Pathogenesis of placental site trophoblastic tumor may require the presence of a paternally derived X chromosome

Placental site trophoblastic tumor (PSTT) is a neoplastic proliferation of intermediate trophoblasts that invades the myometrium at the placental site after a pregnancy. Less than 100 cases have been reported. Information of the sex assignment of the antecedent gestation is available in 21 cases: 18 of these were female. To explore this interesting phenomenon, we have dete rmined the sex chromosome composition of the tumor tissue preserved in para ffin blocks for five new cases of this condition. The last documented gesta tional event included a normal vaginal delivery of female infants in three cases, normal Vaginal delivery of an infant of unknown sex in one case and a molar gestation in one case. Using the X-linked human androgen receptor ( AR) gene as a polymorphic marker, we showed that in all five cases the tumo r had a likely XX chromosomal composition; and in four cases it was possibl e to determine that one of the X chromosomes was of paternal origin. In one case, the paternal X chromosome showed no polymorphism to either maternal X chromosomes. In addition, sensitive semi-nested PCR failed to show a huma n Y chromosome element in any of the five cases of PSTT. Overall, of 21 cas es from the literature and 5 cases of ours, 89% (23 of 26) showed an XX gen omic composition in PSTT, either by history or genetic analysis. These resu lts suggest that most PSTT were derived from the antecedent female conceptu s and were likely to have possessed a functional paternal X chromosome. Met hylation status analysis at the AR locus was performed in the three PSTT in which the paternal X chromosome was identifiable. In two cases, the patern al AR locus was hypomethylated while the corresponding maternal locus was h ypermethylated. The methylation status of other loci was not investigated. Collectively, sex chromosome analysis of five cases of PSTT with literature support suggests a unique genetic basis for the development of PSTT that i nvolves the paternal X chromosome. Although largely speculative, an active paternal X chromosome may be of importance in the pathogenesis of PSTT.