenteric veins had not been invaded. The diagnosis was well-differentiated nonfunctioning PET. The patient had an uneventful postoperative course, and there has been no evidence of recurrence in 12 months.

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.

Impact of CT-based diagnostic imaging on management and outcome of nonfunctioning pancreatic tumors

Sporadic malignant non-functioning pancreatic endocrine tumors (NF-PETs) are an important subset of pancreatic neoplasms. The aim of this study was to assess the impact of improved imaging on these features in a tertiary referral centre within a 20-year follow-up. From 1988 to 2009, 51 patients were treated for sporadic malignant NF-PETs. Forty-one patients who underwent tumor resection were retrospectively attributed according to the date of the initial diagnosis, group 1: 1988-1999 vs. group 2: 2000-2009. Cross-sectional imaging led to positive prediction of NF-PETs in all patients. Curative resection was achieved in 76%. Synchronous metastases were present in 56% with a positive prediction of 43%. In group 1, the mean reported CT-determined tumor size was 56 vs. 54mm in group 2 (p = 0.89). Synchronous metastases were present in 61% in group 1 vs. 57% (p = 0.99) in group 2. Metachronous metastases were recorded in 39% in group 1 vs. 43% (p = 0.84) in group 2. The mean interval from initial resection to diagnosis of metastatic disease was significantly shorter (p = 0.01) in patients from group 1 (14 vs. 61months). Cumulative 5- and 10-year survival rates were 77% and 72% in group 1 vs. a 5-year survival rate of 66% in group 2. So far, improved CT-based imaging has no impact on earlier detection of initial synchronous metastases in sporadic malignant NF-PETs, while metachronous metastases are detected earlier.

Promising Advances in the Treatment of Malignant Pancreatic Endocrine Tumors

Pancreatic neuroendocrine tumors are classified as functional (10 to 30% of the tumors) or nonfunctional (50 to 80%).1 Functional pancreatic neuroendocrine tumors have long fascinated physicians because they produce florid syndromes, owing to ectopic secretion of various biologically active hormones (e.g., insulin and gastrin).1 In the past, the hormone excess syndrome was the leading cause of death; however, with advances in surgical and medical treatments, the natural history of pancreatic neuroendocrine tumors is becoming the major determinant of death in patients with functional tumors, similar to patients with nonfunctional tumors. This is occurring because more than 50% of all pancreatic . . .

Attenuated expression of menin and p27 Kip1 in an aggressive case of multiple endocrine neoplasia type 1 (MEN1) associated with an atypical prolactinoma and a malignant pancreatic endocrine tumor

Tumors in multiple endocrine neoplasia type 1 (MEN1) are generally benign. Since information on the pathogenesis of MEN1 in malignant cases is limited, we conducted genetic analysis and compared the expression of menin, p27(Kip1)(p27)/CDKN1B and p18(Ink4C)(p18)/CDKN2C with levels in benign cases. We describe the case of a 56 year-old male with an atypical prolactinoma and malignant pancreatic neuroenocrine tumor. At age 50, he had undergone transsphenoidal surgery to remove a prolactinoma. However, the tumor relapsed twice. Histological analysis of the recurrent prolactinoma revealed the presence of prolactin, a high MIB-1 index (32.1 %), p53-positive cells (0.2%), and an unusual association with FSH-positive cells. A few years later, he was also found to have a non-functioning pancreatic tumor with probable metastasis to the extradullar region. The metastatic region tested positive for chromogranin and CD56, and negative for prolactin, with 1.2 % of cells p53-positive. Although genetic analyses of the MEN1, p27, and p18 genes demonstrated no mutation, numbers of menin, p27 and p18 immuno-positive cells were significantly down-regulated in the recurrent prolactinoma, but that of p18 was intact in the metastatic region. Furthermore, MEN1 and p27 mRNA levels of the recurrent prolactinoma were down-regulated, particularly the MEN1 mRNA level, compared to levels in 10 cases of benign prolactinoma, while the p18 mRNA level was similar to that of normal pituitary. The tumor in this case may be a subtype of MEN1 showing more aggressive and malignant features probably induced by low levels of menin and p27.

On development of pancreatic endocrine surgery in China

The paper summarized the current situation of diagnosis and treatment of pancreatic endocrine tumors （PETs）in China.In recent sixty years, we understand PETs more deeply, and have all kinds of imaging technique to localize the tumors.It makes more cases having been diagnosed.Operation is the most important and the first choice of treatment.The concept of minimal-invasion runs through the surgical procedure.Multi-model strategy is used in therapy for malignant PETs with liver metastasis.Basic research is focused in mechanism and early diagnosis and it helps the clinical practice.Specialization and co-operation are emphasized in the development of PETs diagnosis and treatment. Key words: Pancreatic endocrine tumor; Diagnosis; Treatment

Rising Incidence of Pancreatic Cancer in France

Time trends in the incidence of pancreatic cancer vary considerably between countries. The aim of this study was to provide time trends in incidence during a 25-year period in a well-defined French population. The cancer registry in Burgundy (France) was used to study time trends between 1981 and 2005 by sex, age, subsite, and histology. They were analyzed using an age-period cohort model. Age-standardized incidence rates increased from 5.7 (1981-1985) to 7.9 per 100,000 (2001-2005) in men and from 2.6 to 4.6 in women. The mean percentage of variation by the 5-year period was +9.9% (P < 0.001, 95% confidence interval, 6.2%-13.6%) and +13.4% (P = 0.004, 95% confidence interval, 9.4%-17.5%), respectively. The increase in incidence was higher for cancers of the tail and corpus than for cancers of the head of pancreas and for malignant pancreatic endocrine tumors than for adenocarcinomas. The cumulative risk of developing a pancreatic cancer rose from 0.51% for men born in 1900 to 1.13% for those born in 1950. It was 0.34% and 0.55% for women, respectively. The incidence of pancreatic cancer has increased sharply in France both by period and by birth cohort. Etiological studies are required to explain the increase in the incidence.

Diagnosis and surgical management of functional pancreatic endocrine tumors: a report of 45 cases

Objective To investigate the diagnosis and treatment of functional pancreatic endocrine tumors (PETs). Methods The clinical data of 45 patients with functional PETs who were admitted to the Southwest Hospital from January 1998 to December 2008 were retrospectively analyzed. Etiologic and localization diagnosis were made preoperatively according to the manifestation and the results of color doppler ultrasound and computed tomography, respectively. Eight patients received resection of the body and tail of the pancreas and spleen, 32 received tumor enucleation, one received resection of the pancreaticobiliary junction and four received pancreaticoduodenectomy. All patients received chemotherapy after the operation. Results Thirty-four cases of the PETs were benign and the rest eleven cases were malignant. Eight cases of the PETs were in the head of the pancreas,26 in the tail of the pancreas, seven in the body of the pancreas and four cases were with multiple PETs. The diameters of the PETs were 0. 3-5.0 cm, and the diameters of the PETs in 19 cases were above 2.0 cm. Eight patients were complicated with pancreatic leakage, two with incision infection and one with abdominal infection. Of the 33 patients with insulinoma, the blood glucose of five patients with multiple PETs was still abnormal after the operation, three patients underwent reoperation and the other two were treated by diazoxide to control the blood glucose in the normal range. The clinical symptoms of the seven patients with gastrinoma disappeared after the operation, and the gastric ulcer was healed, the 12-hour gastric juice volume and the level of the gastric acid were in the normal range after a continuous treatment with proton pump inhibition agents for 6 months. Necrotizing or migratory rash and diabetes of the four patients with glucagonoma were cured three weeks later, and the level of the amino acid was back to normal. Diarrhea and electronic disturbance of one patient with vasoactive intestinal peptide tumor were alleviated after the operation. Thirty-nine patients were followed up for 20-120 months. Of the 32 patients with benign PETs, two patients had tumor recurrence, and three patients died of other diseases. Of the seven patients with malignant PETs, two patients survived, and three patients died of hepatic metastasis or tumor recurrence, two patients died of other diseases. Conclusions Surgical treatment is effective for the treatment of functional PETs. Palliative resection of the tumor also can obviously improve the life quality of patients with fuctional PETs. Key words: Pancreas; Endocrine tumors; Diagnosis; Therapy

Usefulness of EUS combined with contrast-enhancement in the differential diagnosis of malignant versus benign and preoperative localization of pancreatic endocrine tumors

Pancreatic endocrine tumors (PETs) develop in relatively few patients, but they are often difficult to diagnose because of their small size and various clinical symptoms. The aim of this study was to investigate the usefulness of EUS combined with contrast enhancement (CE-EUS) in the preoperative localization of PETs and the differentiation between malignant and benign PETs. Single-center retrospective study. Sixty-two pathologically certified PETs of 41 patients who underwent EUS, multiphasic multidetector computed tomography (MDCT), and transabdominal US at our institute since 2001. Intravenous injection of US contrast media. Comparison of EUS, MDCT, and US in the preoperative identification of PETs, and the characteristic findings of EUS with malignancy. EUS showed high sensitivity (95.1%) in identifying PETs compared with MDCT (80.6%) and US (45.2%). Multivariable logistic regression analysis showed that heterogeneous ultrasonographic texture was the most significant factor for malignancy (OR = 53.33; 95% CI, 10.79-263.58). Most heterogeneous hypoechoic areas and anechoic areas corresponded to hemorrhage or necrosis on pathologic examination. They were identified as filling defects in CE-EUS and were more clearly recognized than in conventional EUS. Retrospective study. EUS has higher sensitivity in preoperative localization of PETs compared with MDCT and US. The characteristics of EUS and CE-EUS findings in malignant PETs were clarified, and they will improve the diagnostic accuracy of PETs.

Neuroendocrine gastroenteropancreatic tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Neuroendocrine gastroenteropancreatic tumours : ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Experience in diagnosis and treatment of malignant pancreatic endocrine tumor

Objective To investigate the clinical features, diagnosis and treatment of malignant pancreatic endocrine tumor. Methods The clinical data of 38 patients with malignant pancreatic endocrine tumor who had been admitted to First Affiliated Hospital of Nanjing Medical University from January 1969 to December 2008 were analyzed retrospectively. Of all patients, 6 were with insulinoma, 23 with pancreatic polypeptide tumor, 4 with glucagonoma and 5 with pancreatic carcinoid. Results All patients except 1 with insulinoma were found with pancreatic lesion by imaging examination. The resection rate was 87% (33/38). Pathological examination found 7 patients with liver metastasis, 5 with lymph node metastasis, 1 with tumor thrombus in vessels and lymphatic vessels, and 28 with local invasion. Twenty-four patients were followed up, and neither recurrence nor metastasis was found except 1 patient with insulinoma who received reoperation for local recurrence and 1 patient with pancreatic carcinoid who received radiofrequency ablation for liver metastasis. Conclusions The diagnosis of pancreatic endocrine tumor mainly depends on imaging examination. The malignancy of pancreatic endocrine tumor is determined after the comprehensive analysis of preoperative imaging findings, intraoperative examination, post-operative pathological examination and the data obtained during follow-up. The malignant pancreatic endocrine tumor should be managed actively by resection because of its relatively low malignancy, high operative resectability and relatively good prognosis. Key words: Pancreatic neoplasms; Islet cells; Diagnosis; Treatment

VHL inactivation is an important pathway for the development of malignant sporadic pancreatic endocrine tumors

A small subset of familial pancreatic endocrine tumors (PET) arises in patients with von Hippel-Lindau syndrome and these tumors may have an adverse outcome compared to other familial PET. Sporadic PET rarely harbors somatic VHL mutations, but the chromosomal location of the VHL gene is frequently deleted in sporadic PET. A subset of sporadic PET shows active hypoxia signals on mRNA and protein level. To identify the frequency of functionally relevant VHL inactivation in sporadic PET and to examine a possible prognostic significance we correlated epigenetic and genetic VHL alterations with hypoxia signals. VHL mutations were absent in all 37 PETs examined. In 2 out of 35 informative PET (6%) methylation of the VHL promoter region was detected and VHL deletion by fluorescence in situ hybridization was found in 14 out of 79 PET (18%). Hypoxia inducible factor 1alpha (HIF1-alpha), carbonic anhydrase 9 (CA-9), and glucose transporter 1 (GLUT-1) protein was expressed in 19, 27, and 30% of the 152 PETs examined. Protein expression of the HIF1-alpha downstream target CA-9 correlated significantly with the expression of CA-9 RNA (P<0.001), VHL RNA (P<0.05), and VHL deletion (P<0.001) as well as with HIF1-alpha (P<0.005) and GLUT-1 immunohistochemistry (P<0.001). These PET with VHL alterations and signs of hypoxia signalling were characterized by a significantly shortened disease-free survival. We conclude that VHL gene impairment by promoter methylation and VHL deletion in nearly 25% of PET leads to the activation of the HIF-pathway. Our data suggest that VHL inactivation and consecutive hypoxia signals may be a mechanism for the development of sporadic PET with an adverse outcome.

Immunohistochemical and clinicopathological correlation of the metastasis-associated gene 1 (MTA1) expression in benign and malignant pancreatic endocrine tumors

Pancreatic endocrine tumors are rare tumors with unpredictable clinical behavior. No histological features or immunohistochemical markers reliably predict malignant progression and the molecular basis of progression of pancreatic endocrine tumors remains unknown. The metastasis-associated gene 1 is thought to play a role in transcription repression and estrogen receptor interaction and is overexpressed in several human cancers, including endocrine neoplasms. The purpose of this study was to analyze the expression of metastasis-associated gene 1 in pancreatic endocrine tumors for its possible role in malignant progression. Twenty-seven pancreatic endocrine tumors were identified from our archive. The mean age at presentation was 57 years (range 28–86); the male/female ratio was 1.25 to 1, and the mean size was 4.5 cm (0.1–18 cm). The clinical follow-up data were examined and tumors were classified according to the 2004 World Health Organization criteria as benign behavior (WHO 1.1), uncertain behavior (WHO 1.2), well-differentiated endocrine carcinoma (WHO 2), and poorly differentiated endocrine carcinoma (WHO 3). Histopathological and immunohistochemical stains were evaluated and metastasis-associated gene 1 expression scored semiquantitatively as absent (1+), weak (2+), moderate (3+), or strong (4+). Statistical analysis was performed using Kruskal–Wallis nonparametric analysis of variance with a significance level of 0.05. Metastasis-associated gene 1 expression was significantly higher in malignant tumors (n=17) with a mean staining intensity of 3.8 compared with 2.9 in benign tumors (n=10, P=0.046). The expression levels were significantly associated with WHO class (P=0.028), as well as size of tumor (P=0.029), and mitotic rate (P=0.035). Metastasis-associated gene 1 expression was associated with local invasion with borderline significance (0.062). We show that metastasis-associated gene 1 expression is significantly associated with malignant behavior in pancreatic endocrine tumors. This may suggest a potential role for metastasis-associated gene 1 in the malignant progression and metastasis and its use as biomarker for malignant pancreatic endocrine tumors.

Comparison of EUS Morphology and Performance of EUS-FNA for Benign and Malignant Pancreatic Neuroendocrine Tumors

Introduction: Pancreatic endocrine tumors (PET) are rare neoplasms frequently evaluated by EUS yet there are limited data comparing EUS findings and sensitivity of EUS-guided fine needle aspiration (EUS-FNA) in benign and malignant tumors. Aim: To compare EUS morphology and sensitivity of EUS-FNA between benign and malignant PET. Methods: We retrospectively identified all patients from 7/95 to 11/06 who underwent EUS for suspected or subsequently confirmed PET. All patients had a pancreatic mass visible by EUS. The diagnosis of a PET was confirmed by: 1) EUS-FNA with (after 1999) or without (before 1999 when test not routinely performed) confirmatory immunochemistry (ICC) with synaptophysin and/or chromogranin of ≥ 1 pancreatic mass or metastatic site; or 2) an alternative biopsy procedure and/or surgical resection of the pancreas or other metastatic site. Patients without positive ICC were required to have biopsy or surgical resection from a pancreatic or extra-pancreatic site to confirm the diagnosis. Malignant PET was defined as tumors that originated in the pancreas with any evidence of tumor beyond the primary pancreatic site. Results: 76 patients (53 male; median age: 57 yrs, range 23-83 yrs) with 36 (47%) benign and 40 (53%) malignant PET were identified. Malignant PET patients were older by an average of 7 years (58 vs. 51 yrs, p=0.03). Benign tumors were more likely to present with hypoglycemia (p=0.02) whereas malignant tumors tended to present with abdominal pain (p=0.007). By EUS, the tumors were located in the pancreatic head, body, tail or were multifocal in 35 (46%), 21 (28%), 15 (20%) and 5 (6%), respectively. Tumor location within the pancreas was similar between benign and malignant PET (head: p=0.11, body: p=0.61, tail: p=0.77). Compared to benign tumors, malignant PET were larger (median diameter: 31 vs. 19mm; p=0.0006) and were more likely to have irregular margins (50% vs. 25%; p=0.03). Echogenicity was similar between both groups (p=1.0). EUS-FNA of a pancreatic mass was performed in 68 (89%) of the 76 PET with subsequently confirmed histopathology. The sensitivity of EUS-FNA for the diagnosis of malignant PET 95% (CI: 81-99%) was greater than that for benign PET 77% (CI: 60-89%; p=0.009) Conclusion: In this single center study of patients undergoing EUS for confirmed PET, patients with malignant PET were more likely to be older, present with abdominal pain and have larger tumors with irregular borders compared to those with benign tumors. The sensitivity of EUS-FNA for the diagnosis of malignant PET is higher than that for benign PET.

The outcomes after surgical resection in pancreatic endocrine tumors: An institutional experience

Aim Sporadic pancreatic endocrine tumors (PET) can be managed surgically with excellent outcomes. The aim of this study was to analyze surgical outcomes and factors influencing survival. Methods Between 1995 and 2007, 96 patients with sporadic PET who underwent surgery at our institution were retrospectively reviewed for clinicopathologic variables and outcomes according to the World Health Organization (WHO) classifications. Results Thirty-nine patients had well-differentiated tumors (WDT) with benign behavior, 23 had uncertain behavior, 27 had low-grade carcinoma, and 7 were diagnosed with high-grade carcinoma. R0 resection was performed in 84 patients. No recurrence was observed in WDT regardless of its behavior or curability but 16 of 34 patients with carcinoma had recurrence. Five-year overall survival (OS) for R0-resected patients with carcinoma was 57%, and OS at 3 years for R1/R2-resected patients was 23% ( P = 0.012). The WHO classification and R0 resection were independent prognostic factors in multivariate analysis. Conclusions This single institutional experience demonstrated that surgical resection is curative for WDT and recurrences are frequent in spite of curative resection for malignant PET. The WHO classification and R0 resection remained independent prognostic factor.

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

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. To evaluate PET EUS-guided FNA (EUS-FNA) microsatellite loss analysis in the context of PET-related mortality. A single institution retrospective cohort. Patients with PET diagnosed by EUS-FNA who underwent DNA microsatellite loss analysis and at least 1 year of follow-up or subsequent death. PET microsatellite loss analysis results and current clinical status were compared. 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 compared with >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. Retrospective design, referral bias, and DNA analysis availability. 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.

Neoadjuvant peptide receptor radionuclide therapy for aninoperable neuroendocrine pancreatic tumor

Pancreatic endocrine tumors are rare but are among the most common neuroendocrine neoplasms of the abdomen. At diagnosis many of them are already advanced and difficult to treat. We report on an initially inoperable malignant pancreatic endocrine tumor in a 33-year-old woman, who received neoadjuvant peptide receptor radionuclide therapy (PRRT) as first-line treatment. This resulted in a significant downstaging of the tumor and allowed its subsequent complete surgical removal. Follow-up for eighteen months revealed a complete remission. This is the first report on neoadjuvant PRRT in a neuroendocrine neoplasm with subsequent successful complete resection.

Overexpression of the Oxygen Sensors PHD-1, PHD-2, PHD-3, and FIH Is Associated with Tumor Aggressiveness in Pancreatic Endocrine Tumors

Tumor hypoxia is associated with poor prognosis and resistance to treatment. Our aim was to assess the expression of proteins that act as cellular oxygen sensors, directly regulating the hypoxia inducible factor (HIF) pathway, i.e., prolyl hydroxylase domain proteins (PHD)-1, PHD-2, PHD-3, and FIH in pancreatic endocrine tumors (PET). Immunohistochemical expression of these markers was examined in 109 PET included in tissue microarrays and representing various stages of tumorigenesis. The results were correlated with histoprognostic factors including Ki-67 index, presence of a fibrotic focus, and microvascular density (MVD). The cytoplasmic and nuclear expressions of the three PHD isoforms were associated, and their expression was significantly higher in aggressive PETS, malignant, with lymph node metastases or with lower MVD. High nuclear expression of the three isoforms highly correlated with HIF-1alpha nuclear expression (P = 0.02, 0.003, and 0.006, respectively). Moreover, high nuclear PHD-1 or PHD-3 expression was associated with a poorer survival (P = 0.01). Cytoplasmic FIH was significantly higher in malignant PETs (P = 0.05) and in PETs with lymph node metastases (P = 0.02), and its expression correlated positively with those of cytoplasmic PHD isoforms (P < 0001). FIH stromal expression was found in 23% of PETs and correlated with higher FIH nuclear expression (P = 0.0004) and poorer disease-free survival (P = 0.0018). HIF regulatory proteins are highly expressed in PET and their expression is correlated with tumor metastases, tumor recurrence, and prognosis. These molecules that play an important role in the control of hypoxia-induced genes may have a function in the regulation of cellular proliferation and differentiation during endocrine tumorigenesis.