Proliferative activity of neuroendocrine tumours of the gastroenteropancreatic endocrine system: DNA flow cytometric and immunohistological investigations.

Abstract

The proliferative activity of 16 tumour specimens from 13 patients with neuroendocrine tumours of the gastroenteropancreatic endocrine system was studied by DNA flow cytometry and immunohistology for the nuclear Ki67 proliferation antigen. Equivalent results were obtained with both methods, which showed the proliferative activity of gastroenteropancreatic neuroendocrine tumours to be heterogeneous. In Since the growth of gastroenteropancreatic neuroendocrine tumours is not yet understood we studied the proliferative activity of benign and malignant gastroenteropancreatic neuroendocrine tumours using two different approaches.Methods A total of 16 tumour specimens (primary tumour and metastases) obtained from 13 patients with gastroenteropancreatic neuroendocrine tumours were investigated. The Table gives details of the patients. There were six men and seven women, median age of 47 years (range 31-63 years). All patients were treated by primary tumour resection. In addition, patients 6, 7, and 8 had hemihepatectomy or enucleation of many liver metastases, or both. No antiproliferative medical treatment was performed before surgery in any patient with metastatic tumours. All specimens used in this study were taken from the tumour margins of the fresh surgical specimen.The diagnosis of neuroendocrine tumours was established on the basis of the typical histology in all cases and was confirmed by immunohistological study of the neuroendocrine cell markers chromogranin A and neuron-specific y-enolase.

Prognostic indicators for carcinoid neuroendocrine tumors of the gastrointestinal tract

“…The difference between the two groups achieved a P-value of only 0.09, perhaps because of the small sample size and the high cut-off to define Ki-67 positivity. Others have proposed that the Ki-67 proliferation index may assist planning of therapy [56,57]. In particular, a high index may characterize a late clinical phase in a neuroendocrine tumor's history and may justify more aggressive treatment such as chemotherapy targeted to a more malignant tumor phenotype.…”

“…This index has been proposed in the WHO classification of GI endocrine tumors: (1) well-differentiated endocrine tumor (carcinoid) <2% Ki-67 positive cells, (2) well-differentiated endocrine carcinoma (malignant carcinoid) 2-15% Ki-67 positive cells, and (3) poorly differentiated endocrine carcinoma (small cell carcinoma) >15% Ki-67 positive cells [9]. Numerous studies have supported the validity of the Ki-67 proliferation index as a prognostic indicator for GI carcinoids, correlating with the size of the primary tumor [49,[51][52][53], lymphatic invasion [53], presence of metastases [49,[53][54][55], higher tumor proliferation activity measured by DNA flow cytometry [56], and shorter patient survival [49,57,58]. A dissenting study by Kawahara et al concluded that Ki-67 staining did not correlate with malignant behavior [59].…”

Correlation between grade and prognosis in metastatic gastroenteropancreatic neuroendocrine tumors

“…Several studies have validated the role of Ki-67 staining in grading NETs of the lung [5,6] and gastrointestinal tract [7][8][9][10]; however, some investigators have questioned the use of Ki-67 as an independent prognostic variable [11][12][13].…”

Accuracy of visual assessments of proliferation indices in gastroenteropancreatic neuroendocrine tumours

“…However, this is time consuming and some histopathologists admit to making eyeball estimates of PI rather than counting a sample of 2000 cells 14. Furthermore, studies demonstrating a relationship between Ki-67 PI and prognosis use different methods to calculate PI; some studies use eyeball methods5 6 while others employ more quantitative methods (eg, calculating the area of positive staining in a fixed area7 or manually counting a sample of cells8 9). Methodological inconsistency in these studies calls into question the applicability of their results to the methods used by histopathologists clinically to calculate PI, and consequently its value as a prognostic indicator in patient management.…”