Testicular germ-cell tumors (TGCTs) of adolescents and adults originate
from intratubular germ cell neoplasia (ITGCN), which is composed of the
malignant counterparts of embryonal germ cells. ITGCN cells are
characterized, among others, by the presence of stem cell factor receptor
c-KIT. Once established, ITGCN will always progress to invasiveness.
Approximately 2.5-5% of patients with a TGCT will develop bilateral
disease and require complete castration, resulting in infertility, a need
for lifelong androgen replacement, and psychological stress. To date, the
only way to predict a contralateral tumor is surgical biopsy of the
contralateral testis to demonstrate ITGCN. We did a retrospective study of
224 unilateral and 61 proven bilateral TGCTs (from 46 patients, in three
independently collected series in Europe) for the presence of activating
c-KIT codon 816 mutations. A c-KIT codon 816 mutation was found in three
unilateral TGCT (1.3%), and in 57 bilateral TGCTs (93%; P < 0.0001). In
the two wild-type bilateral tumors for which ITGCN was available, the
preinvasive cells contained the mutation. The mutations were somatic in
origin and identical in both tumors. We conclude that somatic activating
codon 816 c-KIT mutations are associated with development of bilateral
TGCT. Detection of c-KIT codon 816 mutations in unilateral TGCT identifies
patients at risk for bilateral disease. These patients may undergo
tailored treatment to prevent the development of bilateral disease, with
retention of testicular hormonal function