Suppression of beta 2 adrenergic receptor actions prevent UVB mediated cutaneous squamous cell tumorigenesis through inhibition of VEGF-A induced angiogenesis.

Although beta 2 adrenergic receptors (ß2 ADR) are present in the keratinocytes, their role in cutaneous squamous cell tumorigenesis needs to be ascertained. For the first time, we report here that selective ß2 ADR antagonists by inhibiting ß2 ADR actions significantly retarded the progression of ultraviolet B (UVB) induced premalignant cutaneous squamous cell lesions. These antagonists acted by inhibiting vascular endothelial growth factor-A (VEGF) mediated angiogenesis to prevent UVB radiation-induced squamous cell carcinoma of the skin.

Expanding the differential of superficial tumors with round-cell morphology: Report of three cases of CIC-rearranged sarcoma, a potentially under-recognized entity.

Among sarcomas with a round-cell morphology that lack rearrangement of the EWSR1 gene, rearrangements involving the CIC gene are the most common. In comparison with Ewing Sarcoma, CIC-rearranged sarcomas present at an older average age, arise almost exclusively in soft tissues, are clinically more aggressive, and are more likely to be resistant to the chemotherapy regimens used for Ewing sarcoma. CIC-rearranged sarcomas present more commonly in a deep location, and we suspect that superficial presentations may be under-recognized. In this case series, we report three of such cases. Overall, the morphology is similar to CIC-rearranged sarcomas of deeper locations. We hope to raise awareness among the dermatopathology community by expanding the differential of superficial tumors with round cell morphology.

Polypoid amelanotic melanoma: a diagnostic challenge.

Melanoma is a highly aggressive cutaneous malignancy with considerable risk for metastasis. These malignant tumors are typically pigmented given that they arise from melanocytes capable of producing melanin. Amelanotic melanomas are a rare variant and there is often a delay in diagnosis owing to lack of pigmentation. Although there are various presentations of amelanotic melanoma, a solitary polypoid nodule is unusual and warrants further reporting. Herein, we present a patient with a 3-year history of a tender firm, skin-to-pink colored polypoid nodule. Excisional biopsy and work up showed an aggressive amelanotic melanoma with depth of 20mm and nodal metastasis consistent with stage IIIC disease. This case highlights the necessity of recognition and prompt management of this rare subtype of melanoma.

Differential mutation frequencies in metastatic cutaneous squamous cell carcinomas versus primary tumors.

BACKGROUND: Exome and targeted sequencing studies have identified potential driver mutations for a variety of tumor types. Cutaneous squamous cell carcinoma (cSCC) is one of the most highly mutated cancers but typically is associated with low rates of metastasis and high survival rates. Nevertheless, metastatic cSCC is a significant health threat; up to 8800 individuals die each year of this disease. METHODS: Because it is difficult to predict which cSCCs are more likely to metastasize, and because to the best of the authors' knowledge there are no targeted therapies specifically designated for patients with metastatic cSCC, exome and/or targeted sequencing of 18 metastatic and 10 primary cSCCs was performed to identify mutations that were more frequent in metastatic tumors and might be targeted for therapeutic benefit. The authors compared their results with published sequencing results of an additional 223 primary tumors and 68 metastatic cSCCs. RESULTS: The authors identified genes demonstrating higher mutation frequencies in metastatic cSCC compared with primary tumors, including the chromatin remodeling gene lysine methyltransferase 2D (KMT2D) and the classic skin tumor suppressor tumor protein p53 (TP53), which was found to be mutated in 54% of primary tumors compared with 85% of metastatic tumors (P<.0001). CONCLUSIONS: These studies appear to uncover potential pathways that are important in metastatic cSCC and that broaden understanding of the biology contributing to aggressive tumor behavior. These results may lead to new therapeutic strategies. Cancer 2017;123:1184-1193. © 2016 American Cancer Society.

Classification of Indeterminate Melanocytic Lesions by MicroRNA Profiling.

PURPOSE: Identification of indeterminate melanocytic skin lesions capable of neoplastic progression is suboptimal and may potentially result in unnecessary morbidity from surgery. MicroRNAs (miRs) may be useful in classifying indeterminate Spitz tumors as having high or low risk for malignant behavior. METHODS: RNA was extracted from paraffin-embedded tissues of benign nevi, benign Spitz tumors, indeterminate Spitz tumors, and Spitzoid melanomas in adults (n = 62) and children (n = 28). The expression profile of 12 miRs in adults (6 miRs in children) was analyzed by real-time polymerase chain reaction. RESULTS: Benign Spitz lesions were characterized by decreased expression of miR-125b and miR-211, and upregulation of miR-22, compared with benign nevi (p < 0.05). A comparison of Spitzoid melanomas to benign nevi revealed overexpression of miR-21, miR-150, and miR-155 in the malignant primaries (p < 0.05). In adults, Spitzoid melanomas exhibited upregulation of miR-21, miR-150, and miR-155 compared with indeterminate Spitz lesions. Indeterminate Spitz lesions with low-risk pathologic features had lower miR-21 and miR-155 expression compared with Spitzoid melanoma tumors in adults (p < 0.05), while pathologic high-risk indeterminate Spitz lesions had increased levels of miR-200c expression compared with low-risk indeterminate lesions (p < 0.05). Pediatric Spitzoid melanomas exhibited increased miR-21 expression compared with indeterminate Spitz lesions (p < 0.05). Moreover, miR-155 expression was increased in indeterminate lesions with mitotic counts >1 and depth of invasion >1 mm, suggesting miR-155 expression is associated with histological characteristics. CONCLUSIONS: miR expression profiles can be measured in indeterminate Spitz tumors and correlate with markers of malignant potential.

CUL4A abrogation augments DNA damage response and protection against skin carcinogenesis.

It is intuitively obvious that the ability of a cell to repair DNA damage is saturable, either by limitation of enzymatic activities, the time allotted to achieve their function, or both. However, very little is known regarding the mechanisms that establish such a threshold. Here we demonstrate that the CUL4A ubiquitin ligase restricts the cellular repair capacity by orchestrating the concerted actions of nucleotide excision repair (NER) and the DNA damage-responsive G1/S checkpoint through selective degradation of the DDB2 and XPC DNA damage sensors and the p21/CIP1/WAF1 checkpoint effector. We generated Cul4a conditional knockout mice and observed that skin-specific Cul4a ablation dramatically increased resistance to UV-induced skin carcinogenesis. Our findings reveal that wild-type cells do not operate at their full DNA repair potential, underscore the critical role of CUL4A in establishing the cellular DNA repair threshold, and highlight the potential augmentation of cellular repair proficiency by pharmacological CUL4A inhibition.

Global microRNA profiling for diagnostic appraisal of melanocytic Spitz tumors.

BACKGROUND: Melanoma skin cancer remains the leading cause of skin cancer-related deaths. Spitz lesions represent a subset of melanocytic skin lesions characterized by epithelioid or spindled melanocytes organized in nests. These lesions occupy a spectrum ranging from benign Spitz and atypical Spitz lesions all the way to malignant Spitz tumors. Appropriate management is reliant on accurate diagnostic classification, yet this effort remains challenging using current light microscopic techniques. The discovery of novel biomarkers such as microRNAs (miR) may ultimately be a useful diagnostic adjunct for the evaluation of Spitz lesions. miR expression profiles have been suggested for non-Spitz melanomas but have yet to be ascribed to Spitz lesions. We hypothesized that distinct miR expression profiles would be associated with different lesions along the Spitz spectrum. MATERIALS AND METHODS: RNAs extracted from paraffin-embedded, formalin-fixed tissues of 11 resected skin lesions including benign nevi (n = 2), benign Spitz lesions (n = 3), atypical Spitz lesions (n = 3), and malignant Spitz tumors (n = 3) were analyzed by the NanoString platform for simultaneous evaluation of over 800 miRs in each patient sample. RESULTS: Benign Spitz lesions had increased expression of miR-21-5p and miR-363-3p compared with those of benign nevi. Malignant Spitz lesions exhibited overexpression of miR-21-5p, miR-155-5p, and miR-1283 relative to both benign nevi and benign Spitz tumors. Notably, atypical Spitz tumors had increased expression of miR-451a and decreased expression of miR-155-5p expression relative to malignant Spitz lesions. Conversely, atypical Spitz lesions had increased expression of miR-21-5p, miR-34a-5p, miR-451a, miR-1283, and miR-1260a relative to benign Spitz tumors. CONCLUSIONS: Overall, distinct miR profiles are suggested among Spitz lesions of varying malignant potential with some similarities to non-Spitz melanoma tumors. This work demonstrates the feasibility of this analytic method and forms the basis for further validation studies.

Hair Follicle Nevus With Features of Comedo Nevus: An Expanding Spectrum.

Hair follicle nevus (HFN) is a rare hamartomatous lesion of the folliculosebaceous unit, with or without admixed fibroadipose or muscular tissue. It typically has a congenital presentation in the preauricular area of infants and is frequently confused with an accessory tragus. Acquired tumors with similar histopathologic features have been described infrequently during adolescence and adult life. We report yet another unique presentation of this unusual lesion in a 4-year-old girl who had a long-standing tumor of the nasal columella that started growing rapidly after trauma. Histopathologic examination revealed increased numbers of hair follicles, some of which were associated with diminutive sebaceous glands, with no associated central cystic structure. In addition, the infundibula of the follicles were dilated and filled with keratinous debris. Although these hamartomas are common in the head and neck region, to our knowledge, this is the first report of a HFN at this anatomic location. In addition, this tumor has an overall architecture of a HFN but is accompanied by features of a comedo nevus. We also present a review of the literature and summarize the current diagnostic criteria for HFN.

Allele-specific imbalance mapping identifies HDAC9 as a candidate gene for cutaneous squamous cell carcinoma.

More than 3.5 million nonmelanoma skin cancers were treated in 2006; of these 700,000 were cutaneous squamous cell carcinomas (cSCCs). Despite clear environmental causes for cSCC, studies also suggest genetic risk factors. A cSCC susceptibility locus, Skts5, was identified on mouse chromosome 12 by linkage analysis. The orthologous locus to Skts5 in humans maps to 7p21 and 7q31. These loci show copy number increases in ∼10% of cSCC tumors. Here, we show that an additional 15-22% of tumors exhibit copy-neutral loss of heterozygosity. Furthermore, our previous data identified microsatellite markers on 7p21 and 7q31 that demonstrate preferential allelic imbalance (PAI) in cSCC tumors. On the basis of these results, we hypothesized that the human orthologous locus to Skts5 would house a gene important in human cSCC development and that tumors would demonstrate allele-specific somatic alterations. To test this hypothesis, we performed quantitative genotyping of 108 single nucleotide polymorphisms (SNPs) mapping to candidate genes at human SKTS5 in paired normal and tumor DNAs. Nine SNPs in HDAC9 (rs801540, rs1178108, rs1178112, rs1726610, rs10243618, rs11764116, rs1178355, rs10269422 and rs12540872) showed PAI in tumors. These data suggest that HDAC9 variants may be selected for during cSCC tumorigenesis.

Mismatch repair protein deficiency is common in sebaceous neoplasms and suggests the importance of screening for Lynch syndrome.

The association between Lynch syndrome and sebaceous neoplasms is well characterized. The absence of expression of mismatch repair proteins (MMRPs) by immunohistochemistry (IHC) is often used in other Lynch-associated tumors to guide testing. IHC for MLH1, PMS2, MSH2, and MSH6 was performed on 36 benign and malignant sebaceous neoplasms with the absence of one or more MMRP in 38.9% of cases. Among lesions with abnormal IHC, 71.4% were missing both MSH2 and MSH6, 21.4% lacked MLH1 and PMS2, and 7.1% lacked only MSH6. Of the 10 patients with absent MMRP, 5 had gene-test confirmed Lynch syndrome, 3 had no suggestive personal or family medical history and 2 had no recorded data. Tumor-infiltrating lymphocytes in neoplasms with absent MMRP were statistically significantly greater than in those with intact MMRP (16.5 vs. 9.7, P = 0.027). MMRP deficiency is common in sebaceous neoplasms, suggesting the importance of screening for Lynch syndrome in these patients.

Phosphatase and tensin homolog immunohistochemical staining and clinical criteria for Cowden syndrome in patients with trichilemmoma or associated lesions.

Trichilemmomas and mucocutaneous papillomatous papules are associated with Cowden syndrome (CS). Germline Phosphatase and tensin homolog (PTEN) mutations have been identified in 34% to 80% of those meeting clinical criteria for CS. PTEN expression has not been well evaluated in large numbers of trichilemmoma. We investigated clinical criteria for CS in trichilemmoma patients and studied PTEN staining to determine how often patients with trichilemmoma have CS and whether PTEN staining is useful. About 102 cases of trichilemmoma or associated lesions from 95 patients were collected. Clinical histories were reviewed to investigate the incidence of CS using International Cowden Consortium operational criteria for diagnosis of CS, version 2000. PTEN staining was performed and graded for intensity and percentage. Although 1 patient had 3 trichilemmoma or associated lesions, and 5 had 2 trichilemmoma or associated lesions, none of 95 patients met clinical criteria for a diagnosis of CS. Twelve of the 89 cases available for staining (13.5%) showed decreased PTEN. Of these, the demographic, clinical, and pathological features were not significantly different compared with PTEN intact cases. None of the cases from the 6 patients with more than 1 trichilemmoma or associated lesions showed decreased PTEN staining. We thus conclude that the likelihood of a clinical diagnosis of CS among patients with a solitary or only a few trichilemmoma is extremely low. PTEN expression is decreased in some sporadic trichilemmomas or associated lesions. This is the largest study investigating clinical history and PTEN staining in patients with trichilemmoma or associated lesions. Because none of our patients met clinical diagnostic criteria for CS, the direct correlation of PTEN in CS and sporadic trichilemmoma remains unclear.

Use of conivaptan for refractory syndrome of inappropriate secretion of antidiuretic hormone in a pediatric patient.

The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is the most common form of hyponatremia in hospitalized patients. The available treatment options for SIADH are limited and not completely effective. A more recent and specific option for treatment of hyponatremia secondary to SIADH are the vasopressin-receptor antagonists. Conivaptan, an intravenous vasopressin-receptor antagonist, is Food and Drug Administration approved for the treatment of euvolemic and hypervolemic hyponatremia in adults; however, data regarding its use in pediatric patients are extremely limited. Conivaptan played an integral role in the treatment of hyponatremia in this situation when conventional treatment modalities were ineffective. This patient did not experience any adverse effects, and his sodium level corrected slowly over a 24-hour period, avoiding complications of rapid sodium correction.

Hidradenoma papilliferum of the orbit.

PURPOSE: Hidradenoma papilliferum (HP) is a cystic lesion of apocrine gland origin that occurs most commonly in the perineal region. Although there are scattered reports of HP involving the eyelid, to our knowledge, we present the first case of HP of the orbit. METHODS: A 63 year-old female presented with progressive left upper eyelid fullness over an 18 month period. RESULTS: The lesion was excised via transconjunctival anterior orbitotomy without incident. CONCLUSIONS: The pathologic features of HP are presented.

A Mixed Methods Investigation on the Relationship Between Perceived Self-Regard, Self-Efficacy, and Commitment to Serve Among Military Medical Students.

INTRODUCTION: Routinely faced with potentially traumatizing situations, resilience is critical for military physicians. However, related studies are limited in scope. The current study distinctively combines hyper-realistic immersion training for military medical students with emotional intelligence and hardiness measures. With self-reflection shown to improve performance, qualitative inquiry was concurrently conducted in a mixed methodology approach to provide a uniquely comprehensive perspective on the resilience training needs of this population. MATERIALS AND METHODS: Thirty-four osteopathic military medical students participated in a week-long training simulating real-life combat and mass casualty events. The Emotional Quotient-Inventory 2.0 (EQ-i 2.0) and Hardiness Resilience Gauge were administered as pre- and post-test measures. Paired t-tests were used to determine statistically significant gains, and a multiple case study analysis of a six-student focus group allowed for the synchronization of quantitative and qualitative data. Institutional Review Board approval for the study was obtained through Rocky Vista University with a reciprocal agreement with Touro University California's Institutional Review Board. All students participating in the study received written informed consent. RESULTS: Qualitative findings for this study aligned with this current year's findings of statistically significant results in the improvement of the Overall EQ-i and Overall Hardiness. Qualitative responses thematically analyzed demonstrated environmental realism, adaptation, increased awareness, and positive interpersonal and clinical outlook. Notable increases occurred in all EQ-i domains except Decision-Making and Stress Tolerance. The Self-Perception domain saw significant increases in Self-Regard and Emotional Self-Awareness while Well-Being and Optimism simultaneously improved. CONCLUSION: This unique pilot study showed that quantitative and qualitative results aligned, supporting the finding that a safe trauma-related training environment can improve the confidence and resilience in military medical students. The goal of this training was to promote resilience and mitigate trauma. Results demonstrate improved self-efficacy and enhanced commitment. Increases in self-awareness and confidence made participants more inclined to see their worth and strengthened their sense of duty as described in their qualitative responses. Pervasive gains suggest that the training aligned well with its purpose, and the methods employed enhanced participant experience. Long-term follow-up studies are needed to assess outcome sustainability.

Calciphylaxis following coronary artery bypass surgery: an underappreciated cause of wound complications?

Wound complications following cardiac surgery are typically infectious and associated with a high morbidity and mortality. Calciphylaxis, vascular calcification of small and medium sized vessels, often associated with end-stage renal disease, can result in extensive tissue necrosis. We hypothesize that calciphylaxis is an under-recognized and under-reported precipitating wound and breast complication following coronary artery bypass surgery and thereby necessitates further study.

Dopamine Prevents Ultraviolet B-induced Development and Progression of Premalignant Cutaneous Lesions through its D2 Receptors.

Although the role of dopamine (DA) in malignant tumors has been reported, its function in premalignant lesions is unknown. Herein we report that the stimulation of DA D2 receptors in endothelial cells in ultraviolet B (UVB)-induced cutaneous lesions in mice significantly reduced the tumor number, tumor burden, and malignant squamous cell carcinoma in these animals. DA D2 receptor agonist inhibited VEGFA-dependent proangiogenic genes in vitro and in vivo. However, the mice pretreated with selective DA D2 receptor antagonist inhibited the actions of the agonist, thereby suggesting that the action of DA was through its D2 receptors in the endothelial cells. To our knowledge, this study is the first to report DA-mediated regulation of pathogenesis and progression of UVB-induced premalignant skin lesions. PREVENTION RELEVANCE: This investigation demonstrates the role of dopamine and its D2 receptors in UVB induced premalignant squamous cell skin lesions and how DA through its D2 receptors inhibits the development and progression of these lesions and subsequently prevents squamous cell carcinoma of the skin.

MicroRNA Expression Profiling of Cutaneous Squamous Cell Carcinomas Arising in Different Sites.

OBJECTIVE: To examine the microRNA (miRNA) expression profile of cutaneous squamous cell carcinoma (cSCC) tumors from aggressive head and neck locations compared with nonaggressive anatomic sites and normal controls. STUDY DESIGN: Retrospective analysis of miRNA expression. SETTING: Tertiary care center. SUBJECTS AND METHODS: Tissue samples were collected from 3 anatomic regions: aggressive head and neck sites (ie, ears/lip), nonaggressive locations (ie, extremities/trunk), and adjacent normal skin. RNA was isolated from tissue cores of 45 samples (18 aggressive sites, 15 nonaggressive sites, and 12 normal-adjacent skin). miRNA expression analysis was completed for approximately 800 miRNAs using the NanoString nCounter panel. Five candidate miRNAs were selected for validation. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed on the original samples plus 30 additional tissue samples (7 aggressive sites, 14 nonaggressive sites, and 9 normal-adjacent skin). RESULTS: Five candidate miRNAs with significant differences in miRNA expression (P < 0 ≤ .001) from discovery samples were selected: miR-21, miR-31, let-7g, miR-93, and miR-22. Relative expression for these miRNAs using qRT-PCR in the new sample set did not reveal any significant differences using 1-way analysis of variance. When sets were combined, miR-21 showed increased expression in aggressive tumors relative to nonaggressive tumors (P = .009), but no others reached statistical significance. CONCLUSION: cSCC behaves more aggressively when originating from specific anatomical subsites of the head and neck. Of 5 miRNAs evaluated, only miR-21 showed significantly higher expression in tumors from aggressive sites relative to nonaggressive sites. Larger sample sizes are needed to evaluate other miRNAs.

Telepathology in Mohs micrographic surgery.

Intraoperative histopathology consultation during Mohs micrographic surgery (MMS) with a dermatopathologist is advantageous in some cases requiring a clarification of a diagnosis but may be difficult because in comparison to the Mohs laboratory, the dermatopathology facility can be remote. Telepathology technology provides a time-efficient means of consultation during MMS via the electronic transmission of pathology images, which can foster case discussions, and expedite the confirmation of diagnosis and treatment decisions.