Practical roles for molecular diagnostic testing in ovarian adult granulosa cell tumour, Sertoli–Leydig cell tumour, microcystic stromal tumour and their mimics

Abstract

Within the last decade, molecular advances have provided insights into the genetics of several ovarian sex cord–stromal tumours that have otherwise been enigmatic. Chief among these advances are the identification of FOXL2, DICER1 and CTNNB1 mutations in adult granulosa cell tumours, Sertoli–Leydig cell tumours (SLCTs), and microcystic stromal tumours (MCSTs), respectively. As access to molecular diagnostic laboratories continues to become more widely available, the potential roles for tumour mutation testing in the pathological diagnosis of these tumours merit discussion. Furthermore, links to inherited cancer susceptibility syndromes may exist for some women with SLCT (DICER1 syndrome) and MCST [familial adenomatous polyposis (FAP)]. This review will address practical issues in deciding when and how to apply mutation testing in the diagnosis of these three sex cord–stromal tumours. The pathologist's role in recommending referral for formal risk assessment for DICER1 syndrome and FAP will also be discussed.

Ovarian sex cord-stromal tumors: an update on clinical features, molecular changes, and management

“…24 Nuclear expression of β-catenin occurs in microcystic stromal tumors. 25 The somatic exon 3 missense CTNNB1 mutation is a hallmark of most ovarian microcystic stromal tumors. 25 The CTNNB1 gene encodes the β-catenin protein, and this mutation leads to the loss of a phosphorylation site in the β-catenin protein.…”

“…25 The somatic exon 3 missense CTNNB1 mutation is a hallmark of most ovarian microcystic stromal tumors. 25 The CTNNB1 gene encodes the β-catenin protein, and this mutation leads to the loss of a phosphorylation site in the β-catenin protein. Also, microcystic stromal tumors may be associated with familial adenomatous polyposis, which is an autosomal dominant inherited disease caused by germline mutations of the adenomatous polyposis coli gene on chromosome 5 (q21-22).…”

“…This single missense mutation is a rather pathognomonic hallmark of adult granulosa cell tumors, and is rarely seen in other ovarian tumors. 25 54 55 This makes FOXL2 a highly sensitive and relatively specific marker for adult granulosa cell tumors, as well as a useful diagnostic test for distinguishing between adult and juvenile granulosa cell tumors types and other sex cord-stromal tumors. 56 FOXL2 has been shown to interact directly with other genes involved in the pathogenesis of adult granulosa cell tumors, including CCND2, GATA4, and SMAD3.…”

“…86 Sertoli-Leydig cell tumors are associated with both somatic and germline DICER1 mutations, which encode an RNA endoribonuclease that cleaves microRNA precursors to generate mature microRNA. 25 However, tumors without DICER1 hot spot mutations exhibit no androgenic manifestations and usually present in elderly patients. 87 A case study of metastasizing Sertoli-Leydig cell tumors showed the presence of trisomy 8 as the sole karyotypic abnormality in ovarian Sertoli-Leydig cell tumors.…”

Molecular Pathways and Targeted Therapies for Malignant Ovarian Germ Cell Tumors and Sex Cord–Stromal Tumors: A Contemporary Review

“…FOXL2 is a transcription factor that is involved in regulation of hormone production, cell cycle, and apoptosis [102,103]. The precise mechanism by which this mutation promotes tumor formation is unclear; FOXL2 possibly serves as a tumor suppressor [40,104], but others have postulated that it acts as an oncogene [105]. The somatic mutation may lead to dysregulation of multiple cellular processes.…”