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      Prognostic value of a three-scale grading system based on combining molecular imaging with 68Ga-DOTATATE and 18F-FDG PET/CT in patients with metastatic gastroenteropancreatic neuroendocrine neoplasias

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          Abstract

          We investigated on the added prognostic value of a three-scale combined molecular imaging with 68Ga-DOTATATE and 18F-FDG PET/CT, (compared to Ki-67 based histological grading), in gastroenteropancreatic neuroendocrine neoplasia patients. 85 patients with histologically proven metastatic gastroenteropancreatic neuroendocrine neoplasias, who underwent combined PET/CT imaging were retrospectively evaluated. Highest Ki-67 value available at time of 18F-FDG PET/CT was recorded. Patients were classified according to World Health Organization/European Neuroendocrine Tumor Society histological grades (G1, G2, G3) and into three distinct imaging categories (C1: all lesions are 18F-FDG negative/ 68Ga-DOTATATE positive, C2: patients with one or more 18F-FDG positive lesions, all of them 68Ga-DOTATATE positive, C3: patients with one or more 18F-FDG positive lesions, at least one of them 68Ga-DOTATATE negative). The primary endpoint of the study was Progression-Free Survival, assessed from the date of 18F-FDG PET/CT to the date of radiological progression according to Response Evaluation Criteria In Solid Tumors version 1.1. Classification according to histological grade did not show significant statistical difference in median Progression-Free Survival between G1 and G2 but was significant between G2 and G3 patients. In contrast, median Progression-Free Survival was significantly higher in C1 compared to C2 and in C2 compared to C3 patients, revealing three distinctive imaging categories, each with highly distinctive prognosis. Our three-scale combined 68Ga-DOTATATE/ 18F-FDG PET imaging classification holds high prognostic value in patients with metastatic gastroenteropancreatic neuroendocrine neoplasias.

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          18F-fluorodeoxyglucose positron emission tomography predicts survival of patients with neuroendocrine tumors.

          Ulrich Knigge, Annika Loft, Tina Binderup … (2010)
          (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) is currently not used on a routine basis for imaging of neuroendocrine (NE) tumors. The aim of this study was to investigate the prognostic value of FDG-PET in patients with NE tumors. Ninety-eight prospectively enrolled patients with NE tumors underwent FDG-PET imaging. FDG uptake was quantified by maximal standardized uptake value (SUVmax). The prognostic value of FDG uptake, proliferation index, chromogranin A, and liver metastases were assessed. During the 1-year follow-up, 14 patients died. The diagnostic sensitivity of FDG-PET was 58% (n = 57) and a positive FDG-PET result was associated with a significantly higher risk of death with a hazard ratio (HR) of 10.3 [95% confidence interval (CI), 1.3-78.9]. Thirteen of the 57 (23%) FDG-PET-positive patients died compared with 1 of 41 (2%) FDG-PET-negative patients. By univariate analysis, a SUVmax of >9 and a high Ki67 index were significant predictors of overall survival with a HR of 8.8 (95% CI, 2.7-28.7) and a HR of 2.6 (95% CI, 1.3-5.1), respectively. In a multivariate analysis including a SUVmax of >3, Ki67, and chromogranin A, SUVmax of >3 was the only predictor of progression-free survival (HR, 8.4; P < 0.001). This study shows a strong prognostic value of FDG-PET for NE tumors, which exceeds the prognostic value of traditional markers such as Ki67, chromogranin A, and liver metastases. FDG-PET may obtain an important role for NE tumors.
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            Pathology reporting of neuroendocrine tumors: application of the Delphic consensus process to the development of a minimum pathology data set.

            B Wiedenmann, R Modlin, Saul Suster … (2010)
            Epithelial neuroendocrine tumors (NETs) have been the subject of much debate regarding their optimal classification. Although multiple systems of nomenclature, grading, and staging have been proposed, none has achieved universal acceptance. To help define the underlying common features of these classification systems and to identify the minimal pathology data that should be reported to ensure consistent clinical management and reproducibility of data from therapeutic trials, a multidisciplinary team of physicians interested in NETs was assembled. At a group meeting, the participants discussed a series of "yes" or "no" questions related to the pathology of NETs and the minimal data to be included in the reports. After discussion, anonymous votes were taken, using the Delphic principle that 80% agreement on a vote of either yes or no would define a consensus. Questions that failed to achieve a consensus were rephrased once or twice and discussed, and additional votes were taken. Of 108 questions, 91 were answerable either yes or no by more than 80% of the participants. There was agreement about the importance of proliferation rate for tumor grading, the landmarks to use for staging, the prognostic factors assessable by routine histology that should be reported, the potential for tumors to progress biologically with metastasis, and the current status of advanced immunohistochemical and molecular testing for treatment-related biomarkers. The lack of utility of a variety of immunohistochemical stains and pathologic findings was also agreed upon. A consensus could not be reached for the remaining 17 questions, which included both minor points related to extent of disease assessment and some major areas such as terminology, routine immunohistochemical staining for general neuroendocrine markers, use of Ki67 staining to assess proliferation, and the relationship of tumor grade to degree of differentiation. On the basis of the results of the Delphic voting, a minimum pathology data set was developed. Although there remains disagreement among experts about the specific classification system that should be used, there is agreement about the fundamental pathology data that should be reported. Examination of the areas of disagreement reveals significant opportunities for collaborative study to resolve unanswered questions.
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              Effect of tumor heterogeneity on the assessment of Ki67 labeling index in well-differentiated neuroendocrine tumors metastatic to the liver: implications for prognostic stratification.

              David Klimstra, Zhaohai Yang, Hongmei Tang (2011)
              The Ki67 labeling index is known to correlate with survival in patients with neuroendocrine tumors (NETs). A grading scheme recently endorsed by the World Health Organization for gastroenteropancreatic NETs classifies well-differentiated NETs into 2 categories based on the Ki67 labeling index: low (G1) and intermediate grades (G2). Tumor heterogeneity is a common finding in many tumors including NETs. Metastatic NETs to the liver are often diagnosed by radiographically guided needle core biopsy from which the Ki67 index is determined, which randomly samples the lesion without being targeted to regions that may show a higher proliferative rate. Whether the Ki67 index obtained from this type of limited material represents the whole tumor has been questioned. Forty-five surgically resected liver metastases of well-differentiated NETs were retrieved. A 9 core (3 core-triplets) tissue microarray (TMA) was constructed from the paraffin blocks of each tumor, each triplet considered to represent a virtual biopsy. Immunohistochemical staining for Ki67 was performed on TMA and whole slides, and the Ki67 labeling indices were determined by digital image analysis. Correlation of the Ki67 index with patient survival was analyzed. Forty-seven percent of cases showed intratumoral heterogeneity in Ki67 index that translated into discrepant grades among subsections on the whole slide. A similar trend was recapitulated on the virtual biopsies, although to a lesser degree. When the definitive grade of the tumor was based on the highest Ki67 index identified on the whole slide, the virtual biopsies perfectly predicted G1 cases (100%), but were much less accurate for G2 cases (47.8% with 3 biopsies and 34.8% with single biopsy). Accordingly, the predictive value for G1 on the virtual biopsies was low (64.7% and 59.5% for 3 and 1 biopsy, respectively), but was perfect for G2 (100%). By Kaplan-Meier survival analysis, there was a statistically significant difference between G1 and G2 in terms of overall survival, disease-free survival, and progression-free survival when graded on either whole-slide subsections or virtual biopsies. On the whole slides, the highest Ki67 grade showed a better correlation with overall survival than the mean Ki67 grade. In summary, by image analysis, we found that about half of the NETs metastatic to the liver show intratumoral heterogeneity resulting in discrepant Ki67 grade. In most cases, in particular G1, the virtual biopsy is representative of the whole slide, but for G2 the representation is <50%. Nevertheless, grades based on virtual biopsy had statistically significant prognostic values on patient survival, and there is no clear difference between the 3 and single virtual biopsy. Ki67 staining of core biopsies usually provides an adequately reliable method of proliferation assessment for prognosis of metastatic NETs to the liver, although the choice of treatment may be affected by intratumoral grade heterogeneity.
              Article 0 comments Cited 88 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Oncotarget
                Journal ID (iso-abbrev): Oncotarget
                Journal ID (publisher-id): Oncotarget
                Journal ID (publisher-id): ImpactJ
                Title: Oncotarget
                Publisher: Impact Journals LLC
                ISSN (Electronic): 1949-2553
                Publication date Collection: 11 February 2020
                Publication date (Electronic): 11 February 2020
                Volume: 11
                Issue: 6
                Pages: 589-599
                Affiliations
                1 Nuclear Medicine Department, Institut Jules Bordet-Université Libre de Bruxelles (ULB), Brussels, Belgium
                2 Radiology/Medical Imaging Department, Institut Jules Bordet-Université Libre de Bruxelles (ULB), Brussels, Belgium
                3 Digestive Oncology Department, Institut Jules Bordet-Université Libre de Bruxelles (ULB), Brussels, Belgium
                Author notes
                Correspondence to: Ioannis Karfis, ioannis.karfis@ 123456bordet.be
                Article
                Publisher ID: 27460
                DOI: 10.18632/oncotarget.27460
                PMC ID: 7021233
                PubMed ID: 32110279
                SO-VID: 7b93abeb-4fa1-4969-b719-a44ae41e70e1
                Copyright © Copyright: © 2020 Karfis et al.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 02 October 2019
                Date accepted : 13 January 2020
                Categories
                Subject: Research Paper

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: gastroenteropancreatic neuroendocrine neoplasias,molecular imaging,prognostic biomarkers,68ga-dotatate pet/ct,18f-fdg pet/ct
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: gastroenteropancreatic neuroendocrine neoplasias, molecular imaging, prognostic biomarkers, 68ga-dotatate pet/ct, 18f-fdg pet/ct

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