A Single Institution's 26-Year Experience With Nonfunctional Pancreatic Neuroendocrine Tumors A Validation of Current Staging Systems and a New Prognostic Nomogram

ArticleinAnnals of surgery 259(2) · May 2013with18 Reads
DOI: 10.1097/SLA.0b013e31828f3174 · Source: PubMed
OBJECTIVE:: To validate the 2010 American Joint Committee on Cancer (AJCC) and 2006 European Neuroendocrine Tumor Society (ENETS) tumor staging systems for pancreatic neuroendocrine tumors (PanNETs) using the largest, single-institution series of surgically resected patients in the literature. BACKGROUND:: The natural history and prognosis of PanNETs have been poorly defined because of the rarity and heterogeneity of these neoplasms. Currently, there are 2 main staging systems for PanNETs, which can complicate comparisons of reports in the literature and thereby hinder progress against this disease. METHODS:: Univariate and multivariate analyses were conducted on the prognostic factors of survival using 326 sporadic, nonfunctional, surgically resected PanNET patients who were cared for at our institution between 1984 and 2011. Current and proposed models were tested for survival prognostication validity as measured by discrimination (Harrel's c-index, HCI) and calibration. RESULTS:: Five-year overall-survival rates for AJCC stages I, II, and IV are 93% (88%-99%), 74% (65%-83%), and 56% (42%-73%), respectively, whereas ENETS stages I, II, III, and IV are 97% (92%-100%), 87% (80%-95%), 73% (63%-84%), and 56% (42%-73%), respectively. Each model has an HCI of 0.68, and they are no different in their ability to predict survival. We developed a simple prognostic tool just using grade, as measured by continuous Ki-67 labeling, sex, and binary age that has an HCI of 0.74. CONCLUSIONS:: Both the AJCC and ENETS staging systems are valid and indistinguishable in their survival prognostication. A new, simpler prognostic tool can be used to predict survival and decrease interinstitutional mistakes and uncertainties regarding these neoplasms.
    • "As expected, the number of cells in all active phases (G1, S, G2, and M) of cell cycle is much higher than that of the cells in the M phase. As a result, low grade tumors with very low number of Ki67 positive cells contain so scarce mitotic figures that it may be difficult to find without PHH3 immunohistochemistry. Therefore, it is not surprising that Ki67 yields a better overall performance than mitotic count in general and it has been shown to be an independent prognostic marker in large cohorts of panNETs252627. Our results also expand this data by showing that a longer DFS is better predicted by accurate tumor grading, which is mainly determined by Ki67 grade category. "
    [Show abstract] [Hide abstract] ABSTRACT: This study investigated the impact of phosphohistone-H3 (PHH3)-assisted mitotic count by comparing its performance with conventional mitotic count and Ki67 score as well as the status of distant metastasis. A total of 43 surgically resected pancreatic neuroendocrine tumors (panNET) with complete follow-up information has been subjected to a standardized assessment with respect to mitotic count (both conventional and PHH3-assisted) and Ki67 score. Five participants assessed mitotic count and the time spent was recorded in both methods. All tumors were assigned to a G1 category of mitotic rate on conventional mitotic count that failed to identify three tumors with a G2 category of mitotic rate on PHH3. Near-perfect and fair agreements were achieved among observers when using PHH3 and conventional method, respectively. The mean time spent to determine mitotic count on PHH3-stained slides was significantly shorter (p < 0.001). The performance of PHH3-assisted mitotic grade category was significant as the three cases with a G2 mitotic category were associated with distant metastasis (p = 0.01). Despite its performance, the PHH3-assisted mitotic count downgraded 17 cases that were classified as G2 based on Ki67 scores in this series. The Ki67 grade category was either the same or higher than the mitotic grade category. Ten patients developed distant metastasis. Eleven tumors exhibited vascular invasion characterized by intravascular tumor cells admixed with thrombus. Our results indicate that PHH3-assisted mitotic count facilitates an accurate mitotic count with a perfect agreement among observers. The small size of this cohort is an important limitation of the current study, a G2 mitotic grade category based on PHH3 immunohistochemistry was one of the correlates of panNETs with distant metastasis. While the prognostic impact of PHH3-assisted mitotic count needs to be clarified in larger cohorts, Ki67 scores designated higher grade category in all cases; thus, it was the best determinant of the tumor grade. More importantly, the presence of vascular invasion along with the Ki67 grade category was found to be independent predictors of distant metastasis.
    Full-text · Article · Mar 2016
    • "We propose this novel IPS score and our final PFS to identify patients at higher risk of disease recurrence and death following surgical resection. Furthermore, our results could be considered at least as significant as other prognostic models, including the ENETS or the AJCC staging systems [33]. One of the challenges of measuring methylated DNA is its low specificity compared with genomic alterations. "
    [Show abstract] [Hide abstract] ABSTRACT: Pancreatic neuroendocrine tumor (PanNET) is a neoplastic entity in which few prognostic factors are well-known. Here, we aimed to evaluate the prognostic significance of N-myc downstream-regulated gen-1 (NDRG-1), O6-methylguanine DNA methyltransferase (MGMT) and Pleckstrin homology-like domain family A member 3 (PHLDA-3) by immunohistochemistry (IHC) and methylation analysis in 92 patients with resected PanNET and follow-up longer than 24 months. In multivariate analyses, ki-67 and our immunohistochemistry prognostic score (IPS-based on MGMT, NDRG-1 and PHLDA-3 IHC expression) were independent prognostic factors for disease-free-survival (DFS), while age and IPS were independent prognostic factors for overall survival (OS). Our IPS could be a useful prognostic biomarker for recurrence and survival in patients following resection for PanNET.
    Full-text · Article · Feb 2016
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