Cylindroma

Updated: Feb 08, 2016
  • Author: Noah S Scheinfeld, JD, MD, FAAD; Chief Editor: Dirk M Elston, MD  more...
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Overview

Background

Cylindromas are benign skin appendage tumors. They can be seen in conjunction with spiradenomas and trichoepitheliomas. Cases of spiradenocylindromas, demonstrating characteristics of both spiradenoma and cylindroma in the same tumor mass, have also been observed, suggesting similar derivation of both tumors.

They most commonly occur on the head and neck as solitary or multiple tumors. Solitary cylindromas occur sporadically and typically are not inherited. Multiple tumors are observed in an autosomal dominantly inherited manner. When nodules enlarge and coalesce on the scalp, they form the distinctive turban tumor feature.

Malignant cylindromas are very rare. Malignant transformation may develop within solitary cylindromas, or they may complicate the multiple variant (more common).

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Pathophysiology

Cylindromas are appendage tumors previously thought to be of apocrine differentiation. While phenotypic features differ between cylindromas and spiradenomas, recent studies have shown immunohistological and cytomorphological overlap, with both tumors exhibiting apocrine, eccrine, secretory, and ductal features. Therefore, the cellular origin of cylindromas remains unknown. Cylindromas are most likely a very primitive sweat gland tumor differentiating toward either the eccrine or apocrine line.

Brooke-Spiegler syndrome (BSS) has been described as an autosomal dominant disease characterized by the development of multiple skin appendage tumors such as cylindromas, trichoepitheliomas, and spiradenomas, with a variable preponderance of any of the aforementioned subsets. Other lesions reported with BSS include parotid basal cell adenomas, organoid nevi, syringomas, and basal cell carcinomas. Despite variable phenotypic expressions of a predominant tumor in BSS, the gene responsible for multiple cylindromas, CYLD, is localized to band 16q12-q13. The mechanism of genotypic similarity and phenotypic variance is not yet understood. [1, 2]

In 2006, Zhang et al [3] reported a large consanguineous Chinese family with BSS demonstrating intrafamily phenotypic variability. Upon examination, some persons only manifested discrete, small, skin-coloured growths, while the proband manifested an expansion of multiple large growths on the nose and numerous dome-shaped papules on the scalp. Biopsy showed both trichoepitheliomas and cylindromas in the affected persons. By sequence analysis, Zhang et al identified a recurrent mutation 2272C→T (R758X) of the CYLD gene in the affected familial persons that had been previously identified in other ethnic kindreds with familial cylindromatosis.

In 2007, Stegmeier et al [4] noted that the CYLD gene encodes a deubiquitinating enzyme. The enzyme removes Lys-63–linked ubiquitin chains from I-kappaB kinase signaling components. By this mechanism, the enzyme inhibits NF-kappaB pathway activation. They demonstrated that CYLD is also required for the cell's timely entry into mitosis. Consistent with a cell-cycle regulatory function, CYLD localizes to microtubules in interphase and the midbody during telophase. CYLD 's protein levels decrease as cells exit from mitosis. Stegmeier et al identified the protein kinase Plk1 as a potential target of CYLD as a regulator of mitotic entry, and they suggested this because of the physical interaction and similar loss-of-function and over-expression phenotypes.

These findings raise the possibility that, as with other genes that regulate tumorigenesis, CYLD has both tumor-suppressing (apoptosis regulation) and tumor-promoting activities (enhancer of mitotic entry). They suggested that this additional function of CYLD could provide an explanation for the benign nature of most cylindroma lesions.

Massoumi and Paus [5] and explained the manner in which CYLD interferes with tumor necrosis factor-alpha or Toll-like receptor–mediated signaling and with JNK or NF-kappaB-dependent p65/50 signaling to limit inflammation. Additionally, the manner by which CYLD interferes with activation of the proto-oncogene BCL3 and with cyclin D1 expression to limit tumorigenesis was also explained. Finally, the researchers discussed how tumor growth-promoting agents or UV light and inflammatory mediators may activate CYLD.

Researchers have noted a MYB-NFIB gene fusion, which provides a new genetic link between dermal cylindroma and adenoid cystic carcinoma. [6]

As of 2012, researchers have identified 68 unique mutations with variable penetrance and expression (which are both intrafamilial and interfamilial) in CYLD. CYLD functions as a putative tumor suppressor gene that encodes for a deubiquitinating enzyme with functions in cell proliferation and inflammation. [7]

In 2013, a major international study noted 86 CLYD mutations in BSS and multiple familial trichoepitheliomas syndrome (MFT). [8] Of the 76 tumors from 32 patients with a germline CYLD mutation, 26 were cylindromas, 12 were spiradenomas, 15 spiradenocylindromas, 7 were other tumor types, and 15 were trichoepitheliomas. Causes of mutations included frameshift mutations, nonsense mutations, missense mutations, splice-site mutations, somatic mutations, sequence alteration, and loss of heterozygosity. Sometimes the source of mutations remained unknown. The variability of somatic mutations is underlined by this study.

Down-regulation of CLYD occurred in a case of breast cancer and may be an independent genetic mutation associated with poor prognosis. [9]

In a study of 97 tumors, all spiradenomas (27) and cylindromas (30) expressed CD200, while other eccrine (hidradenomas, poromas, dermal duct tumors, and hidroacanthoma simplex) were CD200-negative. CK15 distinguished between spiradenomas and cylindromas. This shows that cylindromas and spiradenomas are follicular tumors; specifically, Sellheyer proposed that both cylindromas and spiradenomas are adnexal neoplasms that were derived from the hair follicle bulge and that therefore cylindromas and spiradenomas represent the least differentiated follicular tumors. [10]

BSS with a new nonsense germline proband mutation of CYLD (c.1783C>T pGln 595*) has been noted. [11]

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Epidemiology

Frequency

United States

Cylindromas are uncommon. The exact incidence is not known. They continue to be reported regularly at dermatology conferences, in particular when linked to BSS. [7]

International

The exact international incidence of cylindromas is not known. A case of Brooke-Spiegler syndrome that included cylindroma was reported in China in 2013. [12]

Race

No racial disparity is reported for cylindromas.

Sex

The incidence of cylindroma is more common in females than in males. Female-to-male ratios of 6:1 and 9:1 have been reported.

Age

Solitary cylindromas are lesions that affect middle-aged and elderly persons. Multiple, inherited cylindromas usually begin in early adulthood and increase in size and number throughout life.

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Prognosis

Most cylindromas are benign but some are malignant and potentially lethal27; at least 14 reports have described malignant transformation. The prognosis is not good with malignancy because visceral metastasis frequently follows.

Multiple cylindromas can cover the entire scalp and cause the disfiguring turban tumor appearance, which necessitates extensive reconstructive surgery.

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Patient Education

Advise genetic counseling for the multiple variant of cylindromas.

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