HDAC3 ensures stepwise epidermal stratification via NCoR/SMRT-reliant mechanisms independent of its histone deacetylase activity.

Chromatin modifiers play critical roles in epidermal development, but the functions of histone deacetylases in this context are poorly understood. The class I HDAC, HDAC3, is of particular interest because it plays divergent roles in different tissues by partnering with tissue-specific transcription factors. We found that HDAC3 is expressed broadly in embryonic epidermis and is required for its orderly stepwise stratification. HDAC3 protein stability in vivo relies on NCoR and SMRT, which function redundantly in epidermal development. However, point mutations in the NCoR and SMRT deacetylase-activating domains, which are required for HDAC3's enzymatic function, permit normal stratification, indicating that HDAC3's roles in this context are largely independent of its histone deacetylase activity. HDAC3-bound sites are significantly enriched for predicted binding motifs for critical epidermal transcription factors including AP1, GRHL, and KLF family members. Our results suggest that among these, HDAC3 operates in conjunction with KLF4 to repress inappropriate expression of Tgm1, Krt16, and Aqp3 In parallel, HDAC3 suppresses expression of inflammatory cytokines through a Rela-dependent mechanism. These data identify HDAC3 as a hub coordinating multiple aspects of epidermal barrier acquisition.

Central centrifugal cicatricial alopecia in males.

BACKGROUND: Central centrifugal cicatricial alopecia (CCCA) is a scarring alopecia seen primarily in women of African descent but rarely reported in men. The etiology of CCCA is unknown, but genetic variants, type 2 diabetes mellitus, and bacterial infections may play a role. OBJECTIVES: We aimed to characterize the demographics, medical histories, and clinical findings of male patients with CCCA with the hypothesis that features may differ from women. METHODS: This was a case series of adult male patients with biopsy-confirmed CCCA seen at an academic dermatology department between 2012 and 2022. RESULTS: In total, 17 males had a scalp biopsy and clinical findings consistent with CCCA. The average age was 43 years, and 88.2% of cases identified as Black race. Scalp pruritus was the most common symptom, and few patients endorsed high-risk hair care practices. None of the cases had diagnosis of type 2 diabetes mellitus, but 17.6% had history of latent tuberculosis, and 47.1% had a positive family history of alopecia. We observed 8 patients with atypical CCCA, and 29.4% had an overlapping scalp diagnosis. LIMITATIONS: This study is limited by the single center, retrospective design and small sample size. CONCLUSIONS: It is important to consider CCCA in the differential diagnosis of alopecia in adult Black males.

Cytoplasmic chromatin triggers inflammation in senescence and cancer.

Chromatin is traditionally viewed as a nuclear entity that regulates gene expression and silencing. However, we recently discovered the presence of cytoplasmic chromatin fragments that pinch off from intact nuclei of primary cells during senescence, a form of terminal cell-cycle arrest associated with pro-inflammatory responses. The functional significance of chromatin in the cytoplasm is unclear. Here we show that cytoplasmic chromatin activates the innate immunity cytosolic DNA-sensing cGAS-STING (cyclic GMP-AMP synthase linked to stimulator of interferon genes) pathway, leading both to short-term inflammation to restrain activated oncogenes and to chronic inflammation that associates with tissue destruction and cancer. The cytoplasmic chromatin-cGAS-STING pathway promotes the senescence-associated secretory phenotype in primary human cells and in mice. Mice deficient in STING show impaired immuno-surveillance of oncogenic RAS and reduced tissue inflammation upon ionizing radiation. Furthermore, this pathway is activated in cancer cells, and correlates with pro-inflammatory gene expression in human cancers. Overall, our findings indicate that genomic DNA serves as a reservoir to initiate a pro-inflammatory pathway in the cytoplasm in senescence and cancer. Targeting the cytoplasmic chromatin-mediated pathway may hold promise in treating inflammation-related disorders.

Clinical, pathologic, and molecular analyses of superficial low-grade fibromyxoid sarcoma in two young patients: A rare and deceptive mimic of benignancy.

Low-grade fibromyxoid sarcoma (LGFMS) is a histopathologically deceptive soft tissue neoplasm with bland cytology, which is typically encountered in deep soft tissue of adults. We report two cases of superficial LGFMS in young patients (16 and 21 years old, respectively), which were difficult to diagnose on histopathologic and clinical findings alone. LGFMS commonly mimics benign neoplasms such as cellular neurothekeoma, fibromatosis, neurofibroma, and perineurioma. Malignancies included in the differential diagnosis are soft tissue neoplasms such as dermatofibrosarcoma protuberans and myxofibrosarcoma. A high degree of reported variation in pattern and cellularity among LGFMS further complicates the diagnosis. Careful examination and appropriate immunohistochemistry panels including MUC4 are essential for narrowing the differential diagnosis. Molecular studies for possible FUS translocation can confirm the diagnosis of LGFMS. Sufficient sampling and workup of these lesions are critical, especially in younger patients. Young age and superficial presentation can easily sway dermatopathologists/dermatologists toward an incorrect diagnosis of benignancy.

Cutaneous Ganglioneuromas With Overlying Epidermal Hyperplasia: A Case Series Presentation and Proposal of Potential Etiopathogenesis.

ABSTRACT: Cutaneous ganglioneuromas (GNs) are exceptionally uncommon tumors, and many reported cases describe association with overlying epidermal hyperplasia that may be interpreted as seborrheic keratosis (SK) or SK-like proliferation. We report 5 cases of cutaneous GN in adult patients; all of which were discovered incidentally in the immediate vicinity of epidermal hyperplasia. A review of the literature demonstrates the current-although likely imperfect-understanding of the etiopathogenesis of both SK and GN in the skin. We explore the putative pathophysiologies of other common, well-characterized skin lesions and, taking them into account, provide rationale for the coexistence of cutaneous GN with overlying SK and SK-like epidermal changes. However, we ultimately acknowledge a dilemma of causality and, given the rarity of their co-occurrence, objectively question whether occasional cameo appearances by GN lying subjacent to SK and SK-like hyperplasia may be due merely to chance.

Molecular Mechanisms of Cutaneous Squamous Cell Carcinoma.

Non-melanoma skin cancers are cutaneous malignancies representing the most common form of cancer in the United States. They are comprised predominantly of basal cell carcinomas and squamous cell carcinomas (cSCC). The incidence of cSCC is increasing, resulting in substantial morbidity and ever higher treatment costs; currently in excess of one billion dollars, per annum. Here, we review research defining the molecular basis and development of cSCC that aims to provide new insights into pathogenesis and drive the development of novel, cost and morbidity saving therapies.

Downregulation of Src-family tyrosine kinases by Srcasm and c-Cbl: A comparative analysis.

AIM: Elevated Src-Family tyrosine kinase (SFK) activity drives carcinogenesis in vivo and elevated SFK activity is found ubiquitously in human cancers. Although human squamous cell carcinomas (SCCs) demonstrate increased SFK activity, in silico analysis of SCCs demonstrates that only 0.4% of lesions contain mutations that could potentially increase SFK activity; similarly, a low frequency of activating SFK mutations is found in other major cancers. These findings indicate that SFK activation in cancers likely is not due to activating mutations but alternative mechanisms. To evaluate potential alternative mechanisms, we evaluated the selectivity of c-Cbl and Srcasm in downregulating native and activated mutant forms of SFKs. MATERIALS AND METHODS: We co-transfected native and activated forms of Src and Fyn with c-Cbl and Srcasm into HaCaT cells and monitored the ability of Srcasm and c-Cbl to downregulate native and activated forms of SFKs by Western blotting. The mechanism of downregulation was probed using mutant forms of Srcasm and c-Cbl and using proteosomal and lysosomal inhibition. RESULTS: The data indicate that Srcasm downregulates native Fyn and Src more effectively than c-Cbl, whereas c-Cbl preferentially downregulates activated SFK mutants, including Fyn Y528F, more effectively than Srcasm. Srcasm downregulates SFKs through a lysosomal-dependent mechanism while c-Cbl utilizes a proteosomal-dependent mechanism. CONCLUSION: Given the rarity of activating SFK mutations in human cancer, these data indicate that decreasing Srcasm level/function may represent a mechanism for increasing SFK activity in SCC and other human tumors.

A rare case of a periorbital respiratory (choristomatous) cyst.

Respiratory cysts are benign lesions lined by normal respiratory epithelium. There are few reported cases localized to the orbit, while those of the eyelid are exceedingly rare. Respiratory cysts usually arise either from a non-hereditary congenital malformation, where they are distinguished as choristomatous, or from trauma. Here, we report a case of a 53-year-old man who presented with a large right lower eyelid cyst that was histopathologically diagnosed as a respiratory cyst.

Ethical and professionalism issues in dermatopathology: A cross-sectional survey of American Society of Dermatopathology Members.

BACKGROUND: Data regarding ethical/professional issues affecting dermatopathologists are lacking despite their importance in establishing policy priorities and educational content for dermatopathology. METHODS: A 14-item cross-sectional survey about ethical/professional issues in dermatopathology was distributed over e-mail to members of the American Society of Dermatopathology from June to September 2019. RESULTS: Two hundred sixteen surveys were completed, with a response rate of 15.3%. Respondents ranked appropriate and fair utilization of healthcare resources (n = 83 or 38.6%) as the most often encountered ethical/professional issue. Conflict of interest was ranked as the most urgent or important ethical/professional issue (n = 83 or 39.3%). One hundred thirty-three (61.6%) respondents felt "somewhat" or "not at all" well equipped to handle ethical dilemmas in practice and 47 (22.8%) respondents identified a major or extreme burden (eg, have considered resigning/retiring) due to ethical challenges. CONCLUSIONS: Areas of priority in ethics and professionalism issues can guide future policy and educational content in dermatopathology.

Voriconazole enhances UV-induced DNA damage by inhibiting catalase and promoting oxidative stress.

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer and is associated with cumulative UV exposure. Studies have shown that prolonged voriconazole use promotes cSCC formation; however, the biological mechanisms responsible for the increased incidence remain unclear. Here, we show that voriconazole directly increases oxidative stress in human keratinocytes and promotes UV-induced DNA damage as determined by comet assay, 8-oxoguanine immunofluorescence and mass spectrometry. Voriconazole treatment of human keratinocytes potentiates UV-induced apoptosis and activation of the p38 MAP kinase and 53BP1 UV stress response pathways. The p38 MAP kinase activation promoted by voriconazole exposure can be mitigated by pretreating keratinocytes with N-acetylcysteine. Voriconazole increases oxidative stress in keratinocytes by directly inhibiting catalase leading to lower intracellular NADPH levels and the triazole moieties in voriconazole are critical for inhibiting catalase. Furthermore, voriconazole is shown to promote UV-induced dysplasia in an in vivo model. Together, these data demonstrate that voriconazole potentiates oxidative stress in UV-irradiated keratinocytes through catalase inhibition. Use of antioxidants may mitigate the pro-oncogenic effects of voriconazole.

Characterization of the inflammatory features of central centrifugal cicatricial alopecia.

Central centrifugal cicatricial alopecia (CCCA) is a scarring alopecia that primarily affects women of African descent. Although histopathological features of CCCA have been described, the pathophysiology of this disease remains unclear. To better understand the components of CCCA pathophysiology, we evaluated the composition of the inflammatory infiltrate, the distribution of Langerhans cells (LCs), and the relationship between fibrosis and perifollicular vessel distribution. Our data indicate that CCCA is associated with a CD4-predominant T-cell infiltrate with increased LCs extending into the lower hair follicle. Fibroplasia associated with follicular scarring displaces blood vessels away from the outer root sheath epithelium. These data indicate that CCCA is an inflammatory scarring alopecia with unique pathophysiologic features that differentiate it from other lymphocytic scarring processes.

Lupus Miliaris Disseminatus Faciei of the Posterior Eyelids: A Case Report.

A 70-year-old woman with a history of Demodex blepharitis presented with a 1-year history of red-yellow nodules in the tarsus of her eyelids. Excisional biopsy revealed robust caseating granulomatous inflammation, consistent with the diagnosis of lupus miliaris disseminatus faciei. Lupus miliaris disseminatus faciei is a rare granulomatous dermatosis of unknown etiology. Estimated 200 cases have been reported to date, but none have been reported affecting the posterior lamellae of the eyelids. Lupus miliaris disseminatus faciei classically presents as symmetric yellow or brown papules on the central face and eyelid skin. Infectious etiologies and systemic granulomatous disease need to be ruled out with histologic staining and serologies.

Topical kinase inhibitors induce regression of cutaneous squamous cell carcinoma.

Actinic keratoses (AKs) and squamous cell carcinoma in situ (SCCIS) are precursor lesions for cutaneous squamous cell carcinoma (cSCC), the second most common form of cancer. Current topical therapies for AKs and SCCIS promote skin inflammation to eradicate lesions and do not directly target the biological mechanisms driving growth. We hypothesized that topical small molecule inhibitors targeting kinases promoting keratinocyte growth in AKs and SCCIS could induce regression of these lesions with less inflammation. To test this hypothesis, we determined the efficacy of topical dasatinib, 5-fluorouracil and BEZ-235 in inducing regression of cSCCs in the K14-Fyn Y528 transgenic mouse model. Topical dasatinib induced regression of cSCC with less inflammation, no ulceration and no mortality compared to 5-fluorouracil. Topical BEZ-235 induced cSCC regression similar to dasatinib without erythema or ulceration. These data indicate that topical small molecule kinase inhibitors targeting drivers of AK/SCCIS/cSCC growth represent a promising therapeutic approach to treat these common skin lesions.

Expression of p15 in a spectrum of spitzoid melanocytic neoplasms.

BACKGROUND: Accurate classification of spitzoid melanocytic lesions is difficult due to overlapping clinical and histopathologic features between Spitz nevi, atypical Spitz tumors (ASTs), and spitzoid melanomas. Expression of p16 (CDKN2A) has been used as a marker of spitzoid lesions. However, its expression may be variable. p15 is a tumor suppressor encoded by CDKN2B, loss of which has been recently shown to promote transition from nevus to melanoma. We sought to determine whether p15 is a useful immunohistochemical marker to distinguish Spitz nevi from spitzoid melanomas and to compare p15 and p16 staining in this population. METHODS: Immunohistochemistry for p15 and p16 was performed on Spitz nevi (n = 19), ASTs (n = 41), and spitzoid melanomas (n = 17). Immunoexpression was categorized by a four-tiered system: 0 (negative), 1+ (weak), 2+ (moderate), 3+ (strong). RESULTS: 3+/strong p15 staining was observed in 68.4% of Spitz nevi, 34.2% of ASTs, and 17.7% of spitzoid melanomas. By contrast, we observed 3+ p16 staining in roughly equivalent percentages of Spitz nevi (57.9%), ASTs (56.1%), and spitzoid melanomas (58.8%). CONCLUSION: These data illustrate that p15 may be more useful than p16 as a biomarker to help distinguish benign from malignant spitzoid lesions.

Introduction to the 2016 JID Beijing Workshop: Precision Medicine in Dermatology.

On May 23-25, 2016, investigators from the United States, Europe and China came together for a meeting on "Precision Medicine in Dermatology" at the Beijing Landmark Hotel. This meeting brought together investigators in cutaneous biology from the United States, Europe, and China in a forum to exchange scientific ideas and foster new collaborations. The meeting was hosted and organized by Heng Gu, Yong Cui, and Xuejun Zhang. John Seykora, with valuable assistance from Barbara Gilchrest and Elizabeth Blalock, organized the European and American speakers. The meeting speakers represented 4 universities in the United States, 3 universities from Europe, and 12 institutions in China. There were approximately 200 attendees, and 68 abstracts were submitted.

Srcasm Regulates Tyrosine Kinases in Skin Cancer: Implications for Precision Medicine.

Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer in humans, with an incidence of approximately 700,000 cases per year in the United States (Rogers et al., 2010). It is known that cSCC is strongly associated with sun exposure, specifically UVB and UVA, as well as other risk factors, such as human papillomavirus infection, immunodeficiency, and specific medications (Ratushny et al., 2012). However, the precise sequence of biological events leading to tumor development remains unknown. With projected higher incidence of patients with cSCCs in the future, there is a strong need to elucidate the molecular pathways that regulate formation of cSCCs.

p15 Expression Differentiates Nevus from Melanoma.

Most melanomas are driven by BRAF(V600E)-activating mutations, while nevi harboring the same mutations have growth arrest. Although decreased p16 expression has been associated with melanoma formation, in recent work, p15 represented a primary effector of oncogene-induced senescence in nevomelanocytes that was diminished in melanomas. This study determined whether decreased p15 levels represent a general biomarker for the transition from nevus to melanoma. We performed p15 and p16 IHC analyses on a random series of nevi and melanomas. Staining was evaluated and graded for percentage and intensity to determine the H score. For real-time quantitative RT-PCR analysis of p15, RNA was extracted from FFPE sections from 14 nevus and melanoma samples via macrodissection. A two-sided t-test was used to evaluate between-group differences in mean H scores and qΔCt values. p15 Expression was significantly increased in melanocytic nevi compared with melanomas (mean H scores, 254.8 versus 132.3; P < 0.001). On p15 staining, the H score differential was greater than that with p16 staining [122.5 (P < 0.001) and 64.8 (P = 0.055), respectively]. Real-time quantitative RT-PCR analysis revealed a lower mean qΔCt value in melanomas, consistent with lower p15 expression (P = 0.018). Together, these data support the hypothesis that decreased p15 expression is a robust biomarker for distinguishing nevus from melanoma.