Intramuscular fast-flow vascular anomaly contains somatic MAP2K1 and KRAS mutations

Abstract

Background: The term "intramuscular hemangioma capillary type" (IHCT) refers to a fast-flow vascular lesion that is classified as a tumor, although its phenotype overlaps with arteriovenous malformation (AVM). The purpose of this study was to identify somatic mutations in IHCT.

Methods: Affected tissue specimens were obtained during a clinically indicated procedure. The diagnosis of IHCT was based on history, physical examination, imaging and histopathology. Because somatic mutations in cancer-associated genes can cause vascular malformations, we sequenced exons from 446 cancer-related genes in DNA from 7 IHCT specimens. We then performed mutation-specific droplet digital PCR (ddPCR) to independently test for the presence of a somatic mutation found by sequencing and to screen one additional IHCT sample.

Results: We detected somatic mutations in 6 of 8 IHCT specimens. Four specimens had a mutation in MAP2K1 (p.Q58_E62del, p.P105_I107delinsL, p.Q56P) and 2 specimens had mutations in KRAS (p.K5E and p.G12D, p.G12D and p.Q22R). Mutant allele frequencies detected by sequencing and confirmed by ddPCR ranged from 2 to 15%.

Conclusions: IHCT lesions are phenotypically similar to AVMs and contain the same somatic MAP2K1 or KRAS mutations, suggesting that IHCT is on the AVM spectrum. We propose calling this lesion "intramuscular fast-flow vascular anomaly."

Keywords: Arteriovenous malformation; Capillary type; Hemangioma; Intramuscular; KRAS; MAP2K1; Malformation; Vascular.

Figure 1.

Study cohort with intramuscular hemangioma capillary type listed in Table. (A) Patient 1, (B) Patient 2, (C) Patient 3, (D) Patient 6.

Figure 2.

Clinical, radiological, and histopathological findings of Patient 4 (Table) with a KRAS mutation. (A) Clinical appearance showing a subcutaneous mass of the left arm. (B) Axial fat saturated T2- weighted and (C) post-contrast, T1-weighted MR images demonstrating focal well-defined T2-hyperintense lesion with enlarged vessels in the left deltoid muscle. Note strong enhancement post-contrast. (D) Gray-scale (E) and color Doppler ultrasound longitudinal images showed heterogenously hyperechoic subfascial lesion containing large vessels. (F) Skeletal muscle (M) involved by large capillarous lobules (circles), abnormal veins, and a small amount of adipose tissue (H & E, x40). (G) Portion of capillarous lobule on left adjacent to vein (V) with focal loss of smooth muscle and mural expansion by vascularized neointimal hyperplasia (stars) (H & E, x 100).

Figure 3.

Clinical, radiological, and histopathological findings of Patient 5 (Table) with a MAP2K1 mutation. (A) Clinical and (B) MRI appearance. (C) Intraoperative view of lesion prior to resection. (D) Excised lesion illustrates adipose component. (E) Skeletal muscle infiltrated by capillarous strands, clusters (arrow heads), lobules (circles), and anastomosing bands. Thin-walled irregularly muscularized vein present (V) (H & E, x100). (F) Typical lobule with branching capillaries with small lumens, plump endothelial cells with slight orientational disarray, relatively inconspicuous pericytes, and delicate palely stained lobular stroma (S) (H & E, x 400).