Spiradenoma

Etiology

Spiradenomas appear to be caused by a defective tumor suppressor gene. A mutation in the CYLD gene on chromosome 16 is found in Brooke-Spiegler syndrome, which features multiple spiradenomas.[3] The specific cause of solitary spiradenomas is not clear. Originally thought to be of eccrine differentiation, recent studies have suggested that spiradenomas may be derived from apocrine glands or the folliculosebaceous unit.

The cause of malignant spiradenomas is also unknown. Increased expression of p53 is seen, though the significance of this finding in the malignant transformation of spiradenomas has not been determined.[4]

Epidemiology

Spiradenomas are usually benign and most often occur in patients between 15 and 35, though cases have been reported in infants. There is no racial or sexual predilection for spiradenomas. To date, approximately 15 cases of either linear, zosteriform, nevoid, blaschkoid, or multiple spiradenomas have been reported in the literature.[5][6][7] Although benign spiradenomas are quite rare, malignant spiradenomas are even rarer and occur in patients older than the age of 50 years, with an average age of 59 years.[8]

Pathophysiology

The pathogenesis of the formation of spiradenomas is not completely understood. A defect in the tumor suppressor gene, CYLD, is thought to contribute to their development in Brooke-Spiegler syndrome, which also features multiple cylindromas.[3] A transition between cylindromas and spiradenomas has been shown to occur in patients with CYLD gene mutations. Derangements in intercellular bridge proteins that maintain epithelial organization, including claudin-4, cadherin, and beta-catenin, have also been suggested to contribute to neoplasm formation.[9] Two studies found intense nuclear immunoreactivity for beta-catenin in spiradenomas, supporting the role of alterations in the beta-catenin pathway in their development. Professionals postulate that an abnormal clone arising during embryogenesis produces multiple abnormal cells that result in presentations involving multiple nevoid, blaschkoid, or linear spiradenomas.

Historically, spiradenomas were thought to be of eccrine lineage, though many lesions have been shown to demonstrate apocrine differentiation. Alternatively, 1 study using immunohistochemical markers for stem cells and CD200 suggests that spiradenomas and cylindromas are follicular-based tumors instead of derived from eccrine or apocrine glands. Other studies have shown spiradenomas to have either apocrine or folliculosebaceous differentiation.[10] Increased expression of p53 has been observed in malignant spiradenomas.[11]

Histopathology

On histopathology, spiradenomas show 1 or more large, sharply demarcated basophilic nodules of the dermis. Two types of cells are seen in the nodules. These cells are either small, dark, basaloid cells with hyperchromatic nuclei or larger, pale, and with ovoid nuclei. These lighter cells tend to be toward the center of the lesion. Duct-like structures of uninterpretable differentiation and cystic cavities filled with finely granular eosinophilic material may be seen.[12][13] The material within the cystic cavities is diastase resistant and periodic acid-Schiff positive. A lymphangiectatic variant has rarely been described. Immunohistochemical staining shows increased expression of S-100 in the large, pale-staining cells and human milk fat globulin (HMFG) and lysozyme in the tubular cells.[10] Spiradenomas also stain positive for epithelial membrane antigen, carcinoembryonic antigen, and the myoepithelial stains p63 and SMA. The cytokeratin patterns include expression of keratins 7, 8, 14, and 18.[14][15]

Malignant spiradenomas demonstrate increased mitotic rates, necrosis, nuclear atypia, pleomorphism, hyperchromasia, loss of nested growth patterns, and loss of the dual cell population. In histologic studies, two patterns of malignant spiradenomas were observed. One was an abrupt transition between a benign spiradenoma and high-grade carcinoma, while the second showed contiguity between the benign and malignant areas.

History and Physical

Spiradenomas typically present as dermal or subcutaneous nodules on any area, though more commonly seen on the head, neck, and trunk and less commonly on the arms and legs. Several spiradenomas have been reported on the ears, eyelids, and papular lesions of the proximal nail fold. On physical examination, lesions are typically small, though they can grow to several centimeters in diameter and have a blue, gray, or purple hue. Spiradenomas can be strikingly painful, though most are asymptomatic. Although the typical presentation is a solitary lesion, there can be linear, blaschkoid, or grouped spiradenomas. Multiple spiradenomas can be seen, and if present with cylindromas and trichoblastomas, Brooke-Spiegler syndrome must be considered.[16] Based on the physical exam, the differential diagnosis of spiradenomas typically includes cylindromas, epidermal inclusion cysts, dermatofibromas, leiomyomas, poromas, and basal cell carcinomas.

Though rare, spiradenomas have occurred in infancy, representing less than 1% of all reported cases of spiradenoma. These typically present as more superficial dermal nodules than seen in adults.

Rapid growth in a long-standing lesion may indicate malignant transformation. Malignant spiradenomas also tend to ulcerate and have a predilection for the trunk and extremities. A change in the lesion's color can signify malignant transformation. Metastases from malignant spiradenomas can occur in lymph nodes, the lungs, the brain, or the liver.

Evaluation

Lesions should be excised for histopathologic examination. On histopathology, spiradenomas show 1 or more large, sharply demarcated basophilic nodules of the dermis. Two types of cells are seen in the nodules. These cells are either small, dark, basaloid cells with hyperchromatic nuclei or larger, pale, and with ovoid nuclei. Malignant spiradenomas demonstrate increased mitotic rates, necrosis, nuclear atypia, pleomorphism, hyperchromasia, loss of nested growth patterns, and loss of the dual cell population.[4] Imaging studies, including MRI, CT, or ultrasound, can help determine if metastatic foci are present in malignant spiradenoma.

Treatment / Management

Although spiradenoma is considered a benign adnexal neoplasm with a low recurrence rate, malignant transformation can occur in long-standing lesions, particularly in patients older than 50. The rate of metastasis for malignant spiradenocarcinoma is about 50%. Conservative surgical excision of spiradenomas is therefore recommended. In cases of multiple spiradenomas, adjunctive treatment with a carbon dioxide laser may be employed after surgical debulking.

Malignant spiradenomas tend to be aggressive tumors with high rates of metastasis and mortality. Radiation and chemotherapy may be used after tumor resection for malignant spiradenomas.

Differential Diagnosis

The differential diagnoses for spiradenoma include the following:

• Angiolipoma
• Dermatofibroma
• Epidermal inclusion cyst
• Leiomyoma
• Poroma
• Schwannoma