What is cylindroma

Cylindromas are rare benign skin appendage tumors that typically present as a skin colored, reddish or bluish nodule(s) that may range in size from a few millimeters to several centimeters (Figure 1). Cylindromas can be seen in conjunction with spiradenomas and trichoepitheliomas. Multiple tumors are observed in an autosomal dominantly inherited manner may be seen in familial autosomal dominant cylidromatosis/Brooke-Spiegler syndrome  or multiple familial trichoepitheliomas syndrome (cylindromas, trichoepitheliomas, and spiradenomas) typically appear after puberty with slowly growing and often numerous lesions. 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.

Cylindromas most commonly occur on the scalp, head and neck as solitary or multiple tumors. They occur sporadically, are solitary and occasionally painful. Solitary cylindromas occur sporadically and typically are not inherited. When nodules enlarge and coalesce on the scalp, they form the distinctive “turban” tumor feature.

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.

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.

Cylindromas are benign but incomplete biopsy/removal may result in local recurrence.

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

Multiple lesions are disfiguring and require extensive surgical management to restore anatomic appearance. An association with familial autosomal dominant cylindromatosis and basal cell carcinoma has been reported. Brooke-Speigler syndrome has been associated with other cutaneous findings, unilateral hearing loss, and manifesting with pegged teeth.

Figure 1. Cylindroma

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Cylindroma causes

Sporadic, nonhereditary cylindromas are skin adnexal tumors with immunohistochemical and cytologic features of apocrine differentiation. Cylindromas are most likely a very primitive sweat gland tumor differentiating toward either the eccrine or apocrine line. The cellular origin of cylindromas remains unknown.

Brooke-Spiegler syndrome/familial cylindromatosis is characterized by a heterozygous germ-line mutation in the carboxyl-terminal end of the CYLDgene (16q12-q13). The CYLD gene appears to function in tumor-suppressor gene regulation, since tumorigenic epidermal cells have been shown to diminish the deubiquitinating activity of the endogenous CYLD, resulting in increased expression of several angiogenic factors leading to accelerated proliferation and migration of tumoral cells. Brooke-Spiegler syndrome 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 Brooke-Spiegler syndrome include parotid basal cell adenomas, organoid nevi, syringomas, and basal cell carcinomas. Despite variable phenotypic expressions of a predominant tumor in Brooke-Spiegler syndrome, 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 ².

In 2006, Zhang et al ³ reported a large consanguineous Chinese family with Brooke-Spiegler syndrome 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 ⁷ 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.

In 2013, a major international study ⁸ noted 86 CLYD mutations in Brooke-Spiegler syndrome and multiple familial trichoepitheliomas syndrome (MFT). 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.

Brooke-Spiegler syndrome with a new nonsense germline proband mutation of CYLD (c.1783C>T pGln 595*) has been noted ¹¹.

Cylindroma histology

Cylindroma is a dermal tumor without attachment to the epidermis. The lesion is composed of numerous oval and polygonal nests molded into a jigsawlike pattern. Masses of epithelial cells are surrounded and penetrated by a hyaline sheath closely resembling a basement membrane. This sheath separates the tumor from the dermal mesenchyme, yet does not interfere with tumor growth and proliferation.

Malignant cylindromas demonstrate islands of cells displaying marked anaplasia and pleomorphism of nuclei. Mitoses are increased and are abnormal. Besides invasion into surrounding tissue, loss of the delicate hyaline sheath occurs.

Tumor islands are composed of 2 cell types. Peripheral cells are small and highly basophilic; palisading is suggested. Larger, more pale-staining cells are seen centrally. Small tubal lumina are sometimes found with careful observation.

A lack of lymphoid tissue is a histological feature that differentiates cylindromas from spiradenomas. Spiradenomas show a unique prominent presence of lymphocytes. Cylindromas, on the other hand, demonstrate a large number of prominent dendritic cells that most likely represent Langerhans cells that permeate the tumor. S-100 protein–, HLA-DR–, and CD1a-positive cells can be seen in cylindromas and represent the existence of Langerhans cells.

Hyaline bands, which surround tumor islands, are mostly composed of type IV collagen. This is equivalent to the subepidermal lamina densa. Fragments of anchoring fibrils, identical to type VII collagen, are also seen. These anchoring fibrils can also be seen embedded in basement membrane on electron microscopy (EM).

The hyaline membrane is highly enlarged compared with the dermoepidermal junction, as observed by electron microscopy. Electron microscopy demonstrates a basement membrane of 2.7-4.3 µm, compared with the dermoepidermal junction average basement membrane thickness of 60-90 nm. Electron microscopy also demonstrates that cylindromas lack clear distinction of lamina densa. Numerous abnormal inclusions of fibrillar material are noted and appear similar to lamina lucida.

Although hemidesmosomes (HDs) are seen with electron microscopy, they are irregularly spaced and can only be seen in high power, compared with normal basal keratinocytes, in which hemidesmosomes are seen at low power. Hemidesmosomes noted in the cylindroma cells have greater size variation and half the normal number of basal keratinocytes.

Immunohistochemical studies on cylindromas demonstrate a variation in cell matrix proteins compared with normal epidermal basal keratinocytes. Alpha-6-beta-4 integrin expression in tumor cells is weaker. In normal basal keratinocytes, laminin-5 is understood as necessary for hemidesmosome and basement membrane formation. Further studies have shown an improper processing of laminin-5 in cylindromas. This may explain the lower percentage of hemidesmosomes in cylindromas. Cylindromas also demonstrate low expression of alpha-6-beta-4 integrins. These changes may be the cause the structural abnormalities seen in the basement membranes of cylindromas.

Immunohistochemical analysis has demonstrated myoepithelial, apocrine, eccrine, ductal, and secretory features in both cylindromas and spiradenomas. Alpha-SMA, indicating myoepithelial differentiation, has been shown to be expressed in the basaloid cells of both tumors. Both tumors also demonstrate S-100 protein expression, a marker designating eccrine differentiation and apocrine markers, human milk fat globulin, and lysozyme. In addition, expression of keratin polypeptides 10 and 14, specific for ductal epithelium, and keratins 7, 8, and 18, specific for secretory cells, have been observed in both cylindromas and spiradenomas.

Nerve growth factor, S-100 protein, CD44, and CD34 are other markers that have been found to be expressed in or surrounding eccrine coils and are not expressed in the eccrine duct or apocrine gland. These markers have all been found to varying degrees in cylindromas. Other immunohistochemical studies linking cylindromas to eccrine differentiation include positive expression of cytokeratins 19 and 1/10/11. IKH-4 is a monoclonal antibody specific for the eccrine gland and will not stain apocrine glands. This marker can also be used to differentiate eccrine from apocrine tumors and is positive in eccrine cylindromas and spiradenomas ¹².

Immunohistochemical studies linking cylindromas to apocrine differentiation include the expression of alpha-1-antichymotrypsin, alpha smooth muscle actin (1A4), and cytokeratins 8 and 18.

Staining for cytokeratin 15, a marker specific for hair follicle stem cells, has also been shown in some cylindromas and spiradenomas. The expression of follicular, apocrine, and eccrine features in cylindromas suggests that the tumor may be derived from epithelial stem cells of immature differentiation.

Markers expressed in cylindromas and both eccrine and apocrine glands include epithelial membrane antigen, carcinoembryonic antigen, mucinlike carcinoma-associated antigen (B12), laminin, collagen IV, fibronectin, and CD34(QBEND/10).

Cylindroma diagnosis

Dermatoscopic examination of cylindromas demonstrates arborizing telangiectasia and scattered white globules on a background of white to salmon-pink. The vascular branches appear more pronounced when examined at the periphery. The vascular branches extend from the periphery into the center of the cylindroma ¹³.

Biopsy is required to confirm the diagnosis and to histologically characterize the neoplasm. Light microscopy with ordinary hematoxylin and eosin (H&E) staining is sufficient for diagnosis of cylindroma. Histologically, angular and ovoid dermal islands composed of an inner larger basaloid polygonal cell population and outer small round cell population are delineated from the stroma by a basement membrane and are arranged in a mosaic or jigsaw pattern (Figure 3). Lobules may contain hyaline deposits and small tubular lumina.

Cylindromas are distinguished microscopically from basal cell carcinomas, which contain irregular basaloid lobules with peripheral palisading of nuclei, often with a connection to the epidermis, that have artifactual retractions from a mucinous stroma on sun-damaged skin. Cylindromas may have similar cytologic features similar to those of spiradenomas; however, the rounded tumor lobules in spiradenomas often contain a vascular stroma containing lymphocytes and lack the mosaic pattern.

A breast cylindroma that displays MYB expression is a benign tumor, with CYLD gene mutations differing from an adenoid cystic carcinoma. In the breast, the diagnosis of a benign cylindroma was made using reverse-transcription polymerase chain reaction, fluorescence in situ hybridization, whole-exome sequencing, immunohistochemistry, and revealing a MYB-NFIB fusion gene absence and decreased levels of expression of MYB protein with a clonal somatic CYLD splice site mutation accompanying a wild-type allele linked with an absence of heterozygosity showing a benign cylindroma ¹⁴.

Cylindroma treatment

For solitary lesions, the treatment of choice is surgical excision. Other treatments include electrodesiccation/curettage and cryotherapy ¹⁵.

For small cylindromas, the carbon dioxide laser may be used ¹⁶. Retamar et al ¹⁷ used carbon dioxide laser to treat facial trichoepitheliomas in 2 patients, with good results.

Multiple cylindromas usually require extensive plastic surgery that may be obviated by progressively excising a group of nodules in multiple procedures.

Long-term monitoring

Follow-up care of patients with multiple cylindromas is recommended because of the tendency for new lesions to develop. Follow-up care is also recommended because of the risk of malignant degeneration.

Cylindroma 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.

References

1. Inherited cylindromas: lessons from a rare tumour. The Lancet Oncology Volume 16, ISSUE 9, Pe460-e469, September 01, 2015 https://doi.org/10.1016/S1470-2045(15)00245-4
2. Bowen S, Gill M, Lee DA, et al. Mutations in the CYLD gene in Brooke-Spiegler syndrome, familial cylindromatosis, and multiple familial trichoepithelioma: lack of genotype-phenotype correlation. J Invest Dermatol. 2005 May. 124(5):919-20.
3. Zhang G, Huang Y, Yan K, et al. Diverse phenotype of Brooke-Spiegler syndrome associated with a nonsense mutation in the CYLD tumor suppressor gene. Exp Dermatol. 2006 Dec. 15(12):966-70
4. Stegmeier F, Sowa ME, Nalepa G, Gygi SP, Harper JW, Elledge SJ. The tumor suppressor CYLD regulates entry into mitosis. Proc Natl Acad Sci U S A. 2007 May 22. 104(21):8869-74.
5. Massoumi R, Paus R. Cylindromatosis and the CYLD gene: new lessons on the molecular principles of epithelial growth control. Bioessays. 2007 Dec. 29(12):1203-14.
6. Fehr A, Kovács A, Löning T, Frierson H Jr, van den Oord J, Stenman G. The MYB-NFIB gene fusion-a novel genetic link between adenoid cystic carcinoma and dermal cylindroma. J Pathol. 2011 Jul. 224(3):322-7
7. Trufant J, Robinson M, Patel R. Brooke-Spiegler syndrome. Dermatol Online J. 2012 Dec 15. 18(12):16.
8. Grossmann P, Vanecek T, Steiner P, et al. Novel and Recurrent Germline and Somatic Mutations in a Cohort of 67 Patients From 48 Families With Brooke-Spiegler Syndrome Including the Phenotypic Variant of Multiple Familial Trichoepitheliomas and Correlation With the Histopathologic Findings in 379 Biopsy Specimens. Am J Dermatopathol. 2013 Feb. 35(1):34-44
9. Hayashi M, Jono H, Shinriki S, Nakamura T, Guo J, Sueta A, et al. Clinical significance of CYLD downregulation in breast cancer. Breast Cancer Res Treat. 2014 Jan 8.
10. Sellheyer K. Spiradenoma and cylindroma originate from the hair follicle bulge and not from the eccrine sweat gland: an immunohistochemical study with CD200 and other stem cell markers. J Cutan Pathol. 2014 Oct 29.
11. Pinho AC, Gouveia MJ, Gameiro AR, Cardoso JC, Gonçalo MM. Brooke-Spiegler Syndrome – an underrecognized cause of multiple familial scalp tumors: report of a new germline mutation. J Dermatol Case Rep. 2015 Sep 30. 9 (3):67-70.
12. Ishihara M, Mehregan DR, Hashimoto K, et al. Staining of eccrine and apocrine neoplasms and metastatic adenocarcinoma with IKH-4, a monoclonal antibody specific for the eccrine gland. J Cutan Pathol. 1998 Feb. 25(2):100-5
13. Cohen YK, Elpern DJ. Dermatoscopic pattern of a cylindroma. Dermatol Pract Concept. 2014 Jan 31. 4(1):67-8
14. Fusco N, Colombo PE, Martelotto LG, De Filippo MR, Piscuoglio S, Ng CK, et al. Resolving quandaries: basaloid adenoid cystic carcinoma or breast cylindroma? The role of massively parallel sequencing. Histopathology. 2016 Jan. 68 (2):262-271
15. Cylindroma Treatment & Management. https://emedicine.medscape.com/article/1056630-treatment
16. Rallan D, Harland CC. Brooke-Spiegler syndrome: treatment with laser ablation. Clin Exp Dermatol. 2005 Jul. 30(4):355-7
17. Retamar RA, Stengel F, Saadi ME, et al. Brooke-Spiegler syndrome – report of four families: treatment with CO2 laser. Int J Dermatol. 2007 Jun. 46(6):583-6.