Carcinosarcoma Arising in a Patient with Multiple Cylindromas

Abstract

Familial cylindromatosis (Brooke-Spiegler syndrome) is a rare autosomal dominant inherited disease characterized by the development of adnexal tumors, mostly cylindromas, but also trichoepitheliomas and spiradenomas. Malignant tumors may occur, usually with the features of a cylindrocarcinoma. The authors describe the case of a 75-year-old woman with the Brooke-Spiegler syndrome who presented with multiple nodules of the scalp, face, and trunk. In 1997 she underwent surgical excision of the entire forehead and scalp with skin grafting. Histologic examination revealed multiple cylindromas, some with areas of spiradenoma and one with an extensive adenomatous component; some trichoepitheliomas were also evident. In 2002, a nodule of the trunk suddenly increased in size and became painful. The lesion was excised and histologic and immunohistochemical evaluation revealed a malignant cutaneous biphasic tumor extending into the subcutis, consisting of a major portion with the features of an adnexal carcinoma and of a minor one of atypical spindle cells. Biphasic malignant skin tumors are rare and only a limited number have been described, none in association with the Brooke-Spiegler syndrome. The authors discuss the morphogenesis of the folliculosebaceous-apocrine unit from which the tumors in this syndrome derive, and the pivotal role of mesenchymal cells in determining the process. Since the Brooke-Spiegler syndrome is characterized by a germline mutation in the CYLD oncosuppressor gene, a biphasic tumor in this setting may represent a true carcinosarcoma.

An inactivating CYLD mutation promotes skin tumor progression by conferring enhanced proliferative, survival and angiogenic properties to epidermal cancer cells

“…In the case of melanoma, in which it has been described that reduced levels of CYLD promote the aggressiveness of the tumors, the reduction in CYLD expression also takes place after previous mutation/s have caused the tumor development (Massoumi et al, 2006). This could explain why malignization of cylindromas in patients of FC occurs with very low frequency (Durani et al, 2001;De Francesco et al, 2005); it could be due to the early age of outcome of the disease (from childhood to the second decade of the life) when previous mutations have not had time to occur in these patients.…”

“…Cylindromatosis patients carry heterozygous germ-line mutations in the carboxyl-terminal end of the CYLD gene, but the wild-type CYLD allele undergoes loss of heterozygosity, indicating that CYLD appears as a tumor-suppressor gene (Bignell et al, 2000). Cylindromas are usually benign, although occasionally they can malignize (Durani et al, 2001;De Francesco et al, 2005). Additional studies have associated Cyld downregulation with the development of other types of human cancer including tumors of colon, lung and kidney, as well as melanomas and cervical and hepatocellular carcinomas (Strobel et al, 2002;Hashimoto et al, 2004;Hirai et al, 2004;Costello et al, 2005;Hellerbrand et al, 2007;Keats et al, 2007;Zhong et al, 2007;Massoumi et al, 2009).…”

Cylindromatosis and the CYLD gene: new lessons on the molecular principles of epithelial growth control

“…Even though this is a very rare event, they can become life-threatening, since cylindroma can undergo malignant transformation into cylindrocarcinoma, resulting in local infiltrative growth and metastatic disease. (3,4) What makes these-usually benign-tumors most interesting, from a growth control and tumor biology perspective, is their association with an autosomal dominantly inherited disease in which multiple cylindromas develop: the BrookeSpiegler syndrome. (5,6) In patients with this syndrome, mutations in the CYLD gene have now been identified, and CYLD has been reported to be the only tumor suppressor gene associated with the development of inherited familial cylindromatosis.…”

Malignant Cylindroma of the Scalp Arising in a Setting of Multiple Cylindromatosis: A Case Report

“…The number of cases still remains variable since not all cases are well documented. We present the demographics, family history, age of onset, metastasis, therapy, local recurrence, follow-up for a total of 34 cases including the present case (Table 1) [2,5,7,[15][16][17][18][19].…”