Background
Cylindromas, also known as cutaneous or dermal cylindromas, are rare and benign skin appendage tumors. Taking into account nomenclature, this disease should be differentiated from adenoid cystic carcinomas (ACCs), which—although histologically similar [1, 2, 3, 4, 5, 6] and are also often described as cylindromas—categorically fall under the larger umbrella of salivary gland neoplasms. Cylindromas can be seen in conjunction with spiradenomas and trichoepitheliomas. Cases of spiradenocylindromas, which demonstrate characteristics of both spiradenoma and cylindroma in the same tumor mass, have also been observed, suggesting similar derivation of both tumors. [7]
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). [2, 8]
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 very primitive sweat gland tumors differentiating toward either the eccrine or apocrine line.
Sporadic cylindromas
Researchers have noted an MYB-NFIB gene fusion, which provides a new genetic link between dermal cylindroma and adenoid cystic carcinoma. In instances in which no positive result is found for fusion, MYB activation may be enough to manifest a subset of sporadic cylindromas. [3, 9]
Inherited cylindromas
In contrast to sporadic cylindromas, according to one study, the fusion of MYB-NFIB genes was absent for CYLD-defective tumors in inherited disorders. Like sporadic dermal cylindroma, however, MYB activation was also commonly noted. [3, 10] CYLD cutaneous syndrome is new nomenclature proposed to cover inheritable CYLD germline mutations, grouping together Brooke-Spiegler syndrome (BSS), familial cylindromatosis, and multiple familial trichoepithelioma 1. [11] One other autosomal dominant familial disorder to display cylindroma is neurofibromatosis type 1; however, it has only been documented in one case report as of 2015. [12]
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. [13, 14]
In 2006, Zhang et al [15] 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 [16] 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 [17] 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.
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. [18]
In 2013, a major international study noted 86 CYLD mutations in BSS and multiple familial trichoepitheliomas (MFT) syndrome. Of the 76 tumors from 32 patients with a germline CYLD mutation, 26 were cylindromas and 15 spiradenocylindromas. 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. [19]
While BSS with a new nonsense germline proband mutation of CYLD (c.1783C>T pGln 595*) has also been noted. [20]
In 2018, a case series reported a patient presenting solely with cylindromas having a mutation of c.2109-2A>C. Prior to this, this mutation had only been noted in a family with trichoepitheliomas. [21] These and other studies further underline the variability and expression of somatic mutations. [22]
Another study on BSS was unable to find any correlation between genotype and phenotype in its sample pool. [23]
Down-regulation of CYLD occurred in a case of breast cancer and may be an independent genetic mutation associated with poor prognosis. [24] One study found another marker, DOG1, to be common in mammary and apocrine-eccrine tumors, including cylindroma. [25]
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, therefore, cylindromas and spiradenomas represent the least differentiated follicular tumors. [26]
Etiology
The cause of sporadic, solitary cylindromas is largely unknown; however, genetic studies of sporadic cylindromas show loss of heterozygosity at and around the CYLD locus in a substantial number of cases, suggesting that this gene also plays a role in the development of sporadic tumors.
The tyrosine kinase pathway might be a treatment target in tumors with defective CYLD. [27]
Familial cylindromatosis is inherited in an autosomal dominant fashion, and the responsible gene, CYLD, is located on band 16q12-13. Tumors exhibit loss of heterozygosity, implicating the gene as a tumor suppressor gene. The precise biological function of the CYLD gene is yet to be elucidated. It has four functional motifs: CAP-GLY domains, proline-rich domains, metal-binding fingerlike domains, and regions with homology to UCH-catalytic domains. The CYLD gene consists of 20 exons; the first three are untranslated and the latter 17 are coding exons. Various mutations have been observed, such as frameshift, nonsense (p.R758X), or splice site mutations. [28] Most mutations occur in 3'2/3rds of the C-terminal coding portion of the gene, in exons 9-20.
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. [18]
International
The exact international incidence of cylindromas is not known. However, inherited CYLD cutaneous syndrome—often presenting with cylindromas—was estimated to occur in 1 case per 100,000 population in the United Kingdom. [29] Additional cases have been reported in China, India, and continental Europe. [2, 30, 31]
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. [10]
Prognosis
Most cylindromas are benign, but some are malignant and potentially lethal; 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.
Patient Education
Advise genetic counseling for the multiple variant of cylindromas. The families of patients who are found to have cylindromas as part of CYLD mutations should be advised that they are also at 50% probability of having a mutation as well, even if currently asymptomatic. [29]
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Dermal cylindroma. Hematoxylin and eosin stain. High magnification. Courtesy of Nephron (own work), via Wikimedia Commons.
