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

Abstract

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-

Tissue heterogeneity contributes to suboptimal precision of WHO 2010 scoring criteria for Ki67 labeling index in a subset of neuroendocrine neoplasms of the pancreascriteria for Ki67 labeling index in a subset of neuroendocrine neoplasms of the pancreas

“…Such modification resulted previously in statistically significant differences in survival between G1 and G2 cases in multivariate analyses adjusted for stage, in contrary to original 2(3)% cut-off [47,48]. This result was confirmed by meta-analysis [49], which showed better ability of 5% value for prognostication in NET.…”

“…Five-percent Ki67 LI cut-off value for G1/G2 distinction do not improve grading precision Some investigators proposed 5% Ki67 LI as optimal cut-off value for distinguishing G1 and G2 NET [46,47,48]. Such modification resulted previously in statistically significant differences in survival between G1 and G2 cases in multivariate analyses adjusted for stage, in contrary to original 2(3)% cut-off [47,48].…”

“…Such an observation was reported in a single study [68]. In some studies stage-independent prognostic value of Ki67 LI was proven only when cut-off value of 4.8% [46] or 5% [47,48] was applied, instead of 2(3)%, or alternatively, when study population included also gastric and duodenal neoplasms [69].…”

PTCH 1 staining of pancreatic neuroendocrine tumor (PNET) samples from patients with and without multiple endocrine neoplasia (MEN-1) syndrome reveals a potential therapeutic target

“…This included grading of the tumors according to their pattern and cytologic features and assessment of mitotic rate and proliferative activity as determined by immunostaining for Ki67. 27,28 The tumors were diagnosed as Neuroendocrine Tumor grade 1 or 2 or Neuroendocrine carcinoma (NEC or Tumor grade 3).…”

Reassessing the grade of gastroenteropancreatic neuroendocrine neoplasms

“…However, it is increasingly recognized that there are genetic and biological differences among these different NETs, so it is quite possible that site-specific different parameters would more optimally stratify the behavior. Indeed, studies on pancreatic NETs have suggested that a different Ki67 index (5 % rather than 3 %) optimally separates G1 and G2 [6]. Because of the potential for grading and staging criteria to evolve as more data accumulate, it is recommended that pathology reports document the actual values of the parameters in addition to the specific grade and stage, so that retrospective reclassification can be performed easily should the criteria evolve [7].…”