Primary cutaneous extraskeletal osteosarcoma of the pretibial leg: A case report and summary of the literature.

Primary cutaneous extraskeletal osteosarcoma is a rare tumor, with fewer than 30 known cases worldwide. We report the case of a 60-year-old female who presented with a solitary right pretibial nodule of 3 mm. She had no known comorbidities, trauma to the area, or prior malignancy. The biopsy specimen showed abundant mineralized osteoid, in which pleomorphic and spindled cells with anaplastic features were embedded. The osteoid matrix in this case contained overtly malignant cells, with frequent mitotic figures, as well as multinucleated giant cells. Immunohistochemistry and imaging led to the conclusion that this nodule represented a primary cutaneous extraskeletal osteosarcoma. The previously reported cases are variable in location, size, gross appearance, and clinical course. The prognosis of osteosarcoma is typically poor, with aggressive behavior; this, however, may be less severe in these strictly cutaneous tumors, though additional follow-up would be beneficial to determine long-term outcomes for the known cases. Ultimately, despite the fact that this is an extremely rare entity, primary cutaneous extraskeletal osteosarcomas should be considered when relevant.

Use of PRAME immunostaining to distinguish early melanoma in situ from benign pigmented conditions.

BACKGROUND: PRAME (PReferentially expressed Antigen in MElanoma) is an antigen that shows marked overexpression in melanoma compared to normal skin melanocytes. PRAME immunohistochemistry has proven effective in distinguishing melanocytic nevi from melanoma, but it is unclear if it may be used to distinguish melanoma in situ from other benign pigmented lesions. In particular, differentiating from melanocytic hyperplasia in sun-damaged skin is sometimes clinically and histopathologically challenging. We hypothesized that PRAME staining of solar lentigo, sun-damaged skin, and melanoma in situ would aid in setting a threshold of positivity that could be useful in evaluating such conditions. METHODS: We collected and stained typical examples of solar lentigo, melanoma in situ, and non-lesional sun-damaged skin by PRAME immunohistochemistry to assess a potential cutoff of PRAME positivity. RESULTS: Solar lentigo and non-lesional sun-damaged skin had 10 or fewer PRAME-positive cells per millimeter (mean 1.2), on the other hand melanoma in situ had at least 16 (mean 75.1). CONCLUSIONS: PRAME immunostaining appears sensitive and specific in the current series. This could be clinically useful for distinguishing melanoma in situ from benign melanocytic hyperplasia in sun-damaged skin. However, further studies are required to determine if 10 cells per millimeter is an acceptable threshold of positivity.

Treatment of Self-Harm Scars: A Scoping Review.

BACKGROUND: Self-harm scars are a consequence of deliberate self-injury, serving as a visual reminder for involved individuals. Patients often reach out to their providers seeking treatment for their scars. However, there is currently no standard for treating self-harm scars, because multiple options are being explored. OBJECTIVE: A scoping review was conducted to identify and characterize the body of literature on different treatments for self-harm scars, including surgical, laser, and vitamin A management. METHODS: Thorough literature searches were conducted in PubMed/MEDLINE, EMBASE, and CINAHL Complete. The search strategy was designed and implemented by a medical librarian. RESULTS: Of 510 retrieved articles, 4 described laser treatments, 8 described surgical treatments, and 2 described vitamin A treatments. CONCLUSION: A multidisciplinary approach is critical for the selection and outcome of the treatment of self-harm scars.

Ethnic distribution of populations in the highest and lowest dermatologist-dense areas: is there more to the story?

Several studies in the past decade have highlighted the lack of adequate dermatological care in skin of color (SOC) patients. This inquiry has led to further research to identify the sources of this disparity. Previous studies have highlighted the uneven geographic distribution of dermatologists, with a higher density of dermatologists in urban areas compared to other areas. However, the exact ethnic populations served by these dermatologists has remained largely uncharacterized. The purpose of this study was to compare the ethnic distributions in the ten highest and lowest dermatologist-dense areas across the United States to determine if there is equal access to dermatological care for minorities. Stratified by ethnicities, the highest dermatologist-dense areas consisted of 60% White alone (not Hispanic or Latino), 13% Hispanic or Latino, 13% Asian alone, and 12% Black or African American. Conversely, the least dermatologist-dense areas consisted of 45% White alone (not Hispanic or Latino), 28% Black or African American, 21% Hispanic or Latino, and 4% Asian alone. Our analysis highlights the presence of larger proportions of SOC patients in the lowest dermatologist-dense areas and this lack of access to dermatologists may contribute to inferior dermatological care and outcomes in Hispanic or Latino, and Black or African American minorities.

Malignant Proliferating Trichilemmal Tumor of the Scalp: A Systematic Review.

OBJECTIVES: Malignant proliferating trichilemmal tumors of the scalp can exhibit aggressive presentation and recurrences. Our objective was to perform an evidence-based systematic review evaluating clinical presentation, tumor characteristics, and treatment modalities used to determine which treatment strategies had the best outcomes. METHODS: The databases PubMed, Embase, and Cochrane Library were searched for relevant literature by the authors. Patient demographics, imaging, treatments, and other clinical characteristics were obtained. The results were reported using the Preferred Reporting Systems for Systematic Reviews and Meta-Analysis guidelines. RESULTS: Thirty-nine studies with a total of 65 patients were identified. The most common presentation was a history of slow-growing, painless swollen mass on the scalp. In total, 10 patients (15.4%) presented with spread to the regional lymph nodes and 6 (9.2%) additional patients presented with metastasis to distant locations. In total, 61 patients (93.8%) underwent surgery. Various chemotherapy and radiation therapy regimens were used. Of the 45 cases with documented follow-up, 11 (24.4%) patients had one or multiple instances of local, lymph node or metastatic tumor recurrence. CONCLUSIONS: Surgery is favored, and the exact approach should be based on clinical judgment. However, Mohs micrographic surgery should strongly be considered because of its superior margin control against such an invasive tumor. Radiotherapy and chemotherapy have been used as adjuvant therapy in aggressive cases or recurrence. Patients should be followed closely and examined often to frequently assess recurrence or metastasis. Randomized controlled trials are needed to further clarify these findings.

Pleomorphic Fibroma: A Clinicopathologic Case Series With the Review of the Literature.

BACKGROUND: Pleomorphic fibromas are rare flesh-colored benign neoplasms first described in 1989. Their histopathology is notable for nuclear pleomorphism of spindle cells and multinucleate giant cells but lacking mitoses. The cellular origin of these tumors is unknown. This case series describes an additional 18 lesions with discussion of histopathology and immunohistochemistry. METHODS: This case series of 18 pleomorphic fibromas uses immunohistochemical staining for CD34, CD68, factor XIIIa, and S-100 and general histopathologic examination under light microscopy to describe the lesions. RESULTS: Immunohistochemical stains for CD34 showed nearly universal positivity of the pleomorphic spindle cells, although some more focally. The pleomorphic cells were negative for CD68, variably positive for factor XIIIa, and universally negative for S-100. All the lesions showed characteristic nuclear pleomorphism with absent mitoses. Collagen thickening was variable, mucin was absent, and perivascular inflammation was present in all lesions. CONCLUSIONS: Pleomorphic fibromas are fibrous lesions with benign clinical course and histopathologic findings including nuclear pleomorphism. Immunohistochemical staining characteristics of the lesion, along with unique spindle cells and multinucleate giant cells help to differentiate this from other tumors.

A dose-response study of a novel method of selective tissue modification of cellular structures in the skin with nanosecond pulsed electric fields.

BACKGROUND AND OBJECTIVES: This study describes the effects of nanosecond pulsed electric fields (nsPEF) on the epidermis and dermis of normal skin scheduled for excision in a subsequent abdominoplasty. NsPEF therapy applies nanosecond pulses of electrical energy to induce regulated cell death (RCD) in cellular structures, with negligible thermal effects. Prior pre-clinical studies using nsPEF technology have demonstrated the ability to stimulate a lasting immune response in animal tumor models, including melanoma. This first-in-human-use of nsPEF treatment in a controlled study to evaluate the dose-response effects on normal skin and subcutaneous structures is intended to establish a safe dose range of energies prior to use in clinical applications using nsPEF for non-thermal tissue modification. STUDY DESIGN/MATERIALS AND METHODS: Seven subjects with healthy tissue planned for abdominoplasty excision were enrolled. Five subjects were evaluated in a longitudinal, 60-day study of effects with doses of six nsPEF energy levels. A total of 30 squares of spot sizes 25mm2 or less within the planned excision area were treated and then evaluated at 1 day, 5 days, 15 days, 30 days, and 60 days prior to surgery. Photographs were taken over time of each treated area and assessed by three independent and blinded dermatologists for erythema, flaking and crusting using a 5-point scale (0 = low, 4 = high). Punch biopsies of surgically removed tissue were processed and evaluated for tissue changes using hematoxylin and eosin, trichome, caspase-3, microphthalmia transcription factor, and elastin stains and evaluated by a dermatopathologist. The skin of two subjects received additional treatments at 2 and 4 hours post-nsPEF and was evaluated in a similar manner. RESULTS: Most energy settings exhibited delayed epidermal loss followed by re-epithelization by day 15 and a normal course of healing. Histologic analysis identified the appearance of activated caspase-3 at two and four hours after nsPEF treatment, but not at later time points. At the 1-day time point, a nucleolysis effect was observed in epidermal cells, as evidenced by the lack of nuclear staining while the epidermal plasma membranes were still intact. Cellular structures within the treatment zone such as melanocytes, sebaceous glands, and hair follicles were damaged while acellular structures such as elastic fibers and collagen were largely unaffected except for TL6 which showed signs of dermal damage. Melanocytes reappeared at levels comparable with untreated controls within 1 month of nsPEF treatment. CONCLUSIONS: The selective effect of nsPEF treatment on cellular structures in the epidermal and dermal layers suggests that this non-thermal mechanism for targeting cellular structures does not affect the integrity of dermal tissue within a range of energy levels. The specificity of effects and a favorable healing response makes nsPEF ideal for treating cellular targets in the epidermal or dermal layers of the skin, including treatment of benign and malignant lesions. NsPEF skin treatments provide a promising, non-thermal method for treating skin conditions and removing epidermal lesions. © 2019 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc.

A dose-response study of nanosecond electric energy pulses on facial skin.

Nanosecond pulsed electric fields, also known as Nano-Pulse Stimulation or NPS, can trigger regulated cell death to clear skin lesions that are cellular in nature. Before treating facial lesions, it is important to demonstrate the effects of these pulses on normal facial skin. Here we have applied a range of NPS energies to the epidermis and dermis of normal facial skin scheduled for excision to establish a safe dose range of energies prior to use in clinical applications. This was an open-label, non-randomized study under the direction of a single Principal Investigator. The time course of the treated tissue changes was determined by histological analysis. All energy settings generated a delayed epidermal loss followed by re-epithelialization by day 7 and a normal course of healing. One day after NPS treatment, the cellular membranes of the treated epidermis were intact, but their nuclei no longer stained with H&E, resulting in a hollow appearance that has been referred to as "ghost cells." Cellular structures in the dermis, such as sebaceous glands and melanocytes, exhibited regulated cell death observed by 1 day post treatment. Melanocytes recovered to their normal density within 7 days. The 60-day samples indicated that epidermis, hair follicles, and eccrine glands appeared normal. The selective effect of NPS treatment on cellular structures in the epidermal and dermal layers suggests that this non-thermal modality of energy delivery is ideal for treating cellular targets including benign and malignant skin lesions. NPS skin treatments provide a promising method for clearing skin lesions with a cellular basis.

Melanoma Biomarkers and Their Potential Application for In Vivo Diagnostic Imaging Modalities.

Melanoma is the deadliest form of skin cancer and remains a diagnostic challenge in the dermatology clinic. Several non-invasive imaging techniques have been developed to identify melanoma. The signal source in each of these modalities is based on the alteration of physical characteristics of the tissue from healthy/benign to melanoma. However, as these characteristics are not always sufficiently specific, the current imaging techniques are not adequate for use in the clinical setting. A more robust way of melanoma diagnosis is to "stain" or selectively target the suspect tissue with a melanoma biomarker attached to a contrast enhancer of one imaging modality. Here, we categorize and review known melanoma diagnostic biomarkers with the goal of guiding skin imaging experts to design an appropriate diagnostic tool for differentiating between melanoma and benign lesions with a high specificity and sensitivity.

Cancer-testis antigens as biomarkers for Merkel cell carcinoma: Pitfalls and opportunities.

BACKGROUND: The prognosis and treatment options for metastatic Merkel cell carcinoma (MCC) are poor. The immune-privileged status of cancer-testis (CT) antigens imparts tumor specificity, making them ideal candidates for targeted immunotherapy. We investigate the usefulness of the CT antigens SPA17 (sperm protein-17 [SP-17]), IGF2BP3 (insulin-like growth factor-II mRNA-binding protein 3 [IMP-3]), and transmembrane protein with epidermal growth factor (EGF)-like and two follistatin-like domains 1 (TMEFF1) as potential MCC biomarkers and evaluate their possible utility in immunotherapy and molecularly targeted image-guided treatment. METHODS: The CT antigens SP-17, IMP-3, and TMEFF1 were selected using transcriptome profiling to identify CT antigens expressed in MCC tumors. Antibodies directed against these CT antigens were stained. Twelve normal skin tissue samples were used as a control. The average percentage of positive cells in each tumor was computed. RESULTS: Twelve of 14 (86%) MCC cases showed crisp nuclear staining for SP-17, with 2.06% of cells staining positive. IMP-3 showed crisp, perinuclear staining in all 14 MCC cases, with 52.93% MCC cells staining positive. TMEFF1 showed perinuclear staining in all 14 MCC cases, with 96.51% of tumor cells staining positive. CONCLUSIONS: CT antigens were found to be expressed in both MCC and some control tissues. SP-17 was the most specific yet the least sensitive. IMP-3 and TMEFF1 were both sensitive but not specific. CT antigens may represent valuable treatment targets in MCC.

Photoacoustic/Ultrasound/Optical Coherence Tomography Evaluation of Melanoma Lesion and Healthy Skin in a Swine Model.

The marked increase in the incidence of melanoma coupled with the rapid drop in the survival rate after metastasis has promoted the investigation into improved diagnostic methods for melanoma. High-frequency ultrasound (US), optical coherence tomography (OCT), and photoacoustic imaging (PAI) are three potential modalities that can assist a dermatologist by providing extra information beyond dermoscopic features. In this study, we imaged a swine model with spontaneous melanoma using these modalities and compared the images with images of nearby healthy skin. Histology images were used for validation.

An overview of methods to mitigate artifacts in optical coherence tomography imaging of the skin.

BACKGROUND: Optical coherence tomography (OCT) of skin delivers three-dimensional images of tissue microstructures. Although OCT imaging offers a promising high-resolution modality, OCT images suffer from some artifacts that lead to misinterpretation of tissue structures. Therefore, an overview of methods to mitigate artifacts in OCT imaging of the skin is of paramount importance. Speckle, intensity decay, and blurring are three major artifacts in OCT images. Speckle is due to the low coherent light source used in the configuration of OCT. Intensity decay is a deterioration of light with respect to depth, and blurring is the consequence of deficiencies of optical components. METHOD: Two speckle reduction methods (one based on artificial neural network and one based on spatial compounding), an attenuation compensation algorithm (based on Beer-Lambert law) and a deblurring procedure (using deconvolution), are described. Moreover, optical properties extraction algorithm based on extended Huygens-Fresnel (EHF) principle to obtain some additional information from OCT images are discussed. RESULTS: In this short overview, we summarize some of the image enhancement algorithms for OCT images which address the abovementioned artifacts. The results showed a significant improvement in the visibility of the clinically relevant features in the images. The quality improvement was evaluated using several numerical assessment measures. CONCLUSION: Clinical dermatologists benefit from using these image enhancement algorithms to improve OCT diagnosis and essentially function as a noninvasive optical biopsy.

Swept-Source Optical Coherence Tomography-Supervised Biopsy.

BACKGROUND: Currently, only skin biopsy can provide definitive histological confirmation for the diagnosis of skin diseases. To improve the diagnostic accuracy and to assist the dermatologist, various imaging techniques have been added to the examination of skin. Among all these techniques, the recent advances in optical coherence tomography (OCT) have made it possible to image the skin up to 2 millimeters in depth. OBJECTIVE: To testify the feasibility of OCT imaging in skin biopsy, the authors investigated the OCT imaging for real-time visualization of needle insertion and punch biopsy techniques in both a tissue phantom and biological tissue. MATERIALS AND METHODS: A swept-source OCT with 1,305-nm central wavelength was used in this study. The euthanized mouse was used for real-time visualization of needle insertion. A gelatin phantom with India ink was used to demonstrate the punch biopsy using OCT. RESULTS: Optical coherence tomography can provide guidance for skin injections as well as real-time imaging to assist in the performance of punch biopsy. CONCLUSION: Optical coherence tomography holds potential not only as a diagnostic tool in dermatology. It can also allow for visualization for more accurate drug delivery, and noninvasively assess the response to treatment.

Multi-Center, Double-Blind, Vehicle-Controlled Clinical Trial of an Alpha and Beta Defensin-Containing Anti-Aging Skin Care Regimen With Clinical, Histopathologic, Immunohistochemical, Photographic, and Ultrasound Evaluation.

BACKGROUND/OBJECTIVES: Anti-aging strategies utilizing stem cells are in the forefront. Alpha and beta defensins are natural immune peptides that have been shown to activate an LGR6-positive stem cell locus in the hair follicle, identified as the source of most new epidermal cells during acute wound healing. We investigated the ability of biomimetic alpha and beta defensin molecules, supplemented with supportive cosmetic ingredients, formulated into three skin care products, at improving the structure and function of aging skin. METHODS: A participant- and investigator -blinded, placebo-controlled, multi-center trial was performed in outpatient settings. Forty-four healthy female subjects, aged 41-71 years, skin types I-V, completed the study with 2/3 receiving full formula and 1/3 receiving the placebo formula. A skin care regimen of 3 products (serum, cream, and mask) containing alpha-defensin 5 and beta-defensin 3, and other cosmetic ingredients, was applied to the face, post-auricular, and neck skin two times per day for 12 weeks in those receiving full formula, whereas the placebo group received the identically packaged regimen without the active ingredients. Methods of evaluation included histopathology and immunohistochemistry (7 subjects), clinical evaluation of pores, superficial and deep wrinkles based on Griffiths scale, and high-resolution photography (all subjects). In addition, a subset of 15 patients were evaluated with the QuantifiCare system (3-dimensional imaging and skin care scores for evenness, pores, oiliness) and Cortex measurements (high-resolution skin ultrasound, TEWL, elasticity, color, and hydration). Data points for evaluation included baseline, 6 weeks, and 12 weeks. All patients used the same sunscreen and cleanser, which was provided to them. RESULTS: The full formula regimen caused a significantly (P equals 0.027) increased thickness of the epidermis as seen in histology, not seen in the placebo group, with no signs of inflammation. No excessive cell proliferation was detected in either group as measured by Ki67-immunohistochemistry. Reduction in visible pores, superficial wrinkles, oiliness, pigmentation, and improvement of skin evenness, were statistically significant. A trend for improvement was also observed in skin elasticity, TEWL, and hydration; these did not achieve statistical significance. Ultrasound and histopathology demonstrated increases in dermal thickness in individual patients, without statistical significance. Comprehensive improvement in all 5 parameters, including visible pores, hyperpigmentation, superficial and deep wrinkles, and epidermal thickness, was statistically significant when the subset of participants assigned for histology in full formula group was compared with the placebo group participants. CONCLUSIONS: A 3-product skin care regimen containing alpha and beta defensins globally improves the visual appearance and structure of aging skin without irritation, dryness, or inflammation. Specifically, this regimen increases epidermal thickness, reduces appearance of pores, reduces wrinkles, and reduces melanin. This skin care regimen stimulates rejuvenation without evidence of increase of a marker of carcinogenic stimulation. This data is consistent with the hypothesis that a defensin-containing skin care regimen activates the body's own dormant stem cells to generate healthy new epidermal cells.

J Drugs Dermatol. 2018;17(4):426-441.

Semi-automated localization of dermal epidermal junction in optical coherence tomography images of skin.

Identifying the location of the dermal epidermal junction (DEJ) in skin images is essential in several clinical applications of dermatology such as epidermal thickness determination in healthy versus unhealthy skins, such as basal cell carcinoma. Optical coherence tomography (OCT) facilitates the visual detection of DEJ in vivo. However, due to the granular texture of speckle and a low contrast between dermis and epidermis, a skin border detection method is required for DEJ localization. Current DEJ algorithms work well for skins with a visible differentiable epidermal layer but not for the skins of different body sites. In this paper, we present a semi-automated DEJ localization algorithm based on graph theory for OCT images of skin. The proposed algorithm is performed in an interactive framework by a graphical representation of an attenuation coefficient map through a uniform-cost search method. For border thinning, a fuzzy-based nonlinear smoothing technique is used. For evaluation, the DEJ detection method is used by several experts, and the results are compared with manual segmentation. The mean thickness error between the proposed algorithm and the experts' opinion in the Bland-Altman plot is computed as 14 µm; this is comparable to the resolution of the OCT. The results suggest that the proposed image processing method successfully detects DEJ.

Identifying Toll-like receptor expression in cutaneous sarcoidosis.

Toll-like receptors (TLRs) are known to be expressed in the skin. Antigenic stimulation of TLRs in the skin has been implicated in several inflammatory dermatologic diseases including psoriasis, syphilis, atopic dermatitis, and cutaneous T-cell lymphoma. However, the expression of TLRs in cutaneous sarcoidosis has not yet been defined. Expression of TLRs 1-9 was examined in cutaneous sarcoid by immunohistochemical staining. It was found that TLRs 5 and 6 stained most intensely in both the granulomas and epidermis of the sarcoid cases. TLRs 2, 3, 4, 7, and 8 stained more intensely compared with normal skin. All sarcoidosis cases showed an increased level of staining compared with the control. The nuclear factor-kappa B activation pathway was confirmed by staining for p65. All cases strongly stained for p65 in the granulomas and varied in staining intensity in the epidermis. The identified TLR expression in cutaneous sarcoidosis indicates that a bacterial antigen could be an etiologic agent of the disease. Future studies that clearly define the etiology of sarcoid will lead to better therapies and a better prognosis for affected patients.