Glomus Tumors

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Background

Glomus tumors are rare soft-tissue neoplasms originating from the glomus body (see the image below).[1]  The glomus body is a neuromyoarterial apparatus composed of vascular structures, nerve cells, and smooth-muscle cells. The glomus body is responsible for thermoregulation.



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Glomus tumor.

Glomus bodies are found in the dermis throughout the body, with the highest concentrations in the hands and feet. Glomus tumors most frequently occur in those locations, including subungual regions of the fingers and the deep dermis of the hand (palm), forearm, and foot (sole). Most lesions are solitary.

Glomus tumors typically present in adults (ages 20-40 y) as small papules or nodules of the distal extremities, with most cases involving subungual sites.[2] The subcutaneous nodules may be red, purple, or blue depending on their depth.

Pain is the usual presenting symptom of a glomus tumor.  Patients may report paroxysmal pain in response to temperature changes (especially cold) or pressure. However, the classic triad of point tenderness, pain, and sensitivity to cold is not always found.

Local soft-tissue tenderness and thickening may be present. A mass is sometimes detectable in the area of tenderness. On clinical examination, a positive result with the Love test and the Hildreth sign suggest the diagnosis. See Presentation for more detail.

Because the diagnosis of glomus tumor is primarily clinical, laboratory workup usually is not needed. If the diagnosis is uncertain in view of the patient's history and physical findings, imaging studies are warranted.

Surgical excision of the tumor is the mainstay of treatment. Pain relief should be provided until the procedure is performed. Excision should be limited to symptomatic lesions. Sclerotherapy and laser treatment have been used to destroy the tumor as therapeutic alternatives to surgical excision.

Pathophysiology

Glomus bodies play an important role in thermoregulation via arteriovenous shunting. The glomus body is composed of an afferent arteriole, anastomotic vessel (termed Sucquet-Hoyer canal), primary collecting vein, intraglomerular reticulum, and a capsular portion. These specialized arteriovenous anastomoses are particularly concentrated in the reticular dermis of the fingers.

Glomus tumors are thought to represent hamartomatous proliferations of modified smooth muscle cells originating from preexisting normal glomus cell populations. The three components of most glomus tumors include glomus cells, vasculature, and smooth muscle cells. The most common type of glomus tumor is the solid glomus tumor, characterized by a prominent smooth muscle cell component.[3] No evidence of mitosis is observed in the structure.

While glomus tumors predominate on the hands and fingers, these tumors can occur in a wide anatomic distribution, including sites not known to contain glomus cells, such as deep soft tissues, nerve, bone, and abdominal viscera. In fact, gastric glomus tumors account for approximately 2% of benign gastric tumors.[4] These tumors may arise from perivascular cells or pluripotent mesenchymal cells capable of differentiating into glomus cells.

Most glomus tumors are solitary and sporadic. However, glomus tumors have been reported in 5% of patients with neurofibromatosis type 1. In these cases the tumors are most often subungual and are often multiple; the presence of such tumors may be an important clue to the diagnosis of neurofibromatosis.[5]

A distinct but related condition known as glomuvenous malformations (GVMs) differ clinically from glomus tumors in that they occur more often in children and adolescents, are typically multifocal, and do not have a predilection for subungual sites. GVMs are more likely to be hereditary and painless. GVMs are thought to have different etiologies from glomus tumors, with GVMs resembling venous malformations and containing more dilated venous channels than glomus tumors.

Cases of GVM may be sporadic, but familial cases with autosomal dominant inheritance have also been described. The familial GVM trait has been mapped to 1p21-22 and is thought to result from loss-of-function mutations in the cytoplasmic protein glomulin.[6, 7, 8]

Rarely, glomus tumors can undergo malignant transformation or malignant glomus tumors can arise de novo. Malignant glomus tumors are termed glomangiosarcomas; they have a high local recurrence rate but very low rate of metastasis. Most reported cases have been in the abdominal viscera or lower extremity.[9, 10, 11, 12, 13, 14, 15, 16, 17, 18]

Findings in malignant glomus tumors have included the following[18] :

BRAF mutations have been found in glomus tumors with malignant histologic characteristics, suggesting that this may be a marker of malignant potential and/or a therapeutic target. However, further study is needed.[19]

Etiology

Glomus tumors are neoplasms caused by a proliferation of glomus cells, which make up a portion of the glomus body. The initiating event for glomus cell proliferation is unknown. Some authors have postulated that trauma induces solitary subungual glomus tumors, although this theory is not well studied.

Familial glomuvenous malformations (GVMs) are inherited in an autosomal dominant pattern with incomplete penetrance. Most hereditary GVMs are associated with defects in the glomulin gene (GLMN) located on chromosome 1.[6, 7, 8]

Epidemiology

Frequency

Glomus tumors account for 1-5% of all soft-tissue tumors of the upper extremity, occurring in most cases in the nail bed[2] ; however, the true incidence of glomus tumors could be even higher, likely as a result of misdiagnosis of many of these lesions as hemangiomas or venous malformations.

Glomuvenous malformations (GVMs) are much less common than glomus tumors.[8] GVMs are seen more frequently in children, with many patients reporting a positive family history.

Sex

Glomus tumors in general show no sex predilection; however, solitary subungual lesions are more commonly observed in women and multiple lesions are slightly more common in men.[20, 21, 22]

Age

Solitary glomus tumors can occur at any age. While previously thought to occur predominantly in young adults (ages 20-40 y), they have also been reported to be frequent in older adults (ages 40-70 y).[23] GVMs are often multifocal and typically are present at birth or early in life.

Prognosis

The prognosis for patients with glomus tumors is excellent. Excision of painful lesions most often results in cure, with a low recurrence rate for solitary lesions.[24, 25] With subungual glomus tumors, the most important complications are recurrence and nail deformity; recurrence requires repeat wide excision.[20] If the tumor extends into the germinal matrix of the nail bed, it may affect nail growth. Additionally, one case report describes infection due to rupture of a subungual glomus tumor.[26]

Malignant glomus tumors are usually locally infiltrative/aggressive. Their overall prognosis is good if they are treated with wide excision; otherwise, there is a risk of local recurrence. For example, a study of malignant glomus tumors of the head and neck that included a literature review and single-institution experience reported recurrence in 45% of patients.[13] While extremely rare, metastases have been described and are associated with a poor prognosis.[9, 10, 11, 12]

History

Patients with solitary glomus tumors usually have paroxysmal pain, which can be severe and can be exacerbated by pressure or temperature changes, especially cold. The classic triad of symptoms comprises severe pain, with pinpoint localization, and cold hypersensitivity. 

Glomus tumors are classically red, blue, or purple (see the image below). However, skin-colored glomus tumors have been reported; this may delay diagnosis and complicate excision. 

 



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Glomus tumor.

Glomuvenous malformations (GVMs), which may be multiple, are typically less painful than glomus tumors. However, they may become more painful with menstruation or pregnancy. 

While glomus tumors are most often found on the hand, the presence of characteristic symptoms should raise suspicion for glomus tumor in other locations, for example in the thigh or lower limb.[27] In the absence of pain, glomus tumor should still be considered in the differential diagnosis of nodules, even in uncommon locations such as the mouth.[28, 29] Additionally, subungual glomus tumors  have been reported to result in various nail changes, including color change, erythronychia, splitting, and thickening of the nail bed.[30] Therefore, any subungual nodule causing color and/or nail change should raise suspicion for glomus tumor. Rupture of a subungual glomus tumor has been reported.[26]

Patients with multiple lesions (see the image below) often seek medical attention because they are worried or have cosmetic concerns. Because multiple glomus tumors are inherited as an autosomal dominant condition, a family history of similar lesions may be helpful for diagnosis. However, multiple glomus tumors may also be a presenting feature of neurofibromatosis type 1.[5]

 



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Multiple glomus tumors.

Extracutaneous sites have been reported, including involvement of the gastrointestinal tract, trachea, nerve, bone, mediastinum, liver, pancreas, kidney, and ovary.[31, 32, 33, 34, 35] Cases of benign and malignant glomus tumors of the kidney have been reported.[12, 36, 37] Pulmonary glomus tumors have been reported, in patients presenting with obstructive pneumonia or cough and hemoptysis.[38, 39] A case report describes upper gastrointestinal bleeding due to a gastric glomus tumor.[40]

Physical Examination

Solitary glomus tumors have the following characteristics:

Local soft-tissue tenderness and thickening may be present. A mass is sometimes detectable in the area of tenderness. Subungual tumors may be associated with deformity of nail growth. 

Three useful findings for diagnosing glomus tumors, particularly solitary painful glomus tumors (especially those under a nail), are the following[41, 42, 43] :

If those findings are present, ultrasound or magnetic resonance imaging can be used to confirm the diagnosis.[44]

Features of malignant glomus tumors (glomangiosarcomas) may include the following[9] :

Glomuvenous malformation (GVM) is subdivided into regional or localized, disseminated, and congenital plaquelike forms, as follows:

Laboratory Studies

Routine laboratory studies are not helpful in patients with glomus tumors. The rare exception would be in a patient with widely disseminated lesions in which platelet sequestration is a concern. In such a case, a complete blood cell count is indicated.[45]

Imaging Studies

While the diagnosis of a glomus tumor is often made based on clinical presentation and histologic findings, imaging may prove useful,[46] especially in cases in which the diagnosis is in doubt. Imaging can also be useful in planning for excision.

Dermoscopy may play a useful role in the diagnosis of subungual glomus tumors, in particular through better detection of ramified vessels in bluish spots.[47]

Plain radiography may reveal bony erosions, especially in the case of subungual lesions. However, radiography may not be sensitive in a large percentage of cases.[48]

Ultrasonography, especially color-duplex ultrasonography, has a high detection rate and no false-negative results, at least in one series; additionally, ultrasonography can detect glomus tumors as small as 2 mm.[49, 50, 51] Ultrasound may be a particularly useful tool for exploring tumors involving the nail, with glomus tumors often visualized as small, solid, hypoechoic or isoechoic nodules with hypervascularity on Doppler.[52] In one small study, ultrasound findings suggested the diagnosis of glomus tumors in patients who had only cold sensitivity or local tenderness on physical examination, and had no abnormalities on computed tomography or magnetic resonance imaging (MRI).[53]

MRI may be particularly useful for the detection of multiple tumors[54, 55] or in cases in which the diagnosis or specific location of the lesion is in question.[24] High-resolution MRI can be particularly helpful in delineating the relationship of subungual tumors to surrounding structures during pretreatment planning.[48, 56] Although the positive predictive value of MRI for glomus tumor has been found to be high, the negative predictive value is low.[57]  Mundada et al provide a detailed review of nail tumors and the use of MRI in diagnosis and management.[56]

Magnetic resonance angiography (MRA) is especially helpful in diagnosing small lesions that may be missed with other imaging studies.[58, 59]

Histologic Findings

Solitary glomus tumors and glomuvenous malformations (GVMs) have distinct histopathologic features. The World Health Organization classifies glomus tumors based on their predominance of glomus cells, vascular structures, and smooth muscle cells, as follows[60] :

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



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Glomus tumor (4X). The tumor is composed of uniformly round, small, glomus cells with pale eosinophilic cytoplasm associated with conspicuous vasculat....



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Glomus tumor (10X).

GVMs are less well circumscribed and appear less solid than their solitary counterparts. Multiple lesions have the overall appearance of a hemangioma. They contain multiple irregular, dilated, endothelium-lined vascular channels that contain red blood cells. The vascular spaces are larger than those in a solitary glomus tumor. Small aggregates of glomus cells are present in the walls of these channels and in small clusters in the adjacent stroma. Multiple glomus tumors have more narrow and focal aggregates of glomus cells than solitary lesions. The overall appearance of multiple glomus tumors accounts for their alternate name, glomangiomas. Note the images below.



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Glomangioma (2X). In this variant, blood vessels predominate.



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Glomangioma (10X). Note the typical small, round glomus cells, often distributed in a monolayer or bilayer within the vessel walls.

Glomangiosarcomas (malignant glomus tumors) resemble benign glomus tumors. However, glomangiosarcomas have more atypia, pleomorphism, and mitotic figures, and they have a locally invasive growth pattern. Most often, malignant lesions are correlated with foci of benign glomus tumor. However, glomangiosarcomas may also arise de novo.

While 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. Glomus tumors also have abundant type IV collagen. These markers can be useful in distinguishing glomus tumors from hemangiomas. It is also important to note that glomus tumors are distinct from paragangliomas, which are positive for S100.[23, 13]

Surgical Care

The treatment of choice for symptomatic solitary glomus tumors is total surgical excision,[61] which is curative. While various other treatment modalities have been reported, including laser ablation and sclerotherapy, in the case of solitary glomus tumors, complete removal of the tumor capsule is recommended to relieve pain and minimize risk for recurrence.

Most subungual lesions are treated with total nail avulsion followed by excision. However, several additional techniques have been described, including nail-preserving techniques such as the following[62]  :

Pain relief is usually immediate after surgical excision. If symptoms persist after 3 months or recur, exploration should be repeated.

Recurrence rates of subungual glomus tumors after surgical excision have generally ranged from 2-13% (highest reported at 50%), while rates of nail bed deformity have been reported to be 0-19%.[20, 61, 64, 67, 68, 69]  Recurrence can be due to incomplete excision or development of a new lesion, with the probability of recurrence of glomus tumors in general being highest for subungual glomus tumors.

Glomus tumors that are skin-colored or located in the nail matrix have a higher incidence of recurrence. However, the use of preoperative MRI or ultrasound studies in preoperative planning is associated with a lower incidence of recurrence and may be helpful in these cases.[67]

For glomus tumors of the distal phalanx in which considerable erosion of the bone has occurred, Ge et al reported that satisfactory outcomes may be achievable by means of Kirschner wire (K-wire) fixation followed by autogenous bone grafting.[70]

For multiple glomus tumors, excision may be more difficult because of their poor circumscription and the large number of lesions. Excision should be limited to symptomatic lesions. Other reported treatment modalities that are more useful in treating multiple lesions, include argon, carbon dioxide, or Nd:YAG laser therapy, as well as sclerotherapy with hypertonic saline or sodium tetradecyl sulfate.[71, 72, 73, 74]

The treatment recommendations for glomangiosarcoma are based on a few case reports. Wide local excision remains the treatment of choice. In a case report of malignant glomus tumors involving the brachial plexus, which were incompletely resected because of potential morbidity, the glomus tumor was found to be sensitive to BRAF kinase inhibitor therapy with dabrafenib and trametinib, which led to moderate reduction in tumor size.[15]

Follow-up is important, especially for malignant glomus tumors. One case report highlighted a patient with multiple episodes of local recurrence of malignant glomus tumor treated with excision over a period of 40 years.[75]

Author

Vernon J Forrester, MD, FAAD, FACMS, Faculty, Department of Dermatology, Division of Micrographic Surgery & Dermatologic Oncology, Southeastern Skin Cancer and Dermatology

Disclosure: Nothing to disclose.

Coauthor(s)

Jacqueline S Stevens, PhD, University of Virginia School of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

Christen M Mowad, MD, Professor, Department of Dermatology, Geisinger Medical Center

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Erin L Spillane, MD, Staff Dermatologist, Department of Dermatology, Womack Army Medical Center

Disclosure: Nothing to disclose.

Jon H Meyerle, MD, Assistant Professor, Department Dermatology, Uniformed Services University of the Health Sciences; Assistant Professor, Department of Dermatology, Johns Hopkins University School of Medicine; Chief, Immunodermatology, Walter Reed National Military Medical Center

Disclosure: Nothing to disclose.

Seema N Varma, MD, Attending Physician, Division of Hematology and Oncology, Department of Medicine, Sanford R Nalitt Institute for Cancer and Blood Related Diseases, North Shore-Long Island Jewish Health System/Staten Island University Hospital; Hospice Medical Director, University Hospice, Staten Island University Hospital

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors Omar P. Sangueza, MD, and Michael B. Reynolds, MD, to the original writing and development of this article.

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Glomus tumor.

Glomus tumor.

Multiple glomus tumors.

Glomus tumor (4X). The tumor is composed of uniformly round, small, glomus cells with pale eosinophilic cytoplasm associated with conspicuous vasculature.

Glomus tumor (10X).

Glomangioma (2X). In this variant, blood vessels predominate.

Glomangioma (10X). Note the typical small, round glomus cells, often distributed in a monolayer or bilayer within the vessel walls.

Glomus tumor.

Multiple glomus tumors.

Glomus tumor (4X). The tumor is composed of uniformly round, small, glomus cells with pale eosinophilic cytoplasm associated with conspicuous vasculature.

Glomus tumor (10X).

Glomangioma (2X). In this variant, blood vessels predominate.

Glomangioma (10X). Note the typical small, round glomus cells, often distributed in a monolayer or bilayer within the vessel walls.