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 (Po0.0001). 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. Modern Pathology (2010) 23, 824-833; doi:10.1038/modpathol.2010 published online 19 March 2010 Keywords: pancreas; tumors; endocrine; staging; TNM; grading; prognosis Pancreatic endocrine tumors are rare and clinically taxing diseases, as their natural history is largely unknown. 1-4 Affected patients seek medical assistance due to symptoms resulting from either hormonal hypersecretion or mass. Thus, pancreatic endocrine tumors are clinically defined as functioning or nonfunctioning depending on the presence of a syndrome related to inappropriate hormone secretion. Such distinction, however, does not provide prognostic information. Pancreatic endocrine tumors are histologically divided into well-

Since gastro-entero-pancreatic endocrine tumors are rare and heterogeneous diseases, their prognosis and long-term survival are not well known. This study aimed at identifying prognostic factors and assessing long-term survival in gastro-entero-pancreatic endocrine tumors. A total of 156 patients enrolled. Prognostic factors were determined by univariate/multivariate analysis; survival rates were assessed by the Kaplan-Meier method. The tumors were non-functioning in 59.6% of patients, and originated from the pancreas in 42.9%. At diagnosis, 64.3% of patients had metastases. The tumors were well differentiated in 89.6% of patients. Ki67 was >2% in 39.6% of patients. Primary tumor size was >3 cm in 49.6% of cases studied. For the univariate analysis, the negative prognostic factors were: pancreatic origin (rate ratio 4.64, P = 0.0002), poorly differentiated tumor (rate ratio 7.70, P = 0.0001), primary tumor size >3 cm (rate ratio 4.26, P = 0.0009), presence of distant metastases (liver: rate ratio 5.88, P = 0.01; distant extra-hepatic: rate ratio 13.41, P = 0.0008). The pancreatic site, the poor degree of differentiation and the distant metastases were confirmed as negative prognostic factors at multivariate analysis. Overall 5-year survival rate was 77.5%. Survival rates differed according to: primary tumor site (62% for pancreatic vs 89.9% for gastrointestinal tract, P = 0.0001) and size (65.7% for >3 cm vs 88.8% for £ 3 cm, P = 0.0003), degree of differentiation (22% for poor vs 86.8% for good, P<0.0001), Ki67 (53.5% for >2% vs 90.1% for £ 2%, P = 0.003), metastases (96.1, 77, 73.3 and 50.1% for absent, local, liver and distant extra-hepatic metastases respectively), age at diagnosis (85.3% for £ 50 years vs 70.3% for >50 years, P = 0.03). Although 64.3% of gastro-entero-pancreatic endocrine tumors present metastases at diagnosis, the 5-year survival rate is 77.5%. Pancreatic site, a poor degree of tumor cell differentiation and distant extra-hepatic metastases are the major negative prognostic factors.

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.