[Current views on the treatment of insulinoma].

RELEVANCE: Insulinoma is the most common hormonally active neuroendocrine tumor (NET) of the pancreas. In recent years, there has been a trend towards an increase in the incidence of NET especially insulinoma. AIM: Summarizing and analyzing current data on various approaches to the treatment of insulinoma. Our review includes a comprehensive assessment of the advantages and disadvantages of currently available insulinoma treatment methods in comparison with past experience, as well as a review of promising methods that are not currently widely used. MATERIALS AND METHODS: Analysis of literature from such databases as scientific electronic library elibrary.ru, Pubmed, Google Scholar, MedLine, Scopus and Web of Science. RESULTS: The most common treatment for insulinoma is surgery. For patients with high operative risk, alternative methods such as alcohol ablation, radiofrequency ablation, and tumor embolization may be used. Medications include the use of somatostatin analogues, diazoxide. The literature describes the potential benefit of the use of beta-blockers, phenytoin, glucagon, however, in clinical trials, these drugs have not demonstrated a significant effect. For the treatment of malignant and metastatically advanced insulinoma, targeted therapy (primarily Everolimus), chemotherapy, as well as embolization (including chemoembolization, radioembolization), radiofrequency ablation (RFA), microwave ablation and cryoablation, ultrasound ablation (HIFU), laser ablation, brachytherapy, irreversible electroporation are used. CONCLUSION: The study of new drugs is an important task for scientists, among medications the most promising are new generations of somatostatin analogues, targeted drugs and chemotherapy drugs. The rare frequency of insulinoma makes it difficult to conduct randomized controlled trials and prospective studies. That is why physicians and scientists need to maintain close contacts with each other and take into account the experience of treating each patient with such disease, which will help develop effective treatment algorithms in the future.

Pancreatic endocrine tumors or apudomas.

INTRODUCTION AND OBJECTIVE: pancreatic endocrine tumors (PET) are difficult to diagnose. Their accurate localization using imaging techniques is intended to provide a definite cure. The goal of this retrospective study was to review a PET series from a private institution. PATIENTS AND METHODS: the medical records of 19 patients with PETs were reviewed, including 4 cases of MEN-1, for a period of 17 years (1994-2010). A database was set up with ten parameters: age, sex, symptoms, imaging techniques, size and location in the pancreas, metastasis, surgery, complications, adjuvant therapies, definite diagnosis, and survival or death. RESULTS: a total of 19 cases were analyzed. Mean age at presentation was 51 years (range: 26-67 y) (14 males, 5 females), and tumor size was 5 to 80 mm (X: 20 mm). Metastatic disease was present in 37% (7/19). Most underwent the following imaging techniques: ultrasounds, computed tomography (CT) an magnetic resonance imaging (MRI). Fine needle aspiration punction (FNA) was performed for the primary tumor in 4 cases. Non-functioning: 7 cases (37%), insulinoma: 2 cases [1 with possible multiple endocrine neoplasia (MEN)], Zollinger-Ellison syndrome (ZES) from gastrinoma: 5 (3 with MEN-1), glucagonoma: 2 cases, 2 somatostatinomas; carcinoid: 1 case with carcinoide-like syndrome. Most patients were operated upon: 14/19 (73%). Four (4/14:28%) has postoperative complications following pancreatectomy: pancreatitis, pseudocyst, and abdominal collections. Some patients received chemotherapy (4), somatostatin (3) and interferon (2) before or after surgery. Median follow-up was 48 months. Actuarial survival during the study was 73.6% (14/19). CONCLUSIONS: age was similar to that described in the literature. Males were predominant. Most cases were non-functioning (37%). Most patients underwent surgery (73%) with little morbidity (28%) and an actuarial survival of 73.6% at the time of the study.

Diagnostic and prognostic implications of the World Health Organization classification of neuroendocrine tumors.

BACKGROUND: Neuroendocrine differentiation of tumors is often difficult to establish. In the same manner, the evaluation of the prognostic role of neuroendocrine differentiation may constitute a relevant clinical problem. Although different classifications are used for neuroendocrine tumors (NET) of different origin, the last World Health Organization (WHO) classification of NET, originally proposed for gastroenteropancreatic tumors, has proved to be a practical tool to allow pathologists to uniform the diagnoses and re-classify these tumors into 3 main categories. AIM: The present study was carried out in order to evaluate diagnostic and prognostic implications of NET reclassification according to the last WHO classification of NET. MATERIALS AND METHODS: Thirty-one tumors with an initial diagnosis referable to a NET achieved before 1999 were independently evaluated by 3 pathologists on the basis of the 2000 WHO classification of NET. Immunohistochemistry for panneuroendocrine markers and Ki-67 was also performed in all cases. RESULTS: Twelve, 14, and 4 tumors were respectively reclassified as well-differentiated NET, well-differentiated neuroendocrine carcinoma and poorly differentiated neuroendocrine carcinoma; 1 tumor was reclassified as mixed endocrine-exocrine tumor. Two or more neuroendocrine markers were expressed in all NET regardless of histotype, differentiation degree, and site of primary tumor. After revision, 10 of the 31 tumors under study (32%) changed histo-prognostic category when compared to the initial diagnosis. Ki-67 score was the best predictor of survival at the multivariate analysis. CONCLUSION: The WHO classification is suitable to accurately reclassify tumors with an initial diagnosis referable to a NET and to separate these tumors in 3 well-distinct histo-prognostic categories with relevant clinical implications. Ki-67 score seems to be a better predictor of survival than the degree of differentiation.

Proliferation of antigen MIB-1 in metastatic carcinoid tumours removed at liver transplantation: relevance to prognosis.

BACKGROUND: Metastatic carcinoid tumours are difficult to manage. In spite of a multidisciplinary approach, including orthotopic liver transplantation, the recurrence rate is high with a poor prognosis. Histopathology generally fails to provide prognostic information, hence it is essential to try to identify markers of prognosis in these tumours before considering orthotopic liver transplantation. The MIB-1 antibody, which detects cell proliferative activity, has been shown to be a useful prognostic marker for a variety of neoplasms. AIMS: To assess the value of MIB-1 immunostaining as a prognostic marker of the duration to recurrence and the survival of patients undergoing orthotopic liver transplantation for metastatic carcinoid/neuroendocrine tumours of the liver. METHODS: Fourteen patients were included in the study. Formalin-fixed, paraffin-embedded tissue sections of the tumours were stained with routine haematoxylin and eosin and chromogranin. The cell proliferative activity was assessed by MIB-1 antibody labelling using the immunoperoxidase method. Results were correlated with the time of tumour recurrence and the length of patients' survival after transplantation. RESULTS: No correlation was found between MIB-1 labelling index and age, gender, clinical and histological type of tumour (i.e. carcinoid, APUDOMA, secreting or non-secreting). The patients with higher MIB-1 indices ( 5%) showed a trend toward earlier recurrence and poorer survival than those with low MIB-1 indices ( 5%). The predictive value of a MIB-1 index of 2 indicating patient survival of 24 months was 83% (five out of six patients). CONCLUSIONS: The correlation between MIB-1 index and patients' survival suggests that a high proliferative rate, as assessed by MIB-1 immunostaining, may detect those tumours with more aggressive biological behaviour. Prospective studies on a larger number of patients will be needed to determine if, in any individual tumour, this method will provide an additional parameter for a rational approach to therapy.

Carcinoide apendicular en niños / Carcinoid of the appendix in children

El tumor carcinoide del apéndice es una neoplasia de origen neuroendócrino,aunque de escasa frecuencia,es en general,un hallazgo incidental durante una apendicectomía.El objetivo de este estudio retrospectivo es mostrar nuestra experiencia en el hospital Roberto del Río en el manejo de esta patología,entre enero de 1990 y junio de 2001.Sobre un total de 4906 biopsias apendiculares se hallaron 7 con diagnóstico de tumor carcinoide,5 niñas y 2 niños.Las edades oscilan entre 4 y 14 años.La presentación clínica fue de abdomen agudo de origen apendicular,sin sospecha intraoperatoria de tumor carcinoide.La ubicación más frecuente fue el tercio medio y distal.La apendicetomía fue el único procedimiento.Nuestra serie presenta un corto período de seguimiento,lo que debe ser evaluado en una segunda etapa

[Apudoma of Vater's ampulla: case report and review of the literature]. / Apudoma dell'ampolla di Vater: caso clinico e revisione della letteratura.

The Authors report a case of Vater's ampulla apudoma and after having examined the characteristics of these neoplasms they discuss clinical presentation, diagnostic and treatment problems of islet cell adenomas. They review the literature and make some remarks.

[Imaging of neuroendocrine tumors]. / Imaging dei tumori neuroendocrini.

Neuroendocrine tumors (NET) of the pancreas are distinguished in functional (85%) and non functional (15%) in relation to the production and release of the hormone produced. Functional tumors show early, because the neoplasm release the hormone produced when they are still small. Non functional tumors show late when the tumor grows. The localization and the evaluation of the extensive of these tumors has come fundamentally important both in correct presurgical detection and also in the diagnosis of metastases which excluded surgery. Also, as the survival of 20% of the patients with metastases is only five years, the use of non-invasive imaging techniques is very important for the evaluation of results of the various therapies (chemotherapy, interferon, somatostatin). Recent studies have shown that in patients with Zollinger-Ellison syndrome, SRS is the most sensitive non invasive method in localizing primitive tumors and metastases. The accuracy of this technique has not yet been provided in the study of tumors like insulinomas which do not have a high percentage of somatostatine receptors on their cell membranes. The sensitivity obtained in recent studies on a large number of patient and the low cost, lower than all the other imaging technique in use today, surely make SRS the first choice in the study of NET. Where SRS is negative and surgery is possible, Spiral CT or better still MRI is the best tool to check the results of chemotherapy in patients with hepatic metastases (already detected by SRS), because it is easier to compare the changes in size and morphology of metastases.

[Segmental portal hypertension as a rare cause of gastric hemorrhage--case report]. / Segmentalna portalna hipertenzija kao retki uzrok krvavljenja iz zeluca--prikaz bolesnika.

Segmental portal hypertension is a rare pathologic condition, which produce gastric bleeding. Spleen vein thrombosis is more often caused by pancreatic disease (inflammations, tumors). Diagnosis is difficult to perform. Initial treatment is conservative. After successful conservative treatment early surgery should be planned. Unsuccessful conservative treatment indicates surgery. Splenectomy absolutely eliminates risk from rebleeding. Prognosis of these patients depends from etiology of pancreatic disease. We present a 46 old woman who successfully operated in our Department of Surgery due to massive upper gastrointestinal bleeding caused by isolated portal hypertension.

[Oncocytoma of the pancreas. A case report]. / Vurkhu edin sluchai s onkotsitom na pankreasa.

For the first time in the bulgarian literature a case with pancreatic oncocytoma is described, initially diagnosed as carcinoma. The patient survived for 13 years being nowadays in perfect condition.

[Ultrastructural phenotypes of tumor cells of endocrine-cellular neoplasms of hepatopancreatoduodenal organs and their role in determining the degree of malignancy and prognosis of these diseases]. / Ul'trastrukturnye fenotipy opukholevykh kletok éndokrinno-kletochnykh novoobrazovanii organov gepatopankreatoduodenal'noi zony i ikh znachenie v opredelenii stepeni zlokachestvennosti i prognoza étikh zabolevanii.

78 tumors of the hepatopancreoduodenal system were studied clinically, cytologically and ultrastructurally. Hormonal disturbances were observed in 36% of the patients. The 5-year survival after radical surgery did not depend on the tumor size, tumor cell atypia or metastases to the regional lymph nodes. The prognosis was worse when the tumor was located in the liver. Ultrastructural features of the tumor cells were reliable criteria of the malignancy degree and tumor prognosis. The prognosis, recurrence-free interval and survival improve with an increase in the number of ultrastructurally differentiated cells and organoids in cytoplasm, and with a reduction in nuclear polymorphism and number of dark cells. The degree of histologic and ultrastructural differentiation of tumor cells may not coincide.

El sistema APUD en la oftalmología: II. tumores de la cresta neural. Derivados del sistema pigmentario (melanogénico): nevi y melanomas palpebrales y conjuntivales / APUD System in opthalmology: II. neural crest tumors: Pygmentary system derives (melanogenic): nevi and palpebral and conjunctival melanomas

Los tumores de la cresta neural en la oftalmología inclyen entre otros, los derivados del sistema melanogénico de los que sobresalen los siguientes: Nevi de la piel y de la conjuntiva que se clasifican según su localización en superficiales y profundos; dentro de los primeros están los de unión, intradérmico (subepiteliales), mixtos y como profundos los nevi azul fusocelular y celular. Las formas malignas corresponden a los melanomas cutáneos y conjuntivales. Estas neoplasias son tumores de comportamiento biológico muy variable y morfología compleja, el diangnóstico clínico presuntivo es difícil en algunas variedades histológicas. El tratamiento depende de las variantes clínicas y/o histológicas. El objetivo de este trabajo es proporcionar una revisión actual de estos neurolofomas

Pancreatic endocrine tumors: recent advances.

Pancreatic endocrine tumors (PET's) can be divided on a clinical and pathologic basis into ten classes [insulinomas, gastrinomas (Zollinger-Ellison syndrome), VIPomas (Verner-Morrison syndrome, WDHA, pancreatic cholera), glucagonomas, somatostatinomas, ACTH-releasing tumors (ACTHomas), growth hormone-releasing factor secreting tumors (GRFomas), nonfunctioning or pancreatic polypeptide secreting tumors (non-functioning PET), PET's causing carcinoid syndrome and PET's causing hypercalcemia)]. Recent reports suggest calcitonin-secreting PET's also rarely occur but whether they cause a distinct clinical syndrome is unclear. PET's resemble carcinoid tumors histologically; in their ability to synthesize and frequently secrete multiple peptides such as neuroendocrine cell markers (chromogranins); their biologic behavior and their tumor growth patterns. Both groups of tumors are highly vascular, have high densities of somatostatin receptors and similar tumor localization studies including somatostatin receptor scintigraphy are used for both. PET's, similar to carcinoids causing the carcinoid syndrome, require two separate treatment options be considered: treatment directed against the hormone-excess state and treatment directed against the tumor per se because of their malignant nature. In the last few years there have been advances in tumor diagnosis, localization methods, treatment approaches particularly related to the use of synthetic somatostatin analogues, and the definition of the role of surgical procedures in these diseases. Important other advances include insights into the long-term natural history of PET's particularly from studies of gastrinomas, which allow prognostic factors to be identified and the timing of treatment options to better planned, as well as insights into the molecular basis of these disorders. The latter includes both a description of the molecular basis of the genetic inherited syndromes associated with PET's or carcinoid tumors, as well as an increased understanding of the molecular basis for sporadic PET's or carcinoid tumors. Each of these areas will be briefly highlighted in this presentation.

Somatostatin receptor imaging and therapy of pancreatic endocrine tumors.

Somatostatin receptors (SS-Rs) have been found on a variety of neuroendocrine tumors like carcinoids, paragangliomas, as well as on brain and breast tumors. SS-Rs are also present on most pancreatic endocrine tumors, while previous in vitro studies indicate the absence of these receptors on pancreatic duct cancers. Somatostatin receptor scintigraphy with a radionuclide labeled somatostatin analogue, [111In-DTPA0]-octreotide, is a sensitive and specific technique to visualize in vivo the presence of SS-Rs on various tumors. The purpose of this article is to review the somatostatin receptor imaging of pancreatic endocrine tumors and to illustrate the impact of SS-R expression for therapeutic strategies.

Pancreatic endocrine tumours, immunotherapy and gene therapy: chemotherapy and interferon therapy of endocrine tumours.

The various pancreatic endocrine tumors (PETs) share histological features with each other and with the carcinoid. The aspects of chemotherapy and/or interferon concern the management of metastatic disease. The value of chemotherapy is difficult to evaluate from the literature because often no distinction is made between the various types of PETs and carcinoids are often also included. Moreover, it has been shown that not each tumor responds equally to chemotherapy, depending on a functioning or non-functioning state of the tumor. In general the response rate to any cytostatic drug, single agents or combinations, is low.

[Mucinous breast carcinomas with neuroendocrine differentiation]. / Mutsinozni kartsinomi na g'rdata s nevroendokrinna diferentsiatsiia.

Mucinous breast carcinomas, denominated also gelatinous, mucoid and colloid (collomas), represent a heterogeneous group of neoplasms. More than half of them exhibit signs of neuroendocrine differentiation. Eighteen mucus producing carcinomas of the breast are subjected to morphological study. On the ground of demonstrating argyrophilia by the methods of Grimelius and Churukian--Shenk, and presence of secreting granules during electron microscopic study, they are assigned under the heading apudomas, i.e. tumors of the diffuse endocrine system, or the so-called APUD-system. The important practical implications of demonstrating neuroendocrine cells with a special reference to the biological patterns of this particular type of tumors are discussed.

Gastrinomas and the change in their presentation and management in Northern Ireland, UK, from 1970 to 1996.

Thirty-five new cases of gastrinomas were diagnosed in N. Ireland between 1970 and 1996. Over this period, patient care has improved, with advances in imaging techniques and therapeutic regimens. Patients are now no longer presenting in the classical way with severe ulcer diathesis. Diarrhoea is often a major feature, occurring in 46% of patients. Thirty-one percent of patients presented with mixed amine precursor, uptake and decarboxylation (APUD) tumours. Survival has improved, most likely as a result of better detection of tumours, as well as treatment that is aimed at resection and removal of the gastrinoma. The advent of proton pump inhibitors has ensured symptom control in those for whom total tumour removal is impossible. Owing to improved survival, metastatic complications are often associated with patient mortality.