Nectin-4 expression in a subset of cutaneous adnexal carcinomas: A potential target for therapy with enfortumab vedotin.

BACKGROUND: Enfortumab vedotin (EV) is an antibody-drug conjugate directed against Nectin-4 that is used to treat urothelial carcinoma. Nectin-4 is inherently expressed in the skin and adnexal structures. Since therapeutic options for cutaneous adnexal carcinomas are limited, we sought to evaluate Nectin-4 expression in adnexal carcinomas and benign adnexal neoplasms to identify tumors that are potentially targetable with EV. METHODS: Eight sebaceous carcinomas (seven periocular and one lymph node metastasis), eight digital papillary adenocarcinomas, seven squamoid eccrine ductal carcinomas, eight poromas, eight trichilemmomas, and seven sebaceous adenomas were subjected to immunohistochemical staining for anti-Nectin-4 antibody. H-scores for Nectin-4 expression were calculated. RESULTS: Benign adnexal neoplasms had a significantly lower mean (±SD) Nectin-4 H-score (142.6 ± 39.1) than did the adnexal carcinomas (198 ± 90.8; p = 0.006). Nectin-4 was expressed in 91% (21/23) of adnexal carcinomas. Sebaceous carcinomas frequently exhibited high expression of Nectin-4 (88% [7/8]), with a mean (±SD) H-score (258.1 ± 58.4) significantly higher than those for digital papillary adenocarcinomas (197.5 ± 52.5; p = 0.035) and squamoid eccrine ductal carcinomas (131.4 ± 114.1; p = 0.031). Sebaceous carcinomas also had significantly higher H-scores than did sebaceous adenomas (186.4 ± 25.0; p = 0.013). CONCLUSIONS: Increased Nectin-4 expression in a subset of cutaneous adnexal carcinomas, particularly sebaceous carcinomas, reveals that EV is a potential therapeutic option for these tumors.

Treatment of periorbital syringomas with intradermal botulinum toxin A monotherapy versus carbon dioxide laser: a case report.

Syringomas are eccrine-derived benign adnexal neoplasms with the highest prevalence in early adulthood. They predominantly occur in females. They are commonly located on the face, particularly the lower eyelids, which have a high demand for cosmetic enhancement. Periorbital syringomas continue to pose a therapeutic challenge, with no consistently effective treatment available. Intradermal injection of botulinum toxin A is one of the new treatment modalities for periorbital syringomas. We report a case of periorbital syringomas in a 53-year-old female patient successfully treated using intradermal botulinum toxin A monotherapy as a painless cost-effective treatment that produced better long-term results than carbon dioxide laser.

Trichloroacetic Acid Injection for Treatment of Eyelid Apocrine Hidrocystomas in a Cat.

Apocrine hidrocystoma (AH) is a benign cystic lesion infrequently reported in the eyelids of cats. There are several reports of application of trichloroacetic acid (TCA) for treatment of eyelid apocrine hidrocystomas with high success rates in humans. This is the first report of intralesional injection of TCA for the treatment of eyelid AH in a feline. A 12-year-old Persian female spayed cat has been presented for evaluation of cystic masses on the eyelids. The cat had signs of ocular discomfort and two large cysts on the lower eyelid of the right eye. Ophthalmic examination was suggestive of eyelid AH. The cat underwent general anesthesia, and TCA 20 % was injected intracystically. The diagnosis of AH was confirmed by cytology. Two years later, there was no recurrence of the cyst. This case highlights the successful treatment of a large AH in the eyelids of a cat with TCA. Findings suggest that chemical ablation with TCA may be a useful treatment for AH in cats.

High tumour mutational burden and EGFR/MAPK pathway activation are therapeutic targets in metastatic porocarcinoma.

BACKGROUND: Eccrine porocarcinoma (EPC) is a rare skin cancer arising from the eccrine sweat glands. Due to the lack of effective therapies, metastasis is associated with a high mortality rate. OBJECTIVES: To investigate the drivers of EPC progression. METHODS: We carried out genomic and transcriptomic profiling of metastatic EPC (mEPC), validation of the observed alterations in an EPC patient-derived cell line, confirmation of relevant observations in a large patient cohort of 30 tumour tissues, and successful treatment of a patient with mEPC under the identified treatment regimens. RESULTS: mEPC was characterized by a high tumour mutational burden (TMB) with an ultraviolet signature, widespread copy number alterations and gene expression changes that affected cancer-relevant cellular processes such as cell cycle regulation and proliferation, including a pathogenic TP53 (tumour protein 53) mutation, a copy number deletion in the CDKN2A (cyclin dependent kinase inhibitor 2A) region and a CTNND1/PAK1 [catenin delta 1/p21 (RAC1) activated kinase 1] gene fusion. The overexpression of EGFR (epidermal growth factor receptor), PAK1 and MAP2K1 (mitogen-activated protein kinase kinase 1; also known as MEK1) genes translated into strong protein expression and respective pathway activation in the tumour tissue. Furthermore, a patient-derived cell line was sensitive to EGFR and MEK inhibition, confirming the functional relevance of the pathway activation. Immunohistochemistry analyses in a large patient cohort showed the relevance of the observed changes to the pathogenesis of EPC. Our results indicate that mEPC should respond to immune or kinase inhibitor therapy. Indeed, the advanced disease of our index patient was controlled by EGFR-directed therapy and immune checkpoint inhibition for more than 2 years. CONCLUSIONS: Molecular profiling demonstrated high TMB and EGFR/MAPK pathway activation to be novel therapeutic targets in mEPC.

Topical glycopyrrolate followed by microneedling: a novel treatment option for eccrine hidrocystomas.

Eccrine hidrocystomas (EH) are benign cystic tumors of the eccrine glands with no established treatment yet. Eccrine glands are activated by acetylcholine released from innervating sympathetic nerve fibers. Use of oral anti-cholinergic agents is rare due to the possibility of systemic side effects while topical atropine and scopolamine have been found to be ineffective. In our patient, we tried using topical glycopyrrolate over the entire affected region followed by microneedling. Our aim was to create micro-channels through the epidermis and dermis, delivering the drug to EH lesions in the deeper dermis. We only performed microneedling over the left half of the chest to compare the difference made by microneedling. The effective percutaneous delivery of topical glycol was evident by our patient's transient systemic side effects and reduction of the EH lesions. Specifically, the lesions were reduced more significantly over the left where microneedles were applied. Our treatment was effective for our patient and he was satisfied with the improvement in cosmesis. The method described may serve as a therapeutic option for patients with EH.

Botulinum toxin A as monotherapy for syringoma.

Syringoma is a benign adnexal tumor of the skin originating from the eccrine sweat duct. There is a wide variety of treatments, and most of the patients receive multiple unsuccessful therapies. The goal of this report intends to describe a novel technique applicable to syringoma with botulinum toxin A. A 61-year-old female patient with localized syringomas in the periocular and upper lip region, with a long-lasting history, treated with botulinum toxin A 46 IU as monotherapy intradermally distributed and a follow-up for 8 months. Our patient displayed a significant improvement of the syringomas. Botulinum toxin A is an efficient and safe technique to treat syringomas.

Alternative Clinical Indications of Botulinum Toxin.

Botulinum toxin type A (BoNTA) is a powerful neurotoxin that inhibits acetylcholine release from presynaptic vesicles. The potency and safety profile of BoNTA grant the toxin vast therapeutic potential. It has been used off-label for a variety of dermatologic conditions. This review aims to analyze published literature regarding the benefits and risks of the off-label use of BoNTA beyond facial lines, including eccrine hidrocystomas, enlarged pores, keloids and hypertrophic scars, hidradenitis suppurativa, hyperhidrosis, masseter muscle hypertrophy, and salivary gland hypertrophy, among others. A MEDLINE search from January 2000 to December 2019 was conducted on the off-label uses of botulinum toxin in dermatology.

Resolution of Metastatic Subungal Eccrine Porocarcinoma Treated with Intralesional Interleukin-2.

Eccrine porocarcinoma is a rare aggressive cutaneous malignancy. Complete surgical excision is the standard of care, although there are high rates of local and distant recurrence. We present a unique case of locally recurrent and metastatic subungal porocarcinoma successfully treated with intralesional interleukin-2.

Identification of potentially druggable molecular alterations in skin adnexal malignancies.

Skin adnexal cancers (SAC) are a heterogeneous group of rare malignancies with histological differentiation towards epithelial adnexa, which lack effective systemic treatments. The aim of this work is to identify any potentially druggable genomic alterations for possible targeted therapies. Cases of primary or recurrent/metastatic (RM) SAC between 2002 and 2014 were identified by searching the institutional cancer registration database. Histological sections of all referral cases were reviewed by a dedicated pathologist to confirm diagnosis. Immunohistochemistry was performed to assess the expression of androgen receptors (AR) and human epidermal growth factor receptor type 2 (HER2). Targeted next-generation sequencing (T-NGS) was performed to identify targetable mutations (panel of 50 genes analyzed by Cancer Hotspot Panel, Ion-Torrent Personal Genome Machine). Mutational analysis of the PTCH1 gene not present in the T-NGS panel was assessed by Sanger sequencing. A total of 45 cases with available histological samples were identified (35 primary, 10 RM). The most frequent histological type was porocarcinoma (n = 12). Globally, 14 cases (31%) were AR+ (6/10 RM, 60%; 8/35 primary, 23%). HER2 was shown as 2+ in eight of 42 (19%) cases (2/9 RM, 22%; 6/33 primary, 18%). DNA was adequate for T-NGS analysis in 25 cases. In the majority of cases (17 cases, 68%) at least one mutation in oncogenes or tumor suppressor genes was found: the most frequent ones involved TP.53 (13 cases, 76% of mutated SAC) and PIK3CA (three cases, 18%). The rate of PTCH1 mutation was 30%. These findings support the use of molecular screening in patients with advanced SAC.

Suspected eccrine adenocarcinoma on footpad of the right hindlimb in a dog.

A 12-year-old, male miniature dachshund has an ulcer on the footpad of the right hind limb. Despite treatment for longer than 6 months, the ulcer did not heal. Biopsy of the lesion was done to make a definitive diagnosis. Histologically, there were lumens containing weakly eosinophilic fluid surrounded by tumor cells with a similar circular pale nucleus and distinct nucleoli that showed some variation in size. Immunohistochemically, the tumor cells were positive for cytokeratin (AE1/AE3) and vimentin, were negative for S100 and p63. A poorly differentiated eccrine adenocarcinoma was diagnosed. Treatment was started with toceranib, an anti-angiogenic agent, and enlargement of the lesion was not observed during the administration period.