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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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.

TNM stage and grade in predicting the prognosis of operated, non-functioning neuroendocrine carcinoma of the pancreas--a single-institution experience.

OBJECTIVE: To evaluate the prognostic significance of TNM and grading categories in curatively resected non-functioning neuroendocrine pancreatic carcinoma (nfnepC). METHOD: Eighteen nfnepC were retrospectively analyzed for differences in survival. RESULTS: (1) There was a correlation between pT (P = 0.026), respectively pM categories (P = 0.016) and survival. (2) G categories and length of survival were closely correlated (P = 0.0036). (3) Disease stages I-IV had a significant effect on survival (P = 0.051). (4) The WHO classification in well and poorly differentiated carcinomas proved to be the most conclusive predictive factor (P = 0.0009). (5) Subgroups with significantly different prognoses determined by histological grade were present within disease stage II. CONCLUSIONS: The retrospective analysis showed a good correlation between survival and pT, pM, tumor stage, G categories, and WHO classification in well and poorly differentiated carcinomas. Including histological differentiation in the staging system or carrying it out separately in well and poorly differentiated carcinomas, could enhance the predictive potential of TNM-based disease stages.

Support for a postresection prognostic score for pancreatic endocrine tumors.

BACKGROUND: Prognostic scores predicting long-term survival of patients with pancreatic neuroendocrine tumors (PNETs) have been created. The purpose of this study was to validate a prognostic scoring scheme at a single institution. METHODS: We reviewed all resections for PNETs from 1996 to 2004. Prognostic scores based on patient age, tumor grade, and distant metastasis were calculated. Survival was compared with an established postresection prognostic score for PNETs. RESULTS: A total of 34 PNETs were identified. Predicted 5-year survival for prognostic scores of 1, 2, and 3 were 76.7%, 50.9%, and 35.7%, respectively. Final prognostic scores of 1, 2, and 3 were observed in 13 (38%), 18 (53%), and 3 (9%) patients, with observed actual 5-year survivals of 92.3%, 72.2%, and 66.7%, respectively. CONCLUSIONS: PNET prognostic scores were found to be inversely related to survival. PNET postresection prognostic score categories may be useful tools in predicting long-term survival.

Proposed histopathologic grading system derived from a study of KIT and CK19 expression in pancreatic endocrine neoplasm.

Predicting the biologic behavior of pancreatic endocrine neoplasm in the absence of local invasion or metastasis is difficult. We recently proposed an immunohistochemical classification system based on a combination of KIT and CK19 expression: low risk (KIT-/CK19-), intermediate risk (KIT-/CK19+), and high risk (KIT+/CK19+). In the current study, we sought histopathologic features that correlated with the immunohistochemical categories and that could be used in predicting tumor behavior. We assessed histologic findings of 97 pancreatic endocrine neoplasm that had been classified into 3 risk groups based on KIT/CK19 expression. Clinicopathologic associations with prognosis were evaluated using Cox proportional hazards regression models. Tumor size, mitoses, infiltrative border, extrapancreatic extension, perineural invasion, and presence of amyloid were significantly different among the 3 risk groups, and tumor necrosis approached statistical significance as well (P = .089). A scoring system using mitoses, necrosis, and tumor border was developed as follows: mitosis: 0 (0/50 high-power field), 1 (1-3/50 high-power field), and 2 (≥4/50 high-power field); necrosis: 0 (absent) and 1 (present); tumor border: 0 (noninfiltrating) and 1 (infiltrating), giving a possible histology score of 0 to 4. Although there was an overall difference in disease-specific survival among the 4 histology scores (P < .001), there was not a statistically significant difference between patients with scores of 0 and 1 or between patients with scores of 3 and 4. Therefore, a 3-tied grading system was developed by combining score 0 and 1 tumors as grade 1, score 2 tumors as grade 2, and score 3 and 4 tumors as grade 3. There was a significant difference in survival, tumor metastasis, tumor recurrence, and functioning status among the 3 grades. By analyzing histopathologic features in KIT/CK19 risk groups, we developed a 3-tiered histopathologic grading system using reproducible parameters (mitoses, tumor necrosis, and infiltrative border) that are easy to apply in practice.

Pancreatic endocrine tumors: radiologic-clinicopathologic correlation.

Pancreatic endocrine tumors (PETs) are primarily well-differentiated tumors composed of cells that resemble normal islet cells but that arise from pancreatic ductal cells. They are classified as functioning or nonfunctioning according to their associated clinical symptoms; insulinoma, gastrinoma, and glucagonoma are the most common functioning PETs. They also are classified according to their biologic behavior, although all PETs have malignant potential. Most are sporadic, but some are associated with familial syndromes such as multiple endocrine neoplasia type 1, von Hippel-Lindau syndrome, and neurofibromatosis type 1. At imaging, PETs typically appear as well-defined hypervascular masses, a finding indicative of their rich capillary network. Cystic change, calcification, and necrosis are common in large tumors, which are associated with a poorer prognosis and a higher prevalence of local and vascular invasion and metastases than are smaller tumors. Even when metastases are present, many well-differentiated PETs have an indolent course. Poorly differentiated PETs are rare and have an infiltrative appearance; patients with such tumors have a poor prognosis. Knowledge of the characteristic clinical, pathologic, and radiologic features of PETs is important in the evaluation and management of patients with a suspected clinical syndrome or a pancreatic mass.

Diagnostic approach to pancreatic tumors with the specimens of endoscopic ultrasound-guided fine needle aspiration.

Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has enabled clinicians to histologically diagnose pancreatic tumors. However, EUS-FNA specimens often result in tiny fragmented tissues, so auxiliary utilities are necessary. Using immunostaining of CK7, CDX2, neuroendocrine markers and KRAS mutation analysis, we examined 57 FNA cell block sections and 61 surgically-resected specimens (25 invasive ductal carcinomas, 25 endocrine tumors, and 11 acinar cell tumors). In the majority of the matched pairs, the diagnoses between EUS-FNA and surgical specimens were concordant using the following criteria: neuroendocrine markers negative, CK7 positive, and mutated KRAS gene for invasive ductal carcinomas; neuroendocrine markers diffusely positive, CK7 and CDX2 negative, and wild-type KRAS gene for well-differentiated endocrine tumors; and neuroendocrine markers no more than focal positive, CK7 and CDX2 with various staining patterns, and wild-type KRAS gene for acinar cell carcinomas. Expression of CK7 and/or CDX2 in addition to KRAS mutations were occasionally seen in endocrine carcinomas, but not in well-differentiated endocrine tumors, suggesting that ductal differentiation in an endocrine tumor may be a predictor of aggressive disease. The usefulness of these markers was confirmed using 13 additional pancreatic tumors, prospectively. Although minimal in selection, these markers are helpful in making diagnosis from EUS-FNA specimens of the major pancreatic tumors.

Clinicopathological features of pancreatic endocrine tumors: a prospective multicenter study in Italy of 297 sporadic cases.

OBJECTIVES: Information on pancreatic endocrine tumors (PETs) comes mostly from small, retrospective, uncontrolled studies conducted on highly selected patients. The aim of the study was to describe the clinical and pathological features of PETs in a prospective, multicenter study. METHODS: Newly diagnosed, histologically proven, sporadic PETs observed from June 2004 to March 2007 in 24 Italian centers were included in a specific data set. RESULTS: Two hundred ninety-seven patients (mean age 58.6+/-14.7 years, females 51.2%, males 48.8%) were analyzed. In 73 cases (24.6%), the tumor was functioning (F) (53 insulinomas, 15 gastrinomas, 5 other syndromes) and in 232 (75.4%) it was non-functioning (NF); in 115 cases (38.7%), the diagnosis was incidental. The median tumor size was 20 mm (range 2-150). NF-PETs were significantly more represented among carcinomas (P<0.001). Nodal and liver metastases were detected in 84 (28.3%) and 85 (28.6%) cases, respectively. The presence of liver metastases was significantly higher in the NF-PETs than in the F-PETs (32.1% vs. 17.8%; P<0.05), and in the symptomatic than in the asymptomatic patients (34.6% vs. 19.1%; P<0.005). At the time of recruitment, the majority of patients (251, 84.5%) had undergone surgery, with complete resection in 209 cases (83.3%). CONCLUSIONS: This study points out the high number of new cases of PETs observed in Italy, with a high prevalence of NF and incidentally discovered forms. The size of the tumor was smaller and the rate of metastasis was lower than usually reported, suggesting a trend toward an earlier diagnosis.

Improved histologic and clinicopathologic criteria for prognostic evaluation of pancreatic endocrine tumors.

Currently used histopathologic criteria for the diagnosis of pancreatic endocrine tumors are still under discussion as far as to their capacity to identify prognostically different tumor subsets, which are potentially helpful for patient management. A recently developed TNM staging system and a variety of proposed histologic and clinicopathologic parameters still need to be fully validated. One hundred fifty-five pancreatic endocrine tumors encompassing all the main histologic types and stages, operated with intention to cure and then followed up for a median 126 months, were carefully investigated histologically to identify prognostically informative parameters at univariable, bivariable, and multivariable analysis. Ki67 index, mitotic rate, neuroinvasion with or without vascular, peritumoral or stromal infiltrative patterns, as well as tumor size, and association with endocrine syndromes other than insulinoma proved effective in predicting recurrence and disease-specific death among well-differentiated tumors. Poorly differentiated histologic features, more than 10 mitoses/10 high power fields, and necrosis were helpful in the identification of high-grade cancers with an invariably poor prognosis. The TNM system proved to be highly predictive of patient outcome and easy to combine with histologic and clinicopathologic parameters to classify pancreatic endocrine tumors into groups of increasing malignant potential.

Clear-cell variant of solid-pseudopapillary neoplasm of the pancreas: a case report and review of the literature.

Solid-pseudopapillary neoplasm (SPN) of the pancreas is a rare neoplasm reported to have a favourable prognosis because of its slow-growing behaviour. Ignored and misdiagnosed in the past, SPN has recently been increasingly studied. Its clear cell variant creates challenges in distinction from other clear cell tumours in the pancreas. We report a 31-year-old Cambodian woman who presented with abdominal pain and a palpable epigastric mass. Exploratory laparotomy revealed a 5.2 cm well-demarcated tumour in the head of the pancreas, which was treated with Whipple procedure. Microscopically, the tumour showed an extensive solid growth pattern consisting of cells with abundant clear cytoplasm, and papillary areas containing cells with eosinophilic cytoplasm, indicating a clear-cell solid-papillary neoplasm. Perineural and duodenal wall invasion was present. The tumour cells were immunonegative for chromogranin-A and synaptophysin but positive for CD56, cyclin D1, CD10, vimentin, and progesterone receptor. They showed strong nuclear and cytoplasmic expression and reduced membranous expression of beta-catenin protein. In the pseudopapillary area, they showed nuclear E-cadherin localization and absence of membranous staining. The patient was well without local recurrence or metastasis at one year follow-up. Difficulties are recognized in differentiating clear-cell SPN from "sugar" tumours, metastatic renal cell carcinoma, clear-cell variant of pancreatic endocrine neoplasm and ductal adenocarcinoma. When facing such difficulties, nuclear and cytoplamic beta-catenin, nuclear E-cadherin expressions and absence of membranous E-cadherin staining are useful in differentiating clear-cell SPN from other clear cell tumours in the pancreas. Although a rare neoplasm, it is important to recognize this entity for appropriate management.

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.

Usefulness of S100P in diagnosis of adenocarcinoma of pancreas on fine-needle aspiration biopsy specimens.

Even though the cytologic criteria for pancreatic ductal adenocarcinoma (PDA) on fine-needle aspiration biopsy (FNAB) specimens have been well defined, a diagnostic challenge is still present. We immunohistochemically evaluated the diagnostic value of S100P on cell-block and/or smear preparations in 58 cases of FNAB specimens of the pancreas. The 58 cases were divided into 4 groups: 1, 32 cases of PDA; 2, 6 cases with an atypical or "suspicious" diagnosis; 3, 14 cases of benign or reactive ductal epithelium; and 4, 6 cases of endocrine tumor. Positive immunoreactivity for S100P was observed in all cases in groups 1 and 2, whereas only 1 of 14 cases in group 3 was positive for S100P. All cases in group 4 were negative for S100P. S100P is a sensitive and specific marker for the detection of PDA on FNAB specimens on cell-block and smear preparations.

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.

WHO 2004 criteria and CK19 are reliable prognostic markers in pancreatic endocrine tumors.

BACKGROUND: It is difficult to predict the biologic behavior of pancreatic endocrine tumors in absence of metastases or invasion into adjacent organs. The World Health Organization (WHO) has proposed in 2004 size, angioinvasion, mitotic activity, and MIB1 proliferation index as prognostic criteria. Our aim was to test retrospectively the predictive value of these 2004 WHO criteria and of CK19, CD99, COX2, and p27 immunohistochemistry in a large series of patients with long-term follow-up. DESIGN: The histology of 216 pancreatic endocrine tumor specimens was reviewed and the tumors were reclassified according to the 2004 WHO classification. The prognostic value of the WHO classification and the histopathologic criteria necrosis and nodular fibrosis was tested in 113 patients. A tissue microarray was constructed for immunohistochemical staining. The staining results were scored quantitatively for MIB1 and semiquantitatively for CK19, COX2, p27, and CD99. The prognostic value of these markers was tested in 93 patients. RESULTS: The stratification of the patients into 4 risk groups according to the 2004 WHO classification was reliable with regard to both time span to relapse and tumor-specific death. In a multivariate analysis, the CK19 status was shown to be independent of the WHO criteria. By contrast, the prognostic significance of COX2, p27, and CD99 could not be confirmed. CONCLUSIONS: The 2004 WHO classification with 4 risk groups is very reliable for predicting both disease-free survival and the time span until tumor-specific death. CK19 staining is a potential additional prognostic marker independent from the WHO criteria for pancreatic endocrine tumors.

[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.

[A case of mixed duct-islet cell tumor of the pancreas].

A 30-year-old woman was referred to us because of hypoglycemic attack. The tumor on the pancreatic body of 22 mm size was revealed by close inspection, and was diagnosed as insulinoma. Surgical resection was performed, but curative resection was impossible because the component of adenocarcinoma infiltrating into surrounding tissue coexisted with insulinoma. Postoperatively, we make a diagnosis of combined tumor of the pancreas, i.e. mixed duct-islet cell carcinoma. In this paper, we discuss this rare disorder and summarize 33 cases reported in the Japanese literature.