Alterations of G-protein Activating Subunit Genes in Ovarian Hemangiomas: A Molecular Study of 6 Cases Including 3 Anastomosing Hemangiomas With a Cavernous Component

To the Editor: In recent years, alterations in G-protein activating subunit genes, including GNAQ, GNA11, and GNA14, have been identified in a variety of vascular lesions that span anastomosing hemangioma, congenital hemangioma, cherry angioma, papillary hemangioma, tufted angioma, lobular capillary hemangioma, kaposiform hemangioendothelioma, and hepatic small vessel neoplasm1–9. Since, to the best of our knowledge, the molecular underpinnings of benign vascular lesions of the ovary have not been investigated in a series, we retrieved material from our 2015 study of 10 ovarian hemangiomas10 to evaluate a subset of these tumors. Six cases from the previous study10, 3 classified at the time as mixed cavernous and capillary hemangioma and 3 as cavernous hemangioma, were selected for next-generation sequencing. The MayoComplete Comprehensive Sarcoma Panel evaluated mutations in ALK, APC, BAP1, BCOR, BRAF, CDKN2A, CTNNB1, DICER1, EED, EGFR, FGFR4, GNA11, GNA14, GNAQ, GNAS, H3-3A, H3-3B, KIT, MDM2, MED12, MYOD1, NF1, PDGFRA, PDGFRB, PTPRD, ROS1, SMARCB1, SUZ12, TERT promoter, TP53, and TSC2. Sequencing was successful in 5 tumors (Table 1). Two mixed cavernous and capillary hemangiomas had GNAQ mutations; both GNAQ mutations occurred at codon 209, a hotspot associated with anastomosing hemangioma. One tumor with a GNAQ mutation also had a TP53 alteration (case 5). However, the TP53 alteration had a low variant allele frequency (3%), likely indicating a subclonal event or consequence of low tumor purity. Three cavernous hemangiomas were negative for alterations, and one mixed cavernous and capillary hemangioma failed sequencing. TABLE 1 - Ovarian Hemangioma Classification and Molecular Findings Case* Lesion size (cm) Classification from prior publication* Revised classification Next-generation sequencing 1 1.2 Cavernous hemangioma Cavernous hemangioma/malformation No mutations 2 5 Mixed cavernous and capillary hemangioma Anastomosing hemangioma GNAQ (p.Q209H) 4 4 Mixed cavernous and capillary hemangioma Anastomosing hemangioma Failed 5 4.3 Mixed cavernous and capillary hemangioma Anastomosing hemangioma GNAQ (p.Q209H) TP53 (p.R342*) (wild type p53 IHC) 6 1.9 Cavernous hemangioma Cavernous hemangioma/malformation No mutations 7 0.7 Cavernous hemangioma Cavernous hemangioma/malformation No mutations *Case numbers and prior classification correlate with those from the prior published study10.IHC indicates immunohistochemistry. All 6 cases that were processed for molecular analysis also underwent morphologic rereview. Three tumors previously considered mixed cavernous and capillary hemangioma10 were reclassified as anastomosing hemangioma on the basis that each had patchy lobules of capillary-sized sieve-like vascular channels amid distinctive well-demarcated regions of ectatic partly hyalinized vessels resembling cavernous hemangioma (Figs. 1A, B). A component of conventional cavernous hemangioma has been reported in anastomosing hemangiomas of the liver.11,12 Distinct from the cavernous areas, occasional single larger thick-walled vessels were embedded within the lobules of capillary-sized anastomosing vessels (Fig. 1C). Cytologically, the tumors had bland hobnail endothelial cells (Fig. 1D). Fibrin thrombi were noted in a few tumor vessels (Fig. 1E). In addition, p53 immunohistochemistry performed on the tumor with concurrent GNAQ and TP53 alterations (case 5) showed uniformly heterogeneous (wild type) expression (Fig. 1F). Further clinical follow up obtained on this patient (case 5) reported no evidence of disease 117 months after oophorectomy. Three cases previously interpreted as cavernous hemangioma10 were unchanged in classification, although recent recommendations suggest these lesions may be better considered vascular malformations.13FIGURE 1: The ovarian anastomosing hemangiomas demonstrated discrete lobules of capillary-sized vascular channels amid well-defined regions of ectatic partly hyalinized vessels resembling cavernous hemangioma (A, 40×, B, 100×). Some lobules of capillary-sized vascular channels had an embedded larger vessel (C, 100×, also seen in the upper right aspect of A). The vessels showed bland hobnail endothelial cells (D, 200×) and focally contained fibrin thrombi (E, 400×, arrows). p53 immunohistochemistry performed on case 5 due to concurrent GNAQ and TP53 alterations showed uniformly heterogeneous (wild type) expression (F, 200×).We present molecular findings from a series of previously published ovarian hemangiomas. Morphologic rereview, supported by the detection of GNAQ hotspot mutations at codon 209, resulted in the reclassification of three tumors as anastomosing hemangiomas, each with a component of conventional cavernous hemangioma, as has been described in some anastomosing hemangiomas at extra-ovarian sites.11,12 Pure cavernous hemangiomas from the original study lacked alterations.