Granulosa Cell Tumor Pathology and Management

Granulosa cell tumours are rare ovarian neoplasms originating from hormone-producing granulosa cells and encompass adult and juvenile subtypes. Histologically, they display microfollicular or trabecular architecture with characteristic coffee-bean nuclei and abundant inhibin expression. Many adult-type tumours harbour a pathognomonic FOXL2 C402G mutation, while juvenile forms often carry activating mutations in the PI3K-AKT pathway. Clinically, patients present with abdominal discomfort or endocrine symptoms due to oestrogen excess. Primary management centres on surgical resection with staging, with fertility-sparing approaches offered to younger women. Despite high initial cure rates, late recurrences are common. Adjuvant treatments include chemotherapy, anti-hormonal agents and emerging targeted therapies such as AKT or CD47 inhibitors. Surveillance utilises serum inhibin and anti-Müllerian hormone levels alongside imaging. Recent insights into epigenetic dysregulation, immune evasion and molecular drivers are refining risk stratification and opening avenues for personalised therapy.

Research from Nature Portfolio

Recent genomic sequencing of adult-type tumours has revealed recurrent inactivating mutations in the histone methyltransferase KMT2D, more frequent in recurrent disease, implicating epigenetic dysregulation in relapse risk. Parallel investigations in ovarian stromal tumours have identified oncogenic FHL2–GLI2 fusion genes activating Sonic Hedgehog signalling, underscoring the potential of genomic diagnostics and pathway inhibition across sex cord-stromal neoplasms. These discoveries highlight novel driver events and point towards chromatin-modifying and pathway-targeted therapies.

Granulosa Cell Tumor Pathology and Management publication trend

The graph below shows the total number of articles in granulosa cell tumor pathology and management across all publications each year (not limited to Nature Index journals).

Technical terms

Granulosa cell tumour (GCT): A rare ovarian neoplasm derived from granulosa cells, comprising adult and juvenile subtypes.

FOXL2 C402G mutation: A somatic point mutation in the FOXL2 transcription factor, pathognomonic for adult-type GCT.

KMT2D inactivation: Loss-of-function mutations in a histone methyltransferase gene associated with tumour recurrence.

PI3K-AKT pathway: A signalling cascade regulating cell proliferation, often aberrantly activated in juvenile GCT via AKT1 mutations.

CD47: An immune checkpoint protein up-regulated in tumour cells to evade phagocytosis, targetable by specific inhibitors.

Cytoreductive surgery: A surgical approach aiming to remove as much tumour burden as possible to improve outcomes.

References

1. Lineage tracing of mutant granulosa cells reveals in vivo protective mechanisms that prevent granulosa cell tumorigenesis. Cell Death & Differentiation (2023).
2. A Hot-spot of In-frame Duplications Activates the Oncoprotein AKT1 in Juvenile Granulosa Cell Tumors. EBioMedicine (2015).
3. KMT2D/MLL2 inactivation is associated with recurrence in adult-type granulosa cell tumors of the ovary. Nature Communications (2018).
4. Identification of recurrent FHL2-GLI2 oncogenic fusion in sclerosing stromal tumors of the ovary. Nature Communications (2020).
5. The Specificity of the FOXL2 c.402C>G Somatic Mutation: A Survey of Solid Tumors. PLOS ONE (2009).
6. Response to Systemic Therapies in Ovarian Adult Granulosa Cell Tumors: A Literature Review. Cancers (2022).