Adult Granulosa Cell Tumor With High-grade Transformation

Abstract

Adult granulosa cell tumor (AGCT) is a low-grade malignant neoplasm with a significant propensity for late recurrence and metastasis. Almost all AGCTs are composed of cells with bland nuclear features and even when these tumors recur or metastasize, the nuclear features are almost always low-grade. We report 5 cases of AGCT in patients aged 37 to 88 years composed of areas of typical AGCT with low-grade morphology admixed with areas of high-grade morphology, with marked nuclear atypia, often with bizarre multinucleate cells and high mitotic activity; this is the first reported series of high-grade transformation in AGCTs. The high-grade areas often morphologically closely resembled juvenile granulosa cell tumor with abundant eosinophilic cytoplasm, significant mitotic activity, and intermediate sized follicles. Four cases were FIGO stage IA at diagnosis and 1 was stage IIIC with omental involvement. FOXL2 mutation analysis of both the morphologically low-grade and high-grade areas in 4 of 5 cases confirmed the presence of missense point mutation, c.402C>G, p.(Cys134Trp), providing conclusive evidence that the high-grade component represents transformation of typical AGCT rather than the coexistence of another sex cord-stromal tumor, such as juvenile granulosa cell tumor, which has been suggested for such neoplasms. In 3 of 4 cases where immunohistochemistry was undertaken, there was a striking difference between the p53 staining in the low-grade and high-grade components with wild-type staining in the former and diffuse mutation-type immunoreactivity in the latter, suggesting that TP53 mutation is likely to play a role in high-grade transformation. TP53 mutation analysis covering exons 4 to 10 was undertaken in 4 cases and TP53 mutations were identified in the high-grade component of 2 of the cases. In 1 case, there was diffuse block-type p16 staining in the high-grade component. Follow-up in the 4 stage IA neoplasms revealed no evidence of tumor recurrence in 3 (6 to 9 mo follow-up) while the other patient developed mediastinal, peritoneal, and pulmonary metastasis 17 months after diagnosis. High-grade transformation is uncommon in AGCTs and given that one of our cases was advanced stage at diagnosis, another exhibited widespread metastasis within a short period and there have been occasional case reports of aggressive behavior in AGCTs with high-grade transformation, this event may herald an aggressive clinical course.

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

“…In the literature, cases of AGCTs with areas of high-grade malignant morphology in either the primary tumor or recurrence have been reported. One study detected a TP53 mutation in these high-grade components of 2/4 FOXL2 mutant AGCTs and stated that TP53 mutation likely plays a role in the high-grade transformation [31]. A recent case report describes an aggressive AGCT without a FOXL2 mutation with strongly positive p53 immunohistochemistry and numerous mitoses [32], possibly similar to our finding of one FOXL2-wildtype TP53-mutant AGCT with high mitotic activity.…”

“…Four different major signatures were identified in the tumor samples. Two of the derived signatures were related to normal ageing processes being present in all cells (COSMIC 3, 5, 37 and COSMIC 3, 5, 40, respectively), one to platinum treatment (COSMIC 31,35) and one signature with a yet unestablished cause (COSMIC 4,20,38,45). No signatures related to microsatellite instability (MSI) or homologous recombination (HR) deficiency were detected (see Methods).…”

FOXL2 homozygous genotype and chromosome instability are associated with recurrence in adult granulosa cell tumors of the ovary

“…Carcinogenesis is a multistep process that can arise from a combination of mutations in oncogenes or tumor suppressor genes or from epigenetic changes in DNA. It is not yet known which of these processes are involved in aGCT, although recent genetic studies of primary and recurrent tumors have identified mutations in the promoter of the TERT gene (coding for telomerase reverse transcriptase), in the KMT2D gene (coding for a histone lysine methyltransferase) and in the TP53 gene [8,14,26]. These mutations' additional contributions to carcinogenesis (along with the FOXL2 mutations and CIN notably described here) have yet to be determined.…”

“…Recently, Fashedemi et al reported on five cases of aGCT with uncommon areas of high-grade morphology. The researchers showed that the TP53 mutation is likely to be involved in high-grade transformation [8]. Molecular markers that could predict recurrence and/or aggressive disease would be a great asset in the management of aGCT.…”

Development of Pathological Super-resolution Images using Artificial Intelligence based on Whole Slide Image

“…In the present study, we use adult granulosa cell tumor (AGCT) of ovary and uterine leiomyosarcoma as two application scenarios to test our resolution process. AGCT is a low-grade malignant neoplasm with a signi cant propensity for late recurrence and metastasis 9 . Histologically, granulosa cell tumors (GCTs) divided into adult and juvenile, the former accounted for 95% of all GCTs 9−10 .…”