For many years, GIP ETs have been regarded as slow growing neoplasms with distinct morphologic characteristics that behave less aggressively than conventional adenocarcinomas . The malignant potential of endocrine tumors is difficult to predict. In this context, the latest WHO classification provides a useful framework for the evaluation of clinicopathological and functional properties of these neoplasms . However, a disadvantage of the current WHO classification system is that it is not possible to evaluate some of the well known criteria for malignancy, namely the presence of metastases, and deep wall invasion or invasion of nearby tissue in biopsy specimens. Recently, attempts have been made to define histological and immunohistochemical prognostic factors that may aid in predicting the biologic behavior of GIP ETs in the context in which they commonly present to the surgical pathologist. In this context, the study by Hochwald et al  affirmed the clinical usefulness of a two-tiered classification of differentiated pancreatic endocrine neoplasms into low- and intermediate-grade groups on the basis of tumor necrosis (absent or present) and mitotic rate (< 2 mitoses/50 HPFs, or > 2 mitoses/50 HPFs) . Moreover, high-grade ETs were defined as neoplasms characterized by a solid growth pattern, cytologic atypia, > 10 mitoses/10 HPFs (Ki-67 index > 10%), and widespread necrosis [6, 7, 24].
This study investigated the histological grading, Ki-67 index, tumor size, and metastatic behavior in a group of patients with GIP ETs. The goal was to evaluate Ki-67 index using ChromaVision Automated Image Analysis software, and to determine whether histological grade, tumor size, and Ki-67 index had any bearing on metastatic behavior. We observed unexpectedly high aggressiveness (multiple lymphogenous and hematogenous metastases, and peritoneal implants) in small (< 2 cm), low-grade ETs, with low Ki-67 index. These observations are consistent with other reports [16, 18, 25]. In his excellent study, based on analysis of 1914 reported cases with gastrointestinal endocrine tumors, Soga  found a high aggressiveness in metastasis rates in both rectal and gastric small carcinoids exhibiting values significantly higher than those of small carcinomas. We did not find statistically significant correlation between tumor grade and Ki-67 index, as well as between tumor grade, tumor size, Ki-67 index and metastatic behavior of GIP ETs. These observations are in disagreement with earlier positive findings [8, 11, 12, 15, 19]. This disagreement might be explained by methodological differences, or the different antibodies employed. In this context, ChromaVision Automated Ki-67 index analysis provides superior accuracy in comparison to semi quantitative evaluation of Ki-67 positivity. Most importantly, this study shows the limitations of the current WHO classification in assessment of the metastatic behavior of GIP ETs. Thus, we were able to show that small, low-grade ETs, with low proliferative index, which met the criteria of the WHO classification criteria for benignity, behaved in a highly aggressive fashion. On the other hand large, intermediate- and high-grade, with high proliferative index ETs, which met the WHO classification criteria for malignancy, behaved in a benign fashion, i.e. without metastatic disease. Currently, we cannot explain the highly aggressive behavior of small, low-grade, with low proliferative index ETs. Previous studies suggest that tumors with a short cell cycle may grow rapidly but without necessarily manifesting numerous mitotic figures at any moment . In addition, recent reports indicate that nuclear survivin and valosin-containing protein (p97) are useful prognostic factors in ETs [26, 27].
The observed increased risk of synchronous malignancies in GIP ETs is consistent with previous reports [28–30]. The results illustrate the need for a thorough search for additional neoplasms in patients with ileal ETs.