Pathogenesis and treatment of adult-type granulosa cell tumor of the ovary

Abstract

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.

Whole Genome Analysis of Ovarian Granulosa Cell Tumors Reveals Tumor Heterogeneity and a High-Grade TP53-Specific Subgroup

“…Although the disease is frequently described as indolent in behavior, recurrences occur in approximately 50% of the patients of whom 50-80% ultimately die of their disease [5][6][7]. Recurrences often require repeated debulking surgeries since alternative treatment options including chemotherapy, radiotherapy and hormone therapy have thus far shown only limited effect [8]. The current lack of effective systemic treatment emphasizes the need for novel therapeutic strategies.…”

The molecular mechanism of ovarian granulosa cell tumors

“…Some studies examined the transcriptional targets of mutant FOXL2. Wile-type FOXL2 plays a key role in inhibiting granulosa cell proliferation and promoting apoptosis [ 21 ]. However, mutant FOXL2 downregulated the INHA, one of a proliferative signaling ligand [ 22 ].…”

Inhibin B in stromal-cell ovarian tumors

“…Характерной особенностью взрослого типа ГКОЯ является выраженная гормональная активность с гиперпродукцией стероидных и пептидных гормонов, которая обусловливает клиническую картину и течение заболевания [8,9]. Благодаря медленному росту и патогномоничным гормональным симптомам взрослый тип ГКОЯ часто выявляется на ранних стадиях [10].…”