Large cell calcifying Sertoli cell
tumors (LCCSCT) are associated with
Carney complex and
Peutz-Jeghers syndrome. The mechanisms linking these 2 genetic defects to the genesis of this
tumor are obscure. Studies of
CYP19 (
aromatase) and
transforming growth factor (TGF)-beta1
messenger RNA (
mRNA) abundance,
estrogen receptor (ER), TGFbeta1, and
TGFbeta type II receptor (R) immunochemistry were carried out in the testis of a patient with this
tumor to gain information on possible mechanisms of cell
tumor development. Testicular tissue of a prepubertal patient, collected at
gonadectomy, was separated into 2 macroscopically distinct fractions: tumoral nodules (Tu) and extratumoral, normal-looking testicular tissue (ExTu). The patient was a 9.5-year-old boy with a 5-year history of bilateral
gynecomastia (Tanner stage 4), no pubic hair, incipient genital development, and bilateral testicular nodules. Multiple pigmented lesions of the skin were present. Bilateral
mammectomy and
gonadectomy was performed.
RNA was extracted from Tu and ExTu for semiquantitative
reverse transcriptase-polymerase chain reaction of
CYP19 and TGFbeta1.
Protein expression of ER, TGFbeta1, and
TGFbeta type II R in Tu and ExTu was detected by immunohistochemistry. Cell proliferation was estimated by
Ki-67 antigen immunochemistry and apoptosis using a modified TUNEL assay. Mean expression of
aromatase and TGFbeta1 mRNAs in Tu was 6- and 2.3-fold higher than in ExTu, respectively (P<0.05). Tumoral cells exhibited ER staining with a predominant extranuclear localization. Positive staining of Sertoli cells in Tu was higher than in ExTu. TGFbeta1 immunostaining of the interstitial cells in Tu was higher than in ExTu.
TGFbeta type II R immunostaining was detected in most Sertoli and interstitial cells, but intensity in ExTu was lower than in Tu. No significant difference was detected in the proliferation index, but in Tu, the percentage of Sertoli cells in apoptosis (1.4%) was significantly lower (P<0.01) than in ExTu (14.0%). The following hypothesis is proposed. The congenital gene defects of
Carney complex or of
Peutz-Jeghers syndrome might trigger a cascade of intracellular events that leads to overexpression of
aromatase in Sertoli cells, favoring the development of a LCCSCT. At some point in the evolution of the disease, a mutational event might induce a higher expression of the ER. Also, TGFbeta1
protein expression is increased in neighboring cells. In this environment, TGFbeta1 might switch from
tumor suppressor to oncogenic factor and, along with
estrogen-ER complexes, might favor
tumor progression by inhibiting apoptosis.