Glomus Tumour

Not clinically relevant

Sporadic benign and malignant glomus tumors of soft tissue or visceral origin harbor recurrent NOTCH gene family rearrangements, with MIR143-NOTCH1/2/3 fusion genes in more than half of cases. Of note, all malignant glomus tumors tested in that study showed the presence of NOTCH2 gene rearrangements. In contrast, NOTCH gene rearrangements have only rarely been detected in other tumors of pericytic origin. In addition, a small subset of sporadic glomus tumors show oncogenic BRAF and KRAS mutations, and BRAF mutations have been associated with malignant histology.

Glomus tumors typically form circumscribed, ovoid or round nodules with a solid or cystic and often hemorrhagic surface on sectioning.

Glomus cells are small, uniform, and rounded, with a centrally placed round nucleus, amphophilic to lightly eosinophilic cytoplasm, and sharply defined cell borders. Occasionally, cases show oncocytic or epithelioid change. Solid glomus tumors account for approximately 75% of cases and are composed of nests of glomus cells surrounding capillary-sized vessels. Glomuvenous malformations (also known as glomangiomas) are most common in patients with multiple or familial lesions, account for approximately 20% of cases, and are characterized by cavernous haemangioma–like vascular structures surrounded by small clusters of glomus cells. Glomangiomyomas show transition from typical glomus cells to elongated cells resembling mature smooth muscle. In some glomus tumors, a branching, haemangiopericytoma-like vasculature is present (glomangiopericytoma). Glomangiomatosis is an extremely rare subtype of glomus tumor with an overall architectural resemblance to a diffuse vascular malformation (so-called angiomatosis), but containing nests of glomus cells investing vessel walls. Symplastic glomus tumors show striking nuclear atypia in the absence of any other features indicative of malignancy (e.g. large size, deep location, mitotic activity, necrosis).
The diagnosis of malignant glomus tumor should be reserved for tumors showing either marked nuclear atypia (with any level of mitotic activity) or atypical mitotic figures. A component of pre-existing benign-appearing glomus tumor is often present. There are two types of malignant glomus tumor: one resembling a leiomyosarcoma or fibrosarcoma and the other resembling a primitive round cell tumor. Immunohistochemical demonstration of SMA and pericellular collagen IV is required for this diagnosis in the absence of a clear-cut benign precursor. Glomus tumors not fulfilling the criteria for malignancy but having at least one atypical feature other than nuclear pleomorphism are designated as being of uncertain malignant potential. Although glomus tumors of > 2 cm in size and deep location were previously considered malignant, subsequent experience suggests that these have uncertain malignant potential. An infiltrative growth pattern, high cellularity, and spindled morphology are also features significantly more common in malignant glomus tumors and glomus tumors of uncertain malignant potential.
Glomus tumors of all types typically express SMA and MSA and have abundant pericellular production of collagen IV. Staining for h-caldesmon is also positive, whereas CD34 expression is focal or absent. BRAF p.Val600Glu expression is seen in the BRAF-mutated molecular subset.

Not clinically relevant

Typical glomus tumors, glomuvenous malformations, and symplastic glomus tumors are benign. Malignant glomus tumors are aggressive, with metastases and death from disease in as many as 40% of patients. Some large, visceral glomus tumors without other atypical features (uncertain malignant potential) have behaved aggressively. The natural history of histologically malignant glomus tumors in the skin may be favorable, although more data are needed.

Detection of NOTCH gene rearrangements and/or BRAF mutations by various molecular strategies can be helpful, especially in malignant examples. BRAF p.Val600Glu mutations have been detected in 6% of glomus tumors, all either malignant or of uncertain malignant potential. BRAF is a potential therapeutic target in patients with progressive disease.

Essential: monomorphic round to epithelioid cells with centrally placed, round nuclei and well-defined cell borders, arranged in perivascular nests; malignant glomus tumors usually may be recognized by an adjacent benign component and show either a spindle or round cell sarcomatous phenotype; in malignant examples lacking a benign component, immunohistochemistry and/or molecular diagnosis is required for definitive diagnosis.

Desirable: immunohistochemical expression of SMAs, h-caldesmon, and collagen IV; NOTCH gene rearrangements are commonly present in malignant cases.