Analysis of c-KIT Expression and KIT Mutations in Gastrointestinal Melanomas: A Multicentric Study from Istituto Toscano Tumori (ITT).
Raffaella Santi, Lisa Simi, Pamela Pinzani, Milena Paglierani, Gabriella Nesi, Marco Santucci, Claudio Orlando, Daniela Massi. University of Florence, Italy
Background: Malignant melanoma involving the gastrointestinal (GI) tract is mainly related to metastatic disease while primary mucosal melanomas are exceedingly rare. Despite multimodal therapeutic approach, primary GI melanomas are associated with a poor prognosis. Recently it has been emphasized that mucosal melanomas may harbour KIT mutations with increased frequency, thus allowing targeted therapies with tyrosine kinase inhibitors in affected patients.
Design: Forty-two GI melanomas observed over the past two decades were retrospectively analyzed. c-KIT protein expression was investigated by immunohistochemistry, whereas KIT gene mutations were analysed by PCR amplification and DNA sequencing of exons 11, 13 and 17. Seven cases with clear cell features were submitted to FISH analysis to exclude the presence of a t(12;22)(q13;q12) translocation (r/o clear cell sarcoma).
Results: There were 24 females and 18 males, ranging from 45 to 89 years of age. The most common anatomical location was the anorectal region (n=26), followed by the large bowel (n=5), small bowel (n=5), stomach (n=2) and oesophagus (n=2). Two patients presented with multiple lesions, involving different and/or distant gastrointestinal tracts and the omentum. Based on the morphological appearance and available clinical history, the cases were tentatively classified as primitive (n=8), metastatic (n=8) or uncertain (n=26). KIT cytoplasmic staining was demonstrated in 35 (83%) cases. Among the KIT-positive cases, 24 (57%) showed a percentage of positive cells greater than 51% and 28 (66%) displayed moderate to strong immunoreactivity. Nine cases (4 primary and 5 of uncertain origin) exhibited KIT gene mutations. Interestingly, none of the metastatic cases was mutated. With the exception of one case, tumours harbouring KIT mutations showed moderate to strong staining in a high percentage of cells.
Conclusions: Due to their rarity and lack of conventional histopathological prognosticators, GI melanomas present a difficult diagnostic and therapeutic challenge. Our preliminary results of this ongoing study support the finding that KIT mutations presumably activating the tyrosine kinase activity of c-KIT can be found in a subgroup of GI melanoma patients who may benefit of tyrosine kinase inhibition. Immunohistochemical expression of c-KIT can be considered as a useful tool to select cases for additional KIT genotyping.
Wednesday, March 2, 2011 9:30 AM
Poster Session V # 63, Wednesday Morning