Dermatologic Manifestations of Glomus Tumor

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Background

Glomus tumors are rare soft-tissue neoplasms of the neuromyoarterial glomus body that account for approximately 2% of all soft-tissue tumors in the extremities.[1, 2] They typically present in adults (ages 20-40 y) as small, blue-red papules or nodules of the distal extremities, with most cases involving subungual sites. These tumors are characteristically painful, often causing paroxysmal pain in response to temperature changes (especially cold) or pressure.

Note the images below.



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Glomus tumor.



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Multiple glomus tumors.

Glomus tumors are thought to arise from the glomus body or Sucquet-Hoyer canal, a thermoregulatory arteriovenous shunt composed of modified smooth muscle cells.[3, 4] Glomus tumors most frequently occur in areas with high concentrations of glomus bodies, including subungual regions of the fingers and the deep dermis of the hand (palm), forearm, and foot (sole). The subcutaneous nodules may be red, purple, or blue depending on their depth. Most lesions are solitary and localized to cutaneous sites.

Glomuvenous malformations (GVMs), formerly known as glomangiomas, have also been described. While once considered a subset of glomus tumors, GVMs are now widely considered to be unrelated in pathogenesis given their differences in clinical and histopathologic features. While the vast majority of glomus tumors are benign, malignant cases have been rarely reported, with such cases typically being locally invasive. Malignant glomus tumors are more likely to be deep, larger than 2 cm, and have atypical features.[5] Metastases are exceedingly rare.[5, 6, 7, 8, 9]

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.[10]

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.[11] These tumors may arise from perivascular cells or pluripotent mesenchymal cells capable of differentiating into glomus cells.

Most glomus tumors are solitary and sporadic. An epidemiologic relationship may exist between glomus tumors and neurofibromatosis, which most often produces subungual glomus tumors.[12, 13, 14] 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.

It is thought that GVMs and glomus tumors have different etiologies, with GVMs resembling venous malformations and containing more dilated venous channels than glomus tumors.

Note that most cases of GVM are sporadic; however, familial cases with autosomal dominant inheritance patterns have also been described. Such familial GVMs have been mapped to 1p21-22 and are thought to result from loss-of-function mutations in the cytoplasmic protein glomulin.[15, 16, 17, 18]

Rarely, glomus tumors can undergo malignant transformation or malignant glomus tumors can arise de novo. Malignant glomus tumors are termed glomangiosarcomas; glomangiosarcomas have a high local recurrence rate but very low rate of metastasis.[5, 6, 7, 19, 20, 21, 22, 23, 24] One case report describes a glomangiosarcoma that occurred at a prior biopsy site of a lower extremity, perhaps due to local recurrence of glomangiosarcoma and/or malignant transformation.[25] In one rare case of malignant glomus tumor involving the brachial plexus, excision was foregone owing to potential morbidity, and the glomus tumor was found to be sensitive to chemotherapy against the oncogenic BRAF, with resultant moderate reduction in tumor size.[22] In fact, other glomus tumors have also been found to have BRAF mutations, suggesting this may be a marker of malignant potential and/or a therapeutic target, although further study is needed.[26]

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.

Most 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.[15, 16, 17]

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[27] ; 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.[17] Such cases are seen more frequently in children, with the majority of patients reporting a positive family history.

An epidemiologic relationship may exist between glomus tumors and neurofibromatosis, which most often produces subungual glomus tumors.[12, 13, 14]

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.[4, 28, 29]

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).[3] 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.[30, 31] With subungual glomus tumors, the most important complications are recurrence and nail deformity; recurrence requires repeat wide excision.[4] Additionally, one case report describes infection due to rupture of a subungual glomus tumor.[32]

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 2017 study of malignant glomus tumors of the head and neck reports recurrence in 45% of patients.[20] While extremely rare, metastases have been described and are associated with a poor prognosis.[5, 6, 7, 19]

Patients with glomus tumors classically present with paroxysmal severe pain, often precipitated by cold, pressure, or dependency. Pain is more common in solitary lesions. The multiple tumors of glomuvenous malformations (GVMs) arise in younger patients and tend to be asymptomatic.

Systemic effects of glomus tumors are rare; however, in one report, a patient with more than 400 glomus tumors developed thrombocytopenia as a result of platelet sequestration.[33]

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 includes severe pain, with pinpoint localization, and cold hypersensitivity. While glomus tumors are classically red, blue, or purple, skin-colored glomus tumors have been reported and may delay diagnosis and complicate excision. Glomuvenous malformations (GVMs) 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.[34] 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.[35, 36] Additionally, subungual glomus tumors have been reported to rupture[32] and have also been reported to result in various nail changes, including color change, erythronychia, splitting, and thickening of the nail bed.[37] Therefore, any subungual nodule causing color and/or nail change should raise suspicion for glomus tumor.

Patients with multiple lesions 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.

Extracutaneous sites have been reported, including involvement of the gastrointestinal tract, trachea, nerve, bone, mediastinum, liver, pancreas, kidney, and ovary.[38, 39, 40, 41, 42] Cases of benign and malignant glomus tumors of the kidney have been reported.[19, 43, 44] Pulmonary involvement was described in a case report of a primary pulmonary glomus tumor in a segmental bronchus manifesting as obstructive pneumonia.[45] More recently, a case of glomus tumor was reported to cause a liver mass[46] and another case of a gastric glomus tumor was reported to cause upper gastrointestingal bleeding.[47]

Physical Examination

Solitary glomus tumors have the following characteristics:

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

Three useful findings for diagnosing glomus tumors, particularly solitary painful glomus tumors (especially those under a nail), are the following[48, 49, 50] :

Features of malignant glomus tumors, or glomangiosarcomas, may include the following[5] :

Laboratory Studies

Routine laboratory studies are not helpful in patients with glomus tumors. The rare exception is in patients with widely disseminated lesions in which platelet sequestration is a concern. In these patients, a complete blood cell count is indicated.

Imaging Studies

While the diagnosis of a glomus tumor is often made based on clinical presentation and histologic findings, imaging may prove useful,[52] especially in cases in which the diagnosis is in doubt. Imaging can also be useful in planning for excision.

Plain radiography has been reported to reveal bony erosions, especially in the case of subungual lesions; however, radiography may not be sensitive in a large percentage of cases.[53] 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.[54, 55, 56] 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.[57] In one study, glomus tumors were excised from a number of patients with a solitary symptom of cold sensitivity and with only positive imaging findings on ultrasound (vs no findings on CT/MRI).[58]

MRI has also been studied and may be particularly useful for the detection of multiple tumors[59, 60] or in cases in which the diagnosis or specific location of the lesion is in question.[30] High-resolution MRI has proven useful as well[53, 61] and can be particularly helpful in delineating the relationship of subungual tumors to surrounding structures during pretreatment planning.[62] Mundada et al provide a detailed review of nail tumors and the use of MRI in diagnosis and management.[62]

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 solid glomus tumors (most common, glomus cell prominence), glomangioma (vascular cell prominence), and glomangiomyoma (vascular and smooth muscle cell prominence).

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, formerly known as glomangiomas, are less well circumscribed and less solid appearing 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.[3, 20]

Surgical Care

The treatment of choice for symptomatic solitary glomus tumors is total surgical excision,[63] which is curative. While various treatment modalities have been reported, to include laser 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, although several additional techniques have been described to include a straightforward excision using a nail bed margin approach,[64] a trap-door technique,[65] and a technique described by Lee et al designed to conserve the nail plate itself.[66] In the transungual approach, the nail plate is removed, the tumor excised, and the nail bed repaired. A lateral subperiosteal approach has also been described, but it may have a higher risk of incomplete excision. Removal of subungual glomus tumors has been reported to have recurrence rates of 2-13% (highest reported at 50%) and nail bed deformity rates of 0-19%.[4, 63, 66, 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 multiple glomus tumors, excision may be more difficult because of their poor circumscription and the large number of lesions. Other reported treatment modalities, 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.[70, 71, 72, 73]

The treatment recommendations for glomangiosarcoma are based on a few case reports. Wide local excision remains the treatment of choice. 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.[74]

Author

Vernon J Forrester, MD, Resident Physician, Department of Dermatology, UVA Health System, University of Virginia School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Barbara B Wilson, MD, Edward P Cawley Associate Professor, Department of Dermatology, University of Virginia School of Medicine

Disclosure: Nothing to disclose.

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

Disclosure: Nothing to disclose.

Richard Harold "Hal" Flowers, IV, MD, Resident Physician, Department of Dermatology, University of Virginia Health System

Disclosure: Nothing to disclose.

Specialty Editors

Michael J Wells, MD, FAAD, Dermatologic/Mohs Surgeon, The Surgery Center at Plano Dermatology

Disclosure: Nothing to disclose.

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

Abby S Van Voorhees, MD, Assistant Professor, Director of Psoriasis Services and Phototherapy Units, Department of Dermatology, University of Pennsylvania School of Medicine, Hospital of the University of Pennsylvania

Disclosure: Received honoraria from Amgen for consulting; Received honoraria from Abbott for consulting; Partner received salary from Merck for management position; Received honoraria from Abbott for speaking and teaching; Received honoraria from Amgen for review panel membership; Received honoraria from Centocor for consulting; Received honoraria from Leo for consulting; Received none from Merck for other.

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.

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.

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.