Serous cystadenoma of head pancreas masquerading as pancreatic neuroendocrine tumor: Treated by Whipple's pancreaticoduodenectomy.

Serous cystadenoma (SCA) is the most common cystic neoplasm of the pancreas. Serous cystadenoma is best diagnosed by imaging with computed tomography scan. Fine-needle aspiration cytology is required for definitive preoperative diagnosis. Serous cystadenoma may be sometime difficult to differentiate from pancreatic neuroendocrine tumor (PNET) in the preoperative stage. Differentiating the two entities are important for proper treatment strategy. Serous cystadenoma may be managed in expectant observation. However, all PNETs will need surgical treatment including pancreaticoduodenectomy (PD). Here, we present a rare presentation of serous cystadenoma head of pancreas masquerading as PNET with local compressive symptoms for which Whipple's PD was done successfully.

Differential Morphological Diagnosis of Various Forms of Congenital Hyperinsulinism in Children.

Introduction: Congenital hyperinsulinism (CHI) has diffuse (CHI-D), focal (CHI-F) and atypical (CHI-A) forms. Surgical management depends on preoperative [18F]-DOPA PET/CT and intraoperative morphological differential diagnosis of CHI forms. Objective: to improve differential diagnosis of CHI forms by comparative analysis [18F]-DOPA PET/CT data, as well as cytological, histological and immunohistochemical analysis (CHIA). Materials and Methods: The study included 35 CHI patients aged 3.2 ± 2.0 months; 10 patients who died from congenital heart disease at the age of 3.2 ± 2.9 months (control group). We used PET/CT, CHIA of pancreas with antibodies to ChrA, insulin, Isl1, Nkx2.2, SST, NeuroD1, SSTR2, SSTR5, DR1, DR2, DR5; fluorescence microscopy with NeuroD1/ChrA, Isl1/insulin, insulin/SSTR2, DR2/NeuroD1 cocktails. Results: Intraoperative examination of pancreatic smears showed the presence of large nuclei, on average, in: 14.5 ± 3.5 cells of CHI-F; 8.4 ± 1.1 of CHI-D; and 4.5 ± 0.7 of control group (from 10 fields of view, x400). The percentage of Isl1+ and NeuroD1+endocrinocytes significantly differed from that in the control for all forms of CHI. The percentage of NeuroD1+exocrinocytes was also significantly higher than in the control. The proportion of ChrA+ and DR2+endocrinocytes was higher in CHI-D than in CHI-F, while the proportion of insulin+cells was higher in CHI-A. The number of SST+cells was significantly higher in CHI-D and CHI-F than in CHI-A. Conclusion: For intraoperative differential diagnosis of CHI forms, in addition to frozen sections, quantitative cytological analysis can be used. In quantitative immunohistochemistry, CHI forms differ in the expression of ChrA, insulin, SST and DR2. The development of a NeuroD1 inhibitor would be advisable for targeted therapy of CHI.

Investigating difficult to detect pancreatic lesions: Characterization of benign pancreatic islet cell tumors using multiparametric pancreatic 3-T MRI.

INTRODUCTION: Pancreatic islet-cell tumors (PICT) often present with atypical signal-characteristics and are often missed on preoperative imaging. The aim of this study is to provide a multiparametric PICT characterization and investigate factors impeding PICT detection. MATERIAL AND METHODS: This is a detailed MRI analysis of a prospective, monocenter study, including 49 consecutive patients (37 female, 12 male; median age 50) with symptoms due to endogenous hyperinsulinemic hypoglycemia (EHH) and mostly negative prior-imaging. All patients received a 3-T MRI and a 68Ga-DOTA-exendin-4-PET/CT. Pooled accuracy, sensitivity, specificity and inter-reader agreement were calculated. Reference-standard was histopathology and 68Ga-DOTA-Exendin-4-PET/CT in one patient who refused surgery. For PICT analyses, 34 patients with 49 PICTs (48 histologically proven; one 68Ga-DOTA-exendin-4-PET/CT positive) were assessed. Dynamic contrast-enhanced (DCE) Magnetic Resonance Images (MRI) with Golden-Angle-Radial-Sparse-Parallel (GRASP) reconstruction, enabling imaging at high spatial and temporal resolution, was used to assess enhancement-patterns of PICTs. Tumor-to-background (T2B) ratio for each sequence and the employed quantitative threshold for conspicuity of PICTs were analyzed in regard to prediction of true-positive PICTs. RESULTS: Evaluation of 49 patients revealed a pooled lesion-based accuracy, sensitivity and specificity of 70.3%, 72.9% and 62.5%, respectively. Mean PICT size was 12.9±5.3mm for detected, 9.0±2.9mm for undetected PICTs (p-value 0.0112). In-phase T1w detected the most PICT (67.3%). Depending on the sequence, PICTs were isointense and poorly visible in 29-68%. Only 2/41(4.9%) PICTs showed typical signal-characteristics across T1w, T2w, DWI and ceT1w combined. 66.6% of PICTs enhanced simultaneously to the parenchyma, 17.8% early and 15.6% late. Predictor screening analysis showed number of sequences detecting a PICT, lesion size and in-phase T1w T2B ratio had the highest contribution for detecting a true-positive PICT. CONCLUSION: The majority of PICTs enhance simultaneously to surrounding parenchyma, present with atypical signal-characteristics and thus are poorly visible. In non-enhancing PICTs, radiologists should search for small lesions most likely conspicuous on unenhanced T1w or DWI.

Non-islet cell tumor hypoglycemia caused by breast tumor: A case report.

INTRODUCTION: Non-islet cell tumor hypoglycemia (NICTH) generally refers to hypoglycemia caused by tumors other than islet cell tumors. Although hypoglycemia is a common clinical emergency, NICTH rarely occurs in patients with breast cancer. PATIENT CONCERNS: A 47-year-old woman presented with repeated hypoglycemia hypoglycemia caused by a lobulated breast tumor. DIAGNOSES: Hypoglycemic symptoms occurred many times during fasting and in the early morning. Insulin and C-peptide levels were decreased; insulin-like growth factor (IGF)-II: IGF-I was greater than 10. Postoperative pathology revealed a lobulated tumor in the breast. After excluding other causes of hypoglycemia, the patient was diagnosed with NICTH due to breast cancer. INTERVENTIONS: Total mastectomy of right breast was performed. OUTCOMES: After 3 years of follow-up, hypoglycemia did not recur. CONCLUSION: Patients with breast cancer may experience recurrent hypoglycemia. After exclusion of insulinomatous and pancreatic origin of hypoglycemia, the possibility of NICTH should be considered, and surgical resection of the primary tumor should be performed as soon as possible.

Elevated Serum Amino Acids Induce a Subpopulation of Alpha Cells to Initiate Pancreatic Neuroendocrine Tumor Formation.

The cellular origin of sporadic pancreatic neuroendocrine tumors (PNETs) is obscure. Hormone expression suggests that these tumors arise from glucagon-producing alpha cells or insulin-producing ß cells, but instability in hormone expression prevents linage determination. We utilize loss of hepatic glucagon receptor (GCGR) signaling to drive alpha cell hyperproliferation and tumor formation to identify a cell of origin and dissect mechanisms that drive progression. Using a combination of genetically engineered Gcgr knockout mice and GCGR-inhibiting antibodies, we show that elevated plasma amino acids drive the appearance of a proliferative population of SLC38A5+ embryonic progenitor-like alpha cells in mice. Further, we characterize tumors from patients with rare bi-allelic germline GCGR loss-of-function variants and find prominent tumor-cell-associated expression of the SLC38A5 paralog SLC7A8 as well as markers of active mTOR signaling. Thus, progenitor cells arise from adult alpha cells in response to metabolic signals and, when inductive signals are chronically present, drive tumor initiation.

Islets and pancreatic ductal adenocarcinoma - An opportunity for translational research from the 'Bench to the Bedside'.

The islet-acinar axis is of prime importance to the optimal functioning of the human pancreas. Not only is this inter-relationship important for normal physiological processes, it is also relevant in diseased states, including chronic pancreatitis and pancreatic ductal adenocarcinoma (PDAC). Early experiments, nearly 4 decades ago, explored the role of islets in the development and progression of PDAC. These led to further studies that provided compelling evidence to support the role of islets and their hormones in PDAC. This association presents oncologists with therapeutic options not only for managing, but potentially preventing PDAC, a cancer that is well known for its poor patient outcomes. This review will discuss the accumulated evidence regarding the role of islets and their hormones in PDAC and highlight areas for future research.

Durable complete response with a short course of streptozotocin plus doxorubicin combination in malignant metastatic insulinoma.

Due to the cytotoxic effects of old chemotherapy regimens used in the islet cell tumors, capecitabine plus temozolomide combination has now become the first choice in the treatment of malignant insulinoma (MIoma). We present this case to emphasize and remind that a durable complete response in advanced stage MIoma may be achieved with a short course of streptozotocin plus doxorubicin combination.

Islet Cell Tumors of the Pancreas.

Islet cell tumors of the pancreas, also known as pancreatic neuroendocrine tumors, constitute less than 5% of pancreatic tumors, and 7% of all neuroendocrine tumors. Most are non-functional, and patients often present with metastatic disease. Functional tumors present with distinct clinical syndromes. Accurate staging is critical as surgery is both the cornerstone of treatment, and the only hope for cure. Medical management involves treating the manifestations of hormonal excess, and using somatastatin analogues when appropriate. Systemic chemotherapy, targeted molecular therapy, and peptide receptor radiotherapy may be used for refractory disease in lieu of or as an adjunct to surgery.

Hypoglycemic Syndrome without Hyperinsulinemia. A Diagnostic Challenge.

The most common cause of organic fasting hypoglycemia in adults is the presence of an insulin-producing pancreatic adenoma, but when high insulin levels are not found, the differential diagnosis is challenging. Misdiagnosis can lead to an unnecessary pancreatectomy. Insulin concentrations may be low in some cases despite a clinical history suggestive of insulinoma. In these cases, a proinsulinoma should be suspected, although the rarity of this condition requires an extensive workup before reaching a final diagnosis. We describe an unusual case of a 38-year-old man with a severe hypoglycemic syndrome due to a proinsulin-secreting pancreatic adenoma. Insulin was measured by the specific assay and suppressed under the lower detection limit during fasting hypoglycemia. Serum proinsulin and C-peptide levels were abnormally elevated, and further tests revealed an islet cell tumor. The tumor was surgically removed, relieving the fasting hypoglycemia. Histopathological study showed a conventional well-differentiated neuroendocrine tumor with high immunoreactivity against proinsulin and with lesser intensity against insulin. Interestingly, GS-9A8 antibody clone used for immunostaining proinsulin did not cross-react with human insulin or C-peptide, providing an unbiased picture of proinsulin secretion. The resolution of symptoms, the fall of proinsulin concentrations after tumor removal and the histopathology study confirmed the diagnosis of proinsulinoma.

Management of Islet Cell Tumours: A Single Hospital Experience.

BACKGROUND/AIMS: Islet cell tumours (ICTs) are uncommon tumours in clinical practice. Surgical resection is the treatment of choice for ICTs, but localisation of these lesions can be challenging. The aim of this study was to analyse the clinical diagnosis and treatment for ICTs. METHODOLOGY: Thirty-one patients with ICTs who were diagnosed and who underwent surgical treatment in the affiliate hospital of Luzhou Medical College from 1 January 2000 to 31 July 2013 were enrolled. The clinical data of these patients were retrospectively reviewed. RESULTS: Among 31 patients (6 males, 25 females), 15 cases (48.39%) had non-functional ICTs and 16 (51.61%) cases were insulinoma: The mean age of patients with non-functional ICTs was 42.73 ± 12.34 years and of those with insulinoma was 48.88 ± 13 years. Non-functional ICTs had a non-specific presentation. Insulinoma makes different clinical presentations mostly with symptoms of hypoglycaemia. CONCLUSIONS: Preoperative and/or intra-operative localisation is needed for ICTs; CT scan or MRI is used routinely as the first choice. If the lesion is very small, DSA is also good for localisation before operation. IOUS is a reliable technique in exactly localising insulinoma. ICTs are considered to be cured with successful surgical removal.

Management of Islet Cell Tumours: A Single Hospital Experience.

BACKGROUND/AIMS: Islet cell tumours (ICTs) are uncommon tumours in clinical practice. Surgical resection is the treatment of choice for ICTs, but localisation of these lesions can be challenging. The aim of this study was to analyse the clinical diagnosis and treatment for ICTs. METHODS: Thirty-one patients with ICTs who were diagnosed and who underwent surgical treatment in the affiliate hospital of Luzhou Medical College from 1 January 2000 to 31 July 2013 were enrolled. The clinical data of these patients were retrospectively reviewed. RESULTS: Among 31 patients (6 males, 25 females), 15 cases (48.39%) had non-functional ICTs and 16 (51.61%) cases were insulinoma. The mean age of patients with non-functional ICTs was 42.73 ± 12.34 years and of those with insulinoma was 48.88 ± 13 years. Non-functional ICTs had a non-specific presentation. Insulinoma makes different clinical presentations mostly with symptoms of hypoglycaemia. CONCLUSIONS: Preoperative and/or intra-operative localisation is needed for ICTs; CT scan or MRI is used routinely as the first choice. If the lesion is very small, DSA is also good for localisation before operation. IOUS is a reliable technique in exactly localising insulinoma. ICTs are considered to be cured with successful surgical removal.

Enalapril and ASS inhibit tumor growth in a transgenic mouse model of islet cell tumors.

Accumulating evidence suggests a role for angiotensin-converting enzymes involving the angiotensin II-receptor 1 (AT1-R) and the cyclooxygenase pathway in carcinogenesis. The effects of ASS and enalapril were assessed in vitro and in a transgenic mouse model of pancreatic neuroendocrine neoplasms (pNENs). The effects of enalapril and ASS on proliferation and expression of the AGTR1A and its target gene vascular endothelial growth factor (Vegfa) were assessed in the neuroendocrine cell line BON1. Rip1-Tag2 mice were treated daily with either 0.6 mg/kg bodyweight of enalapril i.p., 20 mg/kg bodyweight of ASS i.p., or a vehicle in a prevention (weeks 5-12) and a survival group (week 5 till death). Tumor surface, weight of pancreatic glands, immunostaining for AT1-R and nuclear factor kappa beta (NFKB), and mice survival were analyzed. In addition, sections from human specimens of 20 insulinomas, ten gastrinomas, and 12 non-functional pNENs were evaluated for AT1-R and NFKB (NFKB1) expression and grouped according to the current WHO classification. Proliferation was significantly inhibited by enalapril and ASS in BON1 cells, with the combination being the most effective. Treatment with enalapril and ASS led to significant downregulation of known target genes Vegf and Rela at RNA level. Tumor growth was significantly inhibited by enalapril and ASS in the prevention group displayed by a reduction of tumor size (84%/67%) and number (30%/45%). Furthermore, daily treatment with enalapril and ASS prolonged the overall median survival compared with vehicle-treated Rip1-Tag2 (107 days) mice by 9 and 17 days (P=0.016 and P=0.013). The AT1-R and the inflammatory transcription factor NFKB were abolished completely upon enalapril and ASS treatment. AT1-R and NFKB expressions were observed in 80% of human pNENs. Enalapril and ASS may provide an approach for chemoprevention and treatment of pNENs.

Examining the accuracy and clinical usefulness of intraoperative frozen section analysis in the management of pancreatic lesions.

BACKGROUND: Intraoperative frozen section analysis is often performed in the surgical management of pancreatic lesions. This test is used to obtain histologic diagnosis, to assess resectability because of unanticipated locoregional spread, and to ensure negative margins after resection. We sought to define the accuracy and clinical usefulness of intraoperative frozen section analysis in patients with pancreatic lesions and to determine the impact on long-term outcomes. METHODS: A retrospective database review was performed for all patients who underwent pancreatic resection at our institution from 2002 to 2011. Patient demographics, indications for frozen section analysis, final pathology, and long-term outcomes were analyzed. Five-year survival was compared using the Kaplan-Meier method. RESULTS: Sixty-eight patients were identified (mean age 65 ± 14 years, 52% female). Malignancy was identified on final pathology in 38 (56%) patients. Intraoperative frozen section analysis was performed in 59 (87%) patients. Frozen section analysis was performed for histologic diagnosis in 6 (10%) cases, to determine resectability in 15 (25%) cases, and to evaluate margin status in 58 (98%) cases. Frozen section analysis for histologic diagnosis was associated with a sensitivity of 80%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 50% with an overall accuracy of 83%. Frozen section analysis for the determination of resectability was associated with a sensitivity of 38%, specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 58% with an overall accuracy of 66%. Intraoperative frozen section analysis for the determination of the final margin status was associated with a sensitivity of 33%, specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 97% with an overall accuracy of 97%. There were no false-positive results on frozen section analysis. Errors on frozen section analysis interpretation did not negatively impact survival outcomes (mean survival = 2.2 years in those with concordant frozen section analysis vs 1.7 years in those with discordant frozen section analysis, P = .69). CONCLUSIONS: Although intraoperative frozen section analysis is helpful for ensuring negative final margins, its usefulness for obtaining histologic diagnosis and determining resectability is limited by low negative predictive potential. These results highlight the importance of preoperative staging and intraoperative surgical judgment for questionable resectable disease.

Pancreatic endocrine tumour with disseminated pulmonary thromboembolism in an owl monkey (Aotus nancymae).

Pulmonary thromboembolism associated with pancreatic endocrine neoplasia is extremely uncommon in man and animals. Post-mortem examination of an adult owl monkey (Aotus nancymae) revealed extensive pulmonary arterial thromboembolism and a well-demarcated mass attached to the pancreas. Microscopically, the mass consisted of areas of interstitial fibrosis with loss of acini and islets and replacement by nests and sheets of polygonal cells with amphophilic cytoplasm, an eccentric round nucleus with stippled chromatin and, in some cells, with a single prominent eccentric nucleolus. Clusters of these cells were noted within vessels and adjacent lymph nodes. The cells did not express S100 or insulin, but were labelled strongly with SP-1/chromogranin. Rare individual cells expressed glucagon and somatostatin. A few cells in pulmonary thrombi/emboli and the adjacent lymph node also expressed SP-1/chromogranin. Based on cell morphology, location and immunohistochemistry the tumour was classified as pancreatic endocrine (islet cell) carcinoma with metastasis to regional lymph nodes and lung.

Gastrointestinal hormones stimulate growth of Foregut Neuroendocrine Tumors by transactivating the EGF receptor.

Foregut neuroendocrine tumors [NETs] usually pursuit a benign course, but some show aggressive behavior. The treatment of patients with advanced NETs is marginally effective and new approaches are needed. In other tumors, transactivation of the EGF receptor (EGFR) by growth factors, gastrointestinal (GI) hormones and lipids can stimulate growth, which has led to new treatments. Recent studies show a direct correlation between NET malignancy and EGFR expression, EGFR inhibition decreases basal NET growth and an autocrine growth effect exerted by GI hormones, for some NETs. To determine if GI hormones can stimulate NET growth by inducing transactivation of EGFR, we examined the ability of EGF, TGFα and various GI hormones to stimulate growth of the human foregut carcinoid,BON, the somatostatinoma QGP-1 and the rat islet tumor,Rin-14B-cell lines. The EGFR tyrosine-kinase inhibitor, AG1478 strongly inhibited EGF and the GI hormones stimulated cell growth, both in BON and QGP-1 cells. In all the three neuroendocrine cell lines studied, we found EGF, TGFα and the other growth-stimulating GI hormones increased Tyr(1068) EGFR phosphorylation. In BON cells, both the GI hormones neurotensin and a bombesin analogue caused a time- and dose-dependent increase in EGFR phosphorylation, which was strongly inhibited by AG1478. Moreover, we found this stimulated phosphorylation was dependent on Src kinases, PKCs, matrix metalloproteinase activation and the generation of reactive oxygen species. These results raise the possibility that disruption of this signaling cascade by either EGFR inhibition alone or combined with receptor antagonists may be a novel therapeutic approach for treatment of foregut NETs/PETs.

Hypoxia inducible factor-1α is necessary for invasive phenotype in Vegf-deleted islet cell tumors.

In the mouse model of pancreas endocrine tumor, loss of Vegf (VKO) results in dramatically decreased tumor progression; however, the residual microscopic lesions show increased invasion into surrounding exocrine tissue. Double KO mice of Vegf and hypoxia inducible factor-1α (Hif-1α) showed increased life span and suppressed tumor growth due to increased apoptosis. The increased invasiveness of tumors in VKO mice was diminished in DKO mice to the levels of wild-type mice. Compared to VKO mice, DKO mice also exhibited smaller changes in the expression levels of adhesion molecules, including E-cadherin, N-cadherin, and NCAM. These changes of adhesion molecules were not observed in the primary culture of the tumor cells under hypoxic conditions. Thus, the invasive phenotype observed under angiogenesis inhibition requires Hif-1α, but is not directly caused by acute hypoxia.

Immunohistochemical investigation of F344/N rat islet cell tumors from national toxicology program studies.

In this study, we have investigated the immunoexpression of peptide hormones and mediators associated with human islet cell tumors in a group of proliferative islet cell lesions in F344 rats including islet cell hyperplasias, adenomas, and carcinomas, as defined by conventional histopathologic criteria. All proliferative islets expressed synaptophysin, although decreased expression intensity was observed in hyperplasias and adenomas. Most of the proliferative lesions expressed insulin, which generally decreased as lesions progressed toward malignancy. The distribution of glucagon, somatostatin, and gastrin-expressing cells was altered in proliferative islet lesions but did not comprise a large proportion of cells. Islet cell tumors were associated with increased nuclear expression of cyclin-dependent kinase 4 as well as increased proliferating cell nuclear antigen and decreased ß-catenin expression. c-Myelocytomatosis oncogene expression was variable. This is the first study to describe the immunophenotype of islet cell tumors in the F344 rat and to show that islet cell tumors in the F344 rat exhibit similarities in protein expression to the human counterpart.

Pancreatic neuroendocrine tumors: radiographic calcifications correlate with grade and metastasis.

BACKGROUND: Studies to identify preoperative prognostic variables for pancreatic neuroendocrine tumor (PNET) have been inconclusive. Specifically, the prevalence and prognostic significance of radiographic calcifications in these tumors remains unclear. METHODS: From 1998 to 2009, a total of 110 patients with well-differentiated PNET underwent surgical resection at our institution. Synchronous liver metastases present in 31 patients (28%) were addressed surgically with curative intent. Patients with high-grade PNET were excluded. The presence of calcifications in the primary tumor on preoperative computed tomography was recorded and correlated with clinicopathologic variables and overall survival. RESULTS: Calcifications were present in 16% of patients and were more common in gastrinomas and glucagonomas (50%), but never encountered in insulinomas. Calcified tumors were larger (median size 4.5 vs. 2.3 cm, P=0.04) and more commonly associated with lymph node metastasis (75 vs. 35%, P=0.01), synchronous liver metastasis (62 vs. 21%, P<0.01), and intermediate tumor grade (80 vs. 31%, P<0.01). On multivariate analysis of factors available preoperatively, calcifications (P=0.01) and size (P<0.01) remained independent predictors of lymph node metastasis. Overall survival after resection was significantly worse in the presence of synchronous liver metastasis (5-year, 64 vs. 86%, P=0.04), but not in the presence of radiographic calcifications. CONCLUSIONS: Calcifications on preoperative computed tomography correlate with intermediate grade and lymph node metastasis in well-differentiated PNET. This information is available preoperatively and supports the routine dissection of regional lymph nodes through formal pancreatectomy rather than enucleation in calcified PNET.