Cylindroma

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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]

History

The solitary form usually begins in middle age or later as a slow-growing, rubbery nodule exhibiting no symptoms.

The dominantly inherited, multiple variety appears shortly after puberty as numerous, rounded nodules of various sizes ranging from several millimeters to larger than 6 cm. Lesions grow slowly, and additional lesions develop over time.

Loss of CYLD can be linked with development of salivary gland cancers.[11, 32]

Brooke-Spiegler syndrome (BSS) associated with unilateral hearing loss has been reported.[33] BSS manifesting with pegged teeth has also been reported.[34]

 

Physical Examination

Except for BSS, pertinent findings are largely limited to the skin. Histologically similar tumors have been found in the breast, parotid glands, salivary glands, lacrimal gland of the eye, Bartholin glands, the brain, lungs, and kidneys. An interesting case of cylindroma was reported on the breast in 2013.[35, 36]

Skin lesions associated with cylindromas

Solitary lesions are firm, rubbery nodules with pink, red, or sometimes blue coloring that range in size from a few millimeters to several centimeters. Larger solitary growths should not be necessarily ruled out though, because one 7-cm stalked cylindroma with a mushroomlike shape has been observed.[37]

The multiple form has numerous masses of pink, red, or blue nodules, sometimes resembling bunches of grapes or small tomatoes (sometimes called a tomato tumor). One case study of a patient with BSS has reported a plaque with flatter cylindroma rather nodular appearance.[38]

Dermal cylindromas are noted, some which can be in the deep dermis.[39]

Skin distribution of cylindromas

The solitary form is typically found on the head and neck. The multiple form most commonly occurs on the head and neck but can also be seen on the trunk and the extremities.[38]

Complications

A cylindroma occasionally erodes through the skull, after the mass has caused thinning of the neighboring bone.[40]

Anal and rectal spiradenocylindroma-like basaloid carcinomas have been reported, with CYLD gene mutations defined.[41]

Scattered reports exist of malignant transformation of isolated cylindromas, so this must be a consideration for regular follow-up for patients with cylindromas.[40, 42, 43] This includes possible transformation into basal cell carcinoma.[2]

Laboratory Studies

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.[46] Additionally, the expression of both MYB and GATA3 may prove to be useful in differentiating cutaneous adnexal carcinomas and cylindroma (where it is common) from breast and salivary gland metastases (who tend to favor one over the other).[47, 48]

Imaging Studies

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.[49]

Procedures

A skin biopsy may be performed. Light microscopy with ordinary hematoxylin and eosin (H&E) staining is sufficient for diagnosis of cylindroma.

Histologic Findings

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, giving it a cylindrical appearance on histologic cross-section, hence the name cylindroma. This sheath separates the tumor from the dermal mesenchyme, yet it 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 two 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 EM. EM demonstrates a basement membrane of 2.7-4.3 µm, compared with the dermoepidermal junction average basement membrane thickness of 60-90 nm. EM 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 EM, they are irregularly spaced and can only be seen in high power, compared with normal basal keratinocytes, in which HDs are seen at low power. HDs 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 HD and basement membrane formation. Further studies have shown an improper processing of laminin-5 in cylindromas. This may explain the lower percentage of HDs 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.[50]

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).

See the image below.



View Image

Dermal cylindroma. Hematoxylin and eosin stain. High magnification. Courtesy of Nephron (own work), via Wikimedia Commons.

Other Tests

A genetic test can be done for CYLD mutations in both sporadic singular or multiple cylindromas. This test uses a tissue sample (preferably blood in EDTA [ethylenediaminetetraacetic acid]) and polymerase chain reaction amplification of exons 4-20, followed by Sanger sequencing.[29]

Surgical Care

For solitary lesions, the treatment of choice is surgical excision.[51] Other treatments include electrodesiccation/curettage and cryotherapy.

For small cylindromas, the carbon dioxide laser may be used.[52] Retamar et al used carbon dioxide laser to treat facial trichoepitheliomas in two patients, with good results.[53]

Multiple cylindromas usually require extensive plastic surgery that may be obviated by progressively excising a group of nodules in multiple procedures.[54]

Medical Care

Inhibition of NF-κB signalling shows potential to be a therapeutic option outside of surgery for patients with CYLD cutaneous syndrome. Models of TRK signal inhibition almost showed some potential for CYLD-mutation neoplasms.[11]

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.

Author

Angela (Angel) M Crotty, MD, General Medical Officer, Marine Corps Air Station Miramar Branch Clinic, Marine Aircraft Group 11

Disclosure: Nothing to disclose.

Coauthor(s)

Erin B Storie, DO, FAAD, Staff Dermatologist, Naval Hospital Camp Pendleton

Disclosure: Nothing to disclose.

Homavirak Prak, University of California, Los Angeles

Disclosure: Nothing to disclose.

Specialty Editors

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Disclosure: Nothing to disclose.

Christen M Mowad, MD, Professor, Department of Dermatology, Geisinger Medical Center

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Abby S Van Voorhees, MD, Assistant Professor, Director of Psoriasis Services and Phototherapy Units, Department of Dermatology, University of Pennsylvania School of Medicine, Hospital of the University of Pennsylvania

Disclosure: Received honoraria from Amgen for consulting; Received honoraria from Abbott for consulting; Partner received salary from Merck for management position; Received honoraria from Abbott for speaking and teaching; Received honoraria from Amgen for review panel membership; Received honoraria from Centocor for consulting; Received honoraria from Leo for consulting; Received none from Merck for other.

Anusuya Mokashi, MD, MS, Resident Physician, Department of Radiology, Staten Island University Hospital

Disclosure: Nothing to disclose.

Julide Tok Celebi, MD, Assistant Professor of Dermatology, Columbia University, College of Physicians and Surgeons; Consulting Staff, Department of Dermatology, New York Presbyterian Medical Center

Disclosure: Nothing to disclose.

Noah S Scheinfeld, JD, MD, FAAD, † Assistant Clinical Professor, Department of Dermatology, Weil Cornell Medical College; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, New York Eye and Ear Infirmary; Assistant Attending Dermatologist, New York Presbyterian Hospital; Assistant Attending Dermatologist, Lenox Hill Hospital, North Shore-LIJ Health System; Private Practice

Disclosure: Nothing to disclose.

Acknowledgements

Arnold R Oppenheim, MD Assistant Professor, Department of Internal Medicine, Division of Dermatology, Eastern Virginia School of Medicine

Arnold R Oppenheim, MD is a member of the following medical societies: American Academy of Dermatology and American Society for Clinical Pathology

Disclosure: Nothing to disclose.

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Dermal cylindroma. Hematoxylin and eosin stain. High magnification. Courtesy of Nephron (own work), via Wikimedia Commons.

Dermal cylindroma. Hematoxylin and eosin stain. High magnification. Courtesy of Nephron (own work), via Wikimedia Commons.