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DNA damage plays a role in ultraviolet (UV)-induced melanoma. We previously showed that aspirin (ASA) can suppress prostaglandin-E2 (PGE2) and protect melanocytes from UV-induced DNA damage in mice, and suggested that taking ASA before acute sun exposure may reduce melanoma risk. We conducted a prospective randomized placebo-controlled trial to determine if orally administered ASA could suppress PGE2 in plasma and nevi and protect nevi from UV-induced DNA damage. After obtaining plasma and determining the minimal erythemal dose (MED) in 95 subjects at increased risk for melanoma, they were randomized to receive a daily dose of placebo, 81 mg ASA, or 325 mg ASA, in double-blind fashion for one month. After this intervention, one nevus was irradiated (dose = 1 or 2 MED) using a solar simulator. One day later, MED was re-determined, a second plasma sample was obtained, and the UV-irradiated nevus and an unirradiated nevus were removed. ASA metabolites were detected in the second plasma sample in subjects in the ASA arms. There were no significant differences in the pre- and post-intervention MED between those patients receiving ASA and placebo. Significantly reduced PGE2 levels were detected in plasma (second vs. first samples) and in nevi (both unirradiated and UV-treated) in subjects receiving ASA compared to placebo. Comparing UV-treated nevi from the ASA and placebo cohorts, however, did not reveal significant reductions in CD3-cell infiltration or 8-oxoguanine and cyclobutane pyrimidine dimers. Thus ASA did not effectively protect nevi from solar-simulated UV-induced inflammation and DNA damage under the conditions examined.Prevention Relevance:Despite promising rationale, ASA at conventional dosing was not able to protect nevi against UV-induced DNA damage under the conditions examined.See related Spotlight, p. 71.

Contains detailed methods for solar-simulated radiation and RT-PCR reactions, table of subjects' characteristics for phase II trial, results of open-label post-trial study, photographs of UV-irradiated nevi, and GSH data from pilot study.

Supplementary Figure S1 shows UV-induced inflammation in nevi.

Oxidative stress plays a role in UV-induced melanoma, which may arise from melanocytic nevi. We investigated whether oral administration of the antioxidant N-acetylcysteine (NAC) could protect nevi from oxidative stress in vivo in the setting of acute UV exposure. The minimal erythemal dose (MED) was determined for 100 patients at increased risk for melanoma. Patients were randomized to receive a single dose (1,200 mg) of NAC or placebo, in double-blind fashion, and then one nevus was irradiated (1–2 MED) using a solar simulator. One day later, the MED was redetermined and the irradiated nevus and a control unirradiated nevus were removed for histologic analysis and examination of biomarkers of NAC metabolism and UV-induced oxidative stress. Increased expression of 8-oxoguanine, thioredoxin reductase-1, and γ-glutamylcysteine synthase modifier subunit were consistently seen in UV-treated compared with unirradiated nevi. However, no significant differences were observed in these UV-induced changes or in the pre- and postintervention MED between those patients receiving NAC versus placebo. Similarly, no significant differences were observed in UV-induced changes between subjects with germline wild-type versus loss-of-function mutations in the melanocortin-1 receptor. Nevi showed similar changes of UV-induced oxidative stress in an open-label post-trial study in 10 patients who received NAC 3 hours before nevus irradiation. Thus, a single oral dose of NAC did not effectively protect nevi from UV-induced oxidative stress under the conditions examined. Cancer Prev Res; 10(1); 36–44. ©2016 AACR.

Supplementary Data from Use of Oral N-Acetylcysteine for Protection of Melanocytic Nevi against UV-Induced Oxidative Stress: Towards a Novel Paradigm for Melanoma Chemoprevention

Purpose: Induction of oxidative stress has been implicated in UV-induced melanoma. We sought to determine whether the antioxidant N-acetylcysteine (NAC) could be safely administered to protect melanocytic nevi from the oxidative stress resulting from acute UV exposure.Experimental Design: Patients at increased risk for melanoma were recruited from a screening clinic. Induction and detection of oxidative stress (reactive oxygen species and glutathione depletion) was optimized in nevi following ex vivo UV irradiation. Nevi were removed from patients before, and following, oral ingestion of a single (1,200 mg) dose of NAC, and then these nevi were UV irradiated (4,000 J/m2).Results: Oxidative stress was induced in nevi 24 to 48 hours following ex vivo UV irradiation. A single oral dose of NAC was well tolerated in all patients (n = 72). Basal levels of reduced glutathione and the NAC metabolite cysteine were well correlated between similar-appearing nevi from the same patient and were significantly increased in nevi removed 3 hours after NAC ingestion compared with nevi removed before drug ingestion. In approximately half (9 of 19) of patients tested, UV-induced glutathione depletion was attenuated in the postdrug (compared with predrug) nevus.Conclusions: NAC can be safely administered to patients for the purpose of modulating UV-induced oxidative stress in nevi. This study suggests the feasibility of patients taking NAC prophylactically before acute UV exposure, to prevent pro-oncogenic oxidative stress in nevi and ultimately reduce long-term melanoma risk. (Clin Cancer Res 2009;15(23):7434–40)

Supplementary Figure Legend from Melanocyte Expression of Survivin Promotes Development and Metastasis of UV-Induced Melanoma in HGF-Transgenic Mice

We previously found the apoptosis inhibitor Survivin to be expressed in melanocytic nevi and melanoma but not in normal melanocytes. To investigate the role of Survivin in melanoma development and progression, we examined the consequences of forced Survivin expression in melanocytes in vivo. Transgenic (Tg) mouse lines (Dct-Survivin) were generated with melanocyte-specific expression of Survivin, and melanocytes grown from Dct-Survivin mice expressed Survivin. Dct-Survivin melanocytes exhibited decreased susceptibility to UV-induced apoptosis but no difference in proliferative capacity compared with melanocytes derived from non-Tg littermates. Induction of nevi in Dct-Survivin and non-Tg mice by topical application of 7,12-dimethylbenz(a)anthracene did not reveal significant differences in lesion onset (median, 10 weeks) or density (4 lesions per mouse after 15 weeks). Dct-Survivin mice were bred with melanoma-prone MH19/HGF-B6 Tg mice, and all progeny expressing either individual, neither, or both (Survivin/HGF) transgenes were UV-treated as neonates and then monitored for 43 weeks. Melanocytes in neonatal Survivin+/HGF+ mouse skin were less susceptible to UV-induced apoptosis than those from Survivin−/HGF+ mice. Onset of melanocytic tumors was earlier (median, 18 versus 24 weeks; P = 0.01, log-rank test), and overall tumor density was greater (7.7 versus 5.2 tumors per mouse; P = 0.04) in Survivin+/HGF+ compared with Survivin−/HGF+ mice. Strikingly, melanomas arising in Survivin+/HGF+ mice showed a greater tendency for lymph node (35% versus 0%; P = 0.04) and lung (53% versus 22%) metastasis and lower rates of spontaneous apoptosis than those in Survivin−/HGF+ mice. These studies show a role for Survivin in promoting both early and late events of UV-induced melanoma development in vivo. [Cancer Res 2007;67(11):5172–8]

Supplementary Figure 1 from Melanocyte Expression of Survivin Promotes Development and Metastasis of UV-Induced Melanoma in HGF-Transgenic Mice

Nevi of specialized sites (NOSS) occur on the scalp, ears, flexural, acral, and genital areas and display atypical clinical and histologic features. We assessed NOSS recurrence and progression to melanoma, management patterns, and associations between histologic features and treatment recommendations. We queried all histologic diagnoses of NOSS (n = 275) from 2012 to 2017 from a large U.S. academic medical center with reference dermatopathology laboratory and matched these to clinical records. A blinded panel of dermatopathologists re-evaluated lesions, catalogued histologic findings, and gave management recommendation. Associations with dermatopathologist decision and concordance between new and original recommendations were assessed. Of 117 cases with follow-up, 2 locally recurred (1.46%) and none eventuated in melanoma. Clinical features were not associated with original treatment recommendations. After histopathologic review, large melanocytes [odds ratio ratio (ORR) = 8.00, 95% CI, 1.35-47.4] and junctional mitotic figures (ORR = 65.0, 6.5-650) predicted excision recommendation. Likewise, accumulation of many (9) high-risk features was associated with excision recommendation. Panel review changed treatment recommendation in 27% of cases. Fair concordance existed between original and panel recommendations (κ = 0.29, 0.15-0.44). The low rate of recurrence and lack of melanoma occurrence suggest that despite an atypical clinical and histopathologic appearance, these nevi have limited potential for malignant transformation. Histopathologic findings seem to be principal drivers behind the recommendation for excision in this analysis. Variability existed in treatment recommendations; the panel's consensus recommendation tended to downgrade treatment. This highlights the importance of further outcomes-based studies to identify true high-risk features and refine management guidelines.

Gordonia bronchialis is a partially acid-fast, gram-positive rod that has been found in a variety of nosocomial infections, most frequently sternal wound infection following coronary artery bypass surgery. We report a case of a mycetomalike infection due to G bronchialis in an immunocompetent patient with complete resolution after 3 months of oral antibiotics.

Studies characterizing clinical and pathologic details of pretibial pruritic papular dermatitis (PPPD) are scarce. Several cases of PPPD at our institution have displayed lymphocyte atypia and CD30 positivity, resembling lymphomatoid papulosis (LyP). We explore the clinical and histological spectrum of PPPD, with emphasis on lymphocyte atypia.Retrospective observational study of 40 archived pathological specimens (hematoxylin/eosin, CD3, CD20, and CD30 immunohistochemistry) from 38 PPPD patients in an academic center. Clinical photographs were available in 22 cases.Microscopic epidermal changes were focal, but common (spongiosis 75%, parakeratosis 90%, interface changes 43%, Langerhans cell microgranulomas 25%, multinucleated keratinocytes 55%, Civatte bodies 55%, erosion 20%, and more than focal irregular psoriasiform hyperplasia 37%) and certain dermal changes were universal (papillary dermal fibrosis 100%, stellate fibroblasts 100%, and multinucleated fibroblasts 93%). At least focal lymphocyte atypia was present in all cases. Lymphocytes were almost exclusively CD3 T cells with rare CD20 B cells. Up to 30% of lymphocytes exhibited weak CD30 staining. Clinically, all cases exhibited discrete papules, but plaques and erosions were not uncommon.As a retrospective series, clinical images were not available for all cases.This study suggests a broader histological and clinical spectrum of PPPD than previously described. Epidermal changes are common in PPPD, as are atypical lymphocytes and focal CD30 positivity. Although the papular clinical appearance, lymphocyte atypia, and focal CD30 positivity may resemble LyP, the relatively low number of atypical lymphocytes, low intensity of CD30 staining, and absence of spontaneous resolution help to distinguish PPPD from LyP.

Cutaneous angiosarcomas (CASs) are aggressive malignancies with a poor prognosis. Although rare, most cases are seen 1) on the head and neck of elderly men, 2) in irradiated skin after therapy for breast carcinoma, and 3) in the setting of long-standing lymphedema (Stewart-Treves syndrome). Only 5 cases of cutaneous external genital CAS have been reported, usually in the setting of pelvic radiation for gynecologic malignancies.1 Here, we describe a case of rapidly progressive and fatal inguinal epithelioid CAS with visceral involvement.

Background/aims T-cell acute lymphoblastic leukemia (T-ALL) is an uncommon, aggressive malignancy that rarely presents in the skin and is generally not considered as part of the differential diagnosis by dermatologists and dermatopathologists. We describe an unusual case of T-ALL presenting with folliculocentric, erythematous papules on the face, histologically resembling mycosis fungoides (MF). Immunostaining for terminal deoxynucleotidyl transferase (TdT) was positive in tumor cells, supporting the diagnosis of cutaneous involvement by T-ALL. TdT is a nuclear enzyme expressed by immature lymphoid malignancies, but the expression pattern of this marker is not well characterized in the skin. We aimed to assess TdT staining in skin biopsies with similar-appearing lymphocytic infiltrates. Methods We evaluated the immunostaining profile of TdT in a cohort of 23 patients, including 13 cases of MF and 10 cases of spongiotic dermatitis. Results The lymphocytes in the MF and spongiotic dermatitis cases lacked nuclear staining for TdT. Nonspecific, granular, cytoplasmic staining was observed in a small number of background cells. Conclusions TdT may assist dermatopathologists in discriminating malignant infiltrates of T-ALL from other conditions.

In the earliest stage of Mycobacterium leprae infection, bacteria parasitize fine fiber twigs of autonomic peripheral nerves supplying efferent impulses to appendages of the skin. This obligate intracellular pathogen invades Schwann cells, the glial cells of peripheral nerves. Intracellular events inhibit Schwann cell physiology in complex ways, which include demyelination and dedifferentiation. Ultimately, axons embraced by their surrounding dysfunctional glia are damaged by poorly understood mechanisms. Loss of nerve conduction impairs the functions of skin appendages including hair growth, sebaceous gland secretion, sweating, and skin pigmentation. At the clinical level, these changes may be subtle and may precede the more obvious anesthetic skin lesions associated with Hansen’s disease. Recognizing the early signs of skin appendage malfunction may aid in diagnosis leading to initiation of antimycobacterial treatment. Effective therapy administered early during infection may prevent irreversible peripheral nerve destruction, the presage for morbid complications of leprosy.

The goal of early melanoma detection is to biopsy melanomas before they become invasive and avoid unnecessary biopsies of benign pigmented lesions.1 Noninvasive gene expression profile testing has the potential to serve both purposes by improving clinical diagnostic accuracy and informing biopsy decision making. The Pigmented Lesion Assay (PLA) (DermTech, La Jolla, CA) involves tape-stripping lesions to obtain stratum corneum from which RNA is isolated and expression levels of the noncoding long RNA Linc00518 (Linc) and PRAME genes are assessed.2 Lesions showing elevated expression levels of both Linc and PRAME, either Linc or PRAME, or neither gene are interpreted as high, moderate, or low risk, respectively.2 In a validation study of 398 pigmented lesions, Gerami and colleagues3 reported that the PLA test had a 91% sensitivity and 69% specificity for histologic diagnosis of melanoma. Reports of the diagnostic performance of the PLA test have been limited to individual lesions from separate patients. To our knowledge, its utility in screening patients with numerous clinically atypical pigmented lesions has not been described.

Potential anti-inflammatory and anticarcinogenic effects of aspirin (ASA) may be suitable for melanoma chemoprevention, but defining biomarkers in relevant target tissues is prerequisite to performing randomized controlled chemoprevention trials. We conducted open-label studies with ASA in 53 human subjects with melanocytic nevi at increased risk for melanoma. In a pilot study, 12 subjects received a single dose (325 mg) of ASA, metabolites salicylate, salicylurate, and gentisic acid were detected in plasma after 4&ndash, 8 h, and prostaglandin E2 (PGE2) was suppressed in both plasma and nevi for up to 24 h. Subsequently, 41 subjects received either 325 or 81 mg ASA (nonrandomized) daily for one week. ASA metabolites were consistently detected in plasma and nevi, and PGE2 levels were significantly reduced in both plasma and nevi. Subchronic ASA dosing did not affect 5&rdquo, adenosine monophosphate-activated protein kinase (AMPK) activation in nevi or leukocyte subsets in peripheral blood, although metabolomic and cytokine profiling of plasma revealed significant decreases in various (non-ASA-derived) metabolites and inflammatory cytokines. In summary, short courses of daily ASA reduce plasma and nevus PGE2 and some metabolites and cytokines in plasma of human subjects at increased risk for melanoma. PGE2 may be a useful biomarker in blood and nevi for prospective melanoma chemoprevention studies with ASA.

Here we present a case of metastatic cutaneous choriocarcinoma presenting as a lesion on the upper lip. This report briefly discusses choriocarcinoma, cutaneous manifestations, and prognosis.

Purpose: The selective tyrosine kinase inhibitor avapritinib has been shown to improve skin lesions in pts with ISM (Hartmann K et al. EACCI 2020. Abstract 1832). We assessed numbers and immunophenotypic changes of MCs in bone marrow (BM) and skin biopsies from lesional tissue (LT) and non-lesional tissue (NLT) in 39 pts with ISM from Part 1 of the placebo-controlled PIONEER (NCT03731260) study. Methods: BM biopsies and aspirates were obtained at Screening; skin biopsies from LT and NLT were obtained at Screening and end of Week 12 (W12). Immunohistochemistry was performed on formalin-fixed sections using the Ventana Benchmark assay with CD117, tryptase, CD25, CD30, and CD34 antibodies. Samples were centrally reviewed by three pathologists. Statistical significance of MC numbers and immunophenotypic changes were assessed. Data cut-off was December 4, 2020. Results: Screening BM biopsies had median 10% (range, 1-60%) MCs, of which 90% (10-100%) were spindled. BM aspirates had median 1% (0-10%) MCs, of which 5% (2-6%) were immature. Median number of MCs/mm2 was 355 (53-4300) in LT and 90 (10-540) in NLT. At W12, avapritinib reduced median number of MCs/mm2 in LT (143 [33-837]) but not NLT (102 [32-207]). BM biopsies had higher median rates of CD25+ and CD30+ MCs (90% CD25+/50% CD30+) compared with skin LT (2% CD25+/10% CD30+) and NLT (1% CD25+/1% CD30+) (Table). Avapritinib produced significant reductions in the proportion of CD30+ MCs in LT at W12 versus placebo (P=0.0053) and non-significant reductions in CD30+ MCs in NLT (P=0.0988). Conclusions: CD25+ and CD30+ MCs were observed in both LT and NLT skin biopsies; however, at markedly lower levels than seen in BM. Treatment with avapritinib decreased the total number of MCs as well as the number of CD30+ and CD25+ MC in both LT and NLT with statistically significant decreases in the CD30+ MC fraction in LT. This is the first study to examine changes in MCs in LT and NLT or ISM during precision therapy of ISM. Table. Immunophenotypic changes of MCs in BM and skin biopsies at screening and W12MC PhenotypeBone MarrowSkin Lesional TissueSkin Non-Lesional TissueAvapritinibPlaceboAvapritinibPlaceboScreening (n=39)Screening (n=25)W12 (n=17)Screening (n=8)W12 (n=7)Screening (n=25)W12 (n=21)Screening (n=8)W12 (n=7)CD25+, median % (range)90 (0-100)2 (1-40)2 (1-10)3 (1-50)5 (2-5)1 (1-5)2 (1-10)2 (1-5)5 (2-5)CD30+, median % (range)50 (0-100)10 (1-100)1 (1-5)13 (1-80)5 (1-30)1 (1-20)1 (1-2)2 (1-30)1 (1-10)Abbreviations: BM, bone marrow; MC, mast cell; W12, Week 12. Citation Format: Tracy George, Sigurd Broesby-Olsen, David Wada, Scott Florell, Karin Hartman, Frank Siebenhaar, Cem Akin, Kate Newberry, Hongliang Shi, Maria Roche, Marcus Maurer, Hanneke Oude Elberink. Changes in mast cell (MC) numbers and phenotype in patients (pts) with indolent systemic mastocytosis (ISM) treated with avapritinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT168.

Oxidative stress plays a role in UV-induced melanoma, which may arise from melanocytic nevi. We investigated whether oral administration of the antioxidant N-acetylcysteine (NAC) could protect nevi from oxidative stress in vivo in the setting of acute UV exposure. The minimal erythemal dose (MED) was determined for 100 patients at increased risk for melanoma. Patients were randomized to receive a single dose (1,200 mg) of NAC or placebo, in double-blind fashion, and then one nevus was irradiated (1–2 MED) using a solar simulator. One day later, the MED was redetermined and the irradiated nevus and a control unirradiated nevus were removed for histologic analysis and examination of biomarkers of NAC metabolism and UV-induced oxidative stress. Increased expression of 8-oxoguanine, thioredoxin reductase-1, and γ-glutamylcysteine synthase modifier subunit were consistently seen in UV-treated compared with unirradiated nevi. However, no significant differences were observed in these UV-induced changes or in the pre- and postintervention MED between those patients receiving NAC versus placebo. Similarly, no significant differences were observed in UV-induced changes between subjects with germline wild-type versus loss-of-function mutations in the melanocortin-1 receptor. Nevi showed similar changes of UV-induced oxidative stress in an open-label post-trial study in 10 patients who received NAC 3 hours before nevus irradiation. Thus, a single oral dose of NAC did not effectively protect nevi from UV-induced oxidative stress under the conditions examined. Cancer Prev Res; 10(1); 36–44. ©2016 AACR.

UVR promotes skin cancer through multiple mechanisms, including induction of inflammation, oxidative stress, and DNA damage such as 8-oxoguanine and cyclobutane pyrimidine dimers. We investigated whether the anti-inflammatory activities of aspirin (acetylsalicylic acid [ASA]) could protect against UVB-induced DNA damage and skin carcinogenesis. ASA reduced UVB-induced 8-oxoguanine and cyclobutane pyrimidine dimers in Melan-A melanocytes and HaCaT keratinocytes. Skin from UVB-irradiated C57BL/6 mice receiving 0.4 mg ASA daily by gavage exhibited less inflammation, fewer sunburn cells, and reduced 8-oxoguanine lesions than skin from irradiated control animals. ASA similarly reduced UVB-induced sunburn cells, 8-oxoguanine, and cyclobutane pyrimidine dimer lesions in skin of melanoma-prone TN61R mice, and this was associated with decreased prostaglandin E2 in plasma and skin. These effects of ASA, however, did not delay melanoma onset in TN61R mice exposed to a single neonatal dose of UVB. In SKH1-E mice prone to squamous cell carcinoma, ASA reduced plasma and skin prostaglandin E2 levels and indices of UVB-induced DNA damage and delayed squamous cell carcinoma onset induced by chronic UVB. These results indicate that ASA can protect against UVB-induced inflammation in skin and reduce UVB-induced DNA damage in both melanocytes and keratinocytes. These effects translated into greater chemopreventive efficacy for UVB-induced squamous cell carcinoma than melanoma mouse models.

Background Histopathologic vasculitis is often reported in periulcer specimens, but the frequency and clinical significance of this finding have not been evaluated. Objective We evaluated the sensitivity, specificity, negative predictive value, and positive predictive value of histopathologic vasculitis from the periulcer edge for detecting ulcers due to cutaneous vasculitis. Methods We performed a retrospective chart review of patients with leg ulcers at a tertiary hospital between 2009 and 2016. Histopathologic slides were evaluated by 2 dermatopathologists who were blinded to the etiology of ulcer. Focal vasculitis was defined as involvement of fewer than 3 vessels. Results Vasculitis at the periulcer edge was seen in 51.6% of the specimens (32 of 62). Of the specimens with histopathologic vasculitis, focal vasculitis was seen in the majority of specimens (71.9% [23 of 32]), whereas diffuse vasculitis was observed in 28.1% (9 of 32). Periulcer vasculitis yielded a high sensitivity (100% [95% confidence interval, 29%-100%]). Furthermore, the specificity was low (50.9% [95% confidence interval, 38.1%-63.6%]) for detecting vasculitis-induced ulcers. Limitations Small number of vasculitis-induced ulcers. Conclusion Focal vasculitis from the periulcer edge is a nonspecific finding and provides little diagnostic value in determining the etiology of lower leg ulcers. Emphasis should be placed on the combination of clinical history and examination, histology, and laboratory findings when diagnosing ulcers.

Hemangiomas are benign vascular neoplasms which arise in early adulthood. Herein we present a 79-year-old woman with a hemangioma of the lower flank masquerading as a cutaneous manifestation of a systemic fungal infection upon initial histological analysis. Decreased elastin and collagen within the lesion likely accounted for the clumping and splaying of the capillaries into "hyphae-like" structures. Loss of dermal elastic tissue and collagen apparently concentrated the capillary proliferation into an unusual morphology mimicking the hyphal structures. Through additional staining methods the lesion was confirmed to be an unusual presentation of a capillary hemangioma.

Background Benign melanocytic rests are a frequent finding in superficial lymph nodes removed during sentinel lymph node biopsies for melanoma. Whereas the histopathology of these deposits is well understood, very little is known regarding melanocytic lymph node deposits in the setting of giant congenital melanocytic nevi. Methods We analyzed lymph nodes removed from the drainage basin of giant congenital melanocytic nevi in three patients who had developed melanoma within their giant congenital nevi. Results Two of three patients showed widespread, capsular and parenchymal melanocytic deposits in multiple nodes (9 of 11 nodes in one patient and 6 of 8 in the other). Melanocytes were small, non-mitotically active and resembled those in the associated giant congenital melanocytic nevus. Melanocytes were arranged singly and in small nests ∼0.05 mm in diameter, with some larger sheets up to 1 mm. Nodal melanocytes stained for Melan A and S100 on immunohistochemical evaluation, but showed negative or minimal HMB-45 reactivity. Conclusions Evaluation of lymph nodes in the setting of giant congenital melanocytic nevi is complicated by the presence of often numerous, parenchymal melanocytic nevic deposits. Bland cytology and minimal or absent HMB-45 staining may be helpful in differentiating these nodal melanocytic nevi from metastatic melanoma. We term this phenomena large congenital nodal nevus.

Background Histopathologic examination is sometimes inadequate for accurate and reproducible diagnosis of certain melanocytic neoplasms. As a result, more sophisticated and objective methods have been sought. The goal of this study was to identify a gene expression signature that reliably differentiated benign and malignant melanocytic lesions and evaluate its potential clinical applicability. Herein, we describe the development of a gene expression signature and its clinical validation using multiple independent cohorts of melanocytic lesions representing a broad spectrum of histopathologic subtypes. Methods Using quantitative reverse-transcription polymerase chain reaction (PCR) on a selected set of 23 differentially expressed genes, and by applying a threshold value and weighting algorithm, we developed a gene expression signature that produced a score that differentiated benign nevi from malignant melanomas. Results The gene expression signature classified melanocytic lesions as benign or malignant with a sensitivity of 89% and a specificity of 93% in a training cohort of 464 samples. The signature was validated in an independent clinical cohort of 437 samples, with a sensitivity of 90% and specificity of 91%. Conclusions The performance, objectivity, reliability and minimal tissue requirements of this test suggest that it could have clinical application as an adjunct to histopathology in the diagnosis of melanocytic neoplasms.

Objective Clinical detection of melanoma can be challenging. The number of biopsy specimens performed to diagnose 1 melanoma is a measure of efficiency of skin cancer detection, but few data are available to describe this measure from US health care. We studied the diagnosis of melanoma among biopsy specimens of clinically concerning pigmented lesions at an academic dermatology department. Methods We searched for all biopsy specimens that were performed because of clinical suspicion of melanoma in 2013. Characteristics of the patient, lesion, and clinician performing the biopsy, and the final pathology diagnosis were recorded. Results A total of 2643 biopsy specimens from 2213 patients submitted by 43 providers were included. Melanoma was diagnosed in 165 cases (positive predictive value 6.4%, 95% confidence interval 5.5%-7.4%). Older age ( P P = .045), and nontrunk location ( P Limitations Factors influencing the decision to biopsy a lesion may be difficult to evaluate retrospectively. Conclusion At an academic medical center, 16 clinically concerning lesions were biopsied to diagnose 1 melanoma. Biopsy specimens of clinically concerning pigmented lesions larger than 6 mm on older men had the highest yield.

Negative pressure wound therapy (NPWT) has been reported to limit epithelial downgrowth, one of the failure mechanisms of percutaneous devices. In a previous study, when NPWT was applied for 4 weeks (NPWT Group) to porous coated titanium percutaneous devices, downgrowth (5 ± 4%; mean ± one SD) was significantly reduced compared to untreated controls (Untreated Group) (16 ± 6%; p ≤ 0.01). However, it was unclear whether this beneficial effect was sustained when NPWT was discontinued. In order to test this, porous coated titanium percutaneous devices were implanted into 6 hairless guinea pigs. Post-surgery, animals received 4 weeks of NPWT treatment followed by 4 weeks of no treatment (Discontinued Group). At necropsy, the devices and surrounding tissues were harvested and processed. Quantitative downgrowth measurements and qualitative analyses of tissue characteristics were performed, and compared to historical controls (NPWT and Untreated Groups). The Discontinued Group, at 8 weeks, had significantly more downgrowth than the NPWT Group at 4 weeks (23 ± 3% vs. 5 ± 4%; p ≤ 0.01). At 8 weeks, the Discontinued Group qualitatively appeared to exhibit reduced numbers of blood vessels and increased degree of fibrosis compared to the NPWT Group at 4 weeks. This study suggests that NPWT will only be an effective treatment for limiting downgrowth if used continuously. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2018. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 564-572, 2019.

The role of selenium (Se) supplementation in cancer prevention is controversial; effects often depend on the nutritional status of the subject and on the chemical form in which Se is provided. We used a combination of in vitro and in vivo models to study two unique therapeutic windows for intervention in the process of cutaneous melanomagenisis, and to examine the utility of two different chemical forms of Se for prevention and treatment of melanoma. We studied the effects of Se in vitro on UV-induced oxidative stress in melanocytes, and on apoptosis and cell cycle progression in melanoma cells. In vivo, we used the HGF transgenic mouse model of UV-induced melanoma to demonstrate that topical treatment with l-selenomethionine results in a significant delay in the time required for UV-induced melanoma development, but also increases the rate of growth of those tumors once they appear. In a second mouse model, we found that oral administration of high dose methylseleninic acid significantly decreases the size of human melanoma xenografts. Our findings suggest that modestly elevation of selenium levels in the skin might risk acceleration of growth of incipient tumors. Additionally, certain Se compounds administered at very high doses could have utility for the treatment of fully-malignant tumors or prevention of recurrence.

Atypical intradermal smooth muscle neoplasms (AISMN, formerly known as cutaneous leiomyosarcomas) are uncommon neoplasms, which seem to be remarkable for their excellent prognosis in contrast to their deeper counterparts. The rarity of AISMN has posed a challenge for characterizing the morphologic spectrum, immunohistochemical staining pattern, and behavior. In this study we evaluated the histologic and immunohistochemical features of 20 cases of AISMN. Clinical follow-up was available on 19 out of 20 patients and ranged from 1 to 124 months with an average of 35 months and a median of 20 months with a male predominance (male to female ratio was 2.3:1). Our data show a wide variation in differentiation and atypical features. Among these, the presence of mitotic figures is diagnostically valuable in rendering the final diagnosis. A broad panel of immunohistochemical stains revealed that smooth muscle actin and muscle specific actin, when used in combination, identified smooth muscle differentiation in 100% of the cases. With some caveats, CD34, S100, and CK 5/6 were helpful in ruling out other important cutaneous spindle cell neoplasms. Significantly, loss of phosphatase and tensin homolog (PTEN) staining was seen in the majority of our cases (80%), supporting a role for PTEN loss in the etiology of these lesions. Logistic regression analysis revealed that positive margin status was helpful for predicting recurrence (100% sensitivity and 94% specificity). We conclude that AISMN can have significant morphologic variation and overlap with other spindle cell neoplasms of the skin and that a limited panel of key immunohistochemical stains should be used to distinguish this lesion. The different surgical measures such as wide excision versus Mohs procedure showed a similar clinical outcome. Although the significance of frequent PTEN loss supports a molecular mechanism of tumor genesis, the diagnostic utility of the stain remains to be determined.

Southern right whales (SRWs, Eubalena australis) are polymorphic for an X-linked pigmentation pattern known as grey morphism. Most SRWs have completely black skin with white patches on their bellies and occasionally on their backs; these patches remain white as the whale ages. Grey morphs (previously referred to as partial albinos) appear mostly white at birth, with a splattering of rounded black marks; but as the whales age, the white skin gradually changes to a brownish grey color. The cellular and developmental bases of grey morphism are not understood. Here we describe cellular and ultrastructural features of grey-morph skin in relation to that of normal, wild-type skin. Melanocytes were identified histologically and counted, and melanosomes were measured using transmission electron microscopy. Grey-morph skin had fewer melanocytes when compared to wild-type skin, suggesting reduced melanocyte survival, migration, or proliferation in these whales. Grey-morph melanocytes had smaller melanosomes relative to wild-type skin, normal transport of melanosomes to surrounding keratinocytes, and normal localization of melanin granules above the keratinocyte nuclei. These findings indicate that SRW grey-morph pigmentation patterns are caused by reduced numbers of melanocytes in the skin, as well as by reduced amounts of melanin production and/or reduced sizes of mature melanosomes. Grey morphism is distinct from piebaldism and albinism found in other species, which are genetic pigmentation conditions resulting from the local absence of melanocytes, or the inability to synthesize melanin, respectively.This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Fil: Eroh, Guy D.. Huntsman Cancer Institute; Estados Unidos. University of Georgia; Estados Unidos Fil: Clayton, Fred C.. University of Utah; Estados Unidos Fil: Florell, Scott R.. University of Utah; Estados Unidos Fil: Cassidy, Pamela B.. Huntsman Cancer Institute; Estados Unidos. Oregon Health & Science University; Estados Unidos Fil: Chirife, Andrea. Instituto de Conservación de Ballenas. Programa de Monitoreo Sanitario de la Ballena Franca Austral; Argentina Fil: Marón, Carina Flavia. University of Utah; Estados Unidos. Instituto de Conservación de Ballenas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Valenzuela, Luciano Oscar. University of Utah; Estados Unidos. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Sociales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Campbell, Michael S.. University of Utah; Estados Unidos. Cold Spring Harbor Laboratory; Estados Unidos Fil: Seger, Jon. University of Utah; Estados Unidos Fil: Rowntree, Victoria J.. University of Utah; Estados Unidos. Instituto de Conservación de Ballenas. Programa de Monitoreo Sanitario de la Ballena Franca Austral; Argentina. Ocean Alliance; Estados Unidos Fil: Leachman, Sancy A.. Oregon Health & Science University; Estados Unidos. Huntsman Cancer Institute; Estados Unidos

Cutaneous carcinosarcoma is a rare tumor with distinct malignant epithelial and mesenchymal cell populations. The histologic subtypes of epithelial and mesenchymal components in cutaneous carcinosarcoma are variable, as an assortment of carcinomatous and sarcomatous patterns have been described in the literature.Clinical information was obtained from patient charts and archival slides were retrieved and reviewed.We present a novel series of six distinct cases of cutaneous carcinosarcoma and review the literature. Our cases consisted of basal cell, pilomatrical, squamous cell, and trichoblastic variants. These cases occurred in elderly men on sun exposed skin with treatment and follow up was available for 4 of 6 cases. The four cases were treated with Mohs micrographic surgery with mean follow up of nine months.We report six cases of cutaneous carcinosarcoma with distinctive clinical and histologic characterization not previously described in a single series.

The diagnosis of scabies infestation is straightforward in cases where mite parts are largely visible; however, mites are often not captured in a specimen's planes of section. Polariscopic examination is a fast and simple adjunctive diagnostic tool to light microscopy. We describe the unique polariscopic findings in scabies infestation. Two cases of crusted scabies and eight cases of typical scabies were subjected to polariscopic examination. Diagnostic mite parts were visualized in at least one section in all cases. Attached and detached spines as well as scybala (fecal material) are polarizable. Specifically, spines show a polarizable outer sheath with dark central core while scybala show peripherally concentrated, stippled birefringence. Similar stippled birefringence is visible within the gut of some mites whereas significant birefringence is not appreciated in other mite parts. These results suggest that polariscopic examination is a helpful clue in the diagnosis of scabies infestation, especially in cases where the body of the mite is not visualized.