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.

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.

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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Surgical resection and multidisciplinary care for primary and metastatic pancreatic islet cell carcinomas.

INTRODUCTION: The role of multidisciplinary management of islet cell cancers (ICC) has not been fully investigated in a population-based setting. METHODS: The Los Angeles County Cancer Surveillance Program was assessed for patients with ICC between the years 1982 to 2006. Patients were stratified by treatment received and clinicopathologic characteristics and survival were compared. RESULTS: We identified 236 patients with ICC; 86 patients underwent curative-intent surgery with median survival for local, regional, and distant disease of 17.3, 12.2, and 4.0 years, respectively. In comparison, 102 patients underwent medical management alone; survival was significantly shorter when compared to the surgical cohort for local, regional, and distant disease (p < 0.05). To determine whether adjuvant chemotherapy was associated with improved survival, we compared patients who underwent surgery alone compared to patients who underwent surgery followed by adjuvant chemotherapy. Although patients with metastatic disease had 3-year longer survival with adjuvant chemotherapy, these improvements in survival were not statistically significant. CONCLUSION: Surgical resection was associated with improved survival compared to medical management for any extent of disease in patients with ICC. Furthermore, adjuvant chemotherapy was not associated with survival but does warrant further examination in patients with metastatic disease.

Pancreatic islet cell carcinoma presenting with concurrent Cushing's and Zollinger-Ellison syndromes: case series and literature review.

Cushing's syndrome and Zollinger-Ellison syndrome occur occasionally as a result of neuroendocrine cancers. The concurrence of the two syndromes has been considered to confer a poor clinical and therapeutic outcome. In this study, we are reviewing two patients with pancreatic islet cell carcinomas and with both Zollinger-Ellison and Cushing's syndromes, one followed up for more than 5 years, and the other still receiving therapy, 5 years since diagnosis. A literature review showed that surgery has limited utility as the majority of these patients had metastases at the time of diagnosis. Proton-pump inhibitors, ketoconazole, and somatostatin antagonists have a major role in controlling symptoms. Interferon and systemic chemotherapeutic agents play a role in the management of metastatic and fast-growing cases. Chemoembolization and bland embolization show encouraging results in controlling liver metastases. The latter was used effectively and more than once in the two patients presented herein. On the basis of recent molecular genetics studies, target therapy may be helpful, however, ongoing trials will define it's utility. As the data confers a worse prognosis versus other pancreatic neuroendocrine tumors, the relatively favorable outcome of the two patients reported herein may reflect the impact of multiple therapeutic modalities.

Neuroendocrine tumors of the pancreas.

Pancreatic endocrine tumors are rare neoplasms accounting for less than 5% of pancreatic malignancies. They are broadly classified into either functioning tumors (insulinomas, gastrinomas, glucagonomas, VIPomas, and somatostatinomas) or nonfunctioning tumors. The diagnosis of these tumors is difficult and requires a careful history and examination combined with laboratory tests and radiologic imaging. Signs and symptoms are usually related to hormone hypersecretion in the case of functioning tumors and to tumor size or metastases with nonfunctioning tumors. Surgical resection remains the treatment of choice even in the face of metastatic disease. Further development of novel diagnostic and treatment modalities offers potential to greatly improve quality of life and prolong disease-free survival for patients with pancreatic endocrine tumors.

Neuroendocrine tumors of the pancreas.

The neuroendocrine tumors (NET) of the pancreas are very rare lesions with frequency of about 3 to 10 per 1 000 000 inhabitants. The neuroendocrine tumors composes a heterogeneous group of tumors. The gastro-entero-pancreatic tumors (GEP) constitute 70% of all NET and 2% of all digestive system tumors. There have been several attempts to classify those lesions and since 2000 exists WHO classification which divides NET according to malignancy and histologic structure. The most often NET of the pancreas are insulinoma, gastrinoma, glucagonoma, somatostatinoma, VIPoma. There is a recommendation to assay hormonal activity, measure concentration of specific peptides, biogenic amines and hormones produced by NET cells to establish diagnosis. Those tests are useful in monitoring treatment and in prognostication course of the disease. Imaging methods especially useful in localization GEP-NET are: ultrasound (US), endoscopic ultrasound (EUS), somatostatin receptor scintigraphy (SRS), computer tomography (CT), magnetic resonance (MR) and angiography. The most sensitive method in preoperative diagnosis seems to be EUS or less accessible intra ductal ultrasonography (IDUS). Surgical treatment depends on progression of disease as well as on localization of tumor and consists in both radical methods and palliative operations. The gold standard in pharmacological treatment are somatostatin analogs which can induce long-term remission even in inoperable lesions. Although NET of pancreas are very rare. they are still important diagnostic and therapeutic problem and requires interdisciplinary co-operation. The neuroendocrine tumors should be treated in centers with highest rank of references.

Functional MRI evaluation of tumor response in patients with neuroendocrine hepatic metastasis treated with transcatheter arterial chemoembolization.

OBJECTIVE: The purpose of this study was to evaluate contrast-enhanced and diffusion-weighted MRI changes in neuroendocrine tumors treated with transcatheter arterial chemoembolization (TACE). MATERIALS AND METHODS: Sixty-six targeted lesions in 26 patients (18 men, eight women; mean age, 57 years) with hepatic metastasis of neuroendocrine tumors treated with TACE were retrospectively analyzed. MRI studies were performed before and after TACE. Imaging features included tumor size, percentage of enhancement in the arterial and portal venous phases, and diffusion-weighted imaging apparent diffusion coefficients (ADCs) of the tumor, liver, and spleen. Tumor response to treatment was recorded according to World Health Organization criteria and Response Evaluation Criteria in Solid Tumors. Liver function tests were performed, and clinical performance was assessed before and after treatment. Statistical analysis included paired Student's t tests and Kaplan-Meier survival curves. RESULTS: Mean tumor size and percentage enhancement in the arterial and portal venous phases decreased significantly after treatment (p < 0.0001). The tumor ADC increased from 1.51 x 10(-3) mm2/s before treatment to 1.79 x 10(-3) mm2/s after treatment (p < 0.0001), but the ADCs for the liver and spleen remained unchanged. Despite the change in tumor size, no patient in this cohort achieved complete response according to World Health Organization criteria and Response Evaluation Criteria in Solid Tumors. Partial response was achieved in only 27% and 23% of the patients according to the respective criteria. Results of liver function tests and performance status also remained unchanged. The mean survival period for all patients was 78 months. CONCLUSION: Contrast-enhanced and diffusion-weighted imaging showed significant changes after TACE of neuroendocrine tumors and can be used to assess response of targeted tumors.

Pancreatic neuroendocrine tumours.

Pancreatic neuroendocrine tumours (PET) are rare neoplasms of the pancreas accounting for less than 5% of all primary pancreatic malignancies. Included in this group are insulinomas, gastrinomas, glucagonoma and somatostatinomas. Collectively these neoplasms are classified as functional PETs. Where a PET is not associated with a clinical syndrome due to hormone oversecretion, it is referred to as a non-functioning PET. Non-functioning PETs are pancreatic tumours with endocrine differentiation but lack a clinical syndrome of hormone hypersecretion. The incidence of these tumours varied between 15 and 53%. Presentation is related to the mass effect of the tumour with symptoms often non-specific. Treatment is surgical excision with chemotherapy and hormonal therapy is controversial. For functioning PETs, surgery remains the optimal therapy, however, long-term survival can be expected even in the presence of metastases. With advances in medical management, radiolabelled somatostatin therapy, hepatic arterial chemoembolisation and radiofrequency ablation, symptoms may be controlled to optimize quality of life.

[Management of nonfunctioning islet cell tumors of the pancreas].

OBJECTIVE: To analyze the clinical and pathological features in order to investigate appropriate way of diagnosis and treatment for non-functional islet cell tumors of the pancreas (NFICT). METHODS: The data and experience of surgically treated 43 patients with pathologically confirmed NFICT over the last 30 years were retrospectively reviewed. The survival rate was estimated using Kaplan-Meier method and the potential risk factors affecting survival were compared with Log rank test. RESULTS: There were 7 males and 36 females in this series with a mean age of 31.6 years ranged from 8 to 67 years. Twenty-eight patients were diagnosed as having non-functional islet cell carcinomas of the pancreas (NFICC) and 15 patients benign islet cell tumors. The most common symptoms in NFICT were abdominal pain 55.8%, nausea and/or vomiting (32.6%), fatigue (25.6%) and abdominal mass (23.3%). Preoperatively, all of those were found to have a mass in their pancrease by ultrasonic and computed tomography examination, with 21 in the head, 10 in the body and 6 in the tail of the pancreas. Multicemtric tumor were found in one patient. Thirty-nine of these 43 patients (90.7%) underwent surgical resection, with a curative resection in 30 (69.8%) and palliative in 9 (20.9%). The resectability and curative resection rate in 28 patients with nonfunctioning islet cell carcinomas of the pancreas was 78.6% and 60.7%, respectively. None of the 15 patients with benign nonfunctioning islet cell tumor of the pancreas died of this disease. While the overall cumulative 5- and 10-year survival rate in 28 patients with non-functional islet cell carcinomas of the pancreas was only 58.1% and 29.0%, respectively. Curative resection, female, younger than 30 years old and mass diameter < 10 cm were found to be positive prognostic factors. But multivariate Cox regression analysis indicated that radical resection was the only independent prognostic factor (P = 0.007). CONCLUSION: Nonfunctioning islet cell tumor of the pancreas is frequently found in young female. Surgical resection, especially curative resection can achieve satisfactory long-term survival.

Islet cell carcinoma: neuroendocrine tumors of the pancreas and periampullary region.

Most patients who have islet cell tumors, except those who have insulinomas, present with locally advanced or metastatic disease. In contrast with patients who have adenocarcinoma of the pancreas, those who have islet cell carcinomas can achieve long-term survival even if their disease is advanced. Liver-directed therapies, somatostatin analogs, and interferon are not curative but can be used to relieve tumor-associated symptoms. Similarly, palliative chemotherapy has been used with limited success. Advances in our understanding of the molecular mechanisms underlying tumor progression have translated into intense interest in biologically based strategies to treat this disease.

[Endocrine tumors of the pancreas (EPTs) in multiple endocrine neoplasia (MEN1): up-date on prognostic factors, diagnostic procedures and treatment]. / Les tumeurs endocrines du pancréas lors de la néoplasie endocrinienne multiple type 1 (NEM1): actualités sur les facteurs pronostiques, l'imagerie et le traitement.

Endocrine pancreatic tumors (EPTs) are uncommon tumors, representing 1-2% of all pancreatic neoplasms. They are categorized on the basis of their clinical features into functioning and non-functioning tumors. EPTs may be part of the multiple endocrine neoplasia type 1 (MEN 1), an autosomal dominant syndrome due to inactivating germline mutation of the menin gene. Somatic mutations of menin are present in about 20% of sporadic neoplasms, particularly gastrinomas and insulinomas. 30-75% of patients with MEN1 have EPTs. The most prevalent are the gastrinomas (20-60%), then the insulinomas (5-10%), the glucagonamas and VIPomas (6-10%), whereas the nonfunctioning EPTs are present in 20-40% of patients. The most important biochemical screening marker for EPTs is chromogranin A, as it increases in 50-80% of patients. The most important negative prognostic factors are the presence of metastases, the gross invasion of adjacent organs, the angioinvasion, the perineural invasion and an immunopositivity for Ki-67 > 2%. Among the different imaging techniques, echoendoscopy, computed tomography (CT) and magnetic resonance imaging (MRI) are indicated for the detection of the primary tumor, but (III)In-octreotide scintigraphy has the highest sensitivity for detecting metastases. The choice of treatment is still debated and is different when the tumor occurs as a part of the MEN syndrome. The surgical treatment is the first choice for insulinomas and is more controversial for gastrinomas. The medical treatment includes somatostatin analogues (SA), chemotherapy and interferon-alpha (IFN-alpha). SA seem to improve the symptoms and have an antiproliferative effect, the most striking effect being seen in patients with VIPomas. Chemotherapy, which is generally proposed as a combination of streptozotocin (STZ) and 5-fluorouracil (5-FU) or doxorubicin, is indicated when the tumors tend to grow. Interferon-alpha (IFN-alpha) stimulates the immune system, blocks the tumor cells in the G1/S-phase of the cell cycle, inhibits protein and hormone synthesis and inhibits angionenesis. Treatment with IFN has been shown to produce symptomatic response in 40-60% of patients, a biochemical response in 30-60% and tumor shrinkage in 10-15%.

Neuroendocrine tumors. Molecular targeted therapy for carcinoid and islet-cell carcinoma.

Carcinoid and islet-cell carcinoma are often also known as low-grade neuroendocrine carcinomas. They are often slow-growing but can be resistant to standard therapy. While somatostatin analogues are often used to control hormonal syndromes, there is currently no therapy approved in the US for control of carcinoid tumor growth. For islet-cell carcinoma, streptozocin-based chemotherapy may induce tumor shrinkage, but second-line option are limited. This chapter reviews the molecular biology of neuroendocrine tumors, including the roles of MENIN, TSC2, NF-1, vHL, p53, bcl-2, bax, VEGF, IGF, PDGF, EGFR, and mTOR. Recently, there has been interest in developing molecularly targeted therapy for this group of diseases. Phase-II studies with imatinib, bevacizumab, sunitinib, gefitnib, temsirolimus, and everolimus (RAD001) have completed accrual. Encouraging results have been observed in studies with VEGF and mTOR inhibitors. Phase-III study of bevacizumab is planned in the US. Large-scale multinational phase-II and -III studies of everolimus are under way.

Neuroendocrine tumors of the pancreas.

Pancreatic Neuroendocrine tumors (PNET) are rare tumors that require a high degree of suspicion for timely diagnosis. They are best divided into functional and nonfunctional varieties. Functional tumors often are symptom specific and are diagnosed at an earlier stage than nonfunctional tumors. The severity of symptoms and pace of disease should dictate therapy. Surgical extirpation remains the only curative modality for localized disease, but palliation of hormone-related symptoms can be achieved with different modalities (Management of hormonal Excess, biologic therapy, chemotherapy and biochemotherapy, local-regional therapy with hepatic arterial embolization).

Endocrine tumors of the pancreas.

PURPOSE OF REVIEW: Neoplasms of the endocrine pancreas, commonly referenced as pancreatic islet cell tumors, are rare, often well differentiated endocrine neoplasms, whose biology remains poorly characterized. This article reviews the current clinical management of pancreatic islet cell tumors and describes the molecular events that have been studied to guide future therapies of these peculiar neoplasms. RECENT FINDINGS: While some islet cell tumors arise in association with the MEN-1 syndrome, the majority of these neoplasms are sporadic lesions whose underlying genetic and molecular events remain largely unknown. Recent work has identified changes in gene expression occurring in metastatic and non-metastatic islet cell tumors, which appear to correlate with the occurrence of lymph node and liver metastases. Epigenetic alterations of select tumor suppressor genes may influence patient survival, and the presence of gene promoter methylation may be used as a prognostic marker system. In addition, multiple molecular alterations, including changes in expression of cellular proteins with migratory, cell cycle or angiogenic functions, have been demonstrated to influence islet cell tumor growth, invasion and metastatic spread. SUMMARY: Understanding the molecular events underlying the biology of pancreatic islet cell tumors will aid the development of accurate prognostic markers and will guide improved therapeutic modalities in the future.

Hepatic arterial embolization and chemoembolization for the treatment of patients with metastatic neuroendocrine tumors: variables affecting response rates and survival.

BACKGROUND: The objective of this study was to determine the prognostic variables that influence response and survival in patients with metastatic neuroendocrine tumors who are treated with hepatic arterial embolization (HAE) or chemoembolization (HACE). METHODS: Patients with metastatic neuroendocrine tumors who underwent HAE or HACE were included in this retrospective study. Follow-up imaging studies were compared with baseline imaging to determine the radiologic response. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Univariate and multivariate analyses were performed to assess the prognostic variables that affected response and survival. RESULTS: The study included 69 patients with carcinoid tumors and 54 patients with pancreatic islet cell carcinomas. Patients who had carcinoid tumors had a higher response rate (66.7% vs. 35.2%; P = 0.0001) and had longer PFS (22.7 mos vs. 16.1 mos; P = 0.046) and OS (33.8 mos vs. 23.2 mos; P = 0.012) compared with patients who had islet cell carcinomas. For patients with carcinoid tumors, multivariate analysis identified male gender as the only independent risk factor for poor survival (P = 0.05). Octreotide was predictive marginally for PFS (P = 0.06). Patients who were treated with HAE had a higher response rate than patients who were treated with HACE (P = 0.004). For patients with islet cell carcinoma, an intact primary tumor, > or = 75% liver involvement, and extrahepatic metastases were associated with reduced OS in the univariate analysis; the presence of bone metastases was the only risk factor (P = 0.031) in the multivariate analysis. Patients who were treated with HACE had a prolonged OS (31.5 mos vs. 18.2 mos) and improved response (50% vs. 25%) compared with patients who were treated with HAE, although the differences did not reach statistical significance. CONCLUSIONS: Patients with carcinoid tumors had better outcomes than patients with islet cell carcinomas. The addition of intraarterial chemotherapy to HAE did not improve the outcome of patients with carcinoid tumors, but it seemed to benefit patients with islet cell carcinomas. In patients who had carcinoid tumors, male gender predicted a poor outcome, and a trend toward prolonged PFS was observed in patients who received concomitant octreotide. An intact primary tumor, extensive liver disease, and bone metastases were associated with reduced survival in patients with islet cell carcinomas.