Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer that mostly
occurs in the elderly. Merkel cell polyomavirus (MCPyV) is detected in approximately
80% of MCCs and is associated with carcinogenesis. Hedgehog signaling pathway plays
a role in human embryogenesis and organogenesis. In addition, reactivation of this
pathway later in life can cause tumors. Twenty-nineMCPyV-positive and 21 MCPyV-negative
MCCs were immunohistochemically stained with primary antibodies for hedgehog signaling
(SHH, IHH, PTCH1, SMO, GLI1, GLI2, and GLI3) and evaluated using H-score. Polymerase
chain reaction and sequence analysis for SHH and GLI1 exons were also performed. Expression
of SHH was higher in MCPyV-positive MCCs than in MCPyV-negative MCCs (P<.001). Higher
expression of GLI1, MCPyV infection, male sex, and Japanese ethnicity were associated
with better overall survival (P=.034, P=.001, P=.042, and P=.036, respectively). Higher
expression of SHH and MCPyV infection were associated with improved MCC-specific survival
(P=.037 and P=.002, respectively). The mutation analysis of prognosis-related GLI1
and SHH genes in our study revealed a low frequency of mutations in the 10 exons examined,
except GLI1 exon 5 (18/22 cases), all having the same silent mutation of c.576G>A.
Only 2 mutations with amino acid changes were detected in MCPyV-negative MCCs only:
1 missense mutation in GLI1 exon 4 and 1 nonsense mutation in SHH-3B. Expression of
SHH and GLI1 may be useful prognostic markers of MCC because increased expression
was associated with better prognosis. The high rate of c.576G>A silent mutation in
GLI1 exon 5 was a feature of MCC.