A clinicopathological reappraisal of orbital vascular malformations and distinctive GJA4 mutation in cavernous venous malformations

Kuang-Hua Chen; Hsuan-Ying Huang; Tse-Ching Chen; Yu-Jen Liu; I-Chieh Lin; Kwai-Fong Ng; Huei-Chieh Chuang; Shih-Chiang Huang

doi:10.1016/j.humpath.2022.10.002

A clinicopathological reappraisal of orbital vascular malformations and distinctive GJA4 mutation in cavernous venous malformations

Hum Pathol. 2022 Dec:130:79-87. doi: 10.1016/j.humpath.2022.10.002. Epub 2022 Oct 6.

Authors

Kuang-Hua Chen¹, Hsuan-Ying Huang², Tse-Ching Chen¹, Yu-Jen Liu¹, I-Chieh Lin¹, Kwai-Fong Ng¹, Huei-Chieh Chuang³, Shih-Chiang Huang⁴

Affiliations

¹ Department of Anatomic Pathology, Linkou Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taoyuan, 333 Taiwan.
² Department of Anatomical Pathology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Kaohsiung City, 833 Taiwan.
³ Department of Anatomic Pathology, Chiayi Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Chiayi, 613 Taiwan.
⁴ Department of Anatomic Pathology, Linkou Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taoyuan, 333 Taiwan; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, 333 Taiwan. Electronic address: ab86401112@cgmh.org.tw.

PMID: 36209871
DOI: 10.1016/j.humpath.2022.10.002

Abstract

Vascular anomalies are common orbital lesions, while variations in previous nomenclature might hamper robust characterization of their clinicopathological and genetic features. We reviewed and reclassified 92 orbital vascular lesions by the modified International Society for the Study of Vascular Anomalies (ISSVA) classification with reappraising clinicopathological parameters of 4 main types of vascular malformations, including orbital venous malformation 1 (OVM1, cavernous venous malformation), OVM2 (varix), OVM3 (infiltrating venous malformation), and arteriovenous malformation (AVM). GJA4, BRAF, and KRAS mutations were assessed by Sanger sequencing. There were 90 cases of vascular malformations, consisting of 60 OVM1 (67%), 13 AVM (14%), 8 OVM2 (9%), 8 OVM3 (9%), and 1 lymphatic-venous malformation (1%). The prevailing OVM1, histologically characterized by well-delineated borders and a uniform cavernous growth pattern, predominantly occurred in intraconal space (57%, P = .019) with an older median age (49 years) and female predilection (73%). OVM2, OVM3, and AVM exhibited differences in the distributions of patients' ages and lesion locations. Sizes of lesions were significantly correlated with periorbital and intraconal/extraconal locations (P < .001). OVM1 had the lowest rate of residual and recurrent diseases (3%). GJA4 mutations were identified in 75% (44/59) of OVM1 but not in OVM2/3 and AVM. No BRAF or KRAS mutations were detected. In conclusion, the modified ISSVA scheme enables meaningful classification of orbital vascular malformations by highlighting the molecular correlation between the distinct clinicopathological features and specific GJA4 mutation in OVM1, which implies OVM1 as a unique variant of venous malformation genetically akin to cutaneous and hepatic counterparts.

Keywords: Arteriovenous malformation; Cavernous venous malformation; GJA4 mutation; Infiltrating venous malformation; Orbital varix; Orbital vascular malformation.

Publication types

Review

MeSH terms

Arteriovenous Malformations* / genetics
Arteriovenous Malformations* / pathology
Female
Humans
Lymphatic Abnormalities*
Middle Aged
Mutation
Vascular Malformations* / genetics
Vascular Malformations* / pathology
Veins / pathology