Most gastrointestinal stromal tumors (GISTs) can be recognized by their monotonous cytologic features and overexpression of KIT oncoprotein. Altered morphology and loss of CD117 reactivity has been described previously after chronic imatinib treatment; however, this phenomenon has not been reported in imatinib-naive tumors. Eight patients with abrupt transition from a classic CD117-positive spindle cell GIST to an anaplastic CD117-negative tumor were investigated for underlying molecular mechanisms of tumor progression. Pathologic and molecular analysis was performed on each of the 2 components. Genomic DNA polymerase chain reaction for KIT, PDGFRA, BRAF, and KRAS hot spot mutations and fluorescence in situ hybridization for detecting KIT gene copy number alterations were performed. TP53 mutational analysis was performed in 5 cases. There were 7 men and 1 woman, with an age range of 23 to 65 years. Five of the primary tumors were located in the stomach, and 1 case each originated in the small bowel, colon, and rectum. In 3 patients, the dedifferentiated component occurred in the setting of imatinib resistance, whereas the remaining 5 occurred de novo. The dedifferentiated component had an anaplastic appearance, including 1 angiosarcomatous phenotype, with high mitotic activity and necrosis, and showed complete loss of CD117 (8/8) and CD34 (5/8) expression and de novo expression of either cytokeratin (4/8) or desmin (1/8). There was no difference in the KIT genotype between the 2 components. However, 2 imatinib-resistant tumors showed coexistence of KIT exon 11 and exon 13 mutations. Fluorescence in situ hybridization showed loss of 1 KIT gene in 3 cases and low-level amplification of KIT in 2 other cases in the CD117-negative component, compared with the CD117-positive area. TP53 mutation was identified in 1/5 cases tested, being present in both components. In summary, dedifferentiation in GIST may occur either de novo or after chronic imatinib exposure and can represent a diagnostic pitfall. This phenomenon is not related to additional KIT mutations, but might be secondary to genetic instability, either represented by loss of heterozygosity or low level of KIT amplification.
*Department of Pathology, Memorial Sloan-Kettering Cancer Center
¶Weill Medical College of Cornell University, New York, NY
‡Surgical Pathology, Brigham & Women’s Hospital
§Massachusetts General Hospital, Boston, MA
†Treviso General Hospital, Treviso, Italy
∥Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, Republic of China
Conflicts of Interest and Source of Funding: Supported in part by ACS MRSG CCE-106841 (CRA), P01CA47179 (CRA), P50 CA 140146-01 (CRA), Life Raft Group (CRA), GIST Cancer Research Fund (CRA), and Shuman Family Fund for GIST Research (CRA). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.
Correspondence: Cristina R. Antonescu, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021 (e-mail: email@example.com).