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