Cutaneous Cylindromas Research Articles

CYLD-mutant cylindroma-like basaloid carcinoma of the anus: a genetically and morphologically distinct class of HPV-related anal carcinoma

Rare reports of anal carcinoma (AC) describe histologic resemblance to cutaneous cylindroma, but mutations in the tumor suppressor CYLD, the gene responsible for familial and sporadic cylindromas, have not been systematically investigated in AC. Here, we investigate CYLD-mutant AC, focusing on molecular correlates of distinct histopathology. Comprehensive genomic profiling (hybrid-capture-based DNA sequencing) was performed on 574 ACs, of which 75 unique cases (13%) harbored a CYLD mutation. Clinical data, pathology reports, and histopathology were reviewed for each CYLD-mutant case. The spectrum of CYLD mutations included truncating (n = 50; 67%), homozygous deletion (n = 10; 13%), missense (n = 16; 21%), and splice-site (n = 3; 4%) events. Compared with CYLD-wildtype AC (n = 499), CYLD-mutant ACs were significantly enriched for females (88% vs. 67%, p = 0.0001), slightly younger (median age 59 vs. 61 years, p = 0.047), and included near-universal detection of high-risk HPV sequences (97% vs. 88%, p = 0.014), predominantly HPV16 (96%). The CYLD-mutant cohort also showed significantly lower tumor mutational burden (TMB; median 2.6 vs. 5.2 mut/Mb, p < 0.00001) and less frequent alterations in PIK3CA (13% vs. 31%, p = 0.0015). On histopathologic examination, 73% of CYLD-mutant AC (55/75 cases) showed a striking cylindroma-like histomorphology, composed of aggregates of basaloid cells surrounded by thickened basement membranes and containing characteristic hyaline globules, while only 8% of CYLD-wildtype tumors (n = 34/409) contained cylindroma-like hyaline globules (p < 0.0001). CYLD-mutant carcinomas with cylindroma-like histomorphology (n = 55) showed significantly lower TMB compared with CYLD-mutant cases showing basaloid histology without the distinctive hyaline globules (n = 14) (median 1.7 vs. 4.4 mut/Mb, p = 0.0058). Only five CYLD-mutant cases (7%) showed nonbasaloid conventional squamous cell carcinoma histology (median TMB = 5.2 mut/Mb), and a single CYLD-mutant case showed transitional cell carcinoma-like histology. Within our cohort of ACs, CYLD mutations characterize a surprisingly large subset (13%), with distinct clinical and genomic features and, predominantly, a striking cylindroma-like histopathology, representing a genotype-phenotype correlation which may assist in classification of AC.

Inherited pulmonary cylindromas: extending the phenotype of CYLD mutation carriers.

SummaryBackgroundGermline mutations in the tumour suppressor gene CYLD are recognized to be associated with the development of multiple cutaneous cylindromas. We encountered such a patient who presented with breathlessness because of multiple pulmonary cylindromas.ObjectivesTo search for clinical and radiological features of multiple pulmonary cylindromas in a cohort of 16 patients with CYLD mutations.MethodsA retrospective case‐note review was carried out in a tertiary dermatogenetics clinic where CYLD mutation carriers are reviewed on an annual basis. In‐depth investigation was carried out for patients with pulmonary tumours.ResultsFour patients had radiological imaging of their lungs, of which two had multiple pulmonary cylindromas that were confirmed histologically. Serial computed tomography monitoring allowed for pre‐emptive endobronchial laser ablation, preventing major airway obstruction and pulmonary collapse.ConclusionsPulmonary cylindromas are an unrecognized, but infrequently symptomatic, aspect of the phenotype in these patients that can have implications for patient care. They should be considered in patients with a high tumour burden that present with respiratory symptoms, and where appropriate, monitored with serial imaging.

非典型的な血管腫が併存した皮膚円柱腫の 1 例

非典型的な血管腫が併存した皮膚円柱腫の 1 例

Cutaneous cylindroma: it's all about MYB.

Cutaneous cylindroma is a rare benign tumour that occasionally turns into malignant cylindrocarcinoma. The cancer can be sporadic or emerge in the context of Brooke-Spiegler syndrome (BSS), an inheritable condition characterized by mutation of the gene CYLD, encoding a tumour suppressor protein that controls the activity of the transcription factor NF-kB. Sporadic cylindromas present histological features shared with adenoid cystic carcinoma (ACC), a head and neck cancer originating from salivary or other exocrine glands. Like ACCs, sporadic cylindromas express, although at lower frequency, the aberrant fusion transcript MYB-NFIB. In a paper recently published in the Journal of Pathology, the research teams led by Neil Rajan and Goran Stenman demonstrate that CYLD-defective cyclindromas in BSS patients are negative for the MYB-NFIB fusion. Only the wild-type MYB oncoprotein is activated in the majority of these tumours. RNA interference studies in cells derived from BSS patients indicate that ablating MYB expression results in a striking reduction of cylindroma cell proliferation, suggesting that MYB plays a pivotal role in the biology of this cancer. The take-home message of the study is that activation of MYB, in its wild-type form or fusion derivatives, is a common feature of spontaneous and hereditary cylindromas, constituting a potentially actionable therapeutic target. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Overexpression of MYB drives proliferation of CYLD-defective cylindroma cells.

Cutaneous cylindroma is an adnexal tumour with apocrine differentiation. A predisposition to multiple cylindromas is seen in patients with Brooke–Spiegler syndrome, who carry germline mutations in the tumour suppressor gene CYLD. Previous studies of inherited cylindromas have highlighted the frequent presence of bi‐allelic truncating CYLD mutations as a recurrent driver mutation. We have previously shown that sporadic cylindromas express either MYB–NFIB fusion transcripts or show evidence of MYB activation in the absence of such fusions. Here, we investigated inherited cylindromas from several families with germline CYLD mutations for the presence of MYB activation. Strikingly, none of the inherited CYLD‐defective (n = 23) tumours expressed MYB–NFIB fusion transcripts. However, MYB expression was increased in the majority of tumours (69%) and global gene expression analysis revealed that well‐established MYB target genes were up‐regulated in CYLD‐defective tumours. Moreover, knock‐down of MYB expression caused a significant reduction in cylindroma cell proliferation, suggesting that MYB is also a key player and oncogenic driver in inherited cylindromas. Taken together, our findings suggest molecular heterogeneity in the pathogenesis of sporadic and inherited cutaneous cylindromas, with convergence on MYB activation. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Skull Invaders: When Surgical Pathology and Neuropathology Worlds Collide

Skull and dura serve as effective barriers to penetration by most tumors, often preventing masses originating intracranially from extending into the contiguous bone and soft tissues, or those arising in head and neck regions from extending into the dura and brain tissue. We review our 15-year experience with extracranial tumors that had sufficiently invaded adjacent skull, dura, or brain from the "outside-in" to require a neurosurgeon to participate in the surgical resection and discuss our 40 cases in context with the literature. Sinonasal-origin tumors (n = 17) and cutaneous tumors (n = 10) were the most frequent skull-invaders. Most of the cutaneous tumor types were squamous cellcarcinomas (n = 9); diverse sinonasal-origin types included 4 squamous cell carcinomas, 4 adenoid cystic carcinomas, 2 sinonasal undifferentiated carcinomas, 2 sinonasal adenocarcinomas, and single examples each of sinonasal-origin hemangiopericytoma, solitary fibrous tumor, melanoma, mucocele, and teratocarcinoma. There were 9olfactory neuroblastomas, and middle ear-origin basal cell carcinoma,recurrent glomus jugulare, and orbital malignant hidradenoma were also seen. Unique tumors included a cutaneous cylindroma invasive of skull convexity occurring in familial cylindromatosis and a ganglioneuroma of the middle ear with massive bilateral skull base extension. Convexity dural spread, a seldom-reported pattern of dissemination, was seen in 1 olfactory neuroblastoma and 1 adenoid cystic carcinoma. The ability to show skull/dural invasion did not correlate with specific histopathologic features; even benign tumor types can show skull/dural penetration.

Dermoscopy of solitary cylindroma

ejd.2011.1413 Auteur(s) : Aimilios LALLAS emlallas@gmail.com, Zoe APALLA, Thrasivoulos TZELLOS, Ioanna LEFAKI State Clinic of Dermatology, Hospital of Venereal and Skin Diseases, Delfon 124, 54643 Thessaloniki, Greece Cutaneous cylindroma is a benign sweat gland tumor which usually develops as a solitary nodule of the face or scalp [1]. Dermoscopy is a valuable tool for evaluation and differential diagnosis of both malignant and benign skin neoplasms, including adnexal tumors. We present the dermoscopic [...]

Parotid mass in a woman with multiple cutaneous cylindromas

Familial autosomal dominant cylindromatosis (FADC) is a rare disease characterized by multiple cutaneous cylindromas, trichoepitheliomas, and spiradenomas. We present a case of a woman with scalp lesions and a parotid mass. Biopsy of a skin nodule demonstrated cylindroma, and fine-needle aspiration of the parotid mass suggested membranous basal cell adenoma, which was confirmed following superficial parotidectomy. The study includes case report and review of the literature. Eighteen cases of cylindromatosis with coexistent salivary gland membranous basal cell adenoma were reported. Seventeen cases involved the parotid gland; there are 2 reports of malignant transformation. FADC should be considered in anyone with coexistent dermal and salivary gland neoplasms. Membranous basal cell adenoma may be mistaken for adenoid cystic carcinoma on cytologic or histologic examination. Total parotidectomy with facial nerve preservation or superficial parotidectomy with close follow-up is recommended, as multifocality and malignant transformation exist.

Skin type spiradenoma of the parotid gland with malignant transformation: Report of a case with analysis of the CYLD gene

A distinctive variant of basal cell adenoma called membranous basal cell adenoma is well recognized in salivary glands. It appears identical to cutaneous cylindroma, hence the synonym dermal analogue tumor. We present a case of a tumor involving the parotid gland that appeared identical to cutaneous spiradenoma. In addition, the lesion had a malignant component identical to basal cell adenocarcinoma. The patient had no features suggestive of Brooke-Spiegler syndrome. Analysis of the CYLD gene revealed polymorphisms. This is the first report of a "dermal analogue tumor" of the salivary gland that resembled a cutaneous spiradenoma and not a cylindroma.

Distinct expression patterns of α1 (IV) and α5 (IV) collagen chains in cylindroma and malignant cylindroma

Cutaneous cylindromas are considered to derive from cells of the sweat gland apparatus. The composition of the thick hyaline eosinophilic basement membrane (BM)-like zone surrounding epithelial aggregates in cylindromas is similar to that of the dermo-epidermal junction. The presence of type IV collagen has been documented, but the distribution of the different constitutive a chains of collagen IV has not been studied so far. Alterations in the expression of these alpha chains have been described in some other conditions including basal cell carcinomas, testes with spermatogenic dysfunction and colorectal carcinomas. The aim was to study the distribution of the alpha1 (IV) and alpha5 (IV) collagen chains in cylindromas and malignant cylindroma, and to compare it with the BM of sweat glands. Seven cylindromas and one malignant cylindroma were studied. They were formalin-fixed and paraffin-embedded before processing for immunohistochemistry. Immunostaining was assessed using the avidin-biotin-peroxidase technique with antibodies directed to the alpha1 (IV) and alpha5 (IV) collagen chains. In all cylindromas, a thin continuous and sharply limited immunolabelling for the alpha1 (IV) collagen chain was abutted to the tumoral cell aggregates. A speckled immunoreactivity was found in the rest of the hyaline sheath. Globular structures encased in the cell aggregates also exhibited a thin peripheral rim positive for the alpha1 (IV) collagen chain. The immunoreactivity was faint and granular in the center of the globules. With the antibody directed against the alpha5 (IV) collagen chain, 3 cylindromas did not show any staining, 2 cases presented discrete focal positivity in the mid-part of the BM-like zone, and 2 cases exhibited a positive staining pattern similar to that observed for the alpha1 (IV) collagen chain, but with a focal and more discrete intensity. The malignant cylindroma showed a linear immunoreactivity for the alpha1 (IV) collagen chain undistinguishable from the pattern seen in the benign cylindromas. No immunoreactivity was present for the alpha5 (IV) collagen chain in the malignant neoplasm. As reported for other BM components, the expressions of the alpha1 (IV) and alpha5 (IV) collagen chains are altered in the BM-like zone surrounding the epithelial clumps in cylindromas. The molecular alteration is probably related to the ultrastructural particularities of this structure. The distinctive patterns of expression of the alpha1 (IV) and alpha5 (IV) collagen chains may be related to the histogenic sudoral origin of cylindromas without any relationship with the benign or malignant nature of the neoplasm.

Unwrapping the Turban Tumor Gene

A predisposition to the development of multiple cutaneous cylindromas is known to be inherited in an autosomal dominant pattern. The predilection of

Familial cutaneous cylindromas: Investigations in five generations of a family

Background: Multiple cutaneous cylindromas are probably inherited in an autosomal dominant way. Objective: Our purpose was to describe a large family with cutaneous cylindromas, trichoepitheliomas, and milia occurring in five generations and to elucidate further the mode of inheritance. Methods: We examined 39 family members and obtained information on 31 other members from reports of relatives. Results: The pedigree included 237 members, 118 male and 119 female, with 30 affected patients (11 male, 19 female). Between 33% and 100% of the children of affected family members had one or more of these skin lesions. Female-to-female, female-to-male, male-to-female, and male-to-male inheritance occurred. Conclusion: Multiple cutaneous cylindromas are inherited in an autosomal dominant way with variable clinical expression. Penetrance reaches 100% in adult life. This condition is associated with trichoepitheliomas and milia.

Cylindroma expresses immunohistochemical markers linking it to eccrine coil

Nerve growth factor, S-100 protein, CD44, and CD34 have unique expressions in or surrounding eccrine coil but are not found in eccrine duct or apocrine gland. We studied 15 cases of cutaneous cylindroma to see if these antigens are found in this neoplasm. All were found in cylindroma to varying degrees. These results link the histogenesis of cylindroma to the eccrine coil. A unique feature of cylindroma is the large number of prominent dendritic cells most likely representing Langerhans cells that permeate the tumor aggregates.

Autosomal dominant multiple cylindromas associated with solitary lung cylindroma

The occurrence of multiple cutaneous cylindromas constitutes an uncommon autosomal dominant cutaneous disorder whose associations usually are limited to other cutaneous tumors. We report here the first case of a patient with multiple cutaneous cylindromas, who concurrently had a benign lung cylindroma with histologic features identical to her skin lesions. She also had a family history of early death from cardiac disease.

Metamorphosis of dermal cylindroma Possible relation to malignant transformation: Case report of cutaneous cylindroma with direct intracranial invasion

A case of locally invasive cutaneous cylindroma is reported. This neglected scalp tumor, 6.5 cm in greatest dimension, initially invaded the calvaria at the time of the first operation. A recurrence infiltrated the dura and presented as an intracranial space-occupying lesion. No brain invasion was present and distant metastases were not documented. The patient remains well 2 1/2 years after tumor resection. Light and electron microscopic appearance of the recurrent tumor revealed distinct morphologic features, which may be of use in predicting the biologic behavior of cutaneous cylindromas. This case documents the low biologic aggressiveness of cylindroma and stresses the necessity of complete surgical excision of neoplasms with atypical morphologic features.