The Effect of Tumor Heterogeneity on the Prognostic Value of Ki67 Labeling Index in Well-Differentiated Neuroendocrine Tumors (NETs) Metastatic to the Liver
Z Yang, LH Tang, DS Klimstra. Memorial Sloan-Kettering Cancer Center, New York, NY
Background: The Ki67 labeling index correlates with survival in patients with NETs. A proposed grading scheme classifies well-differentiated NETs into two categories based on Ki67 index: low grade (<3%), and intermediate grade (3-20%). Metastatic NETs to the liver are often diagnosed by random needle core biopsy, and the Ki67 index is thus determined on this limited sample. The reliability of the Ki67 index has been questioned based on possible intratumoral heterogeneity.
Design: Forty-three resected cases of NET metastatic to the liver were collected. Triplet tissue cores from three random sites in the paraffin blocks were used to construct a tissue microarray, representing simulated biopsies. Immunohistochemical staining for Ki-67 was performed, and the labeling index was determined by image analysis. The overall Ki67 index was determined for each core triplet, and heterogeneity was defined as the presence of grade discordance among the 3 samples. The mitotic count of the original slides was also determined: low grade <2/10 HPF, and intermediate grade 2-20/10 HPF.
Results: Thirty-four cases had a low Ki67 index, while 8 cases had an intermediate Ki67 index; these included one case that showed an intermediate Ki67 index in one block and low in another. By Kaplan-Meier survival analysis, intermediate overall Ki67 index predicted worse overall, disease-free, and progression-free survival (p<0.005), compared to a low Ki67 index. Intermediate mitotic activity predicted worse progression-free survival (p<0.05), but not overall and disease-free survival. Thirty-eight cases (83%) were considered homogenous for Ki67 index (34 low grade and 4 intermediate grade) on simulated random biopsy, and 8 cases (17%) had heterogeneity. Statistically, there were significantly more overall intermediate grade cases showing Ki67 heterogeneity (Fisher's exact test, p=0.02), and in those cases, the Ki67 indices were close to the 3% cutoff value (range 2.1-3.6%). One of three cases also showed significant Ki67 heterogeneity between different metastatic foci.
Conclusions: By imaging analysis, Ki67 labeling index has significant prognostic value for patients with NETs metastatic to the liver. In most cases in particular the low grade ones, random sampling has no clear effect on the prognostic value of the Ki67 index. Ki67 staining of core biopsies usually provides an adequately reliable method of proliferation assessment for prognosis.
Category: Liver & Pancreas
Tuesday, March 23, 2010 9:30 AM
Poster Session III # 238, Tuesday Morning