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Brooke-Spiegler syndrome (BSS) is an inherited predisposition syndrome presenting with skin appendage tumors, namely cylindromas, spiradenomas and trichoepitheliomas. A minority of patients can also get major and minor salivary glands neoplasms, usually membranous basal cell adenoma.
To date, >100 cases of BSS have been reported in the literature. Increased severity in females is recognized.
BSS typically manifests in adolescence and early adulthood with the appearance of multiple skin tumors including cylindromas, spiradenomas and trichoepitheliomas. Tumor development is progressive and can affect the head and neck as well as torso. Cylindromas present as different sized pink nodules on the scalp which can become confluent (historically called ''turban tumor''). Spiradenomas are painful blue nodules that can measure several centimeters across. Trichoepitheliomas manifest as skin colored papules or firm nodules, bilateral and symmetrically distributed, preferring the central face region, particularly the nose and the surrounding skin. Patients may also develop small milia on the skin of the face. Malignancies arising in preexisting spiradenoma, cylindroma and spiradenocylindroma have been reported. Patients are also at risk of developing tumors of the major and minor salivary glands, typically membranous basal cell adenoma. Familial cylindromatosis (FC) has been used to characterize patients with predominantly cylindromas on the scalp, and multiple familial trichoepithelioma (MFT) to describe patients that predominantly develop trichoepitheliomas.
BSS is due to germline mutations in CYLD gene (16q12-q13), a tumor suppressor gene which encodes a protein that plays a key role in several signaling pathways, such as NF-κB, JNK, Wnt, TGFB and TRK. BSS, FC, and MFT are allelic.
Diagnosis of cylindromas is based mainly on clinical examination. Histopathologic findings of cylindromas comprise well-circumscribed nests of basaloid cells in the dermis, which are each surrounded by eosinophilic, periodic acid-Schiff-positive, basement-membrane material arrayed in a closely packed, jigsaw-like pattern. Ductal structures can be observed within the nests. Spiradenoma displays a well circumscribed tumor nodule arising within the dermis or superficial subcutis. The tumor is comprised of a diffuse dense basophilic cellular proliferation. Some patients may present mixed features of the two tumors on histology, giving rise to the term spiradenocylindroma. Histopathologic findings of trichoepitheliomas include clusters of basaloid germinative cells with keratinizing cystic spaces and superficial follicular differentiation surrounded by a fibrocytic stroma. Intra-stromal clefts may also be observed. Both spiradenomas and cylindromas display CD200+ cells in their tumor islands, consistent with the model that they may arise from hair follicle stem cells.
Differential diagnosis includes pilar cysts and neurofibromatosis type 1. Facial papules in MFT can mimic papules seen in other conditions such as Birt-Hogg-Dubé syndrome and tuberous sclerosis complex (see these terms).
BSS is inherited as an autosomal dominant trait with high penetrance and variable expressivity.
Management and treatment
Tumors that are painful, impair function, ulcerated or are disfiguring are usually excised and the recurrence rate after excision is about 35%. Excision with narrow margins is the standard method of removal of isolated lesions. Scalp sparing techniques such as enucleation may be used but complete scalp excision is considered a final option. Other therapies such as dermabrasion, electrodissection, cryotherapy, laser resurfacing and ablation may be considered, particularly for smaller lesions such as trichoepitheliomas. Radiotherapy should be avoided as this may cause additional new tumors. Although malignant transformation is uncommon, patients are advised to report signs of ulceration, rapid growth and bleeding. These features should prompt excision and histological assessment.
Tumors observed in BSS are usually benign and most patients have a normal life span.