Spiradenoma

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Background

Spiradenomas are benign neoplasms originally thought to arise from sweat glands in the dermal layer of the skin. They were first described in 1956 by Kersting and Helwig as a distinct form of sweat gland tumor ,which they called eccrine spiradenoma. In current practice, they are considered to originate from the hair follicle bulge, rather than the sweat gland.[1]

Spiradenomas are most commonly located on the scalp, neck, and upper body. They appear as solitary nodules ranging from less than 1 centimeter to several centimeters and may be skin colored, blue/gray, pink, red, purple, or yellow. They are often, although not always, painful or tender. The average age range of occurrence is age 15-35 years, although they can arise from infancy to older adulthood. Although usually benign, spiradenomas can rarely be malignant or transform to spiradenocarcinoma.[2]

Spiradenomas typically occur alone; however, they can be seen with other sweat gland tumors such as cylindromas and trichoepitheliomas as part of Brooke-Spiegler syndrome, in which lesions may have combined features of cylindromas and spiradenomas.[3, 4]

Pathophysiology

Spiradenomas arise from the hair follicle bulge rather than the eccrine sweat gland, based on an immunohistochemical study of stem cell markers and with CD200.[1] All 27 spiradenomas and 30 cylindromas in this study were positive for CD200, whereas other tumors thought to be of eccrine lineage were all negative, suggesting that spiradenomas are not eccrine tumors, but rather are follicular tumors derived from the hair follicle bulge and representing the least differentiated follicular tumors.

A defective tumor suppressor gene is believed to result in the development of spiradenomas. In Brooke-Spiegler syndrome, of which spiradenomas are a manifestation, the defective gene is CYLD on chromosome 9. The gene product of CYLD down-regulates the NF-κB signaling pathway, and when this protein is nonfunctional, increased activity of the NF-κB pathway leads to uncontrolled cell proliferation, resulting in the development of adnexal tumors.[5] However, CYLD mutations are not responsible for all sweat gland tumors, since a subset of patients with Brooke-Spiegler syndrome do not have a demonstrable germline CYLD mutation.[6]

In addition to CYLD, other signaling pathways play a role in the development of spiradenomas. Alterations in the beta-catenin pathway, which is involved in several epidermal tumors, are thought to play a role. According to one study, down-regulation of Axin and GSK-3β in the β-catenin pathway was associated with the development of spiradenomas.[7] Additionally, a recurrent missense mutation in the kinase domain of the ALPK1 gene has been found in both spiradenomas and spiradenocarcinomas.[8] The ALPK1 mutation was shown to activate the NF-κB pathway and is mutually exclusive from CYLD mutations.[8] Thus, there are alternative pathways that may be mutated in development of spiradenoma.

In cases of linear/zosteriform/nevoid/blaschkoid multiple spiradenomas, an abnormal clone arising during embryogenesis is thought to result in production of multiple spiradenomas.[4, 9]

Additional mutations are required to produce malignant spiradenoma. High-grade spiradenocarcinomas carry ALPK1 mutations that activate the NF-κB pathway in reporter assays and loss-of-function TP53 mutations.[8] Other studies suggest increased TP53 expression in malignant spiradenomas.[10]

Etiology

Spiradenomas seem to be caused by a defective tumor suppressor gene. In Brooke-Spiegler syndrome, a defect exists in the CYLD gene located on chromosome 9.[11] However, not all spiradenomas have mutations in this gene. Many have mutations in the ALPK1 gene.[8]

The cause of malignant spiradenomas is unclear. Expression of TP53 seems to be increased in some malignant spiradenomas,[10] whereas loss-of-function mutations in TP53 are seen in others.[8] Mutations in CYLD and ALPK1 have also been found[8]

Epidemiology

Frequency

Spiradenomas are rare worldwide, with the exact incidence of benign solitary spiradenoma unknown. Malignant spiradenomas are even rarer, with only about 120 documented cases worldwide.[12] Even more rare are cases of varying morphologies of multiple spiradenomas, with fewer than 40 documented cases in the literature.[9]

Race

No racial link exists for spiradenomas.

Sex

No sexual predilection exists for spiradenomas or malignant spiradenomas.

Age

Most spiradenomas arise in persons aged 15-35 years. They can occur at any age, with reports of a spiradenoma occurring at age 4 weeks.[13]

Malignant spiradenomas tend to develop after age 50 years, with a median age of 60 years.[12] There have been rare reports of malignant transformation of spiradenoma in children.[14]

Prognosis

Spiradenomas are usually benign. They can be painful and they may continue to grow. The rate of malignant transformation is very low.

In cases of malignant spiradenoma, the rate of metastasis is about 20% and can result in death in about 10% of patients.[12]

Patient Education

Patients should understand that the lesions can be painful and do not self-resolve. Only surgery is curative. Patients should be educated on the rare possibility of recurrence after surgical resection, and on the rare possibility of malignant transformation.

History

In evaluating a patient for spiradenoma, it is helpful to gather information on number, location, pain, size, growth, age, timing, and family history. Spiradenoma lesions typically appear as solitary dermal nodules that arise on the head, neck, trunk, and, less commonly, the arms or legs. Lesions tend to be about 1 cm in diameter. They can remain stable in size or they can grow. They can be painful or asymptomatic and range in color. Brooke-Spiegler syndrome should be considered if a patient reports multiple lesions or a family history of similar tumors.

In the initial studies of spiradenoma, 91% of patients reported associated pain or tenderness.[15] However, a more recent study of 49 spiradenomas found pain or tenderness in only 23% of the 35 patients who had well-documented clinical histories.[16] Thus, spiradenomas may be painful, but it is not necessarily a defining characteristic.

Malignant spiradenoma can develop in long-standing lesions,[17] although malignant transformation overall is rare. A history of rapid growth, often associated with an ulceration and a change in color, is suggestive of malignant transformation.

Physical Examination

Spiradenomas are usually flesh-colored, gray, pink, purple, red, or blue nodules about 1 cm in diameter. The lesions tend to occur on the scalp, neck, and upper part of the torso. Spiradenomas tend to be soft and are sometimes tender to palpation.

More rare locations for spiradenoma have been reported, including in the ears, external auditory canals, eyelid, proximal nail fold, and vulva.[18, 19, 20, 21, 22, 23, 24] Giant eccrine spiradenoma of the hand has been reported.[25]

Malignant spiradenomas tend to have slightly different features than benign spiradenomas based on size, appearance, and location. They tend to be larger than benign spiradenomas, with a median diameter at presentation of 3 cm (range, 0.8-25 cm). Malignant spiradenomas also tend to ulcerate. Whereas some studies suggest malignant spiradenomas preferentially involve the trunk and the extremities, more recent literature reviews do not support any location predominance.[12] Other documented cases of spiradenoma have involved the scalp,[26, 27, 28] vulva,[29, 30] toes,[31] and a traumatized area.[32]

Malignant spiradenomas can metastasize. A review of spiradenocarcinomas found a 19% rate of metastasis, with the most common sites being lung, bone, and lymph nodes. Less frequent locations of metastases were liver, kidney, and breast.[12] Thus, it is important to evaluate for potential metastatic disease on physical examination.

Complications

Long-standing lesions of spiradenoma can turn into malignant spiradenoma. Thus, changing skin tumors should prompt evaluation. Malignant spiradenoma can metastasize.

Laboratory Studies

See Histological Findings.

Imaging Studies

MRI, CT, ultrasonography, and plain x-ray films are not diagnostic for spiradenoma, but they can be used to locate metastases in the case of malignant spiradenoma.

Spiradenoma should be considered in the differential diagnosis of a well‐circumscribed hypervascularized, hypoechoic subcutaneous tumor on ultrasonography.[33] It is usually located in the subcutaneous fat layer and has a well-defined margin. Appearance is typically hypoechoic, lobulated, and can be tractlike with a heterogeneous echo texture. Other features reported include internal hypoechoic foci and posterior acoustic enhancement with peripheral blood flow.[34]

Malignant spiradenomas appear on MRI as multiple dispersive foci with clear circumferences in the skin and subcutis. They demonstrate low-signal intensity on T1-weighted images and high-signal intensity on short-tau inversion recovery images.[35]

Procedures

Skin biopsy is necessary to establish the diagnosis of spiradenoma. Surgical excision is the treatment of choice.

Fine-needle cytology of a spiradenoma of the breast can be performed to aid in diagnosis.[36]

Histologic Findings

Spiradenomas consist of one or more large, sharply contrasted, basophilic nodules in the dermis.[15] The nodules of spiradenoma are unattached to the epidermis and sometimes extend into the subcutis. The nodules consist of groups of cells in cords, islands, and/or sheets. A trabecular arrangement of cells can be present.[37]

See the image below.



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Spiradenoma. Vascular channels within a basaloid tumor. Courtesy of Sarahkayb (own work), via Wikimedia Commons.

The two types of cells in the nodules of spiradenoma are small, dark, basaloid cells with hyperchromatic nuclei and cells with large, pale, vesicular, and ovoid nuclei. Pale cells tend to be at the center of the lesions.[15]

Ductlike structures and lymphocytes can also be present at the center of the lesions.[38] Strands of cells are positive for cytokeratin, and the lumina are positive for carcinoembryonic antigen.[38] In contrast to these findings, the nodules of spiradenoma in infants display a less distinct two-cell-type pattern and ductule formation is rare.[39]

The fibrous capsule surrounding spiradenomas usually contains nerves, blood vessels, and ducts. The nerves often invest the tumor or penetrate interlobular septae of the tumor along with the small vessels.[15] One study describes a case of a painful spiradenoma that showed a disorganized nerve fiber encasing the spiradenoma nodules, which seemed to correlate with the intense pain the patient felt.[40] Close examination revealed profiles of cystoid spaces resulting from stromal invagination into the parenchyma.

Malignant spiradenoma is characterized by an increased mitotic rate, necrosis, nuclear atypia, pleomorphism, hyperchromasia, loss of nested and trabecular growth patterns, and an absence of the classic dual-cell population.[41] Two distinctive histologic patterns have been described in malignant spiradenoma, both with focal squamous differentiation .[41] The first is an abrupt transition between a benign spiradenoma and a high-grade carcinoma component with marked pleomorphism. The second is a gradual transition between benign spiradenoma and malignant spiradenoma. In the latter case, the malignant component is defined by an increased nuclear-to-cytoplasmic ratio, hyperchromasia, and marked mitotic activity. For both histological subtypes, areas of benign and malignant spiradenoma coexist.[41] In some cases, malignant spiradenoma demonstrates the typical features of a spiradenoma, with areas of adenocarcinoma, squamous cell carcinoma, and sarcoma.[42]

Electron microscopy

Electron microscopy of spiradenomas shows cellular sheets separated into lobules by strands of amorphous and fibrillar material. Translucent polygonal or round cells with mitochondria, small vesicles, and sometimes glycogen granules are the dominant population of cells in spiradenomas. Sparse, dark cells are also often noted. Lumina may be present, with microvilli on the lining cells.[43]

Immunohistochemistry

Although spiradenomas were historically thought to be of eccrine lineage, more recent studies based on immunohistochemistry suggest this is not the case. Early studies showed spiradenomas stain with antibodies to the eccrine marker IKH-4[44] and are positive for S-100 protein.[38] Spiradenomas also stain with antibodies to epithelial mucin, which is a marker for eccrine and apocrine glands.[45] Spiradenomas and cylindromas also demonstrate cytokeratin staining patterns similar to eccrine and apocrine glands, including expression of keratins 7, 8, and 18.[38]

However, tubular cells in both spiradenomas and cylindromas express human milk fat globulin and lysozyme, two markers associated with apocrine rather than eccrine differentiation.[38]

In addition to these secretory gland markers, spiradenomas and cylindromas express the follicular stem cell marker CD200, differentiating them from tumors of eccrine lineage, which are CD200-negative.[1] Spiradenomas also co-express cytokeratin and smooth muscle actin, suggesting differentiation toward myoepithelial cells.[46] Thus, spiradenoma and cylindroma are thought to represent the least differentiated follicular tumors and have their basis in the hair follicle bulge rather than the eccrine sweat gland.

Approach Considerations

Treatment of spiradenomas is surgical.

Malignant spiradenomas may be treated with surgery, radiation, hyperthermic limb perfusion chemotherapy, and chemotherapy. They may also be sensitive to tamoxifen therapy.[47, 48]

Surgical Care

The mainstay of treatment of spiradenomas and malignant spiradenomas is surgical removal. The lesions do not tend to recur after surgery. Mohs micrographic surgery has been used on the anterior neck to surgically remove infiltrative persistent spiradenoma.[49]

Multiple spiradenomas, such as those found in Brooke-Spiegler syndrome, have been treated with a high-energy continuous wave carbon dioxide laser after debulking with bipolar scissors in one patient.[50, 51]

Consultations

Patients with malignant spiradenoma should see a surgeon, an oncologist, and possibly a radiation oncologist.

Activity

Sometimes, pain can bother patients, but this pain should not affect their activities.

Prevention

Complete excision of lesions should be performed to prevent recurrence.

Long-Term Monitoring

Surgery is usually curative; therefore, further care is not needed. Patients with malignant spiradenomas need to follow up with oncologists and radiation oncologists.

Medication Summary

There is no medication to treat spiradenomas. However, treatment of malignant spiradenoma may include chemotherapy.

Tamoxifen (Nolvadex)

Clinical Context:  Tamoxifen competitively binds to the estrogen receptor, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects.

Class Summary

These agents are used to block the growth of cells that have estrogen receptors.

Author

Nikki A Levin, MD, PhD, Associate Professor of Medicine, Division of Dermatology, University of Massachusetts Medical School

Disclosure: Nothing to disclose.

Coauthor(s)

Holly D Neale, BS, MD Candidate, University of Massachusetts Medical School

Disclosure: Nothing to disclose.

Specialty Editors

David F Butler, MD, Former Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

Disclosure: Nothing to disclose.

Jeffrey P Callen, MD, Professor of Medicine (Dermatology), Chief, Division of Dermatology, University of Louisville School of Medicine

Disclosure: Received honoraria from UpToDate for author/editor; Received royalty from Elsevier for book author/editor; Received dividends from trust accounts, but I do not control these accounts, and have directed our managers to divest pharmaceutical stocks as is fiscally prudent from Stock holdings in various trust accounts include some pharmaceutical companies and device makers for i inherited these trust accounts; for: Allergen; Celgene; Pfizer; 3M; Johnson and Johnson; Merck; Abbott Laboratories; AbbVie; Procter and Gamble; Amgen.

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

Noah S Scheinfeld, JD, MD, FAAD, † Assistant Clinical Professor, Department of Dermatology, Weil Cornell Medical College; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, New York Eye and Ear Infirmary; Assistant Attending Dermatologist, New York Presbyterian Hospital; Assistant Attending Dermatologist, Lenox Hill Hospital, North Shore-LIJ Health System; Private Practice

Disclosure: Nothing to disclose.

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Spiradenoma. Vascular channels within a basaloid tumor. Courtesy of Sarahkayb (own work), via Wikimedia Commons.

Spiradenoma. Vascular channels within a basaloid tumor. Courtesy of Sarahkayb (own work), via Wikimedia Commons.