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

Departments of *Surgery †Pathology ‡Oncology, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD §Vanderbilt University Medical Center, Department of Pathology, Microbiology and Immunology, Nashville, TN ¶The Johns Hopkins Bloomberg School of Public Health, Department of Biostatistics, Baltimore, MD ‖The University of Colorado, Department of Surgery, Aurora, CO.
Annals of surgery (Impact Factor: 8.33). 05/2013; 259(2). 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.

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    ABSTRACT: The grading system for pancreatic neuroendocrine tumors (PanNETs) adopted in 2010 by the World Health Organization (WHO) mandates the use of both mitotic rate and Ki67/MIB-1 index in defining the proliferative rate and assigning the grade. In cases when these measures are not concordant for grade, it is recommended to assign the higher grade, but specific data justifying this approach do not exist. Thus, we counted mitotic figures and immunolabeled, using the Ki67 antibody, 297 WHO mitotic grade 1 and 2 PanNETs surgically resected at a single institution. We quantified the Ki67 proliferative index by marking at least 500 cells in "hot spots" and by using digital image analysis software to count each marked positive/negative cell and then compared the results with histologic features and overall survival. Of 264 WHO mitotic grade 1 PanNETs, 33% were WHO grade 2 by Ki67 proliferative index. Compared with concordant grade 1 tumors, grade-discordant tumors were more likely to have metastases to lymph node (56% vs. 34%) (P<0.01) and to distant sites (46% vs. 12%) (P<0.01). Discordant mitotic grade 1 PanNETs also showed statistically significantly more infiltrative growth patterns, perineural invasion, and small vessel invasion. Overall survival was significantly different (P<0.01), with discordant mitotic grade 1 tumors showing a median survival of 12 years compared with 16.7 years for concordant grade 1 tumors. Conversely, mitotic grade 1/Ki67 grade 2 PanNETs showed few significant differences from tumors that were mitotic grade 2 and either Ki67 grade 1 or 2. Our data demonstrate that mitotic rate and Ki67-based grades of PanNETs are often discordant, and when the Ki67 grade is greater than the mitotic grade, clinical outcomes and histopathologic features are significantly worse than concordant grade 1 tumors. Patients with discordant mitotic grade 1/Ki67 grade 2 tumors have shorter overall survival and larger tumors with more metastases and more aggressive histologic features. These data strongly suggest that Ki67 labeling be performed on all PanNETs in addition to mitotic rate determination to define more accurately tumor grade and prognosis.
    No preview · Article · Oct 2013 · The American journal of surgical pathology
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    ABSTRACT: Neuroendokrine Neoplasien des Pankreas und des Gastrointestinaltrakts sind bzgl. Genese (sporadisch oder hereditär), Phänotyp einschließlich Hormonexpression, klinisch funktioneller Aktivität und v. a. dem Malignitätspotenzial heterogen. Die bioptische Diagnostik nimmt einen hohen Stellenwert bei der Planung des klinisch-therapeutischen Vorgehens ein und basiert im Wesentlichen auf der Tumordifferenzierung (organoides oder diffuses Wachstum) und dem proliferationsbasierten Grading. Letzteres wird anhand der Ki-67-Proliferations- oder der Mitoserate bestimmt und nimmt entscheidend Einfluss auf die aktuell gängige Klassifikation neuroendokriner Neoplasien als neuroendokrine Tumoren G1, neuroendokrine Tumoren G2 oder neuroendokrine Karzinome G3. Gelegentlich findet sich eine Mischdifferenzierung mit nichtneuroendokrinen Karzinomen. Die Marker Synaptophysin und Chromogranin A sind gut zur immunhistochemischen Befundsicherung neuroendokriner Neoplasien geeignet. Darüber hinaus können am Biopsiematerial immunhistochemisch therapeutische Marker wie der Somatostatinrezeptor-2A bestimmt werden sowie bei Bedarf Transkriptionsfaktoren oder Hormone zur Eingrenzung der primären Tumorlokalisation bei metastasierten Tumorleiden oder zur Klärung klinisch funktioneller Aktivität. Schließlich wird am Beispiel des Magens gezeigt, dass die bioptische Diagnostik auch beim Nachweis neuroendokriner Vorläuferläsionen von Nutzen ist und prognostische Signifikanz beinhaltet. Abstract Neuroendocrine neoplasms of the pancreas and the gastrointestinal tract are heterogeneous regarding etiology (e.g. sporadic or hereditary), histomorphology, hormone expression, hormone-related functional activity and especially the malignant potential. In neuroendocrine neoplasms the biopsy-based diagnosis plays an important role for the clinical management of patients. The diagnosis most importantly relies on the differentiation (e.g. organoid versus diffuse growth patterns) and the grading of tumors. The latter is based on the proliferation activity as determined by Ki-67 immunostaining and mitotic count and results in the current tumor classification into neuroendocrine tumors G1, neuroendocrine tumors G2 or neuroendocrine carcinomas G3. Occasionally, tumors may show mixed differentiation containing a non-neuroendocrine cancer component. The neuroendocrine markers synaptophysin and chromogranin A are recommended for the immunohistochemical confirmation of the diagnosis. Furthermore, biopsy material can be used to investigate the expression of therapy-related markers, such as somatostatin receptor-2A. Moreover, if needed, the expression of transcription factors and hormones can be determined to obtain information on the possible site of origin of metastatic neuroendocrine neoplasms or to determine the syndrome-inducing hormone in functionally active neuroendocrine neoplasms. Finally, using the stomach as an example, biopsies may also be successfully used to investigate neuroendocrine precursor lesions which may harbor prognostic significance.
    No preview · Article · Nov 2013 · Der Pathologe
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