Francesco Panzuto

Pancreatic endocrine tumors: improved TNM staging and histopathological grading permit a clinically efficient prognostic stratification of patients.

Pancreatic endocrine tumors are rare diseases and devising a clinically effective prognostic stratification of patients is a major clinical challenge. This study aimed at assessing whether the tumor-node-metastasis (TNM)-based staging and proliferative activity-based grading recently proposed by the European NeuroEndocrine Tumors Society (ENETS) have clinical value. TNM was applied to 274 patients with histologically diagnosed pancreatic endocrine tumors operated from 1991 to 2005, with last follow-up at December 2007. According to World Health Organization (WHO) classification, 246 were well-differentiated neoplasms (51 benign, 56 uncertain behavior, 139 carcinomas) and 28 poorly differentiated carcinomas. Grading was based on Ki67 immunohistochemistry. Survival analysis not only ascertained the prognostic value of the TNM system but also highlighted that in the absence of nodal and distant metastasis, infiltration and tumor dimensions over 4 cm had prognostic significance. T parameters were then appropriately modified to reflect this weakness. The 5-year survival for modified TNM stages I, II, III and IV were 100, 93, 65 and 35%, respectively. Multivariate analysis identified TNM stages as independent predictors of death, in which stages II, III and IV showed a risk of death of 7, 29 and 58 times higher than stage I tumors (P<0.0001). Ki67-based grading resulted an independent predictor of survival with cut-offs at 5 and 20%. In conclusion, WHO classification assigns clinically significant diagnostic categories to pancreatic endocrine tumors that need prognostic stratification by applying a staging system. The ENETS–TNM provides the best option, but it requires some modifications to be fully functional. The modified TNM described in this study ameliorates the clinical applicability and prediction of outcome of the ENETS–TNM; it (i) assigns a risk of death proportional to the stage at the time of diagnosis, and (ii) allows a clinically based staging of patients, as the T parameters as modified permit their clinical-radiological recognition. Ki67-based grading discerns prognosis of patients with same stage diseases.

Prognostic factors at diagnosis and value of WHO classification in a mono-institutional series of 180 non-functioning pancreatic endocrine tumours

BACKGROUND Non-functioning pancreatic endocrine tumours (NF-PETs) are an aggressive gastroenteropancreatic neoplasm. The present study assessed survival, value of World Health Organisation (WHO) classification and prognostic utility of clinicopathological parameters at diagnosis. PATIENTS AND METHODS From 1990 to 2004, 180 patients with NF-PETs were entered in a prospective database, and predictors of prognosis were tested in uni- and multivariate models. RESULTS There were 25 (14%) benign lesions, 38 (21%) neoplasms of uncertain behaviour, 100 well-differentiated carcinomas (56%) and 17 poorly differentiated carcinomas (9%). Radical resection was possible in 93 cases (51.6%). Overall 5-, 10- and 15-year survival rates were 67%, 49.3% and 32.8%, respectively, and were significantly higher in radically resected patients (93%, 80.8% and 65.2%, respectively; P < 0.00001). By multivariate analysis, poor differentiation [hazard ratio (HR) 7.3; P = 0.0001], nodal metastases (HR 3.05; P = 0.02), liver metastases (HR 3.29; P = 0.003), K(i)-67 >5% (HR 2.5; P = 0.012) and weight loss (HR 3.06; P = 0.001) were significantly associated with mortality. CONCLUSION This study confirms the good long-term survival of patients with NF-PETs and the prognostic value of WHO classification, liver metastases, poor differentiation, Ki-67, nodal metastases and weight loss. These latter two parameters have a prognostic value similar to that of liver metastases and Ki-67.

Metastatic and Locally Advanced Pancreatic Endocrine Carcinomas: Analysis of Factors Associated With Disease Progression

PURPOSE Knowledge of clinical course of pancreatic endocrine carcinomas (PECs) is poor. This study aimed to determine the time to progression of advanced PECs, and to identify predictors capable of selecting subgroups with higher risk of progression. PATIENTS AND METHODS In this multicenter retrospective analysis, patients with advanced PECs were enrolled. Staging was according to European Neuroendocrine Tumors Society guidelines. Grading was based on proliferation index using Ki67 immunohistochemistry. The primary end point was progression-free survival (PFS), which was assessed using the Kaplan-Meier method. The Cox regression proportional hazard model was used to identify predictors for tumor progression. RESULTS Two hundred two patients with PECs were enrolled, including 172 with well-differentiated and 30 with poorly differentiated endocrine carcinomas. There were 34 patients with stage III and 168 with stage IV tumors. G1 tumors were present in 19.7% of patients, whereas 60.1% of patients had G2 tumors, and the remaining 20.2% had G3 tumors. Disease progression occurred in 166 patients (82.2%), at a median interval of 10 months (interquartile range, 5 to 22) from diagnosis. Median PFS was 14 months. Different PFS were observed depending on G grade (P < .001) and tumor differentiation (P < .001) and in patients who did not receive any antitumor treatment (P = .002). The major risk factor for progression was the proliferation index Ki67 (hazard ratio, 1.02 for each increasing unit; P < .001). Overall 5-year survival was 44.1%. CONCLUSION The vast majority of patients with advanced PECs undergo disease progression. The major risk factor for progression is Ki67 index, which should lead physicians dealing with PECs to plan appropriate follow-up programs and therapeutic strategies.

Ki-67 grading of nonfunctioning pancreatic neuroendocrine tumors on histologic samples obtained by EUS-guided fine-needle tissue acquisition: a prospective study

BACKGROUND Preoperative determination of Ki-67 expression, an important prognostic factor for grading nonfunctioning pancreatic endocrine tumors (NF-PETs), remains an important clinical challenge. OBJECTIVE To prospectively evaluate the feasibility, yield, and clinical impact of EUS-guided fine-needle tissue acquisition (EUS-FNTA) with a large-gauge needle to obtain tissue samples for histologic diagnosis and Ki-67 analysis in patients with suspected NF-PETs. DESIGN Prospective cohort study. SETTING Tertiary-care academic medical center. PATIENTS Consecutive patients with a single pancreatic lesion suspicious for NF-PET on imaging. INTERVENTION EUS-FNTA with a 19-gauge needle. MAIN OUTCOME MEASUREMENTS Feasibility and yield of EUS-FNTA for diagnosis and Ki-67 expression determination. RESULTS Thirty patients (mean [± SD] age 55.7 ± 14.9 years), with a mean (± SD) lesion size of 16.9 ± 6.1 mm were enrolled. EUS-FNTA was successfully performed without complications in all patients, with a mean (± SD) of 2.7 ± 0.5 passes per patient. Adequate samples for histologic examination were obtained in 28 of the 30 patients (93.3%). Ki-67 determination could be performed in 26 of these 28 patients (92.9%, 86.6% overall), 12 of whom underwent surgical resection. Preoperative and postoperative Ki-67 proliferation indexes were concordant in 10 patients (83.3%), whereas 2 patients were upstaged from G1 to G2 or downstaged from G2 to G1, respectively. LIMITATIONS Single center study with a single operator. CONCLUSION In patients with suspected nonfunctioning low-grade to intermediate-grade pancreatic neuroendocrine tumors (p-NETs), retrieval of tissue specimens with EUS-FNTA by using a 19-gauge needle is safe, feasible, and highly accurate for both diagnosis and Ki-67 determination. A Ki-67 proliferative index acquired through this technique might be of great help for further therapeutic decisions.

Malignant pancreatic neuroendocrine tumour: Lymph node ratio and Ki67 are predictors of recurrence after curative resections

INTRODUCTION Malignant pancreatic neuroendocrine tumours (PNENs) are generally associated with a good prognosis after radical resection. In other pancreatic malignancies predictors of recurrence and the role of lymph node ratio (LNR) are well known, but both have been scarcely investigated for malignant PNETs. METHODS The prospective database from the surgical Department of Verona University was queried. Clinical and pathological data of all patients with resected malignant PNET between 1990 and 2008 were reviewed. Univariate and multivariate analysis were performed. RESULTS Fifty-seven patients (male/female ratio=1) with a median age of 58 years (33-78) entered in the study. Twenty-nine (51%) patients underwent pancreaticoduodenectomy and 28 (49%) distal pancreatectomy. Postoperative mortality was nil with a 37% morbidity rate. There were 36 (63%) patients with lymph node metastases (N1). Of these, 23 (64%) had a lymph node ratio (LNR) >0 and ≤0.20 and 13 (36%) had a LNR >0.20. The median overall survival and the median disease free survival (DFS) were 190 and 80 months, respectively. Recurrent disease was identified in 24 patients (42%) with a 2 and 5-year DFS rate of 82% and 49%, respectively. On multivariate analysis, LNR >0.20 (HR=2.75) and a value of Ki67 >5% (HR=3.39) were significant predictors of recurrence (P<0.02). CONCLUSIONS After resection for malignant PNETs, LNR and a Ki67 >5% are the most powerful predictors of recurrence. The presence of these factors should be considered for addressing patients to adjuvant treatment in future clinical trials.

Utility of combined use of plasma levels of chromogranin A and pancreatic polypeptide in the diagnosis of gastrointestinal and pancreatic endocrine tumors.

Background: Chromogranin A (CgA) is considered the most accurate marker in the diagnosis of gastro-entero-pancreatic (GEP) endocrine tumors. Pancreatic polypeptide (PP) has also been proposed to play this role, but then not used due to its low sensitivity. The aim of the present study was to determine whether the assessment of PP would improve the diagnostic reliability of CgA in patients with GEP tumors. Patients and methods: Both markers were assessed in 68 patients [28 functioning (F), 40 non functioning (NF)]. Twenty-seven patients disease-free (DF) after surgery, and 24 with non-endocrine tumors (non-ETs) were used as control groups. Results: CgA sensitivity was: 96% in F, 75% in NF, 74% in pancreatic, and 91% in gastrointestinal (GI) tumors. Specificity was 89% vs DF, and 63% vs non- ETs. PP sensitivity was: 54% in F, 57% in NF, 63% in pancreatic, and 53% in GI tumors. Specificity was 81% vs DF, and 67% vs non-ETs. By combining the two markers a significant gain in sensitivity vs CgA alone was obtained: overall in GEP tumors (96% vs 84%, p=0.04), in NF (95% vs 75%, p=0.02), and in pancreatic (94% vs 74%, p=0.04). More specifically, a 25% gain of sensitivity was obtained in the subgroup of NF pancreatic tumors (93% vs 68%, p=0.04). Conclusion: The combined assessment of PP and CgA leads to a significant increase in sensitivity in the diagnosis of GEP tumors, particularly in pancreatic NF.

Type I gastric carcinoids: a prospective study on endoscopic management and recurrence rate.

Background: Type I gastric carcinoids (TIGCs) are neuroendocrine neoplasms arising from enterochromaffin-like cells in atrophic body gastritis. Data regarding their evolution in prospective series are scarce, thus treatment and follow-up are not codified. Our aim was to evaluate clinical outcome and recurrence in TIGCs managed by endoscopic approach. Methods: 33 patients (24 females; median age 65 years, range 23–81) were included and managed through endoscopic follow-up every 6–12 months, with lesion removal and multiple gastric biopsies. Baseline clinical and histological features were analyzed as risk factors by Cox regression. Results: At diagnosis, 7 tumors were intramucosal carcinoids and 26 were polyps (median diameter 5 mm, range 2–20), multiple in 17 patients. Associated severe atrophy was present in 21 cases (63.6%), while mild atrophy was found in 6 cases (18.2%). During a 46-month median follow-up, survival was 100% and no metastases occurred. One patient developed a less-differentiated carcinoid that was radically treated by surgery. 21 patients (63.6%) had recurrence after a median of 8 months, 14 of these (66.6%) had a second recurrence after a median of 8 months following the previous carcinoid removal. Median recurrence-free survival was 24 months. Neither clinical nor biochemical recurrence-predicting factors were found. Conclusions: Although about 60% of TIGCs had recurrence after endoscopic resection, endoscopic management may be considered safe and effective.

Molecular pathology and genetics of pancreatic endocrine tumours.

Pancreatic neuroendocrine tumours (PETs) are the second most frequent pancreatic neoplasms. Their poor chemosensitivity, high rate of metastatic disease and relatively long survival make PETs an ideal field to be explored for novel therapies based on specific molecular changes. PETs are generally sporadic but can also arise within hereditary syndromes, such as multiple endocrine neoplasia type 1, von Hippel-Lindau, neurofibromatosis type 1 and tuberous sclerosis complex, which represent a model for sporadic cases too. Among allelic imbalances, main genomic changes involve gain of 17q, 7q and 20q and loss of 11q, 6q and 11p, which identify regions of putative candidate oncogenes or tumour suppressor genes (TSGs), respectively, sometime with potential prognostic significance. Overexpression of Src-like kinases and cyclin D1 (CCND1) oncogene has been described. As for TSGs, P53 (TP53), DPC4/SMAD4 and RB (RB1) are not implicated in PET tumorigenesis, while for p16INK4a (CDKN2A), TIMP3, RASSF1A and hMLH1, more data are available, suggesting a role for methylation as a silencing mechanism. In the last decade, gene expression profile studies, analysis of microRNAs and, more recently, large-scale mutational analysis have highlighted commonly altered molecular pathways in the pathology of PETs. The roles of the mammalian target of rapamycin pathway, and its connection with Src kinases, and the activity of a number of tyrosine kinase receptors seem to be pivotal, as confirmed by the results of recent clinical trials with targeted agents. Mutations of DAXX and ATRX are common and related to altered telomeres but not to prognosis.

Gastric Neuroendocrine Tumors

Gastric carcinoids are rare neuroendocrine tumors, usually classified as type I, if associated with atrophic body gastritis; type II, if associated with Zollinger-Ellison syndrome and multiple endocrine neoplasia type I, and type III, in the absence of any gastric pathology (sporadic tumors). The pathological features, as well as the prognosis of the tumor and the patient’s survival strictly depend on this classification. The correct management of the patient with gastric carcinoid can only be proposed when the tumor has been classified by an accurate pathological and clinical evaluation of the patient. While the therapeutic approach in types I and II is based on a conservative strategy, including endoscopic resection, an adequate follow-up program, and the possible use of somatostatin analogues, an aggressive surgical approach is required in type III.

Large hiatal hernia in patients with iron deficiency anaemia: a prospective study on prevalence and treatment

Background : Although large hiatal hernia may cause bleeding from Cameron erosions, its role in iron deficiency anaemia has been debated, and no data are available on the treatment of these patients with proton pump inhibitors.