Merkel cell carcinoma: correlation of KIT expression with survival and evaluation of KIT gene mutational status

Abstract

Merkel cell carcinoma is one of the most aggressive primary cutaneous malignancies. Since some Merkel cell carcinomas express the receptor tyrosine kinase KIT, we aimed to evaluate the correlation of KIT expression with outcome and the presence of activating mutations in the KIT gene in Merkel cell carcinoma. A total of 49 tumors from 40 patients with a diagnosis of Merkel cell carcinoma were identified of which 30 cases from 21 patients were used in the study. KIT expression was assessed by immunohistochemistry 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, and 18 of the KIT gene spanning the extra-cellular, juxtamembrane and tyrosine kinase domains was performed from cases with high KIT expression. Thirty tumors from 21 patients were analyzed for KIT expression. High KIT expression was seen in 67% of the patients. Five-year survival rates in tumors expressing high versus low levels of KIT were 0% versus 57.8% respectively however, this dramatic difference did not reach statistical significance (p=0.07). A total of 4 point mutations were identified in 18 tumors analyzed. Two of these were silent mutations involving exons 17 and 18, and 2 involved intron 16-17. Two of the identified mutations may represent novel polymorphisms. Our work suggests a correlation between KIT expression and a worse prognosis in Merkel cell carcinoma patients, raising the possibility of an active role of this receptor in tumor progression and metastasis. We did not identify however, KIT activating mutations in any of the tumors analyzed.

Improved detection suggests all Merkel cell carcinomas harbor Merkel polyomavirus

“…In addition, we did not detect any mutations in 4 MCC cell lines that contain MCPyV. Consistent with previous studies, we did not find activating muta tions in PDGFRA or KIT (23,(35)(36)(37)(38). We did identify 3 tumors with p53 point substitutions, most notably in 2 specimens with absent expression of MCPyV large T antigen.…”

High KIT and PDGFRA are associated with shorter patients survival in gastroenteropancreatic neuroendocrine tumors, but mutations are a rare event

“…Interestingly, our results are in concordance with observations in Merkel cell carcinoma (Andea et al 2010), colorectal neuroendocrine carcinoma (Akintola-Ogunremi et al 2003) and squamous cell lung cancer (Micke et al 2004), with the two former showing only a trend to shorter survival and the latter exhibiting a significant value. Before our immunohistochemical analysis, we examined the KIT and PDGFRA staining pattern on standard, full-sized tissue sections and could not see a intratumoral heterogeneity supporting our results.…”

“…This is a smaller number of positive cases than that reported previously in neuroendocrine carcinoma of the skin, in Merkel cell carcinoma (62%) (Andea et al 2010). This might be due to the fact that our tumor collective included not only poorly differentiated carcinomas (NEC 3, high grade), but also well-differentiated tumors (NET G2, intermediate grade 2) and well-differentiated tumors (NET G1, low grade).…”

Recent advances in the biology of Merkel cell carcinoma

“…KIT tyrosine kinase receptor (c-kit) or CD117 expression has also been investigated to identify the association with prognosis, but no association was found in most studies [29,57,63,64]. Recently, Andea et al [65] reported that MCCs with high KIT expression showed worse 5-year survival than those with low (or negative) KIT expression, although the difference did not reach statistical significance (P = .07). Several previous studies found no activating mutations in a hot spot of the KIT gene in MCCs with high KIT expression, suggesting little or no involvement of KIT in the progression of MCC and the ineffectiveness of imatinib mesylate as a treatment of MCC [61,[65][66][67][68].…”