Neuroendocrine Tumors of the Pancreas: Current Concepts and Controversies

Abstract

In the past decade, the clinico-pathologic characteristics of neuroendocrine tumors (NETs) in the pancreas have been further elucidated. Previously termed "islet cell tumors/carcinomas" or "endocrine neoplasms", they are now called pancreatic NETs (PanNETs). They occur in relatively younger patients and may arise anywhere in the pancreas. Some are associated with von Hippel-Lindau, MEN1, and other syndromes. It is now widely recognized that, with the exception of tumorlets (minute incipient neoplasms) that occur in some syndromes like MEN1, all PanNETs are malignant, albeit low-grade, and although they have a protracted clinical course and overall 10-year survival of 60-70 %, even low-stage and low-grade examples may recur and/or metastasize on long-term follow-up. Per recent consensus guidelines adopted by both European and North American NET Societies (ENETS and NANETs) and WHO-2010, PanNETs are now graded and staged separately, unlike previous classification schemes that used a combination of grade, stage, and adjunct prognosticators in an attempt to define "benign behavior" or "malignant" categories. For staging, the ENETs proposal may be more applicable than CAP/AJCC, which is based on the staging of exocrine tumors. Current grading of PanNETs is based on mitotic activity and ki-67 index. Other promising prognosticators such as necrosis, CK19, c-kit, and others are still under investigation. It has also been recognized that PanNETs have a rather wide morphologic repertoire including oncocytic, pleomorphic, ductulo-insular, sclerosing, and lipid-rich variants. Most PanNETs are diagnosed by fine needle aspiration biopsy, in which single, monotonous plasmacytoid cells with fair amounts of cytoplasm and distinctive neuroendocrine chromatin are diagnostic. Molecular alterations of PanNETs are also very different than that of ductal or acinar tumors. Loss of expression of DAXX and ATRX proteins has been recently identified in 45 %. Along with these improvements, several controversies remain, including grading, value of current cutoff ranges, and the best methods for counting ki-67 index (manual count by computer-captured image may be the most practical for the time being). More important is the controversial use of the term "carcinoma", which was previously employed in WHO-2004 only for invasive and metastatic cases but has now been made synonymous with grade 3 group of tumors. It is becoming clear that grade 3 group comprises two distinct categories: (1) differentiated but proliferatively more active tumors which typically have ki-67 indices in the 20-50 % range and (2) true poorly differentiated NE carcinomas as defined in the lung, with ki-67 typically >50 %. Further studies are needed to address these controversial aspects of PanNETs.

Immunohistochemical CD73 expression status in gastrointestinal neuroendocrine neoplasms: A retrospective study of 136�patients

“…Mitotic counts determined by PHH3 staining and H&E staining showed a high concordance rate, but the results need to be validated using many cases (28). For counting with regard to the Ki-67 labeling index, strong, dark-brown nuclear staining is recommended, whereas cytoplasmic staining or weak nuclear staining should not be counted (29). Ki-67 Table III.…”

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

“…Of note, this approach is a reference technique of Ki67 LI assessment in pancreatic NEN [21]. Cells were considered Ki67-positive if they showed immunoreactivity in nucleus or in a mitotic figure, irrespective of the stain intensity [22,39], although it was recognized that some investigators ignored slightly stained nuclei for Ki67 LI assessment in NEN [21,40]. In each HS and CS, 2500 cells were counted in 25 por-tions of 100 cells each.…”

Pancreatic neuroendocrine tumors: correlation between histogram analysis of apparent diffusion coefficient maps and tumor grade

“…Grading classification was based on mitotic count per square millimeter of tumor and Ki-67 index, according to the ENETS [5,6] adopted by the WHO in 2010 (Table 1).…”

“…In 2010, the World Health Organization (WHO) adopted a grading system (G1, G2, and G3) based on the mitotic count per square millimeter of tumor and the Ki-67 index, that was created by the European Neuroendocrine Tumor Society (ENETS) [5,6] (Table 1). In this system, well-differentiated PanNET (WDNET) are divided into low grade (G1) and intermediate grade (G2), while the high grade (G3) refers to poorly differentiated neuroendocrine carcinoma (PDNEC).…”