Surgical intervention for imatinib and sunitinib-resistant gastrointestinal stromal tumors

Imatinib mesylate is an effective treatment for recurrent or metastatic gastrointestinal stromal tumors (GISTs), but secondary resistance has been reported. The tyrosine kinase inhibitor sunitinib malate has shown efficacy in imatinib-resistant GISTs, and has been used as second-line therapy for recurrent or metastatic GISTs. However, it is often difficult to treat patients with imatinib- and sunitinib-resistant GISTs. In this report, we describe a case of surgically resected liver and peritoneal recurrences of GISTs that arose polyclonally and were resistant to imatinib and sunitinib. A 67-year-old man was referred to our hospital with multiple recurrent GISTs after failed imatinib treatment. Sunitinib was administered at 50 mg/day for 4 weeks with 2-week intervals between treatments. Some of the recurrent GISTs were sensitive, but others were resistant, and progressive disease was diagnosed. Extended left hepatectomy and peritoneal tumorectomy were performed. Histologically, tumors sensitive to sunitinib showed degenerative changes, while the resistant tumors consisted of KIT-positive, viable GIST cells. The primary mutation in all the tumors consisted of a deletion at nucleotides 555-560 with an E554D point mutation at exon 11 of the c-kit gene. The sunitinib-resistant liver and peritoneal tumors had different point mutations: T to G and T to A, respectively, although both resulted in an N822K amino acid alteration, indicating the polyclonal evolution of recurrent GISTs. Thus, if R0 resection is expected, surgical intervention under the control of imatinib or sunitinib should be considered for the control of metastatic or recurrent GISTs.