A Molecular Reappraisal of Glomus Tumors and Related Pericytic Neoplasms With Emphasis on NOTCH-gene Fusions

Abstract

Glomus tumors (GT), together with myofibroma (MF), myopericytoma (MP) and angioleiomyoma (AL) are classified as members of the perivascular myoid family of tumors. The reported genetic abnormalities across these neoplasms is dissimilar, arguing against a pathogenetically unified family; half of the GT showing NOTCH-gene fusions and a smaller subset BRAF V600E mutations, while PDGFRB mutations are noted in a subset of MF and MP. The aim of this study was to investigate the prevalence and specificity of NOTCH gene fusions in a large group of GT and correlate with clinical features. BRAF-VE1 and PDGFRB immunoexpression was also investigated in this cohort. 93 GT and 43 other pericytic lesions (11 MP, 13 MF, 19 AL) were selected. All cases were tested by fluorescence in situ hybridization for NOTCH1-4 and MIR143 gene abnormalities and 6 cases were investigated by targeted RNA sequencing. FISH revealed NOTCH gene rearrangements in 50 (54%) GT, 2 MP (18%) and 2 AL (11%). NOTCHrearrangements were present in 34 (68%) benign and 16 (32%) malignant GT. Fusion-positive benign GT were overwhelmingly seen in males with a predilection for extremities, while the malignant GT occurred mostly in viscera. Among the fusion-negative GT, 88% were benign, 9% uncertain malignant potential and 2% malignant. Half of the fusion negative-GTs occurred in the finger/subungual region. In summary, rearrangements of NOTCH genes are seen in over half of GT, with NOTCH2-MIR143 being the most common fusion (73%), while only a small subset of AL and MP share these abnormalities. The common subungual GT subset lack NOTCH gene fusions suggesting an alternative pathogenesis. BRAF-VE1 was negative in all 37 cases studied while strong PDGFRB staining was seen in 14 (21%) cases. Additional studies are needed to investigate the genetic alterations in the fusion-negative cases.

Metastatic Malignant Gastric Glomus Tumour: Multidisciplinary Diagnosis & Treatment of a Rare Clinical Entity

“…In the largest of those studies, Agaram and colleagues uncovered NOTCH-gene fusions in 50 of 93 cases (54%), including all but one malignant glomus tumour. [21] Interestingly, all six glomus tumours with gastrointestinal involvement in that study were malignant which does not re ect previous work suggesting gastric glomus tumours are mostly benign. [6,21] The NOTCH signaling pathway has been implicated in a variety of other cancer types where it might have signi cant treatment implications.…”

CARMN‐NOTCH2 fusion transcript drives high NOTCH2 expression in glomus tumors of the upper digestive tract

“…Thus, CARMN‐NOTCH2 fusion transcript is a hallmark of glomus tumors. Interestingly, in this recent series, a fusion involving NOTCH1 , NOTCH2 , or NOTCH3 genes was detected in 16/17 (94%) versus 34/72 (47%) malignant versus benign glomus tumors, respectively, and in 15/21 (71%) versus 30/65 (46%) of glomus tumors of viscera (including gastrointestinal tract) versus glomus tumors of extremities or fingers, respectively 30 . Our series confirms that NOTCH2 fusions are more frequent in visceral glomus tumors than in those of the extremities.…”

“…Mosquera et al reported novel translocations involving CARMN and NOTCH genes (NOTCH 1, 2, and 3) in 14 out of 21 (67%) glomus tumors 12 . The same translocations were then identified in 67% of cases in a series including 60 other glomus tumors (with five malignant cases originating from the digestive tract) 30 . Thus, CARMN‐NOTCH2 fusion transcript is a hallmark of glomus tumors.…”

“…Germinal inactivating mutations in the glomulin gene are responsible for multiple familial glomovenous malformations (or glomangiomas), 26 while only rare somatic mutations in glomus tumors were reported 12,28‐30 . Mosquera et al reported novel translocations involving CARMN and NOTCH genes (NOTCH 1, 2, and 3) in 14 out of 21 (67%) glomus tumors 12 .…”

Gastric glomus tumor diagnosed by fine needle aspiration of the stomach: A report of two cases and review of the literature

“…A study of 93 glomus tumors and 43 other pericytic lesions found that fluorescence in situ hybridization revealed NOTCH‐gene fusions present in 54% of glomus tumors and only 18% of myopericytomas and 11% of angioleimyomas suggesting these lesions may have alternate pathogenesis 25 . Among the fusion‐negative glomus tumors, the majority (88%) were benign tumors with only 9% with uncertain malignant potential and 2% malignant 25 …”