Evaluation of PRAME immunohistochemistry in cutaneous vascular neoplasms reveals frequent expression in primary and post-irradiation cutaneous angiosarcomas.

BACKGROUND: Preferentially expressed antigen in melanoma (PRAME) has been extensively studied in cutaneous melanocytic tumors and has proven valuable as a diagnostic adjunct in routine dermatopathology practice. However, its expression in cutaneous vascular neoplasms, particularly angiosarcomas (AS), remains largely unexplored. METHODS: To further explore PRAME expression in cutaneous AS, 18 cases of post-irradiation and 13 cases of primary cutaneous AS were evaluated for PRAME. For comparison, sections from 11 deep soft tissue/visceral AS, 10 Kaposi sarcomas, 8 microvenular hemangiomas, 7 infantile hemangiomas, 8 atypical vascular lesions, 6 epithelioid hemangioendotheliomas, 6 pyogenic granulomas, 6 papillary endothelial hyperplasias, 6 epithelioid hemangiomas, 3 capillovenous malformations, 3 hobnail hemangiomas, 2 spindle cell hemangiomas, 2 pseudomyogenic hemangioendotheliomas, and 2 composite hemangioendotheliomas were also retrieved. RESULTS: Overall, 22 of 31 (70.9%; 12 post-irradiation and 10 primary) cutaneous AS were positive for PRAME. In contrast, only 1 of 11 (9.1%) deep soft tissue/visceral AS showed diffuse and strong PRAME nuclear staining. All other tumor types were negative for PRAME, except for 5 of 7 (71.4%) infantile hemangiomas, which demonstrated rare (<5%; four cases) and 1+ (5-25%; one case) nuclear staining. CONCLUSIONS: In this study, we have demonstrated frequent nuclear PRAME expression in cutaneous AS. PRAME immunohistochemistry may serve as a valuable additional marker in selected clinical settings.

MYC-Nonamplified Secondary Lymphatic-Type Angiosarcoma With Prominent Lymphocytic Infiltrate Following Radiation Therapy for Myxoid Liposarcoma.

ABSTRACT: Cutaneous angiosarcomas (AS) are uncommon and morphologically heterogeneous. Recently, a distinctive lymphatic-type AS with prominent lymphocytic infiltrate has been observed. Although conventional AS typically bear poor prognosis, lymphatic-type AS with prominent lymphocytic infiltrate and pseudolymphomatous AS show prolonged survival with rare extracutaneous spread. We describe a unique case of AS in a 55-year-old woman who received surgical resection and radiation therapy for her prior myxoid liposarcoma. She developed a suspected recurrence 15 years later. Microscopically, the lesion showed an infiltration of the reticular dermis by irregular interanastamosing vascular spaces lined by atypical endothelial cells with nuclear "hobnailing" and hyperchromasia. A prominent intratumoral and peritumoral lymphocytic infiltrate obscuring the tumor cells was also present. The tumor cells were diffusely positive for endothelial cell markers, including D2-40. Notably, there was no evidence of MYC gene amplification by FISH. Additional NGS-based molecular analysis demonstrated no significant genetic mutations. The patient is alive with a history of two local recurrences, but no evidence of metastasis. We present this case to raise awareness of MYC-nonamplified secondary lymphatic-type AS with prominent lymphocytic infiltrate (pseudolymphomatous AS) and to discuss its differential diagnosis.

Immunohistochemistry for Preferentially Expressed Antigen in Melanoma in the Differential Diagnosis of Melanocytic Lesions of the Nail Apparatus.

ABSTRACT: Nail unit melanocytic lesions present a unique set of diagnostic challenges because of the unfamiliarity with clinical assessment and the lack of experience with histologic examination. Because the first surgical specimen received in the pathology laboratory is typically small, sometimes suboptimal biopsy, the distinction between melanoma and its histologic mimics can be difficult. For this reason, there has been a continued interest in the development of ancillary markers that may assist in the differential diagnosis of nail unit melanocytic lesions. Upregulation of preferentially expressed antigen in melanoma (PRAME) has been reported to be a common event in melanomas, and PRAME immunohistochemistry has been shown to be helpful in evaluating various melanocytic neoplasms. In this study, we evaluated PRAME protein expression in a series of nail unit melanocytic lesions. Twenty-five nail unit melanomas (including small biopsy and amputation specimens) and 32 control benign melanocytic lesions were retrospectively retrieved. Nuclear PRAME staining was scored as percentage and intensity labeling. All melanoma cases showed the nuclear expression of PRAME, which was usually diffuse and strong. In specimens where the neoplastic cells are limited in number, the staining was restricted to the tumor cells, corresponding to the initial H&E impression. All control cases were negative for PRAME expression. PRAME expression is helpful in distinguishing between melanomas and other nail unit melanocytic lesions. This antibody also proved to be diagnostically valuable in detecting melanoma cells in small specimens with minimal disease.

Anxiety sensitivity as a predictor of acute subjective effects of smoking.

INTRODUCTION: Anxiety sensitivity (i.e., AS; the degree to which one believes that anxiety and its related sensations are harmful) is a stable trait that is associated with habitual smoking. Yet, the mechanisms linking AS and smoking are unclear. A promising hypothesis is that high-AS individuals are more sensitive to the acute subjective reinforcing effects of smoking and are, therefore, more prone to tobacco dependence. This study examined trait AS as a predictor of several subjective effects of cigarette smoking. METHODS: Adult non-treatment-seeking smokers (N = 87; 10+ cigarettes/day) completed a measure of AS during a baseline session. Prior to a subsequent experimental session, participants were asked to smoke normally before their appointment. At the outset of that visit, each participant smoked a single cigarette of their preferred brand in the laboratory. Self-report measures of affect and cigarette craving were completed before and after smoking, and post-cigarette subjective effect ratings were provided. RESULTS: AS predicted greater increases in positive affect from pre- to post-cigarette (ß = .30, p = .006) as well as greater smoking satisfaction and psychological reward (ß = .23 to .48, ps < .03). Each of these effects remained statistically significant after adjusting for anxiety symptom severity. AS did not predict the degree of negative affect and craving suppression or post-cigarette aversive effects. CONCLUSIONS: These findings suggest that positive reinforcement mechanisms may be particularly salient etiological processes that maintain smoking in high-AS individuals.

A Topical Zinc Ionophore Blocks Tumorigenic Progression in UV-exposed SKH-1 High-risk Mouse Skin.

Nonmelanoma skin cancer (NMSC) is the most common malignancy in the United States representing a considerable public health burden. Pharmacological suppression of skin photocarcinogenesis has shown promise in preclinical and clinical studies, but more efficacious photochemopreventive agents are needed. Here, we tested feasibility of harnessing pharmacological disruption of intracellular zinc homeostasis for photochemoprevention in vitro and in vivo. Employing the zinc ionophore and FDA-approved microbicidal agent zinc pyrithione (ZnPT), used worldwide in over-the-counter (OTC) topical consumer products, we first demonstrated feasibility of achieving ZnPT-based intracellular Zn2+ overload in cultured malignant keratinocytes (HaCaT-ras II-4; SCC-25) employing membrane-permeable fluorescent probes. Zinc overload was accompanied by induction of intracellular oxidative stress, associated with mitochondrial superoxide release as substantiated by MitoSOX Red™ fluorescence microscopy. ZnPT-induced cell death observable in malignant keratinocytes was preceded by induction of metal (MT2A), proteotoxic (HSPA6, HSPA1A, DDIT3, HMOX1) and genotoxic stress response (GADD45A, XRCC2) gene expression at the mRNA and protein levels. Comet analysis revealed introduction of formamidopyrimidine-DNA glycosylase (Fpg)-sensitive oxidative DNA lesions. In a photocarcinogenesis model (UV-exposed SKH-1 high-risk mouse skin), topical ZnPT administration post-UV caused epidermal zinc overload and stress response gene expression with pronounced blockade of tumorigenesis. Taken together, these data suggest feasibility of repurposing a topical OTC drug for zinc-directed photochemoprevention of solar UV-induced NMSC.

Targeting NRF2 for Improved Skin Barrier Function and Photoprotection: Focus on the Achiote-Derived Apocarotenoid Bixin.

The transcription factor NRF2 (nuclear factor-E2-related factor 2) orchestrates major cellular defense mechanisms including phase-II detoxification, inflammatory signaling, DNA repair, and antioxidant response. Recent studies strongly suggest a protective role of NRF2-mediated gene expression in the suppression of cutaneous photodamage induced by solar UV (ultraviolet) radiation. The apocarotenoid bixin, a Food and Drug Administration (FDA)-approved natural food colorant (referred to as 'annatto') originates from the seeds of the achiote tree native to tropical America, consumed by humans since ancient times. Use of achiote preparations for skin protection against environmental insult and for enhanced wound healing has long been documented. We have recently reported that (i) bixin is a potent canonical activator of the NRF2-dependent cytoprotective response in human skin keratinocytes; that (ii) systemic administration of bixin activates NRF2 with protective effects against solar UV-induced skin damage; and that (iii) bixin-induced suppression of photodamage is observable in Nrf2+/+ but not in Nrf2-/- SKH-1 mice confirming the NRF2-dependence of bixin-induced antioxidant and anti-inflammatory effects. In addition, bixin displays molecular activities as sacrificial antioxidant, excited state quencher, PPAR (peroxisome proliferator-activated receptor) α/γ agonist, and TLR (Toll-like receptor) 4/NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) antagonist, all of which might be relevant to the enhancement of skin barrier function and environmental stress protection. Potential skin photoprotection and photochemoprevention benefits provided by topical application or dietary consumption of this ethno-pharmacologically validated phytochemical originating from the Americas deserves further preclinical and clinical examination.