Classic Kaposi sarcoma

                              Dr. KS Dhillon

Introduction

Kaposi sarcoma (KS) is an indolent angio-proliferative spindle-cell tumor. It is derived from endothelial and immune cells infected with human herpes virus type 8 (HHV-8; also known as Kaposi sarcoma herpes virus [KSHV]). HHV-8 is the causative agent of KS. It is present in 95-98% of all cases [1]. There are 4 types of KS [2]:

• Epidemic (AIDS related)

• Iatrogenic (immunosuppressant therapy related)

• Classic, or sporadic

• Endemic (African)

• Nonepidemic

Nonepidermic KS occurs in men who have sex with men but have no evidence of HIV infection or immunodeficiency. These cases present in an indolent cutaneous form that resembles classic KS [3,4,5].

All types of KS have in common an infection with HHV-8. However, each has a distinct clinical course which is likely due to other factors, such as the extent and type of immune suppression [6]. The presentation of KS can range from minimal mucocutaneous disease to extensive organ involvement.

KS was first described in 1872 as a rare disease in Eastern European men. In the 1950s, an endemic form of KS was one of the most common neoplasms observed in central Africa, affecting men, women, and children. The cases in children occur due to maternal-child transmission of HHV-8 through saliva [6]. 

A surge in KS cases occurred just prior to the identification of the AIDS epidemic in the early 1980s. In the USA, AIDS-related KS is the most common KS presentation. The risk of KS in people living with HIV from 2009-2012 was 500-fold higher than for the US general population. KS accounts for 12% of cancers in people living with HIV. There are between  765 to 910 new cases per year in the US [7,8,9].

Following the AIDS epidemic, the incidence of KS in Africa increased markedly. From 1968 to 1970, KS accounted for 6.6% of all cancers occurring in men. From 1989 to 1991, KS became the most commonly reported cancer in men [10,11].

Iatrogenic KS cases have also increased. This is due to the greater use of immunosuppression in medical practice, especially in the post-transplant setting and treatment of autoimmune diseases [9].

Pathophysiology

In 1994 Kaposi sarcoma human herpes virus (KSHV) was discovered. This led to rapid progress in understanding the disease’s pathophysiology. Different epidemiologic and clinical presentations of the disease could be related to modifiable risk factors, such as uncontrolled HIV infection and immunosuppressive medications used in transplantation. 

Kaposi sarcoma is caused by an excessive proliferation of spindle cells that have an endothelial cell origin. The tumors are predominantly composed of KSHV genomic material with immunohistochemical markers of lymphoid, spindle, and endothelial cells. 

The cell of origin remains unknown. Increased endothelial factor VIIIa antigen, spindle cell markers such as smooth muscle alpha-actin, and macrophage markers such as PAM-1, CD68, and CD14 expressed by the spindle cells have been observed. The spindle cells proliferate in a background of reticular fibers, collagen, and mononuclear cells such as macrophages, lymphocytes, and plasma cells. They tend to be vascular, involving either the reticular dermis or the entire thickness of the dermis.

KSHV contains a large genome that has more than 85 antigenically competent genes. Immunofluorescent assays and an enzyme-linked immunoassay (ELISA) to major antigens have been developed to measure antibodies to KSHV. Seropositivity is more than 50% in sub-Saharan Africa, 20-30% in Mediterranean countries, and less than 10% in most of Europe, Asia, and the United States. The prevalence of KS is higher in men who have sex with men, Amerindians in South America, and certain ethnic groups in China. 

Previous molecular studies suggested that Kaposi sarcoma originates from a single-cell clone rather than a multifocal origin. More recent data showed that nearly 80% of the tumors arose independently from multiple cells. A few Kaposi sarcomas originate from a single cell. Kaposi sarcoma can independently occur at multiple sites. 

Human herpes virus 8 (HHV-8) genomic sequences have been identified by polymerase chain reaction in more than 90% of all types of Kaposi sarcoma lesions. The current belief is that HHV-8 must be present for the disease to develop. It can be transmitted in saliva. 

Factors that are thought to contribute to the development of Kaposi sarcoma in individuals infected with HHV-8 and HIV include an abnormal cytokine milieu associated with HIV infection.

Kaposi sarcoma may be caused by HHV-8 (KSHV) with stimulation by autocrine and paracrine growth factors secreted by the spindle cells. Coinfection with HIV may create a more aggressive course. The risk of Kaposi sarcoma development is amplified 500-10,000 times in patients coinfected with KSHV and HIV. 

Cofactors

Kaposi sarcoma develops in only a small percentage of HHV-8 seropositive individuals. This points to the importance of other factors. Some of these may be genetic. Individuals with certain polymorphisms in the MDM2 gene, which is involved in the function of the tumor suppressor protein p53, may be at increased risk for Kaposi sarcoma.

Some agents may either stimulate or inhibit the development of Kaposi sarcoma. This depends on the presence of influences such as genetic predisposition, environmental factors, drug intake, or lymphatic system disorders. There is a high prevalence of Kaposi sarcoma in areas where quinine and its derivatives are widely used for the treatment of malaria. The high prevalence may partly be attributable to the immunosuppressant effect of those drugs. However, quinolones are also known to have several effects that could inhibit Kaposi sarcoma development.  Angiotensin-converting enzyme (ACE) inhibitors also induce Kaposi sarcoma in some and inhibit it in others.

Transmission

KSHV is largely transmitted via saliva. It is also associated with sexual risk factors. These may just be a surrogate for close contact. Heterosexual risk factors do not play a role in transmission. Transmission by blood or blood products can occur. Transmission of KSHV may occur during solid organ donation. In solid organ transplant recipients, the incidence of Kaposi sarcoma may be higher in those who are seropositive as compared to those who are seronegative. [57]

Etiology

Etiologic factors for KS include the following:

• Iatrogenic immunosuppression (including corticosteroids)

• Coinfection with  HIV and HHV-8 

• Elevated expression of numerous cytokines and angiogenic growth factors, including tumor necrosis factor alpha, interleukin-6, basic fibroblast growth factor, HIV-tat protein, and oncostatin M

Epidemiology

Before HIV came into existence, Kaposi sarcoma was common in central Africa and prevalent in Mediterranean countries and the Middle East. It rarely occurred in other areas of the world. In Africa, the annual incidence of Kaposi sarcoma is very high. It is at 37.7 per 100,000 in men and 20.5 per 100,000 in women. 

In Europe, the highest rates of classic Kaposi sarcoma are in Ragusa Sicily with 30.1 cases per million in men and 5.4 cases per million in women. In  Sardinia, there are 24.3 cases per million in men and 7.7 cases per million in women.

A meta-analysis of the worldwide epidemiology of Kaposi sarcoma found the following incidence rates per 100,000 person-years:

• General population: 1.53 

• HIV-infected persons: 481.54 

• HIV-infected MSM:1397.11 

• HIV-infected children: 52.94 

• Transplant recipients: 68.59 

Kaposi sarcoma was rare before the AIDS epidemic. Between the years of 1975 and 1980, only 19 cases occurred in men aged 20-54 years in the USA. Just before 1980, at the beginning of the AIDS epidemic, 40-50% of men who had sex with men, who had AIDS, developed Kaposi sarcoma.

The incidence of Kaposi sarcoma reached its peak in 1989 among white men aged 20-54 years. It was the most common AIDS-associated neoplasm. Since than its incidence has dramatically declined.

The incidence and severity of Kaposi sarcoma has lessened following the introduction of highly active antiretroviral therapy. This reduction has been attributed to restoration of the immune system by these drugs. 

In the USA, AIDS-related Kaposi sarcoma occurs primarily in homosexual and bisexual men, as well as in the female sexual partners of bisexual men.

In Africa the Kaposi sarcoma occurs in heterosexual men and women with equal frequency. Kaposi sarcoma occurs primarily in men, with a male-to-female ratio of 10-15:1.

AIDS-related Kaposi sarcoma generally occurs in young to middle-aged adults between the ages of 20-54 years.  Classic Kaposi sarcoma usually occurs in patients aged 50-70 years.  African Kaposi sarcoma occurs in younger people between the age of 35-40 yrs.

Clinical presentation

Lesions in KS can involve the skin, lymph nodes, oral mucosa, and visceral organs. Most of the patients present with cutaneous disease. The visceral disease can occasionally precede cutaneous manifestations.

Cutaneous lesions in patients with KS can be characterized as follows:

• Cutaneous lesions typically are concentrated on the lower extremities and the head and neck region but can occur at any location.

• Lesions can have papular, nodular, macular, or plaque-like appearances.

• Nearly all the lesions are palpable and nonpruritic.

• The size of the lesions may range from several millimeters to several centimeters in diameter.

• Lesions may assume a pink, red, brown, or violaceous color and can be difficult to distinguish in dark-skinned individuals.

• Lesions can be discrete or confluent. They typically appear in a linear, symmetrical distribution, along the Langer lines

• Mucous membrane involvement is common. The lesions can appear on the palate, gingiva, and conjunctiva.

Lesions in the gastrointestinal tract can occur anywhere in the tract. The lesions are usually asymptomatic and clinically indolent. The following signs and symptoms can be present:

• Odynophagia (pain on swallowing), dysphagia

• Nausea, vomiting, and pain in the abdomen

• Hematemesis, hematochezia (fresh blood in stool), melena

• Bowel obstruction

Pulmonary lesions can be an asymptomatic radiographic finding. Signs and symptoms can include the following:

• Chest pain

• Cough

• Dyspnea

• Hemoptysis

Classic Kaposi sarcoma

Classic Kaposi sarcoma has a more indolent course than AIDS-related KS. It progresses over 10-15 years or more, with gradual enlargement of cutaneous lesions. Over the years there is development of new lesions.

Diagnosis

Laboratory studies

For patients with HIV infection CD4 lymphocyte counts and plasma HIV viral-load studies can be performed. 

Imaging studies

Chest radiographic findings are variable and nonspecific in patients with KS. They may include any of the following:

• Interstitial infiltrates

• Diffuse reticulonodular infiltrates

• An isolated pulmonary nodule

• Pleural effusions

• Hilar or mediastinal lymphadenopathy

Thallium and gallium scans can help differentiate pulmonary KS from infection. Pulmonary KS lesions usually demonstrate intense thallium uptake and no gallium uptake. Infection is often gallium avid and thallium negative.

Procedures

A punch biopsy can be carried out. Typical histologic findings in KS include the following:

• Extravasated red blood cells.

• Proliferation of spindle cells

• Prominent, slitlike vascular spaces

Bronchoscopy, esophagogastroduodenoscopy (EGD) or colonoscopy may be required for diagnosis. 

Management

Antiretroviral therapy

Highly active antiretroviral therapy (HAART) is necessary for optimal control of HIV infection in patients with KS. HAART can be tried as the sole modality for the treatment of nonvisceral disease. For visceral disease, chemotherapy can be added.

Local therapy

Local therapies can be used for palliation of locally advanced symptomatic disease or in individuals who have cosmetically unacceptable lesions. Local therapies include:

• Cryotherapy

• Radiation therapy

• Laser therapy

• Intralesional vinca alkaloid therapy

• Topical retinoids

• Surgical excision

Immunomodulation 

Immunomodulation with interferon-alfa has clinical activity in KS. It may be mediated by its antiangiogenic, antiviral, and immunomodulatory properties.

Combination therapy

Combination therapy with drugs such as actinomycin D, bleomycin, and vincristine produces higher response rates than does single-agent therapy such as doxorubicin. Time to progression and overall survival rates, however, are similar.

Cytotoxic agents

There are several single cytotoxic agents for AIDS-related KS. These include:

• Paclitaxel (Taxol) or oral etoposide (VePesid)

• Liposomal doxorubicin (Doxil)

• Liposomal daunorubicin (DaunoXome)

Liposomal technology has now resulted in higher response rates with less myelotoxicity and cardiac toxicity for liposomal doxorubicin and liposomal daunorubicin [12, 13, 14].

Prognosis

AIDS-related Kaposi sarcoma tends to have an aggressive clinical course. In other forms of KS the clinical course is less agressive. Morbidity can occur from extensive cutaneous, mucosal, or visceral involvement. In patients receiving antiretroviral therapy, the disease has a more indolent clinical course or may regress spontaneously. The most common causes of morbidity include cosmetically disfiguring cutaneous lesions, lymphedema, pulmonary involvement, or gastrointestinal involvement. The most common cause of mortality is pulmonary involvement with uncontrolled pulmonary hemorrhage.

References

1. Antman K, Chang Y. Kaposi's sarcoma. N Engl J Med. 2000 Apr 6. 342(14):1027-38.

2. PDQ Adult Treatment Editorial Board. Kaposi Sarcoma Treatment (PDQ®): Health Professional Version. 2018 July 27.

3. Friedman-Kien AE, Saltzman BR, Cao YZ, et al. Kaposi's sarcoma in HIV-negative homosexual men. Lancet. 1990 Jan 20. 335(8682):168-9.

4. Vangipuram R, Tyring SK. Epidemiology of Kaposi sarcoma: review and description of the nonepidemic variant. Int J Dermatol. 2018 Jun 11. 

5. Denis D, Seta V, Regnier-Rosencher E, Kramkimel N, Chanal J, Avril MF, et al. A fifth subtype of Kaposi's sarcoma, classic Kaposi's sarcoma in men who have sex with men: a cohort study in Paris. J Eur Acad Dermatol Venereol. 2018 Jan 29.

6. Mesri EA, Cesarman E, Boshoff C. Kaposi's sarcoma and its associated herpesvirus. Nat Rev Cancer. 2010 Oct. 10 (10):707-19.

7. Robbins HA, Pfeiffer RM, Shiels MS, Li J, Hall HI, Engels EA. Excess cancers among HIV-infected people in the United States. J Natl Cancer Inst. 2015 Apr. 107 (4).

8. Yarchoan R, Uldrick TS. HIV-Associated Cancers and Related Diseases. N Engl J Med. 2018 Mar 15. 378 (11):1029-1041. 

9. Curtiss P, Strazzulla LC, Friedman-Kien AE. An Update on Kaposi's Sarcoma: Epidemiology, Pathogenesis and Treatment. Dermatol Ther (Heidelb). 2016 Dec. 6 (4):465-470.

10. Stein ME, Spencer D, Ruff P, Lakier R, MacPhail P, Bezwoda WR. Endemic African Kaposi's sarcoma: clinical and therapeutic implications. 10-year experience in the Johannesburg Hospital (1980-1990). Oncology. 1994 Jan-Feb. 51 (1):63-9. 

11. Wabinga HR, Parkin DM, Wabwire-Mangen F, Mugerwa JW. Cancer in Kampala, Uganda, in 1989-91: changes in incidence in the era of AIDS. Int J Cancer. 1993 Apr 22. 54 (1):26-36.

12. Northfelt DW, Dezube BJ, Thommes JA, et al. Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine in the treatment of AIDS-related Kaposi's sarcoma: results of a randomized phase III clinical trial. J Clin Oncol. 1998 Jul. 16(7):2445-51.

13. Stewart S, Jablonowski H, Goebel FD, et al. Randomized comparative trial of pegylated liposomal doxorubicin versus bleomycin and vincristine in the treatment of AIDS-related Kaposi's sarcoma. International Pegylated Liposomal Doxorubicin Study Group. J Clin Oncol. 1998 Feb. 16(2):683-91. 

14. Gill PS, Wernz J, Scadden DT, et al. Randomized phase III trial of liposomal daunorubicin versus doxorubicin, bleomycin, and vincristine in AIDS-related Kaposi's sarcoma. J Clin Oncol. 1996 Aug. 14(8):2353-64.

 

                        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. 

References

1. Rettig AC, Strickland JW. Glomus tumor of the digits. J Hand Surg. 1977;2A(4):261–265.

2. Rao AG, Indira D, Kamal J. Extra digital glomangioma. Indian J Dermatol. 2010 Oct. 55 (4):397-8.

3. Shugart RR, Soule EH, Johnson EW Jr. Glomus Tumor. Surg Gynecol Obstet. 1963 Sep. 117:334-40.

4. Mravic M, LaChaud G, Nguyen A, Scott MA, Dry SM, James AW. Clinical and histopathological diagnosis of glomus tumor: an institutional experience of 138 cases. Int J Surg Pathol. 2015 May. 23 (3):181-8. 

5. Chou T, Pan SC, Shieh SJ, Lee JW, Chiu HY, Ho CL. Glomus Tumor: Twenty-Year Experience and Literature Review. Ann Plast Surg. 2016 Mar. 76 Suppl 1:S35-40.

6. Folpe AL, Fanburg-Smith JC, Miettinen M, Weiss SW. Atypical and malignant glomus tumors: analysis of 52 cases, with a proposal for the reclassification of glomus tumors. Am J Surg Pathol. 2001 Jan. 25(1):1-12.

7. Brathwaite CD, Poppiti RJ. Malignant glomus tumor. A case of widespread metastasis in a patient with multiple glomus body hamartomas. Am J Surg Pathol. 1996. 20:233-8.

8. Hiruta N, Kameda N, Tokudome T, et al. Malignant glomus tumor: a case report and review of the literature. Am J Surg Pathol. 1997 Sep. 21(9):1096-103.

9. Bali GS, Hartman DJ, Haight JB, Gibson MK. A rare case of malignant glomus tumor of the esophagus. Case Rep Oncol Med. 2013. 2013:287078.

10. Zhang Y, Li H, Zhang WQ. Malignant glomus tumor of the esophagus with mediastinal lymph node metastases. Ann Thorac Surg. 2013 Oct. 96(4):1464-6.

11. Drapé JL, Idy-Peretti I, Goettmann S, Wolfram-Gabel R, Dion E, Grossin M, et al. Subungual glomus tumors: evaluation with MR imaging. Radiology. 1995 May. 195 (2):507-15.

12. Fabiani P, Benizri E, Michiels JF, Gugenheim J, Saint-Paul MC, Mouiel J. [A new case of gastric glomangioma]. Gastroenterol Clin Biol. 1993. 17 (12):974-5.

13. Harrison B, Moore AM, Calfee R, Sammer DM. The association between glomus tumors and neurofibromatosis. J Hand Surg Am. 2013 Aug. 38 (8):1571-4. 

14. Harrison B, Sammer D. Glomus tumors and neurofibromatosis: a newly recognized association. Plast Reconstr Surg Glob Open. 2014 Sep. 2 (9):e214.

15. Aqil N, Gallouj S, Moustaide K, Mernissi FZ. Painful tumors in a patient with neurofibromatosis type 1: a case report. J Med Case Rep. 2018 Oct 19. 12 (1):319.

16. Lamba G, Rafiyath SM, Kaur H, Khan S, Singh P, Hamilton AM, et al. Malignant glomus tumor of kidney: the first reported case and review of literature. Hum Pathol. 2011 Aug. 42(8):1200-3. 

17. Wolter NE, Adil E, Irace AL, Werger A, Perez-Atayde AR, Weldon C, et al. Malignant glomus tumors of the head and neck in children and adults: Evaluation and management. Laryngoscope. 2017 Dec. 127 (12):2873-2882. 

18. Toti L, Manzia TM, Roma S, Meucci R, Blasi F, Ferlosio A, et al. Rare malignant glomus tumor of the stomach with liver metastases. Radiol Case Rep. 2019 Apr. 14 (4):463-467.

19. Cuviello A, Goyal A, Zick A, Ahlawat S, Rodriguez FJ, Belzberg AJ, et al. Sporadic Malignant Glomus Tumor of the Brachial Plexus With Response to Targeted Therapy Directed Against Oncogenic BRAF. JCO Precis Oncol. 2018. 2018:

20. Ejaz K, Raza MA, Aleem A, Maroof S, Tahir H. Glomangiosarcoma Involving the Heart with an Unknown Primary Lesion. Cureus. 2018 Jul 1. 10 (7):e2907.

21. Rajendran S, Henderson AH, Gillett S. Rare glomangiosarcoma of the tongue. BMJ Case Rep. 2018 Jul 3. 2018. 

22. Boon LM, Brouillard P, Irrthum A, Karttunen L, Warman ML, Rudolph R, et al. A gene for inherited cutaneous venous anomalies ("glomangiomas") localizes to chromosome 1p21-22. Am J Hum Genet. 1999 Jul. 65(1):125-33. 

23. Brouillard P, Ghassibé M, Penington A, Boon LM, Dompmartin A, Temple IK, et al. Four common glomulin mutations cause two thirds of glomuvenous malformations ("familial glomangiomas"): evidence for a founder effect. J Med Genet. 2005 Feb. 42(2):e13. 

24. Brauer JA, Anolik R, Tzu J, Meehan S, Lieber CD, Geronemus RG. Glomuvenous Malformations (Familial generalized multiple glomangiomas). Dermatol Online J. October 2011. 17 (10): 9.

25. Nazerani S, Motamedi MH, Keramati MR. Diagnosis and management of glomus tumors of the hand. Tech Hand Up Extrem Surg. 2010 Mar. 14(1):8-13.

26. D'Acri AM, Ramos-e-Silva M, Basílio-de-Oliveira C, Cerqueira A, Monteiro D, Pretti G, et al. Multiple glomus tumors: recognition and diagnosis. Skinmed. 2002 Nov-Dec. 1 (2):94-8. 

27. Iliescu OA, Benea V, Georgescu SR, Rusu A, Manolache L. Multiple glomus tumors. J Dermatol Case Rep. 2008 Jul 7. 2 (2):24-7.

28. Netscher DT, Aburto J, Koepplinger M. Subungual Glomus Tumor. J Hand Surg Am. 2011 Dec 20. 

29. Gandhi J, Yang SS, Hurd J. The anatomic location of digital glomus tumor recurrences. J Hand Surg Am. 2010 Jun. 35(6):986-9.

30. Lu H, Chen LF, Chen Q. Rupture of a subungual glomus tumor of the finger. BMC Cancer. 2018 May 2. 18 (1):505.

31. McEvoy BF, Waldman PM, Tye MJ. Multiple hamartomatous glomus tumors of the skin. Arch Dermatol. 1971 Aug. 104 (2):188-91.

32. Zou H, Song L, Jia M, Wang L, Sun Y. Glomus tumor in the floor of the mouth: a case report and review of the literature. World J Surg Oncol. 2018 Oct 10. 16 (1):201.

33. Smith MH, Bhattacharyya I, Cohen DM, Hinze SR, Islam MN. Glomus tumor: a comprehensive review of the clinical and histopathologic features with report of two intraoral cases. Oral Surg Oral Med Oral Pathol Oral Radiol. 2019 Jan. 127 (1):62-70.

34. Jayasree P, Kaliyadan F, Elizabeth MJ, Bhaskara KGR. Subungual glomus tumour showing an unusual presentation. Australas J Dermatol. 2019 Mar 8.

35. Chou HP, Tiu CM, Chen JD, Chou YH. Glomus tumor in the stomach. Abdom Imaging. 2010 Aug. 35(4):390-2. 

36. Filice ME, Lucchi M, Loggini B, Mussi A, Fontanini G. Glomus tumour of the lung: case report and literature review. Pathologica. 2008 Feb. 100(1):25-30. 

37. Kang G, Park HJ, Kim JY, Choi D, Min BH, Lee JH, et al. Glomus tumor of the stomach: a clinicopathologic analysis of 10 cases and review of the literature. Gut Liver. 2012 Jan. 6(1):52-7. 

38. Baek SH, Huh DM, Park JH, Kwak EK, Kim BH, Han WK. Glomangiomyoma of the trachea. Korean J Thorac Cardiovasc Surg. 2011 Dec. 44(6):440-3.

39. Oide T, Yasufuku K, Shibuya K, Yoshino I, Nakatani Y, Hiroshima K. Primary pulmonary glomus tumor of uncertain malignant potential: A case report with literature review focusing on current concepts of malignancy grade estimation. Respir Med Case Rep. 2016. 19:143-149.

40. Li L, Xu QX, Zhang XY, Han CH. Unusual location of the glomus tumour in the liver: A case report and literature review. Medicine (Baltimore). 2018 Jun. 97 (26):e11294. 

41. Morte D, Bingham J, Sohn V. Gastric Glomus Tumor: An Uncommon Source for an Acute Upper GI Bleed. Case Rep Gastrointest Med. 2018. 2018:7961981.

42. Vasisht B, Watson HK, Joseph E, Lionelli GT. Digital glomus tumors: a 29-year experience with a lateral subperiosteal approach. Plast Reconstr Surg. 2004 Nov. 114(6):1486-9. 

43. Giele H. Hildreth's test is a reliable clinical sign for the diagnosis of glomus tumours. J Hand Surg Br. 2002 Apr. 27(2):157-8.

44. Sethu C, Sethu AU. Glomus tumour. Ann R Coll Surg Engl. 2016 Jan. 98 (1):e1-2.

45. Glazebrook KN, Laundre BJ, Schiefer TK, Inwards CY. Imaging features of glomus tumors. Skeletal Radiol. 2011 Jul. 40(7):855-62.

46. Drape JL, Idy-Peretti I, Goettmann S, Guerin-Surville H, Bittoun J. Standard and high resolution magnetic resonance imaging of glomus tumors of toes and fingertips. J Am Acad Dermatol. 1996 Oct. 35(4):550-5.

47. Matsunaga A, Ochiai T, Abe I, et al. Subungual glomus tumour: evaluation of ultrasound imaging in preoperative assessment. Eur J Dermatol. 2007 Jan-Feb. 17(1):67-9.

48. Chen SH, Chen YL, Cheng MH, Yeow KM, Chen HC, Wei FC. The use of ultrasonography in preoperative localization of digital glomus tumors. Plast Reconstr Surg. 2003 Jul. 112(1):115-9; discussion 120. 

49. Fornage BD. Glomus tumors in the fingers: diagnosis with US. Radiology. 1988 Apr. 167(1):183-5. 

50. Theumann NH, Goettmann S, Le Viet D, Resnick D, Chung CB, Bittoun J, et al. Recurrent glomus tumors of fingertips: MR imaging evaluation. Radiology. 2002 Apr. 223(1):143-51. 

51. Matloub HS, Muoneke VN, Prevel CD, Sanger JR, Yousif NJ. Glomus tumor imaging: use of MRI for localization of occult lesions. J Hand Surg Am. 1992 May. 17(3):472-5.

52. Drape JL, Idy-Peretti I, Goettmann S, Guerin-Surville H, Bittoun J. Standard and high resolution magnetic resonance imaging of glomus tumors of toes and fingertips. J Am Acad Dermatol. 1996 Oct. 35(4):550-5. 

53. Fujioka H, Kokubu T, Akisue T, et al. Treatment of subungual glomus tumor. Kobe J Med Sci. 2009 Jun 5. 55(1):E1-4. 

54. Mundada P, Becker M, Lenoir V, Stefanelli S, Rougemont AL, Beaulieu JY, et al. High resolution MRI of nail tumors and tumor-like conditions. Eur J Radiol. 2019 Mar. 112:93-105.

55. Lee SH, Roh MR, Chung KY. Subungual glomus tumors: surgical approach and outcome based on tumor location. Dermatol Surg. 2013 Jul. 39(7):1017-22.

56. Wang PJ, Zhang Y, Zhao JJ. Treatment of Subungual Glomus Tumors Using the Nail Bed Margin Approach. Dermatol Surg. 2013 Oct 9. 

57. Pahwa M, Pahwa P, Kathuria S. Glomus tumour of the nail bed treated with the 'trap door' technique: A report of two patients. J Dermatolog Treat. 2010 May 4. 

58. Lee HJ, Kim PT, Kyung HS, Kim HS, Jeon IH. Nail-preserving excision for subungual glomus tumour of the hand. J Plast Surg Hand Surg. 2013 Nov 21.

59. Lin YC, Hsiao PF, Wu YH, Sun FJ, Scher RK. Recurrent Digital Glomus Tumor: Analysis of 75 Cases. Dermatol Surg. 2010 Sept 2010 [ePub 2010 Jul 9]. 

60. Lee W, Kwon SB, Cho SH, Eo SR, Kwon C. Glomus tumor of the hand. Arch Plast Surg. 2015 May. 42 (3):295-301. 

61. Kim YJ, Kim DH, Park JS, Baek JH, Kim KJ, Lee JH. Factors affecting surgical outcomes of digital glomus tumour: a multicentre study. J Hand Surg Eur Vol. 2018 Jul. 43 (6):652-658.

62. Gould EP. Sclerotherapy for multiple glomangiomata. J Dermatol Surg Oncol. 1991 Apr. 17(4):351-2. 

63. Siegle RJ, Spencer DM, Davis LS. Hypertonic saline destruction of multiple glomus tumors. J Dermatol Surg Oncol. 1994 May. 20(5):347-8.

64. Hughes R, Lacour JP, Chiaverini C, Rogopoulos A, Passeron T. Nd:YAG laser treatment for multiple cutaneous glomangiomas: report of 3 cases. Arch Dermatol. 2011 Feb. 147(2):255-6.

65. Moreno-Arrones OM, Jimenez N, Alegre-Sanchez A, Fonda P, Boixeda P. Glomuvenous malformations: dual PDL-Nd:YAG laser approach. Lasers Med Sci. 2018 Dec. 33 (9):2007-2010.