Ectopic insulinoma in a dog with insulin-induced hypoglycemia: a case report.

A 7-year-old spayed female Shih Tzu dog was presented for evaluation of recurrent hypoglycemia. Serum insulin levels during hypoglycemia were 35.3 µIU/mL. Ultrasonography and computed tomography showed a mesenteric nodule between the kidney and the portal vein, but no pancreatic mass was observed. During surgery, the nodule had neither anatomical adhesions nor vascular connections to the pancreas. Pancreatic inspection and palpation revealed no abnormalities. Hypoglycemia improved after resection of the nodule. Histopathological examination confirmed the nodule to be an islet cell carcinoma. Although extremely rare, ectopic insulinoma should be considered as a possible cause of insulin-induced hypoglycemia in dogs.

MULTIHORMONAL ISLET CELL CARCINOMAS IN THREE KOMODO DRAGONS (VARANUS KOMODOENSIS).

Multihormonal pancreatic islet cell carcinomas were found in one female and two male captive geriatric Komodo dragons (Varanus komodoensis). Gross changes in the pancreas were visible in two of the cases. Clinical signs noted in the Komodo dragons were lethargy, weakness, and anorexia. Histologically, the tumors were comprised of nests and cords of well-differentiated neoplastic islet cells with scant amounts of eosinophilic cytoplasm and round, euchromatic nuclei, with rare mitoses. Infiltration by the islet cell tumor into the surrounding acinar tissue was observed in all cases, but no metastatic foci were seen. Multihormone expression was observed in all tumors, which labeled strongly positive for glucagon and somatostatin and focally positive for polypeptide. Pancreatic islet cell neoplasms should be considered in the differential diagnosis for geriatric Komodo dragons presenting with weakness, lethargy, and poor appetite.

Últimos avances sobre los tumores pancreáticos / Latest advances in pancreatic tumours

El cáncer de páncreas continúa siendo una entidad de pésimo pronóstico. Apenas existen avances terapéuticos en los últimos años, por lo que la mayor parte del esfuerzo se centra en prevenir su aparición y diagnosticar lesiones precursoras. El uso de estatinas como factor preventivo y la implementación de programas de cribado en pacientes de alto riesgo van ganando terreno en este sentido. En el campo del tratamiento se profundiza en el papel de la terapia neoadyuvante en el cáncer de páncreas y en el abordaje multimodal de la enfermedad, con apenas avances en cuanto a terapias novedosas y eficaces. Los tumores quísticos del páncreas, en especial el tumor mucinoso papilar intraductal, con su conocido potencial de malignidad, acaparan la mayor parte de trabajos. La validación de las guías internaciones de Fukuoka 2012 y las muy controvertidas guías AGA 2015 son objeto de múltiples trabajos. Destacan los que evidencian el subóptimo valor predictivo positivo y que cuestionan aspectos muy relevantes de estas, como la discontinuación del seguimiento o los criterios de derivación quirúrgica. Entre los procedimientos diagnósticos destacan la quistoscopia y la endomicroscopía láser confocal, asociadas a la punción guiada por ecoendoscopia, como técnicas más prometedoras por su alta eficacia y valor predictivo negativo a la hora de detectar lesiones quísticas mucinosas. Los trabajos sobre historia natural de los tumores mucinosos papilares intraductales, que nos ayudan a profundizar en su conocimiento y en la búsqueda de factores predictivos de desarrollo de cáncer, también proliferan

Pancreatic cancer continues to have a bleak prognosis. Hardly any therapeutic advances have been made in the last few years and consequently most efforts have focused on preventing its development and on diagnosing precursor lesions. In this regard, the use of statins as a preventive factor and the implementation of screening programmes in high-risk patients are gaining ground. In the field of treatment, there is greater focus on the role of neoadjuvant therapy in pancreatic cancer and on a multimodal approach to the disease, with few advances in effective novel therapies. Most studies concerned cystic tumours of the pancreas, especially intraductal mucinous papillary tumour, with its known potential for malignant transformation. Multiple studies were devoted to validation of the 2012 Fukuoka international guidelines and the highly controversial 2015 AGA guidelines. Notable among these studies were those demonstrating the suboptimal positive predictive value and questioning important aspects of the guidelines, such as discontinuation of follow-up or the criteria for surgical referral. Notable among diagnostic procedures were cystoscopy and endoscopic ultrasound-guided needle-based confocal laser endomicroscopy as the most promising techniques due to their high efficacy and negative predictive value in detecting mucinous cystic lesions. There were also a large number of studies on the natural history of intraductal papillary mucinous tumours, which help deepen knowledge of these entities and the search for predictive factors of cancer development

Pancreatic neuroendocrine tumors: contemporary diagnosis and management.

Pancreatic neuroendocrine tumors (PNETs) are neoplasms that arise from the hormone producing cells of the islets of Langerhans, also known as pancreatic islet cells. PNETs are considered a subgroup of neuroendocrine tumors, and have unique biology, natural history and clinical management. These tumors are classified as 'functional' or 'non-functional' depending on whether they release peptide hormones that produce specific hormone- related symptoms, usually in established patterns based on tumor subtype. This manuscript will review pancreatic neuroendocrine tumor subtypes, syndromes, diagnosis, and clinical management.

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 transformation of a nonfunctioning islet cell tumor of the pancreas into a proinsulinoma under conditions of lung metastasis.

We herein report the first case of a nonfunctioning islet cell tumor that transformed into a proinsulinoma during the process of metastasis to the lungs. This phenomenon was confirmed in a 69-year-old woman with an advanced pancreatic islet cell tumor and multiple liver metastases who later developed multiple lung metastases. She underwent pancreatic resection followed by the administration of chemotherapy and survived for seven years. Although the patient initially had hyperglycemia due to diabetes mellitus, she conversely began to manifest hypoglycemic attacks 63 months postoperatively with the concomitant development of multiple lung metastases. An autopsy revealed that only the tumor in the lungs produced proinsulin; no other hormones were detected.

Ecografía pancreática / Pancreatic ultrasonography

La ecografía abdominal continúa siendo la primera exploración a realizar en los pacientes con sospecha de enfermedad pancreática. Pese a los recientes avances tecnológicos en las pruebas de imagen, la ecografía no ha sido desplazada como primer escalón diagnóstico debido a su inocuidad, accesibilidad y bajo coste. Se trata de una técnica fundamental en el estudio de los procesos inflamatorios, ya que no solo valora las alteraciones del parénquima pancreático, sino que orienta la etiología (biliar o alcohólica), es fundamental en la detección y el seguimiento de las posibles complicaciones y sirve como guía en las punciones tanto diagnósticas como terapéuticas. Es también la primera técnica a utilizar en el estudio de los tumores pancreáticos, con una sensibilidad en la detección de los mismos en torno al 70%, y una especificidad del 90% (AU)

Despite the recent technological advances in imaging, abdominal ultrasonography continues to be the first diagnostic test indicated in patients with a suspicion of pancreatic disease, due to its safety, accessibility and low cost. It is an essential technique in the study of inflammatory processes, since it not only assesses changes in pancreatic parenchyma, but also gives an indication of the origin (bile or alcoholic). It is also essential in the detection and tracing of possible complications as well as being used as a guide in diagnostic and therapeutic punctures. It is also the first technique used in the study of pancreatic tumors, detecting them with a sensitivity of around 70% and a specificity of 90% (AU)

SEOM clinical guidelines for the diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) 2014

GEP-NENs are a challenging family of tumors of growing incidence and varied clinical management and behavior. Diagnostic techniques have substantially improved over the past decades and significant advances have been achieved in the understanding of the molecular pathways governing tumor initiation and progression. This has already translated into relevant advances in the clinic. This guideline aims to provide practical recommendations for the diagnosis and treatment of GEP-NENs. Diagnostic workup, histological and staging classifications, and the different available therapeutic approaches, including surgery, liver-directed ablative therapies, peptide receptor radionuclide therapy, and systemic hormonal, cytotoxic or targeted therapy, are briefly discussed in this manuscript. Clinical presentation (performance status, comorbidities, tumor-derived symptoms and hormone syndrome in functioning tumors), histological features [tumor differentiation, proliferation rate (Ki-67), and expression of somatostatin receptors], disease localization and extent, and resectability of primary and metastatic disease, are all key issues that shall be taken into consideration to appropriately tailor therapeutic strategies and surveillance of these patients (AU)

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Osseous metaplasia within a canine insulinoma.

An 11-year-old male castrated mixed-breed dog was presented for exercise intolerance, tetraparesis, and persistent hypoglycemia. Abdominal ultrasound examination revealed 2 nodules within the right limb of the pancreas. Cytology from one nodule was consistent with a carcinoma of neuroendocrine origin, with a primary differential diagnosis of insulinoma. Histologic evaluation and immunohistochemistry for synaptophysin and insulin confirmed the diagnosis of insulinoma. Additionally, there was a solitary nodule of mineralized compact bone composing approximately 60% of the mass. To the authors' knowledge, this is the first report of osseous metaplasia within an insulinoma (islet cell carcinoma).

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

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

Characterization of neuroendocrine tumors of the pancreas by real-time quantitative polymerase chain reaction. A methodological approach.

The aim of this study was to assess the suitability of using real-time quantitative PCR (RT-qPCR) to characterize neuroendocrine (NE) tumors of the pancreas. For a series of tumors, we evaluated several genes of interest, and the data were matched with the "classical" immunohistochemical (IHC) features. In 21 cases, we extracted RNA from formalin-fixed paraffin-embedded (FFPE) blocks, and in nine cases, we also extracted RNA from fresh-frozen tissue. The RT-qPCR procedure was performed using two sets of customized arrays. The test using the first set, covering 96 genes of interest, was focused on assessing the feasibility of the procedure, and the results were used to select 18 genes indicative of NE differentiation, clinical behavior, and therapeutic responsiveness for use in the second set of arrays. Threshold cycle (Ct) values were used to calculate the fold-changes in gene expression using the 2-∆∆Ct method. Statistical procedures were used to analyze the results, which were matched with the IHC and follow-up data. Material from fresh-frozen samples performed better in terms of the level of amplification, but acceptable and concordant results were also obtained from FFPE samples. In addition, high concordance was observed between the mRNA and protein expression levels of somatostatin receptor type 2A (R = 0.52, p = 0.016). Genes associated with NE differentiation, as well as the gastrin-releasing peptide receptor and O-6-methylguanine-DNA methyltransferase genes, were underexpressed, whereas angiogenesis-associated markers (CDH13 and SLIT2) were overexpressed in tissues with malignant behavior. The RT-qPCR procedure is practical and feasible in economic terms for the characterization of NE tumors of the pancreas and can complement morphological and IHC-based evaluations. Thus, the results of the RT-qPCR procedure might offer an objective basis for therapeutic choices.

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.

Streptozotocin-induced diabetic ketoacidosis in a patient with metastatic islet-cell carcinoma.

Here we report a severe life-threatening complication of treatment with streptozotocin in a patient with pancreatic island-cell carcinoma. The patient was admitted to the intensive care unit with severe diabetic ketoacidosis which needed aggressive fluid resuscitation and insulin therapy. We believe it is critical to be aware of the symptoms of diabetic ketoacidosis and monitor glucose levels during streptozotocin treatment.