Merkel Cell Carcinoma: Correlation of KIT Expression with Survival and Evaluation of KIT Gene Mutational Status
A Andea, R Patel, M Kraemer, S Ponnazhagan, S Kumar, D Jhala, I Eltoum, G Siegal. UAB, Birmingham, AL
Background: Merkel cell carcinoma (MCC) is one of the most aggressive primary cutaneous malignancies. Currently there is no effective therapy available for disseminated disease. Most MCCs express KIT by immunohistochemistry (IHC). Since relatively little is known regarding the biological significance of KIT in MCC, we aimed to investigate the effects of KIT expression on tumor progression and to assess the presence of activating mutations in the KIT gene which could provide new therapeutic options for MCC similar to gastrointestinal stromal tumors (GIST) and melanomas.
Design: A total of 40 patients with a diagnosis of MCC were identified with a median follow-up interval of 20 months. KIT expression was assessed by IHC on formalin fixed, paraffin embedded material. Cases were divided into low expressors (0-1+ staining intensity) and high expressors (2-3+ staining intensity). Direct sequencing of exons 9, 11, 13, 17, 18 of the KIT gene spanning the extra-cellular, juxtamembrane and tyrosine kinase domains, previously identified as mutation sites in GIST and melanomas, was performed from cases with high KIT expression.
Results: The overall 5-year survival rate was 37%. A total of 30 tumors from 21 patients were analyzed for KIT expression. High expression was seen in 67% of the patients. Five-year survival rates in tumors expressing high versus low levels of KIT were 0% versus 56.4% respectively however, the difference did not reach statistical significance (p=0.1). A total of 18 tumors from 14 patients with high expression were analyzed for mutational status of the KIT gene. Analysis of 216 electropherograms revealed 4 point mutations. Two of these were silent mutations involving exons 17 (c.2394 C>T -2 cases) and 18 (c.2586 G>C -1 case) and 2 involved the flanking 5' intronic region of exon 17 (-107bp T>A -5 cases and -77bp G>A -7 cases). Two of the identified mutations corresponded to previously reported polymorphisms of the KIT gene.
Conclusions: Expression of KIT protein appears to correlate with a worse prognosis in MCC patients raising the possibility of an active role of this receptor in tumor progression and metastasis. We did not identify KIT activating mutations in the 18 tumors analyzed suggesting that alternative mechanisms, possible involving up- or downstream effectors of KIT pathway are involved in the pathogenesis of MCC. Further studies are warranted to elucidate the biologic significance of KIT protein over-expression in MCC and the potential therapeutic value of KIT inhibitors.
Tuesday, March 10, 2009 8:45 AM
Platform Session: Section E, Tuesday Morning