Key points

Introduction

Tumors of the skin appendages occur sporadically and as part of inherited syndromes. Although these tumors have been described in the medical literature for many years, it is only recently that advances in genetics have allowed clinicians to further understand the origin of these lesions and delineate the clinical syndromes with which they are associated.

Skin appendages are derived from the embryonic ectoderm and include three histologically distinct structures: (1) the pilosebaceous unit (hair follicle and sebaceous glands), (2) the eccrine sweat gland, and (3) the apocrine gland. Tumors of these adnexal structures are classified according to their differentiation as follicular, sebaceous, eccrine or apocrine. Cylindromas are a type of skin appendage tumor thought to arise from hair follicle stem cells. Most present as papules on the skin, mainly on the face and scalp, which can be difficult to differentiate clinically. Diagnosis is often made on histologic assessment of skin biopsy. Although found only rarely on a sporadic basis, cylindromas are the characteristic tumor occurring in multiple numbers in several syndromes.

The autosomal-dominant condition familial cylindromatosis (FC; OMIM 132700 ) is now known to be caused by a germline mutation in the gene CYLD . The first reported case of a patient with FC was described by Ancell in 1842 ( Fig. 1 ) and since then cylindroma, a benign skin appendage tumor, has continued to fascinate, with new mechanistic understandings and insights unfolding up to the present day.

The first patient with multiple cylindromas reported in the medical literature, a 52-year-old English woman, described by Ancell in 1842. She presented with metastatic disease and had a strong family history of cutaneous tumors.

( From Ancell H. History of a remarkable case of tumors, developed on the head and face; accompanied with a similar disease in the abdomen. Med Chir Trans 1842;25:227; with permission.)

In addition to FC, cylindromas are also found in two additional related tumor syndromes. Multiple familial trichoepitheliomas (MFT; OMIM 601606 ) is a condition defined by the trichoepithelioma, a small skin-colored tumor mainly found on the face, with cylindromas coexisting in lower numbers. Brooke-Spiegler syndrome (BSS; OMIM 605041 ) is considered an overlap between FC and MFT, and here cylindroma and trichoepithelioma occur together with another related tumor, spiradenoma. Key early descriptions of these conditions, which led to the eponymous “BSS,” include a report of a British family with multiple trichoepitheliomas by Brooke in 1892, and an Austrian case of cylindromas by Spiegler in 1899.

Cue forward to the year 2000, and the CYLD gene was discovered by positional cloning and Sanger sequencing. In-depth study of pedigrees with FC using a genetic technique called “linkage analysis” pinpointed the CYLD locus to chromosome 16q, which led subsequently to identification of the gene itself. With this came the confirmation that FC, MFT, and BSS are not in fact separate entities, but overlapping phenotypes resulting from mutations leading to loss of functional CYLD. CYLD functions as a recessive tumor-suppressor gene, and cylindromas show loss of heterozygosity at the CYLD locus as a result of a somatic second-hit on top of a pre-existing germline mutation. Collectively, these conditions may be termed CYLD cutaneous syndrome, because individual labels do not prognosticate.

The discovery of CYLD paved the way for several major steps forward that have occurred in the past 16 years. The mechanisms of tumor formation in the skin can now be investigated and understood on a molecular genetic basis. In addition, the wider role of CYLD has been explored and the cell signaling pathways it regulates have become better understood.

This article provides an overview of the features of the cutaneous tumors that arise in CYLD mutation carriers. Current knowledge of the gene and its function are reviewed, before considering how insights gained from this scientific information may be used toward investigating novel therapeutic strategies in patients.

Introduction

Tumors of the skin appendages occur sporadically and as part of inherited syndromes. Although these tumors have been described in the medical literature for many years, it is only recently that advances in genetics have allowed clinicians to further understand the origin of these lesions and delineate the clinical syndromes with which they are associated.

Skin appendages are derived from the embryonic ectoderm and include three histologically distinct structures: (1) the pilosebaceous unit (hair follicle and sebaceous glands), (2) the eccrine sweat gland, and (3) the apocrine gland. Tumors of these adnexal structures are classified according to their differentiation as follicular, sebaceous, eccrine or apocrine. Cylindromas are a type of skin appendage tumor thought to arise from hair follicle stem cells. Most present as papules on the skin, mainly on the face and scalp, which can be difficult to differentiate clinically. Diagnosis is often made on histologic assessment of skin biopsy. Although found only rarely on a sporadic basis, cylindromas are the characteristic tumor occurring in multiple numbers in several syndromes.

The autosomal-dominant condition familial cylindromatosis (FC; OMIM 132700 ) is now known to be caused by a germline mutation in the gene CYLD . The first reported case of a patient with FC was described by Ancell in 1842 ( Fig. 1 ) and since then cylindroma, a benign skin appendage tumor, has continued to fascinate, with new mechanistic understandings and insights unfolding up to the present day.

The first patient with multiple cylindromas reported in the medical literature, a 52-year-old English woman, described by Ancell in 1842. She presented with metastatic disease and had a strong family history of cutaneous tumors.

( From Ancell H. History of a remarkable case of tumors, developed on the head and face; accompanied with a similar disease in the abdomen. Med Chir Trans 1842;25:227; with permission.)

In addition to FC, cylindromas are also found in two additional related tumor syndromes. Multiple familial trichoepitheliomas (MFT; OMIM 601606 ) is a condition defined by the trichoepithelioma, a small skin-colored tumor mainly found on the face, with cylindromas coexisting in lower numbers. Brooke-Spiegler syndrome (BSS; OMIM 605041 ) is considered an overlap between FC and MFT, and here cylindroma and trichoepithelioma occur together with another related tumor, spiradenoma. Key early descriptions of these conditions, which led to the eponymous “BSS,” include a report of a British family with multiple trichoepitheliomas by Brooke in 1892, and an Austrian case of cylindromas by Spiegler in 1899.

Cue forward to the year 2000, and the CYLD gene was discovered by positional cloning and Sanger sequencing. In-depth study of pedigrees with FC using a genetic technique called “linkage analysis” pinpointed the CYLD locus to chromosome 16q, which led subsequently to identification of the gene itself. With this came the confirmation that FC, MFT, and BSS are not in fact separate entities, but overlapping phenotypes resulting from mutations leading to loss of functional CYLD. CYLD functions as a recessive tumor-suppressor gene, and cylindromas show loss of heterozygosity at the CYLD locus as a result of a somatic second-hit on top of a pre-existing germline mutation. Collectively, these conditions may be termed CYLD cutaneous syndrome, because individual labels do not prognosticate.

The discovery of CYLD paved the way for several major steps forward that have occurred in the past 16 years. The mechanisms of tumor formation in the skin can now be investigated and understood on a molecular genetic basis. In addition, the wider role of CYLD has been explored and the cell signaling pathways it regulates have become better understood.

This article provides an overview of the features of the cutaneous tumors that arise in CYLD mutation carriers. Current knowledge of the gene and its function are reviewed, before considering how insights gained from this scientific information may be used toward investigating novel therapeutic strategies in patients.

Skin tumors associated with germline cylindromatosis mutations

Clinical Features

Cylindromas are benign, well-circumscribed, smooth, pale pink nodular tumors, often with arborizing vessels visible ( Fig. 2 ). The tumors are slow growing and vary in size from a few millimeters to more than 5 cm. In severe cases, tumors may cover most of the scalp, which led to the previously used term “turban tumor.” Spiradenomas are benign nodular tumors that are often blue-black in color. They tend to be painful and can grow up to 10 cm in diameter. Trichoepitheliomas are benign tumors, presenting as skin-colored papules. They are mainly found on the face, and are small, usually no more than 2 to 5 mm across. All benign, these skin appendage tumors occur in FC, MFT, and BSS.

Clinical and histologic features of skin tumors in CYLD cutaneous syndrome. Cylindroma: a well-circumscribed, nodular lesion with visible arborizing vessels arising from the scalp. Stain shows typical nests of basaloid cells arranged in a cylinder pattern (hematoxylin-eosin, original magnification ×10). Spiradenoma: a nodular lesion with a characteristic blue hue ( black arrow ). Stain shows a disorganized structure, with densely packed basophilc cells (hematoxylin-eosin, original magnification ×10). Trichoepithelioma: Small skin-colored papules occurring in the typical melolabial distribution ( white arrows ). Stain shows a nodular arrangement of basaloid cells in the dermis (hematoxylin-eosin, original magnification ×10).

Tumors usually start to occur in the second or third decades and accumulate throughout adulthood and most patients with a CYLD mutation present with more than one tumor type. Mutations in CYLD are transmitted in an autosomal-dominant fashion and affect males and females equally. The expression and penetrance of tumor development can vary, however, and there have been reports of a female preponderance to tumors in mutation carriers.

Histologic Features

Cylindromas are thought to arise from precursor cells in the hair follicle epithelium, although previously there has been debate as to the cell of origin, and whether they derive from the follicular, apocrine, or eccrine line (see Fig. 2 ). Cylindromas are nonencapsulated nodular tumors extending into the dermis. They consist of well-defined nests of basaloid cells in a jigsaw pattern, separated by an eosinophilic basement membrane. The term cylindroma is based on the description of the nests of basaloid cells that resemble cylinders when cut in cross-section. Spiradenomas lack the organized structure of cylindromas. They comprise a dense basophilic cellular pattern, vessels may be obvious, and there is often a lymphocytic infiltrate. Some individual lesions show histologic features consistent with both cylindroma and spiradenoma, and have been given the overlap term spiradenocylindromas. Indeed, cylindroma and spiradenoma may represent extremes of a spectrum of the same tumor type, with the transition to spiradenoma being influenced by epigenetic modulation of cell-signaling pathways, such as Wnt. Both tumor patterns express cytokeratins seen in hair follicles, such as CK14 and CK17, and also have regions where cytokeratins seen in eccrine glands are present, such as CK18 and CK77 ( Fig. 3 ). Trichoepitheliomas are nontender skin-colored nodules, with islands of basaloid cells, sometimes displaying peripheral palisading.

Expression of hair follicle and eccrine duct keratins in cylindroma frozen tissue sections. ( A ) Cytokeratin 14 (CK14) is widely expressed in tumor cells. ( B ) Cytokeratin 17 (CK17) is also widely expressed in tumors ( red stain ). Few cells express ki67 ( green stain ) indicating low proliferation. ( C ) Small areas within cylindromas express cytokeratin 18 (CK18). ( D ) Areas of ductal differentiation within tumors express cytokeratin 77 (CK77). DAPI (4′,6-diamidine-2’-phenylindole dihydrochloride) was used for nuclear staining.