Are You Confident of the Diagnosis?
What you should be alert for in the history
Patients with multiple skin appendage tumors usually beginning to appear in the second or third decade. The family history reveals similar multiple skin tumors involving relatives of the affected patient.
Characteristic findings on physical examination
Predominantly three types of tumors, namely trichoepitheliomas, cylindromas and spiradenomas, and some rare neoplasias could be observed that show different clinical pictures:
Trichoepithelioma: Flesh- or pink-colored small, round, shiny, smooth, firm, asymptomatic papule or nodule. The size can vary between 2 to 8mm. Telangiectases may be present on the surface. The lesions are frequently multiple, grouped but discrete. Mostly located on the midface, especially on the nose and nasolabial folds.
Cylindroma: Slowly-growing, firm, rubber-like, pinkish, smooth nodule with prominent telengiectases. Most frequently lesions are multiple varying in size from a few milimeters to several centimeters (
Multiple cylindromas on the face.
Spiradenoma: Flesh- or bluish-colored, firm, large nodule. Mostly located on the trunk and extremities. Sometimes painful.
Spiradenocylindroma: Tumor showing features of both spiradenoma and cylindroma.
Other associated tumors: Milia, trichoblastoma, basal cell carcinoma, neoplasms of the parotid gland, follicular cyst, organoid nevi, malignant transformation of pre-existing tumors (spiradenoma, cylindroma, spiradenocylindroma).
Expected results of diagnostic studies
There are no specific histopathologic features of the syndrome. The appendage tumors show their classical features.
Trichoepithelioma: Different-sized nests or cribriform cords consisting of follicular basaloid cells, surrounded by dense fibrous stroma.
Spiradenomas: Intradermal, well-circumscribed nodules with two types of epithelial component arranged in cords: large pale cells located in the center of the cell cords, and small basaloid cells with dark nuclei present at the periphery.
Cylindromas: Intradermal, sharply-circumscribed nodules. The nodule is composed of lobules with two epithelial cell types, large, pale-staining cells in the center and small basaloid cells at the periphery arranged in a “jigsaw puzzle” pattern. Lobules are surrounded by a thick, hyaline, PAS-positive basement membrane material.
Coexistence of different types of cutaneous adnexal neoplasms described above that are diagnosed histopathologically establish the diagnosis. Various tumors may be seen in other family members. Trichoepitheliomas should be distinguished from basal cell carcinoma. Painful spiradenoma may be mistaken for a leiomyoma, neuroma, glomus tumor, or angiolipoma. Cylindroma may be mistaken for pilomatricoma or pilar cyst, especially on the scalp.
Who is at Risk for Developing this Disease?
Other family members of the patients are at risk for developing the disease. All family members should be examined.
What is the Cause of the Disease?
Brooke-Spiegler syndrome (BSS) is a genetic disorder affecting the folliculosebaceous apocrine unit and consequently leading to different types of adnexal cutaneous tumors. It has an autosomal dominant mode of inheritance of various mutations in the CYLD gene, a tumor-suppressor gene located on chromosome 16q.
Systemic Implications and Complications
Large trichoepitheliomas and cylindromas may occlude the concha and the external auditory meatus.
A kindred with BSS has been reported where an affected mother and daughter developed a malignant lymphoepithelial lesion of the parotid gland.
Therapeutic approaches that are suggested to manage different kinds of skin tumors :
--Laser surgery (CO2 laser, Erbium YAG laser, Neodymium YAG laser)
--Mohs micrographic surgery
--Scalp excision or removal with split-thickness skin grafting (especially in patients with “turban” tumor): In case of entire scalp removal, there are risks like hypotensive shock, graft failure, and blood transfusion.
Optimal Therapeutic Approach for this Disease
No specific treatment for the disease. Tumors may be removed or destroyed surgically when they are painful, ulcerated, bleeding, causing sexual dysfunction, causing cosmetic disturbance or in case of possible malignant transformation. Large trichoepitheliomas and cylindromas may occlude the concha and the external auditory meatus and therefore should be removed.
The family should be informed about the course of disease. Patients should be followed-up closely for possible malignant transformation of the pre-existing tumors. Ulceration, rapid growth, pain and change in color may be suggestive of malignancy. Pathological examination must be performed in these cases. If tumors with malignant degeneration are not treated early, metastases leading to death can occur.
Unusual Clinical Scenarios to Consider in Patient Management
Although rare, one should be alert for possible malignant transformation of the cutaneous tumors and other malignancies.
What is the Evidence?
Blake, PW, Toro, JR. "Update of cylindromatosis gene (CYLD) mutations in Brooke-Spiegler syndrome: novel insights into the role of deubiquitination in cell signaling". Hum Mutat. vol. 30. 2009. pp. 1025-36.(A comprehensive review about the clinical features, molecular genetics, and the animal models of Brooke-Spiegler syndrome.)
Layegh, P, Sharifi-Sistani, N, Abadian, M, Moghiman, T. "Brooke-Spiegler syndrome". Indian J Dermatol Venereol Leprol. vol. 74. 2008. pp. 632-4.(A case report describing a patient diagnosed as Brooke-Spiegler syndrome.)
Kazakov, DV, Zelger, B, Rütten, A, Vazmitel, M, Spagnolo, DV, Kacerovska, D. "Morphologic diversity of malignant neoplasms arising in preexisting spiradenoma, cylindroma, and spiradenocylindroma based on the study of 24 cases, sporadic or occurring in the setting of Brooke-Spiegler syndrome". Am J Surg Pathol. vol. 33. 2009. pp. 705-19.(An article describing a series of 24 malignant neoplasms arising in preexisting benign spiradenoma (20), cylindroma (2), and spiradenocylindroma (2).)
Rajan, N, Trainer, AH, Burn, J, Langtry, JA. "Familial cylindromatosis and Brooke-Spiegler syndrome: a review of current therapeutic approaches and the surgical challenges posed by two affected families". Dermatol Surg. vol. 35. 2009. pp. 845-52.(A review of the therapeutic approaches, especially highlighting the surgical modalities to manage the tumors in familial cylindromatosis and Brooke-Spiegler syndrome.)
Meybehm, M, Fischer, HP. "Spiradenoma and dermal cylindroma: comparative immunohistochemical analysis and histogenetic considerations". Am J Dermatopathol. vol. 19. 1997. pp. 154-61.(Light microscopic findings and immunohistochemical analysis of spiradenomas and cylindromas. The authors postulate that both neoplasms develop from pluripotential cells that may be situated in abortive adnexal glands.)
Kazakov, DV, Soukup, R, Mukensnabl, P, Boudova, L, Michal, M. "Brooke-Spiegler syndrome: report of a case with combined lesions containing cylindromatous, spiradenomatous, trichoblastomatous, and sebaceous differentiation". Am J Dermatopathol. vol. 27. 2005. pp. 27-33.(A case report of Brooke-Spiegler syndrome describing a patient with various types of benign adnexal neoplasms including composite neoplasms.)
Baykal, C, Yazganoglu, KD. "Dermatological diseases of the nose and ears". An IIIustrated Guide. Springer Berlin. 2010.(An illustrated book giving summarized information about different dermatologic diseases affecting the nose and ears. There are clinical pictures of adnexal tumors located at the nose and ear.)
James, WD, Berger, TG, Elston, DM. "Andrews' diseases of the skin". Clinical Dermatology. Saunders Elsevier. 2006.(Detailed textbook especially about clinical dermatology. Skin adnexal tumors are well-described clinically.)
Autio-Harmainen, H, Pääkkö, P, Alavaikko, M, Karvonen, J, Leisti, J. "Familial occurrence of malignant lymphoepithelial lesion of the parotid gland in a Finnish family with dominantly inherited trichoepithelioma". Cancer. vol. 61. 1988. pp. 161-6.(Case report of a BSS kindred showing potential malignant lymphoepithelial lesions within the partotid gland.)
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