Pathology Reporting of Neuroendocrine Tumors: Application of the Delphic Consensus Process to the Development of a Minimum Pathology Data Set

Abstract

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.

Clinicopathological Features and Prognosis of Gastroenteropancreatic Neuroendocrine Tumors: Analysis from a Single-institution

“…NENs can be classified into functional and nonfunctional tumors according to the presence or absence of symptoms associated with hormone overproduction (Klimstra et al, 2010). In this study, the most common initial presentation was abdominal pain, which is not a specific symptom.…”

“…However, the final definite diagnosis depends on the pathological analysis of biopsy or surgical specimens, including cell morphology (as discussed above) and immunohistochemical staining. The European Neuroendocrine Tumor Society (ENETS) and the North American Neuroendocrine Tumor Society (NANETS) have published standards for diagnosis and pathology (Kloppel et al, 2009;Klimstra et al, 2010), respectively. Furthermore, the WHO revised the nomenclature and classification of GEP-NENs in 2010 (version 4).…”

Erratum: Calculation of the Ki67 index in pancreatic neuroendocrine tumors: a comparative analysis of four counting methodologies

“…First, intratumoral heterogeneity (a known problem with pancreatic neuroendocrine tumors), as well as the subjectivity of hot spot selection, can lead to marked variation in tumor grade. 7,[17][18][19]21 The issue of whether to interpret pale brown tumor nuclei as positive is another vexing point. For this, a comparison with background nonneoplastic tissue may be helpful as stromal cells should not stain positively if the assay is correctly performed; in a similar manner, we subscribe to the view that light brown nuclei should generally be disregarded.…”

Hindgut Neuroendocrine Neoplasia

“…They are characterized immunohistochemically by staining for chromogranins & synaptophysin. [3] The cells of NEN often contain special secretory granules which produce biogenic amines and polypeptide hormones. This leads to these tumors being associated with symptoms corresponding to the secretory amines & hormones.…”