Microscopic heterotopic extraovarian sex cord-stromal proliferations were first reported in the literature in 2015 by McCluggege. Afterwards, few similar cases have been described. Herein, we report the fourteenth case of microscopic heterotopic sex cord-stromal proliferation and the third case sited in the pelvic peritoneum. The clinical history of these rare cases suggests their benign nature. Knowledge of this histological pattern is important for differential diagnoses such as malignant pathologies and metastatic diseases.

Adult-type granulosa cell tumor (AGCT) is a rare ovarian malignancy characterized by slow growth and hormonal activity. The prognosis of AGCT is generally favorable, but one-third of patients with low-stage disease experience a late relapse, and over half of them die of AGCT. To identify markers that would distinguish patients at risk for relapse, we performed Lexogen QuantSeq 3\' mRNA sequencing on formalin-fixed paraffin-embedded, archival AGCT tissue samples tested positive for the pathognomonic Forkhead Box L2 (FOXL2) mutation. We compared the transcriptomic profiles of 14 non-relapsed archival primary AGCTs (follow-up time 17-26 years after diagnosis) with 13 relapsed primary AGCTs (follow-up time 1.7-18 years) and eight relapsed tumors (follow-up time 2.8-18.9 years). Non-relapsed and relapsed primary AGCTs had similar transcriptomic profiles. In relapsed tumors three genes were differentially expressed: plasmalemma vesicle associated protein (PLVAP) was upregulated (p = 0.01), whereas argininosuccinate synthase 1 (ASS1) (p = 0.01) and perilipin 4 (PLIN4) (p = 0.02) were downregulated. PLVAP upregulation was validated using tissue microarray RNA in situ hybridization. In our patient cohort with extremely long follow-up, we observed similar gene expression patterns in both primary AGCT groups, suggesting that relapse is not driven by transcriptomic changes. These results reinforce earlier findings that molecular markers do not predict AGCT behavior or risk of relapse.

Pathogenic germline mutations c.1100delC and p.I157T in the CHEK2 gene have been associated with increased risk of breast, colon, kidney, prostate, and thyroid cancers; however, no associations have yet been identified between these two most common European founder mutations of the CHEK2 gene and ovarian cancers of any type. Our review of 78 female heterozygous carriers of these mutations (age > 18 years) found strikingly higher proportion of adult-type granulosa cell tumors of the ovary (AGCTs) among ovarian cancers that developed in these women (~36%) compared to women from the general population (1.3%). Based on this finding, we performed a cross-sectional study that included 93 cases previously diagnosed with granulosa cell tumors, refined and validated their AGCT diagnosis through an IHC study, determined their status for the two CHEK2 mutations, and compared the prevalence of these mutations in the AGCT cases and reference populations. The prevalence ratios for the p.I157T mutation in the AGCT group relative to the global (PR = 26.52; CI95: 12.55−56.03) and European non-Finnish populations (PR = 24.55; CI95: 11.60−51.97) support an association between the CHEK2p.I157T mutation and AGCTs. These rare gynecologic tumors have not been previously associated with known risk factors and genetic predispositions. Furthermore, our results support the importance of the determination of the FOXL2p.C134W somatic mutation for accurate diagnosis of AGCTs and suggest a combination of IHC markers that can serve as a surrogate diagnostic marker to infer the mutational status of this FOXL2 allele.

A combination of ovarian tumors with the same histogenetic origin but different histologic subtype is relatively common, whereas a co-occurrence of tumors with different histogenetic origin is rare. We report a case of mixed ovarian tumor composed of Brenner tumor and adult-type granulosa cell tumor, a combination that to the best of our knowledge has not been reported in the literature until now.

Adult-type granulosa cell tumor is a clinically and molecularly unique subtype of ovarian cancer. These tumors originate from the sex cord stromal cells of the ovary and represent 3-5% of all ovarian cancers. The majority of adult-type granulosa cell tumors are diagnosed at an early stage with an indolent prognosis. Surgery is the cornerstone for the treatment of both primary and relapsed tumor, while chemotherapy is applied only for advanced or non-resectable cases. Tumor stage is the only factor consistently associated with prognosis. However, every third of the patients relapse, typically in 4-7 years from diagnosis, leading to death in 50% of these patients. Anti-Müllerian Hormone and inhibin B are currently the most accurate circulating biomarkers. Adult-type granulosa cell tumors are molecularly characterized by a pathognomonic somatic missense point mutation 402C->G (C134W) in the transcription factor FOXL2. The FOXL2 402C->G mutation leads to increased proliferation and survival of granulosa cells, and promotes hormonal changes. Histological diagnosis of adult-type granulosa cell tumor is challenging, therefore testing for the FOXL2 mutation is crucial for differential diagnosis. Large international collaborations utilizing molecularly defined cohorts are essential to improve and validate new treatment strategies for patients with high-risk or relapsed adult-type granulosa cell tumor. Key Messages: Adult-type granulosa cell tumor is a unique ovarian cancer with an indolent, albeit unpredictable disease course. Adult-type granulosa cell tumors harbor a pathognomonic somatic missense mutation in transcription factor FOXL2. The key challenges in the treatment of patients with adult-type granulosa cell tumor lie in the identification and management of patients with high-risk or relapsed disease.

BACKGROUND: Ovarian adult-type granulosa cell tumors (GCTs) are characterized as low-malignant and late-recurrent ovarian tumors. Although some clinical and pathological prognostic factors have been reported, other factors have yet to be sufficiently investigated for necessary confirmation. The aim of this study was to test the correlation between clinical factors and outcome, based on patients seen in a single institute.
METHODS: Thirty patients with pathologically confirmed adult-type GCTs between 1984 and 2010 were reviewed retrospectively. Among them, eight (26.7%) had recurrence, which subsequently contributed to two mortalities.
RESULTS: In a comparison of the clinical characteristics of the premenopausal and postmenopausal women with GCT, all of the postmenopausal women had symptoms (100% vs. 63.6%, p = 0.01). With regard to disease recurrence, only abnormal preoperative serum cancer antigen 125 level (≥ 35 U/mL) was significant (50% vs. 11%, p = 0.03), and residual tumor showed a borderline trend (100% vs. 21.4%, p = 0.06). Other factors, including International Federation of Gynecology and Obstetrics stage, tumor size, tumor rupture prior to or during operation, body mass index, parity, serum estrogen level, and adjuvant therapy, were not statistically significant.
CONCLUSIONS: Physicians should be alert to the difference in the symptom presentation of GCTs between pre- and postmenopausal women, giving particular attention to the usefulness of the preoperative serum level of cancer antigen 125 in patients with GCTs. More evidence is needed to confirm this observation.