The aim of this study was to investigate the occurrence of (pre)neoplastic lesions in overtly normal Fallopian tubes from women predisposed to developing ovarian carcinoma. The presence of (pre)neoplastic lesions was scored in histological specimens from 12 women with a genetically determined predisposition for ovarian cancer, of whom seven tested positive for a germline BRCA1 mutation. A control group included 13 women. Immunohistochemistry was used to determine the expression of p21, p27, p53, cyclin A, cyclin D1, bcl-2, Ki67, HER-2/neu, and the oestrogen and progesterone receptors. Loss of heterozygosity (LOH) analysis on the BRCA1 locus was also assessed on dysplastic tissue by PCR studies. Of the 12 women with a predisposition for ovarian cancer, six showed dysplasia, including one case of severe dysplasia. Five harboured hyperplastic lesions and in one woman no histological aberrations were found in the Fallopian tube. No hyperplastic, dysplastic or neoplastic lesions were detected in the Fallopian tubes of control subjects. In the cases studied, morphologically normal tubal epithelium contained a higher proportion of Ki67-expressing cells (p=0.005) and lower fractions of cells expressing p21 (p<0.0001) and p27 (p=0.006) than in the control group. Even higher fractions of proliferating cells were found in dysplastic areas (p=0.07) and accumulation of p53 was observed in the severely dysplastic lesion. Expression patterns of other proteins studied, including the hormone receptors, were similar in cases and controls. One subject, a germline BRCA1 mutation carrier, showed loss of the wild-type BRCA1 allele in the severely dysplastic lesion. In conclusion, the Fallopian tubes of women predisposed to developing ovarian cancer frequently harbour dysplastic changes, accompanied by changes in cell-cycle and apoptosis-related proteins, indicating an increased risk of developing tubal cancer.

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Adult granulosa cell tumors (AGCTs) harbor a somatic FOXL2 c.402C>G mutation in ~95% of cases and are mainly surgically removed due to limited systemic treatment effect. In this study, potentially targetable genomic alterations in AGCTs were investigated by whole genome sequencing on 46 tumor samples and matched normal DNA. Copy number variant (CNV) analysis confirmed gain of chromosome 12 and 14, and loss of 22. Pathogenic TP53 mutations were identified in three patients with highest tumor mutational burden and mitotic activity, defining a high-grade AGCT subgroup. Within-patient tumor comparisons showed 29–80% unique somatic mutations per sample, suggesting tumor heterogeneity. A higher mutational burden was found in recurrent tumors, as compared to primary AGCTs. FOXL2-wildtype AGCTs harbored DICER1, TERT(C228T) and TP53 mutations and similar CNV profiles as FOXL2-mutant tumors. Our study confirms that absence of the FOXL2 c.402C>G mutation does not exclude AGCT diagnosis. The lack of overlapping variants in targetable cancer genes indicates the need for personalized treatment for AGCT patients.

Objective: The aim of this study is to assess our results of treatment of women with stage I cervical cancer > 2 cm in diameter seeking fertility preservation. Treatment consisted of Laparoscopic Pelvic and Paraaortic Lymphadenectomy (LPPLND), and when no nodal metastasis was detected, neoadjuvant chemotherapy (NACT) followed by radical vaginal trachelectomy (RVT). Patients with positive lymph nodes underwent primary chemoradiation. Methods: A cohort of women younger than 40 years of age with stage I disease > 2 cm who underwent LPPLND and either NACT and RVT or chemoradiation. Oncological outcome was evaluated prospectively. Results: Eighteen women were eligible for this study. Twelve (67%) women were diagnosed with metastasis in one or more pelvic and/or paraaortic lymph nodes, and thus received primary chemoradiation. After a mean follow-up of 25.5 months, three out of these 12 women (25%) developed a recurrence. Six women (33%) underwent NACT and RVT. Three patients experienced complete response to NACT and three patients showed more than 50% tumor size reduction. After a mean follow-up of 30.6 months all six women are free of recurrence. One patient delivered a healthy infant. Conclusions: Staging LPPLND allows separating patients in high or low recurrence risk groups. NACT and RVT seem to be safe for women with completely staged stage I cervical cancer > 2 cm in diameter, whereas even after primary chemoradiation, patients with positive lymph nodes experienced recurrence. Therefore, selection of patients with stage I cervical carcinoma > 2 cm, eligible for fertility preservation should include histopathologic evaluation of lymph node status before any further treatment. © 2012 Elsevier Inc. All rights reserved