BRAF V600E Mutations Occur in a Subset of Glomus Tumors, and Are Associated With Malignant Histologic Characteristics

Abstract

Glomus tumors are rare mesenchymal neoplasms with a phenotype akin to the modified smooth muscle cells of the glomus body. Most are benign, but rare examples show malignant histologic characteristics and aggressive behavior. We recently encountered a malignant glomus tumor with BRAF V600E mutation. We sought to study a large cohort for this mutation, with particular attention to associated malignant histologic characteristics. Tumors were classified based on WHO criteria as benign, uncertain malignant potential (glomus tumors of uncertain malignant potential-GT-UMP), or malignant. Tumors were screened for BRAF V600E by immunohistochemistry, and positive staining was evaluated further by Sanger sequencing. A total of 102 glomus tumors were included and classified as benign (57, 56%), GT-UMP (15, 15%) and malignant (30, 29%). Tumors occurred in patients aged 8 to 89.9 years (median: 50.2), without sex predilection (55% men). Most occurred in the superficial soft tissue (84%) and upper extremities (55%). Six of 95 tested cases had BRAF V600E mutation (6%), including 0 of 57 benign tumors, 3 of 14 GT-UMP (21%), and 3 of 24 malignant tumors (12%). Follow-up was obtained for 59 cases (median: 75.7 mo, range: 7.8 to 268.5). Three of 11 malignant tumors (27%) had progressive disease: 1 with metastasis to brain and heart, 1 with enlarging residual disease, and 1 with recurrence. Two of 4 GT-UMP (50%) had progressive disease: 1 with metastasis to lung, and 1 with local recurrence (50%). Three of 44 benign tumors (7%) had local recurrence. Two of 5 patients with BRAF V600E had progression, including 1 GT-UMP with local recurrence and 1 malignant tumor with enlarging residual disease. In summary, BRAF V600E mutation was detected in 6% of glomus tumors, all of which were malignant or GT-UMP. This mutation may be associated with a malignant phenotype, although study of additional cases is needed. In patients with progressive disease, BRAF could be a promising therapeutic target.

Glomus tumor in the floor of the mouth: a case report and review of the literature

“…Tumors > 2 cm in size with atypical mitotic figures, moderate-to-high nuclear grade, and > 5 mitotic figures per 50 high-power fields are considered highly suspicious for malignancy [ 40 ]. A recent study found that BRAF V600E mutations may be associated with a malignant phenotype in glomus tumors [ 41 ]; however, larger cohorts and multicenter studies are required to confirm this finding.…”

Glomus tumors with malignant features of the extremities: a case series

“…Although a rare occurrence, malignant glomus tumors and glomus tumors of uncertain malignant potential have been shown to both be locally aggressive and have the potential to metastasize [ 3 , 9 , 10 ]. Once metastasis occurs, prognosis is poor [ 6 , 8 ]. Wide local excision is the current gold standard treatment option given low potential for glomus tumors with malignant features to metastasize, however surgeons should be privy to this potential outcome prior to surgical intervention [ 11 ].…”

“…Although the risk of metastasis is low, there have been reports of locally aggressive disease as well as distant metastasis [ 3 ]. Metastatic disease in particular has only been observed in malignant glomus tumors and glomus tumors of uncertain malignant potential [ 8 ], and once metastasized, the disease has a poor prognosis. One study showed 38% (8 of 21 patients) of the patients whose glomus tumors met criteria for malignancy metastasized, and of those patients with metastatic disease, 6 out of the 8 were dead from their disease after 3 years [ 6 ].…”

BRAF Alteration in Central and Peripheral Nervous System Tumors

“…Most glomus tumors are superficial, less than 2 cm, and surgically curable (52). BRAF V600E appears with a frequency of 6-11% (50,51,53). Its presence in glomus tumors may predict a more aggressive phenotype (53).…”

“…BRAF V600E appears with a frequency of 6-11% (50,51,53). Its presence in glomus tumors may predict a more aggressive phenotype (53). Karamzadeh et al reviewed 102 cases, largely originating from the extremities (53).…”