K-RAS mutations are the most frequent molecular genetic alteration in serous ovarian
tumors of borderline
malignancy (SBOT). The pathogenesis of associated contralateral
tumors and extraovarian implants and Müllerian inclusion
cysts is obscure. We hypothesized that the comparison of K-RAS mutations in these lesions might help to distinguish multifocal from metastatic foci. Eight cases of SBOT with known K-RAS mutation (RAS+) and two cases without mutation (RAS-) were analyzed for comparison.
DNA was extracted from multiple samples of 58
paraffin-embedded and
laser-microdissected ovarian and extraovarian lesions (10 ovarian borderline
tumors, 8 contralateral
tumors, 25 implants, 15 inclusion
cysts; total: 97 samples). K-RAS exon 1 was amplified by PCR and analyzed by denaturing gradient gel electrophoresis and cycle sequencing. In 12 of 14 SBOT and in 2 of 2 extraovarian implants, the K-RAS mutation could be found in different areas of the same lesion, indicating monoclonality. All RAS+ ovarian borderline
tumors with contralateral
tumors (six of six) harbored an identical mutation in both ovaries (in one case, a separate surface borderline
tumor component contained a different mutation in addition). In 4 of 5 RAS+ ovarian
tumors with extraovarian lesions, RAS mutations were also found in implants (15/21 implants [71%]) and more rarely in inclusion
cysts (3 of 12 lesions [25%]). These extraovarian mutations were always identical to the one in the ovary (18 of 18 [100%]). Regarding the contralateral and extraovarian lesions of the two RAS- SBOT, only one extraovarian implant contained a RAS mutation. The demonstration of K-RAS mutations in Müllerian inclusion
cysts and implants of SBOT suggests that K-RAS mutations represent a pivotal event during neoplastic transformation of ovarian and extraovarian serous epithelium. Considering our observations, the two putative pathogenetic mechanisms for the development of implants and endosalpingiosis-multifocal
tumorigenesis and spread from the ovarian primary
tumor-seem to coexist.