Glomus Tumor

                                   Dr. KS Dhillon

Introduction

Glomus tumors are rare soft-tissue neoplasms of the neuromyoarterial glomus body. The normal glomus body is located in the stratum reticulare throughout the body but is more concentrated in the digits [1]. Glomus tumors account for approximately 2% of all soft-tissue tumors in the extremities [2,3]. They typically present in adults between the ages of 20-40 years as small, blue-red papules or nodules on the distal extremities. Most cases involve the subungual sites. These tumors are painful and they often cause paroxysmal pain in response to temperature changes especially cold. There is pain when pressure is applied on the tumor.

Glomus tumors are thought to arise from the glomus body or the Sucquet-Hoyer canal, a thermoregulatory arteriovenous shunt composed of modified smooth muscle cells [4,5]. Glomus tumors usually occur in areas with high concentrations of glomus bodies and that includes subungual regions of the fingers and the deep dermis of the palm, forearm, and sole of the foot. The subcutaneous nodules may be purple, red, or blue depending on the depth of the tumor. Most of the lesions are solitary and are localized to cutaneous sites.

Glomuvenous malformations (GVMs), formerly known as glomangiomas, were once considered as a subset of glomus tumors. GVMs are now widely considered to be unrelated to glomus tumors. Their pathogenesis is different in clinical as well as histopathologic features. The majority of glomus tumors are benign but malignant tumors have also been rarely reported. The malignant tumors are typically locally invasive. Malignant glomus tumors are deep-seated, larger than 2 cm, and have atypical features [6]. Metastases are very rare. [6-10].

Pathophysiology

The important role played by glomus bodies is in thermoregulation via arteriovenous shunting. The glomus body is made up of an afferent arteriole, anastomotic vessel also known as the Sucquet-Hoyer canal, a primary collecting vein, intraglomerular reticulum, and a capsular portion. These arteriovenous anastomoses are concentrated in the reticular dermis of the fingers.

Glomus tumors are hamartomatous proliferations of modified smooth muscle cells originating from preexisting normal glomus cell population. There are three components of most glomus tumors and that include glomus cells, vasculature, and smooth muscle cells. Solid glomus tumor is the most common type of glomus tumor. It is characterized by a prominent smooth muscle cell component [11]. 

Glomus tumors are usually found on the hands and fingers. These tumors, however, can have a wide anatomic distribution, including sites not known to contain glomus cells, such as deep soft tissues, nerve, bone, as well abdominal viscera. Gastric glomus tumors account for approximately 2% of benign gastric tumors [12]. These tumors can arise from perivascular cells or pluripotent mesenchymal cells. 

The majority of glomus tumors are solitary and sporadic. There may be an epidemiologic relationship between glomus tumors and neurofibromatosis, which often produces subungual glomus tumors [13-15].  Glomuvenous malformations (GVMs) differ clinically from glomus tumors in that they occur more often in children and adolescents, are usually multifocal, and they do not have a predilection for subungual sites. GVMs are often hereditary and painless.

GVMs and glomus tumors have different etiologies. GVMs resemble venous malformations and contain more dilated venous channels than glomus tumors.

Most cases of GVM are sporadic though familial cases with autosomal dominant inheritance patterns have also been described. 

Glomus tumors can undergo malignant transformation. Malignant glomus tumors can arise de novo as well. Malignant glomus tumors are known as glomangiosarcomas. Glomangiosarcomas have a high local recurrence rate but very low metastasis rate [ 6, 7,8,16,17,18,19,20,21].

 The glomus tumor is sensitive to chemotherapy against the oncogenic BRAF. Glomus tumors have been found to have BRAF mutations. This suggests that this may be a marker of malignant potential and/or a therapeutic target. 

Etiology

Proliferation of glomus cells in the glomus body leads to the production of neoplasms called glomus tumors. The initiating event for glomus cell proliferation is not known. Some authors have postulated that trauma induces solitary subungual glomus tumors. This theory, however, has not been well studied.

Most glomuvenous malformations are inherited in an autosomal dominant pattern. Most hereditary GVMs are associated with defects in the glomulin gene (GLMN) that is located on chromosome 1 [22-24]. 

Epidemiology

Glomus tumors account for 1-5% of all soft-tissue tumors of the upper extremity. Most cases occur in the nail bed [25]. However, the true incidence of glomus tumors could be even higher since the diagnosis is often missed. They are often misdiagnosed as hemangiomas or venous malformations.

Glomuvenous malformations are much less common than glomus tumors [24]. Such malformations are seen more often in children, with the majority of patients reporting a positive family history.

There is an epidemiologic relationship between glomus tumors and neurofibromatosis, that most often produces subungual glomus tumors [13,  14,15].

There is no sex predilection among patients with glomus tumors. However, solitary subungual lesions are more commonly seen in women and multiple lesions are more common in men [5,26,27].

Glomus tumors can occur at any age. They occur predominantly in young adults between the ages of 20-40 years. They have also been reported to be frequent in older adults between the ages of 40-70 years [4]. GVMs are quite often multifocal and typically are present at birth or early in life.

Prognosis

The prognosis for patients with glomus tumors is usually excellent. Excision of the painful lesions usually results in a cure. The recurrence rate for solitary lesions is low [28,29]. With subungual glomus tumors, the most common complications are recurrence and nail deformity. Recurrence will require repeat wide excision [5]. Infection due to rupture of a subungual glomus tumor has been reported [30]. 

Malignant glomus tumors usually infiltrate aggressively. They should be treated with wide excision to prevent local recurrence. A study of malignant glomus tumors of the head and neck reported a recurrence rate of 45% [17]. Metastases have been described and are associated with a poor prognosis [6,7,8,16].

Systemic effects of glomus tumors are rare. In one report, a patient with more than 400 glomus tumors developed thrombocytopenia as a result of platelet sequestration [31]. 

Clinical presentation

History

Patients with solitary glomus tumors usually have paroxysmal pain. The pain can be severe and it is exacerbated by pressure or temperature changes, especially cold. The classic triad of symptoms of glomus tumors includes severe pain, with pinpoint localization, and cold hypersensitivity. Glomus tumors are classically red, blue, or purple. Skin-colored glomus tumors have also been reported. 

Glomuvenous malformations (GVMs) are usually less painful than glomus tumors. However, they may become more painful with menstruation or pregnancy. In the absence of pain, glomus tumors should still be considered in the differential diagnosis of nodules, even in uncommon locations such as the mouth [32,33]. Glomus tumors have also been reported to result in various nail changes, including color change, erythronychia, splitting, and thickening of the nail bed [34]. 

Multiple glomus tumors are inherited as an autosomal dominant condition, hence, a family history of similar lesions may be useful for the diagnosis.

Besides the cutaneous sites, glomus tumors have been reported in extracutaneous sites such as the gastrointestinal tract, liver, pancreas, kidney, trachea, nerve, bone, mediastinum, and ovary [35-38]. A primary pulmonary glomus tumor in a segmental bronchus can manifest as obstructive pneumonia [39]. Glomus tumor can produce a liver mass [40] Gastric glomus tumor can cause upper gastrointestinal bleeding [41]. 

Physical Examination

Solitary glomus tumors have the following characteristics:

• Red or blue blanchable papules or nodules in deep dermis or subcutis

• Acral location, most commonly subungual

• Usually smaller than 2 cm

Glomuvenous malformation (GVM) can be subdivided into the following forms:

• Regional variant - Consists of purple to blue partially compressible papules or nodules that are grouped with a cobblestone-like appearance and are limited to a specific area, most often on an extremity

• Disseminated type - Consists of multiple lesions distributed over the body with no specific grouping; less common than the regional variant

• Congenital plaque-like glomus tumors - Consist of either grouped papules that coalesce to form indurated plaques or clusters of discrete nodules; rarest variant

There are three useful findings for diagnosing solitary painful glomus tumors (especially those under a nail) [42-44]: 

• Love test (>90% sensitivity) - Pressure on the suspected areas with a pencil tip or pinhead produces exquisite localized pain.

• Hildreth sign (>90% sensitivity) - Reduction of pain and tenderness with the Love test by inducing transient ischemia with a tourniquet. 

• Cold sensitivity test - Immersing the affected area in cold water elicits severe pain around the lesion.

Features of malignant glomus tumors or glomangiosarcomas include the following [6]:

• Growth larger than 2 cm

• Rapid growth

• Involvement of deeper soft-tissue

Differential Diagnoses

• Blue Nevi- Two clinically recognized variants of blue nevus exist. They are the common blue nevus and the cellular blue nevus.

• Blue Rubber Bleb Nevus Syndrome- This is a rare condition that is characterized by numerous malformations of the venous system that significantly involve the skin and visceral organs.

• Dermatologic Manifestations of Kaposi Sarcoma(KS)- There are 4 types of KS. HHV-8 has been linked convincingly with all 4 types. Immunosuppression appears to be a significant cofactor.

• Dermatologic Manifestations of Neurilemmoma (Schwannoma)- A neurilemmoma, also known as schwannoma, neurolemmoma, and peripheral fibroblastoma, is a benign, encapsulated neoplasm derived from Schwann cells.

• Eccrine Spiradenoma-Eccrine spiradenoma is an uncommon benign tumor of skin adnexa originating from eccrine glands. It usually appears as a single nodule, but can rarely also appear as multiple nodules, and be distributed as a linear form or zosteriform. 

• Fibroma- A noncancerous (benign) tumor or growth consisting of fibrous, connective tissue.

• Hemangioma- A benign vascular tumor derived from blood vessel cell types.

• Leiomyoma- Benign soft-tissue neoplasms that arise from smooth muscle.

• Maffucci Syndrome- An extremely rare disorder characterized by benign overgrowths of cartilage (enchondromas), skeletal deformities, and cutaneous lesions composed of abnormal blood vessels.

• Mucoid cysts- They are thin sacs that contain clear fluid. They are usually smooth or shiny in appearance and bluish-pink in color. The cysts can vary in size.

• Subungual exostosis- They are benign osteocartilaginous tumors that occur beneath the nail bed.

• Venous Malformations- They are developmental errors composed of dysmorphic channels lined by flattened endothelium exhibiting slow turnover. They present in various ways, from a vague blue patch to a soft blue mass.

Laboratory Studies

Laboratory studies are not helpful in patients with glomus tumors. The rare exception is patients with widely disseminated lesions in which platelet sequestration can occur. In such patients, a complete blood cell count is useful.

Imaging Studies

Imaging may be useful in making a diagnosis of glomus tumors [45]. 

Plain radiography can reveal bony erosions, especially in patients with subungual lesions. Radiography may not be useful in a large percentage of cases [46]. Ultrasonography, especially color-duplex ultrasonography, has a high detection rate and no false-negative results. Ultrasonography can detect glomus tumors as small as 2 mm [47-49]. 

MRI can be particularly useful for the detection of multiple tumors [50,51] and in cases where the diagnosis is in question [28]. High-resolution MRI has proven to be useful as well [52,53] and can be particularly useful in delineating the relationship of subungual tumors to surrounding structures during pretreatment planning [54].

Histologic Findings

Glomus tumors and glomuvenous malformations have distinct histopathologic features. The World Health Organization classifies glomus tumors based on their predominance of glomus cells, vascular structures, and smooth muscle cells. They classify them as solid glomus tumors (most common, glomus cell prominence), glomangioma (vascular cell prominence), and glomangiomyoma (vascular and smooth muscle cell prominence).

Solitary lesions are solid, well-circumscribed nodules surrounded by a rim of fibrous tissue. They contain endothelium-lined vascular spaces that are surrounded by clusters of glomus cells. The glomus cells are monomorphous, round, or polygonal with plump nuclei and scant eosinophilic cytoplasm. 

GVMs, formerly known as glomangiomas, are less well-circumscribed and less solid appearing. When the lesions are multiple their overall appearance is that of a hemangioma. They contain multiple irregular, dilated, endothelium-lined vascular channels with red blood cells in them. The vascular spaces are usually larger than those in a solitary glomus tumor. Small aggregates of glomus cells are present in the walls of these channels as well as in small clusters in the adjacent stroma. Glomangiosarcomas resemble benign glomus tumors but they have more atypia, pleomorphism, and mitotic figures, and they have a locally invasive growth pattern. 

Glomus cells can be epithelioid in appearance. They are immunoreactive with markers for a-smooth muscle actin (aSMA), muscle-specific actin (MSA), and h-caldesmon. The tumors also have abundant type IV collagen. These markers are useful in distinguishing glomus tumors from hemangiomas. The glomus tumors are distinct from paragangliomas, which are positive for S100 [4,17]. 

Treatment

Symptomatic solitary glomus tumors are treated by total surgical excision [55]. Other treatment modalities include laser and sclerotherapy. In the case of solitary glomus tumors, complete removal of the tumor capsule is recommended to relieve pain and minimize the risk of recurrence.

Most subungual lesions are treated with total nail avulsion followed by excision. Several additional techniques have been described that include a straightforward excision using a nail bed margin approach [56], a trap-door technique [57], and a technique described by Lee et al designed to conserve the nail plate itself [58]. In the transungual approach, the nail plate is removed, the tumor excised, and the nail bed is repaired. A lateral subperiosteal approach has also been described. This technique may have a higher risk of incomplete excision. 

The recurrence rates after removal of subungual glomus tumors have been reported to be between 2-13% (highest reported at 50%). Nail bed deformity rates are between 0-19% [5,55,58,59,60,61].

Recurrence can be due to incomplete excision or the development of a new lesion. The probability of recurrence of glomus tumors is highest for subungual glomus tumors.

Glomus tumors that are located in the nail matrix or are skin-colored have a higher incidence of recurrence. The use of preoperative MRI or ultrasound studies in preoperative planning is associated with a lower incidence of recurrence [59]. 

Multiple glomus tumors are more difficult to excise because of their poor circumscription and a large number of lesions. Other treatment modalities that are more useful in treating multiple lesions include argon, carbon dioxide, or Nd: YAG laser therapy, as well as sclerotherapy [62-65. 

Wide local excision remains the treatment of choice for the treatment of glomangiosarcomas. Follow-up is important for malignant glomus tumors to detect local recurrence. 

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