Renal Cell Carcinoma before and after Sunitinib Therapy. Morphological and Molecular Changes
Rukma Doshi, Marie O'Donnell, Axel Bex, Luis Beltran, Anju Sahdev, John Peters, David J Harrison, Grant D Stewart, Thomas Powles, Daniel M Berney. Barts Cancer Institute, London, United Kingdom; University of Edinburgh, Edinburgh, United Kingdom; Whipps Cross Hospital, London, United Kingdom; Netherlands Cancer Institute, Amsterdam, Netherlands
Background: The use of tyrosine kinase inhibitors (TKI) has transformed the treatment of clear cell renal cell carcinoma (ccRCC). We have previously published 48 patients with metastatic ccRCC, treated with Sunitinib for 16 weeks and then given a nephrectomy, if feasable. Pretreatment biopsy material was taken for diagnostic purposes. Little translational work on this treated tissue is available. Changes in morphology after TKI therapy are not well documented and the possibility of a 'regression score' in treated cancers may aid further therapy.
Design: Pretreatment biopsies and nephrectomies were analysed for standard pathological parameters (grade, stage, type and necrosis). After initial review, a number of non-standard pathological parameters were scored semi-quantitively: necrosis associated with acute inflammation (NAI), chronic lymphoplasmacytic infiltrate (CLI), fibrinoid eosinophilic debris (FED) and areas of small endothelial vessels (SEV). A tissue microarray was constructed from the biopsy material and nephrectomies. Ki-67 expression was scored in these specimens.
Results: 48 patients with ccRCC were diagnosed on renal biopsy. Of the 25 patients who had a nephrectomy after Sunitinib treatment, NAI was seen in 8(32%), CLI in 21 (84%), FED in 18(72%) and SEV in 23(92%). These changes were seen significantly less frequently in the pretreatment biopsies NAI, 2(8%), CLI 3(12%), FED 3(12%) and SEV 4(16%) though comparison is difficult due to the limited nature of the biopsies. A Wilcoxon matched paired test showed the Ki-67 expression to be significantly higher in the post treatment nephrectomies (p=0.02) than in the pre treatment samples.
Conclusions: There appear to be recognisable stigmata of Sunitinib therapy. Areas of small vessels are the most prominent feature and may be due to either endothelial proliferation or tumor regression creating packed vessel clusters. We speculate that the possible vessel proliferation as well as the inflammatory response and associated unusual necrosis and fibrinoid areas are due to chemokine induction by pathway alterations secondary to TKI therapy. The increase in Ki-67 after treatment suggests that in spite of the regressive changes induced by the TKI, there is an induction of resistant clones showing high levels of proliferation, ultimately resulting in drug failure. Creation of a regression score linked to outcome analysis may aid future drug development strategies.
Category: Genitourinary (including renal tumors)
Monday, March 19, 2012 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 142, Monday Morning