Comprehensive molecular and clinicopathological analysis of vascular malformations: A study of 319 cases

Abstract

Vascular malformations are part of overgrowth syndromes characterized by somatic mosaic mutations or rarely by germline mutations. Due to their similarities and diversity, clinicopathological classification can be challenging. A comprehensive targeted Next Generation Sequencing screen using Unique Molecular Identifiers with a technical sensitivity of 1% mutant alleles was performed for frequently mutated positions in ≥21 genes on 319 formalin‐fixed paraffin‐embedded samples. In 132 out of 319 cases pathogenic mosaic mutations were detected affecting genes previously linked to vascular malformations e.g. PIK3CA (n=80), TEK ( TIE2 ) (n=11), AKT1 (n=1), GNAQ (n=7), GNA11 (n=4), IDH1 (n=3), KRAS (n=9), and NRAS (n=1). Six cases harbored a combination of mutations in PIK3CA and in GNA11 (n=2), GNAQ (n=2), or IDH1 (n=2). Aberrations in PTEN and RASA1 with a variant allele frequency approaching 50% suggestive of germline origin were identified in six out of 102 cases tested; four contained a potential second hit at a lower allele frequency. Ninety‐one of the total 142 pathogenic mutations were present at a variant allele frequency <10% illustrating the importance of sensitive molecular analysis. Clinicopathological characteristics showed a broad spectrum and overlap when correlated with molecular data. Sensitive screening of recurrently mutated genes in vascular malformations may help to confirm the diagnosis and reveals potential therapeutic options with a significant contribution of PIK3CA/mTOR and RAS‐MAPK pathway mutations. The co‐existence of two activating pathogenic mutations in parallel pathways illustrates potential treatment challenges and underlines the importance of multigene testing. Detected germline mutations have major clinical impact.

Soft Tissue Special Issue: Perivascular and Vascular Tumors of the Head and Neck

“…WT1 immunohistochemistry can be helpful in discriminating vascular neoplasms from malformations with absence of cytoplasmic staining in lymphatic, venous and capillary malformations [42]. Mutationally affected genes include PIK3CA, TEK (TIE2), AKT, GNAQ, GNA11, KRAS, NRAS, PTEN and RASA [43].…”

Peripheral Vascular Anomalies – Essentials in Periinterventional Imaging

“…Periinterventional imaging should verify the clinically suspected diagnosis of a vascular anomaly and provide sufficient information for precise treatment planning [12,13]. The goal of this over-view of the essentials in periinterventional imaging of peripheral vascular anomalies is to simplify the diagnostic approach and the interdisciplinary management of this rare disease.…”

Klippel–Trenaunay and Sturge–Weber Overlap Syndrome with KRAS and GNAQ mutations

“…12 Intriguingly, a recent study revealed that several somatic KRAS mutations like KRAS c.64C>A (p.Gln22Lys) and c.436G>A (p.Ala146Thr) were associated with combined phenotypes of Klippel-Trenaunay syndrome and port-wine stains. 2 In this study, we found a novel KRAS c.182_183delinsTC (p.Q61L) mutation in the patient with Klippel-Trenaunay syndrome.…”

“…1 In contrast, Klippel-Trenaunay syndrome is a sporadic congenital vascular malformation with the most common somatic PIK3CA mutations as well as infrequent KRAS mutations, and distinguished by extensive portwine stains involving limbs and/or trunk associated with hypertrophy of soft tissue or bone and venous varicosities. 2,3 To date, Klippel-Trenaunay and Sturge-Weber overlap syndrome has been reported in several studies, where only the most common somatic GNAQ c.548G>A (p.R183Q) mutation without any other known mutations has been found. [4][5][6] Nevertheless, whether a single somatic GNAQ mutation is responsible for the whole phenotypes remains to be determined.…”