CYLD cutaneous syndrome (CCS) encompasses three rare inherited cutaneous adnexal tumor syndromes: multiple familial trichoepithelioma (MFT1) (also termed epithelioma adenoides cysticum and epithelioma adenoides cysticum of Brooke), Brooke–Spiegler syndrome (BSS), and familial cylindromatosis (FC). Cutaneous adnexal tumors are a large group of skin tumors that consist of tissues that have differentiated (i.e. matured from stem cells) towards one of the four primary adnexal structures found in normal skin: hair follicles, sebaceous sweat glands, apocrine sweat glands, and eccrine sweat glands. CCS tumors are hair follicle tumors.
Individuals with the MFT1, BSS, and FC forms of CCS carry a germline (i.e. present in the germ cells which give rise to an individual) mutation in one of their two CYLD (i.e. CYLD lysine 63 deubiquitinase) genes. These individuals have skin tumors that tend to cluster into MFT1, BSS, and/or FC types that differ from each other in their locations, organizations, and microscopic appearances. Nonetheless, members of a single family with CCS can manifest either a FC-, MFT1- or BSS-type pattern. Furthermore, these different patterns have little or no impact on the prognoses or course of individuals with CCS. The term "CYLD cutaneous syndrome" as applied to individuals with MFT1, BSS, or FC hair follicular tumors and carrying a hereditary CYLD mutation was first proposed by Rajan et al. in 2009.
Individuals with CCS generally develop increasing numbers of benign skin tumors beginning in their youth and continuing throughout most of their lives. In uncommon cases, they develop malignant tumors many of which appear to arise from their benign tumors. Tumors that are unacceptably symptomatic, highly disfiguring, or malignant are treated by surgical excision methods plus, in cases of malignancy or other medial considerations, radiation therapy. Radiation therapy alone may be used in cases of surgically inaccessible tumors. All individuals with CCS should have routine yearly or more frequent follow-up examinations to check for the development of malignant tumors. Individuals with CCS along with their close family members should be offered access to in depth genetic counselling. Research is needed to find the best treatments, including drugs, for these tumors.
Presentation Individuals with CCS generally have a family history of this disease and present with multiple (sometimes more than 100) benign hair follicle tumors most often on their head and torso. The tumors usually begin at puberty and progressively accumulate throughout adulthood although they have occurred in children as young as 1 year of age. In severe cases, the tumors are highly disfiguring, extend throughout most of the scalp, face, and/or other hair-bearing sites such as the pubic area, and uncommonly are malignant and may metastasize to non-cutaneous sites. Milia, i.e. inconspicuous small cutaneous white spots caused by clogged eccrine sweat glands, may also occur in CCS and sometimes are the only indication that an individual has CCS; these individuals may develop tumors later in life and are at risk of having children with the full-blown disease. CCS presentations are related to the microscopic histopathologies (see next section) of their tumors. i.e. their tumors may resemble non-familial cylindromas, spiradenomas, and/or trichoepitheliomas. Cylindroma-like CCS tumors appear as smooth nodular masses that are typically pink in color, may be translucent, may have superficial blood vessels, grow progressively over many years, and can reach several centimeters (cm) in size. Two or more of these tumors may merge to form far larger sized tumors. Spiradenoma-like CCS tumors also appear as nodular tumors but these may be blue/black in color, painful, rapidly growing and, like cylindromas, may merge to form large-size tumors. Features of both cylindroma-like and spiradenoma-like tumors (i.e. spiradenocylindromas) can occur in a single tumor. Trichoepithelioma-like CCS tumors appear as skin-coloured, small, papules usually located in the skin around the nose, nasolabial fold, and/or forehead. In individuals of European ancestry, the papules are usually 0.3-0.4 cm in size but in individuals of African, Indian, and Chinese ancestry may be larger.
The MFT1 form of CCS typically presents with multiple trichoepithelioma-like tumors, the BSS form presents with cylindroma-, spiradenoma-, and/or trichoepithelioma-like tumors or papules, and the FC form typically presents with multiple cylindroma-like papules. Uncommonly, individuals with CCS develop malignant tumors that occur within or near to their benign tumors; they are primarily malignant counterparts to the cylindromas, spiradenomas, trichoepitheliomas and are termed cylindrocarcinomas, spiradenocarcinomas, and trichoblastic carcinomas, respectively. Some of these tumors resemble basal-cell carcinomas or adenocarcinomas. These malignant tumors may metastasize to non-cutaneous tissues such as the salivary glands (i.e.basal cell adenocarcinomas of a salivary gland), liver, lungs, and/or bones. Malignant CCS tumors occur more often in older individuals and tend to be larger (i.e. ranging up to 17.5 cm in size) than their benign counterparts.
Non-familial cylindromas, spiradenomas, spiradenocylindromas and their malignant counterparts present as a single isolated tumor or, less commonly, multiple tumors. These tumors are sporadic (i.e. not inherited) and may or may not consist of cells bearing a CYLD gene mutation. If present, the mutated CYLD gene's location is restricted to the tumor cells. These sporadic tumors are neither manifestations of nor diagnosed as CCS.
Histopathology As determined by the microscopic histopathological appearance of their hematoxylin and eosin-stained samples, CCS tumor tissues resemble sporadic cylindromas, spiradenomas, or trichoepitheliomas. Cylindroma-like CCS tumors are non-encapsulated nodular lesions that extend into the dermis, consist of basal cells (i.e. small, round cells similar to those seen in the lowest layer of the skin's epidermis), and are arranged in ("jigsaw-like") cylindrical patterns separated by thickened basement membranes. Spideradenoma-like CCS tumors consist of a relatively disorganized and dense array of proliferating basophilic cells (i.e. cells appearing blue because of their abnormally large uptake of the hematoxylin stain). Lymphocytes commonly populate these tumors' tissues. Some CCS tumors (i.e. spiradenocylindromas) merge the histopathological features of cylindromas and spiradenomas. Trichoepithelioma-like CCS papules are composed of islands and cords of uniform basaloid cells (i.e. cuboid-shaped cells resembling skin germinative cells) in a fibrous stroma, epithelial structures resembling hair papillae or incompletely-formed hair follicles, small keratocysts (i.e. skin cysts) lined by stratified squamous epithelium, and foci of calcification. The basaloid cells typically express epithelial cell adhesion molecule as detected by immunohistochemical analyses using the BerEp4 antibody. The tumor tissues of trichoepithelioma-like CCS tumors may also contain Merkel cells that express the CK20 protein. Cylindrocarcinoma and spiradenocarcinoma tumors, unlike their benign counterparts, consist of low-grade or high-grade, atypical appearing cells that are rapidly proliferating (as defined, for example, by the cells showing high levels of the Ki67 protein marker of cell proliferation), may not express the Myb protein, and, with respect to spiradenocarcinoma tumors, usually do not have lymphocytes. Trichoblastic carcinomas differ from their benign counterparts by consisting of hypercellular, fibrous, non-myxoid stroma, often resemble and may be diagnosed as basal cell carcinomas, and in high-grade tumors have extensive areas of necrosis (i.e. dead tissue); the cells in these tumors are rapidly proliferating.
Genetics CCS is an autosomal dominant disorder inherited from a parent carrying an inactivating mutation in one of his or her two CYLD genes. The mutation apparently causes hair follicle stem cells to differentiate into the cells which form cylindroma-, spiradenoma-, trichoepithelioma-, and/or spiradenocylindroma-like lesions. Penetrance (i.e. the percentage of individuals with CCS that exhibit symptoms of the disease) has ranged from 44% to 100% (overall average, 72%) in different studies. However, these studies usually assayed blood leukocyte samples for expression of the mRNA encoded by the CYLD gene to infer its presence. Recent studies find many cases of CCS involve mutations that go undetected by this method because they are: 1) mosaic mutations which distribute CYLD to blood leukocytes but little or none to hair follicles; 2) deep intronic mutations (i.e. mutations that occur deep within a CYLD gene's introns) to result in the formation of mRNAs that do not code for an active protein but are detected as "normal" CYLD mRNA; and 3) copy number variation mutations that result in the development of CYLD mRNA levels that vary widely in and within different tissues and in blood leukocytes samples may be high enough to give positive results but in hair follicles are too low to prevent tumor formation. Genetic Tests which analyzed skin tumors rather than blood leukocytes, analyzed two or more skin tumors or blood leucocyte samples, and/or used sensitive next-generation sequencing of the CYLD gene have found evidence for inactivating CYLD gene mutations in cases that otherwise would be regarded as CYLD gene positive and therefore not CCS.
Recent studies of 14 individuals with CCS indicate that their tumor cells have lost expression of both CYLD genes. This double gene mutation in CCS tumor cells was found in all benign and some malignant CCS tumors suggesting that it may be a consistent feature in CCS. In this view, individuals with CCS carry an inherited, germline mutation in one CYLD gene that is widely distributed to the cells throughout the body plus am uninherited, acquired mutation in the second CYLD gene (see loss of heterozygosity) that is restricted to their CCS tumor cells. The lose of both CYLD genes in hair follicle stem cells may be required for the development of CCS tumors.
CYLD gene's mechanism of action The CYLD gene is located in band 12.1 on the long (or "q") arm of chromosome 16. It is classified as a tumor suppressor gene, i.e. a gene that regulates cell growth and when inactivated by a mutation leads to uncontrolled cell growth and the formation of tumors. Inactivating CYLD gene mutations occur in T-Cell Acute Lymphoblastic Leukemia, multiple myeloma, hepatocellular carcinoma, neuroblastoma, pancreatic cancer, uterine cancer, stomach cancer, colon cancer, lung cancer, and human papillomavirus-associated cancers. In a study of 95 mutations in CCS, 48% were frameshift, 27% were nonsense, 12% were missense, and 11% were splice site mutations. Uncommonly, individuals with CCS have deep intronic mutations (i.e. mutations occurring in an intron that is more than 100 base pairs away from an exon–intron boundary) or large scale mutations that delete most or all of the CYLD gene. All of these mutations are inactivating mutations.