Targeted therapy of cancer: new roles for pathologists in identifying GISTs and other sarcomas

Abstract

Once a poorly understood pathologic entity, gastrointestinal stromal tumor (GIST) has emerged in recent years as a distinct oncologic-molecular paradigm that is now a leading model for kinase-targeted therapies in oncology. Most GISTs are KIT-expressing and KIT signaling-driven mesenchymal tumors, many of which have KIT-activating mutations. A small subset of GIST show activating mutations in PDGFRA, encoding a related member of the type III receptor tyrosine kinase family. The revelation of KIT expression as a diagnostic signature of GIST has not only revolutionized the pathologic criteria in classifying GIST, but also shed light on the histogenesis of these tumors. The similarities in KIT immunoreactivity and ultrastructural appearance between GISTs and the intestinal pacemaker, the interstitial cells of Cajal (ICC), suggested that GISTs derive from or differentiate toward the ICC lineage. KIT plays a significant role in proliferation, survival, and differentiation of hematopoietic stem cells, mast cells, melanocytes, and interstitial cells of Cajal; activating KIT mutations have been identified in tumors affecting most of these cell lineages. This review will include a summary of the biology behind the specific targeted therapies, emphasizing the central role of KIT and PDGFRA oncogenic mutations in GISTs and their clinical and pathologic correlates. The role of KIT immunohistochemistry vs mutation testing will be discussed, with an insight into the indications for KIT/PDGFRA genotyping in GIST. The morphologic and molecular changes that appear with imatinib treatment, such as response and acquired imatinib resistance, are being discussed. The success GIST story based on targeted molecular paradigm may be applied in other imatinib-responsive sarcoma, such as dermatofibrosarcoma protuberans.

The Scandinavian Sarcoma Group

“…STS elegantly demonstrate how conventional hiselegantly demonstrate how conventional histopathology and molecular genetics can complement each other (Helman et al 2003, Oliveira et al 2004, Antonescu 2006, Antonescu 2008, Bridge 2008. Molecular pathology is increasingly applied as a diagnostic adjunct to morphology and molecular characterization has in several STS types identified recurrent derangement of central signaling pathways.…”

Sarcomatoid carcinoma of the upper urinary tract: clinical outcome and molecular characterization

“…This process can be identified by immunohistochemical staining for c-kit. Targeted therapy with the tyrosine kinase inhibitor imatinib (Gleevec; Novartis Pharmaceuticals Corp, East Hanover, NJ) has demonstrated great clinical efficacy in the management of advanced/metastatic gastrointestinal stromal tumors as well as in chronic myelogenous leukemia [28]. Because we did not identify c-kit expression in any of our 8 cases of sarcomatoid carcinoma of the upper urinary tract, it appears unlikely that c-kit is involved in the pathogenesis of this cancer, and the use of targeted therapy against the KIT proto-oncogene may not be justified in these patients.…”

Tissue Biomarker Development in a Multicentre Trial Context: a Feasibility Study on the PETACC3 Stage II and III Colon Cancer Adjuvant Treatment Trial

“…First adjuvant treatment, although rationally addressing the risk of recurrent disease, tends to be beneficial for a limited proportion of patients because it cannot be predicted who will recur or which recurring patient will respond to the adjuvant treatment. Biomarkers, capable of predicting recurrent disease as well as (non)response to adjuvant treatment modality, potentially provide a solution to this problem, as exemplified by the predictive value of c-Kit mutations for the response of GIST to the tyrosine-kinase inhibitor imatinib (1) or of KRAS mutations to epidermal growth factor receptor blocking agents (2,3). Second, the long duration of clinical trials, which usually have outcome (disease free or overall survival) as end-point, hampers rapid introduction of new treatment modalities (4).…”