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Abstract As natural landscapes are modified and converted into simplified agricultural landscapes, the community composition and interactions of organisms persisting in these modified landscapes are altered. While many studies examine the consequences of these changing interactions for crops, few have evaluated the effects on wild plants. Here, we examine how pollinator and herbivore interactions affect reproductive success for wild resident and phytometer plants at sites along a landscape gradient ranging from natural to highly simplified. We tested the direct and indirect effects of landscape composition on plant traits and reproduction mediated by insect interactions. For phytometer plants exposed to herbivores, we found that greater landscape complexity corresponded with elevated herbivore damage, which reduced total flower production but increased individual flower size. Though larger flowers increased pollination, the reduction in flowers ultimately reduced plant reproductive success. Herbivory was also higher in complex landscapes for resident plants, but overall damage was low and therefore did not have a cascading effect on floral display and reproduction. This work highlights that landscape composition directly affects patterns of herbivory with cascading effects on pollination and wild plant reproduction. Further, the absence of an effect on reproduction for resident plants suggests that they may be adapted to their local insect community.

Competing Interests: None disclosed.

Abstract: Nevus sebaceus is a rare congenital hamartoma with clinical and histopathological features that change with puberty. It has been associated with a number of secondary neoplasms, most of which are thought to derive from follicular germ cells. In this article, the authors describe a total of 3 cases of combined melanocytic nevus and nevus sebaceus to highlight this rare finding., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Exposure to inorganic arsenic (As) is recognized as a risk factor for non-melanoma skin cancer (NMSC). We followed up with 7000 adults for 6 years who were exposed to As. During follow-up, 2.2% of the males and 1.3% of the females developed basal cell carcinoma (BCC), while 0.4% of the male and 0.2% of the female participants developed squamous cell carcinoma (SCC). Using a panel of more than 400 cancer-related genes, we detected somatic mutations (SMs) in the first 32 NMSC samples (BCC = 26 and SCC = 6) by comparing paired (tissue-blood) samples from the same individual and then comparing them to the SM in healthy skin tissue from 16 participants. We identified (a) a list of NMSC-associated SMs, (b) SMs present in both NMSC and healthy skin, and (c) SMs found only in healthy skin. We also demonstrate that the presence of non-synonymous SMs in the top mutated genes (like PTCH1 , NOTCH1 , SYNE1 , PKHD1 in BCC and TP53 in SCC) significantly affects the magnitude of differential expressions of major genes and gene pathways (basal cell carcinoma pathways, NOTCH signaling, IL-17 signaling, p53 signaling, Wnt signaling pathway). These findings may help select groups of patients for targeted therapy, like hedgehog signaling inhibitors, IL17 inhibitors, etc., in the future.

Next-generation sequencing (NGS) is increasingly being utilized as an ancillary tool for diagnostically challenging melanocytic neoplasms. It is incumbent upon the pathology community to perform studies assessing the benefits and limitations of these tools in specific diagnostic scenarios. One of the most challenging diagnostic scenarios faced by skin pathologists involves accurate diagnosis of desmoplastic melanocytic neoplasms (DMNs). In this study, 20 expert melanoma pathologists rendered a diagnosis on 47 DMNs based on hematoxylin and eosin sections with demographic information. After submitting their diagnosis, the experts were given the same cases, but this time with comprehensive genomic sequencing results, and asked to render a diagnosis again. Identification of desmoplastic melanoma (DM) improved by 7%, and this difference was statistically significant ( P <0.05). In addition, among the 15 melanoma cases, in the pregenomic assessment, only 12 were favored to be DM by the experts, while after genomics, this improved to 14 of the cases being favored to be DM. In fact, some cases resulting in metastatic disease had a substantial increase in the number of experts recognizing them as DM after genomics. The impact of the genomic findings was less dramatic among benign and intermediate-grade desmoplastic tumors (BIDTs). Interobserver agreement also improved, with the Fleiss multirater Kappa being 0.36 before genomics to 0.4 after genomics. NGS has the potential to improve diagnostic accuracy in the assessment of desmoplastic melanocytic tumors. The degree of improvement will be most substantial among pathologists with some background and experience in bioinformatics and melanoma genetics., Competing Interests: Conflicts of Interest and Source of Funding: P.G. has served as a consultant for Castle Biosciences and has received an honorarium for this, he has also received royalties for textbooks from Elsevier. For the remaining authors, none were declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Drivers of Spitz neoplasms include activating point mutations in HRAS and Spitz-associated genomic fusions. It has become evident that some BRAF -mutated melanocytic neoplasms can morphologically mimic Spitz tumors (STs). These have been termed BRAF mutated and morphologically spitzoid (BAMS). In this study, 17 experts from the International Melanoma Pathology Study Group assessed 54 cases which included 40 BAMS and 14 true STs. The participants reviewed the cases blinded to the genomic data and selected among several diagnostic options, including BAMS, ST, melanoma, and other. A total of 38% of all diagnostic selections in the BAMS cases were for BAMS, whereas 32% were for ST. In 22 of the BAMS cases, the favored diagnosis was BAMS, whereas in 17 of the BAMS cases, the favored diagnosis was ST. Among the 20 cases in the total group of 54 with the highest number of votes for ST, half were BAMS. Of BAMS, 75% had a number of votes for ST that was within the SD of votes for ST seen among true ST cases. There was poor interobserver agreement for the precise diagnosis of the BAMS (kappa = 0.16) but good agreement that these cases were not melanoma (kappa = 0.7). BAMS nevi/tumors can closely mimic Spitz neoplasms. Expert melanoma pathologists in this study favored a diagnosis of ST in nearly half of the BAMS cases. There are BAMS cases that even experts cannot morphologically distinguish from true Spitz neoplasms., Competing Interests: Conflicts of Interest and Source of Funding: P.G. has served as a consultant for Castle Biosciences and has received royalties for textbooks from Elsevier. For the remaining authors, none were declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Mycosis fungoides has previously been reported in 'invisible' form, when biopsy of normal-appearing skin in the background of undifferentiated chronic pruritus demonstrated histopathologic findings of the malignancy. Asymptomatic cases have been reported more infrequently on biopsies of individual skin lesions. We present a case of invisible and asymptomatic mycosis fungoides, confirmed with immunohistochemical and T-cell receptor gene rearrangement studies, diagnosed on a re-excision specimen of an atypical melanocytic nevus. The case highlights the importance of alert examination of all tissue specimens for evidence of unrelated pathologic findings., Competing Interests: The authors declare no conflicts of interest.., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: There is considerable variation in the literature regarding the dermatopathologic diagnostic features of and reporting guidelines for actinic keratosis (AK) and cutaneous squamous cell carcinoma (cSCC)., Objective: To develop consensus recommendations regarding diagnostic criteria, nomenclature, and reporting of AK and cSCC., Methods: Literature review and cross-sectional multiround Delphi process including an international group of expert dermatopathologists followed by a consensus meeting., Results: Consensus was achieved regarding the key dermatopathologic features necessary for diagnosing cSCC, AK, and associated variants; grading of degree of cellular differentiation in cSCC; utility of immunohistochemistry for diagnosis of cSCC; and pathologic features that should be reported for cSCC and AK., Limitations: Consensus was not achieved on all questions considered., Conclusion: Despite the lack of clarity in the literature, there is consensus among expert dermatopathologists regarding diagnostic criteria and appropriate reporting of AK and cSCC. Widespread implementation of these consensus recommendations may improve communication between dermatopathologists and clinicians, facilitating appropriate treatment of AK and cSCC., Competing Interests: Conflicts of interest None disclosed., (Copyright © 2023 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Abstract: Endovascular procedures that use a hydrophilic polymer-coated device carry a risk of embolization and ischemic complications when used intravascularly. Because these coatings are increasingly used worldwide, it is important to identify potential adverse effects early. Cutaneous complications of hydrophilic polymer emboli are rare and not commonly described in the literature. Therefore, we report a case of hydrophilic polymer embolization with cutaneous findings in a patient who underwent a recent transcatheter aortic valve replacement., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: A standardized pathology classification system for melanocytic lesions is needed to aid both pathologists and clinicians in cataloging currently existing diverse terminologies and in the diagnosis and treatment of patients. The Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) has been developed for this purpose., Objective: To revise the MPATH-Dx version 1.0 classification tool, using feedback from dermatopathologists participating in the National Institutes of Health-funded Reducing Errors in Melanocytic Interpretations (REMI) Study and from members of the International Melanoma Pathology Study Group (IMPSG)., Evidence Review: Practicing dermatopathologists recruited from 40 US states participated in the 2-year REMI study and provided feedback on the MPATH-Dx version 1.0 tool. Independently, member dermatopathologists participating in an IMPSG workshop dedicated to the MPATH-Dx schema provided additional input for refining the MPATH-Dx tool. A reference panel of 3 dermatopathologists, the original authors of the MPATH-Dx version 1.0 tool, integrated all feedback into an updated and refined MPATH-Dx version 2.0., Findings: The new MPATH-Dx version 2.0 schema simplifies the original 5-class hierarchy into 4 classes to improve diagnostic concordance and to provide more explicit guidance in the treatment of patients. This new version also has clearly defined histopathological criteria for classification of classes I and II lesions; has specific provisions for the most frequently encountered low-cumulative sun damage pathway of melanoma progression, as well as other, less common World Health Organization pathways to melanoma; provides guidance for classifying intermediate class II tumors vs melanoma; and recognizes a subset of pT1a melanomas with very low risk and possible eventual reclassification as neoplasms lacking criteria for melanoma., Conclusions and Relevance: The implementation of the newly revised MPATH-Dx version 2.0 schema into clinical practice is anticipated to provide a robust tool and adjunct for standardized diagnostic reporting of melanocytic lesions and management of patients to the benefit of both health care practitioners and patients.

Exposure to inorganic arsenic (As) is recognized as risk factor for basal cell carcinoma (BCC). We have followed-up 7000 adults for 6 years who were exposed to As and had manifest As skin toxicity. Of them, 1.7% developed BCC (males = 2.2%, females = 1.3%). In this study, we compared transcriptome-wide RNA sequencing data from the very first 26 BCC cases and healthy skin tissue from independent 16 individuals. Genes in “ cell carcinoma pathway”, “Hedgehog signaling pathway”, and “Notch signaling pathway” were overexpressed in BCC, confirming the findings from earlier studies in BCC in other populations known to be exposed to As. However, we found that the overexpression of these known pathways was less pronounced in patients with high As exposure (urinary As creatinine ratio (UACR) > 192 µg/gm creatinine) than patients with low UACR. We also found that high UACR was associated with impaired DNA replication pathway, cellular response to different DNA damage repair mechanisms, and immune response. Transcriptomic data were not strongly suggestive of great potential for immune checkpoint inhibitors; however, it suggested lower chance of platinum drug resistance in BCC patients with high UACR compared high platinum drug resistance potential in patients with lower UACR.

When not all the histopathologic and clinical features necessary for a pathology diagnosis are present in a particular specimen, pathologists may use modifying phrases to convey various degrees of certainty, e.g., "consistent with…" and "suggestive of…." However, it is unclear whether pathologists use such phrases consistently or whether treating physicians fully understand their intended meaning. A questionnaire concerning six common modifying phrases ("consistent with, suggestive of, suspicious for, highly consistent with, highly suggestive of, some features of") was sent to all physicians from a single institution who either issued or routinely received surgical pathology reports. Physicians were asked to rank their understanding of each phrase on a printed scale between 1 ("no evidence of") and 10 ("diagnostic of"). One hundred sixty physicians (74.3%) responded. Despite wide variation, there was a hierarchy (from more to less diagnostic): highly consistent > highly suspicious > consistent > suspicious > suggestive > some features (p < 1 × 10 -7 ). There were no significant differences between pathologists and treating physicians (p = 0.72) or attendings and residents (p = 0.9). Pathologists and treating physicians share an overall common understanding of their hierarchical relationship, albeit with wide ranges. Based upon our results, we propose to use only three qualifying phrases to convey the degree of certainty for a particular diagnosis: "suggestive of" (> 25 ≤ 50% certainty), "suspicious for" (> 50 ≤ 75%), and "consistent with" (> 75%). The phrase "no evidence of" should probably be used only when there is ≤ 5% confidence in a diagnosis, and conversely, "diagnostic of" should probably be used only when there is ≥ 95% confidence in a diagnosis., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background/objectives: Follicular keratosis (FK) is a poorly understood disorder presenting with multiple, grouped hyperkeratotic follicular papules typically affecting the chin or jawline. This study describes the clinical presentation, histopathology, management, and outcomes of a series of pediatric patients of color with FK of the face, thought to be related to rubbing or friction on the skin., Methods: Retrospective review of 20 pediatric patients with FK of the face who presented to our pediatric dermatology practice between April 2019 and October 2021., Results: Twenty patients (mean age 12.1 years, 13 females), all self-identified as Black/African American, were included. All presented with an initially asymptomatic, hyperpigmented patch containing multiple hyperkeratotic follicular papules, located on the cheek, chin, upper lip, and/or jawline. Five patients endorsed a history of rubbing the site. Nine patients had onset of the lesions during the COVID-19 pandemic. Treatments included topical vitamin D analogs, corticosteroids, and/or retinoids. Topical vitamin D analogs and retinoids improved the texture and hyperpigmentation of the follicular lesions in only four patients, while topical corticosteroids had no effect. Histopathological examination of two patients revealed multiple dilated follicles containing keratinized material and associated with a sparse dermal inflammatory infiltrate in one patient and granulomatous inflammation within the dermis in the other., Conclusions: In our cohort of pediatric patients with FK, patients of color were preferentially affected, and all cases were associated with hyperpigmentation. Some patients presented during the COVID-19 pandemic suggesting that friction from facial mask wearing may have induced or exacerbated this uncommon condition., (© 2022 Wiley Periodicals LLC.)

Atypical Spitzoid melanocytic tumors are diagnostically challenging. Many studies have suggested various genomic markers to improve classification and prognostication. We aimed to assess whether next-generation sequencing studies using the Tempus xO assay assessing mutations in 1711 cancer-related genes and performing whole transcriptome mRNA sequencing for structural alterations could improve diagnostic agreement and accuracy in assessing neoplasms with Spitzoid histologic features. Twenty expert pathologists were asked to review 70 consultation level cases with Spitzoid features, once with limited clinical information and again with additional genomic information. There was an improvement in overall agreement with additional genomic information. Most significantly, there was increase in agreement of the diagnosis of conventional melanoma from moderate (κ=0.470, SE=0.0105) to substantial (κ=0.645, SE=0.0143) as measured by an average Cohen κ. Clinical follow-up was available in all 70 cases which substantiated that the improved agreement was clinically significant. Among 3 patients with distant metastatic disease, there was a highly significant increase in diagnostic recognition of the cases as conventional melanoma with genomics (P<0.005). In one case, none of 20 pathologists recognized a tumor with BRAF and TERT promoter mutations associated with fatal outcome as a conventional melanoma when only limited clinical information was provided, whereas 60% of pathologists correctly diagnosed this case when genomic information was also available. There was also a significant improvement in agreement of which lesions should be classified in the Spitz category/WHO Pathway from an average Cohen κ of 0.360 (SE=0.00921) to 0.607 (SE=0.0232) with genomics., Competing Interests: Conflicts of Interest and Source of Funding: This study was supported by the IDP Foundation Inc. R.A.S. is supported by a National Health and Medical Research Council of Australia (NHMRC) Program Grant and Practitioner Fellowship. P.G. has received royalties from Elsevier for textbooks and has served as a consultant for Castle Biosciences and DermTech Inc. K.B. has received royalties from Elsevier for textbooks. R.A.S. has received fees for professional services from Qbiotics, Novartis, Merck Sharp & Dohme, NeraCare, AMGEN Inc., Bristol-Myers Squibb, Myriad Genetics, and GlaxoSmithKline. C.R.S. has received fees for professional services from Myriad Genetics, Novartis, Orlucent, and SkinCure Oncology. M.T.T. has served as a consultant and advisor for Myriad Genetics, Merck Sharp & Dohme, Nanostring LLC, and Novartis. For the remaining authors none were declared., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Cidofovir is a broad-spectrum antiviral agent that has shown efficacy against skin lesions caused by human papillomavirus (HPV). We present a case of extensive verruca vulgaris lesions refractory to imiquimod that was responsive to topical cidofovir therapy, and analyze other case series in the literature of successful treatment of benign HPV-associated skin lesions with topical cidofovir. Topical cidofovir's favorable response rate and tolerability make it a useful treatment option for patients of differing ages and immune status who have nonmalignant HPV-associated skin lesions and desire topical therapy.

Introduction: An image-guided form of superficial ionizing radiation therapy (IGSRT) is becoming a commonly used alternative to surgery for non-melanoma skin cancer (NMSC). However, there is little literature evidence evaluating the efficacy and safety of this approach. This study evaluates the efficacy and safety of IGSRT in treating a large number of patients with NMSC., Methods: The medical records of 1632 stage 0-II patients with 2917 invasive and in situ NMSC lesions treated from years 2017 to 2020 were reviewed. No patients had clinical evidence of regional lymph node or distant disease at presentation., Results: Treatment, guided by pre-treatment ultrasound imaging to adjust radiation energy and dose, combined with a fractionation treatment schedule of 20 or more treatment fractions, was safe and well tolerated. Of 2917 NMSC lesions treated, local tumor control was achieved in 2897 lesions, representing a 99.3% rate of control., Conclusion: IGSRT should be considered as a first-line option for treating NMSC tumors in suitable early stage patients. Cure rates observed in this initial period of follow-up are similar, and potentially superior with further follow-up, to traditional superficial radiation therapy (SRT) and surgical options.

Here we show that FTO as an N 6 -methyladenosine (m 6 A) RNA demethylase is degraded by selective autophagy, which is impaired by low-level arsenic exposure to promote tumorigenesis. We found that in arsenic-associated human skin lesions, FTO is upregulated, while m 6 A RNA methylation is downregulated. In keratinocytes, chronic relevant low-level arsenic exposure upregulated FTO, downregulated m 6 A RNA methylation, and induced malignant transformation and tumorigenesis. FTO deletion inhibited arsenic-induced tumorigenesis. Moreover, in mice, epidermis-specific FTO deletion prevented skin tumorigenesis induced by arsenic and UVB irradiation. Targeting FTO genetically or pharmacologically inhibits the tumorigenicity of arsenic-transformed tumor cells. We identified NEDD4L as the m 6 A-modified gene target of FTO. Finally, arsenic stabilizes FTO protein through inhibiting p62-mediated selective autophagy. FTO upregulation can in turn inhibit autophagy, leading to a positive feedback loop to maintain FTO accumulation. Our study reveals FTO-mediated dysregulation of mRNA m 6 A methylation as an epitranscriptomic mechanism to promote arsenic tumorigenicity.

Background: Increasingly widespread use of programmed cell death protein 1 (PD-1) immune checkpoint inhibitors (ICIs) for treatment of a variety of progressive malignancies continues to reveal a range of immune-related adverse events (irAEs), necessitating immunosuppressive therapy for management. While a single course of systemic corticosteroids may be sufficient for many irAEs, no clear standard-of-care guidelines exist for steroid-refractory cases. We present an unusual case of a patient who developed several steroid-refractory novel irAEs on pembrolizumab despite ongoing B cell-directed immunosuppressive therapy with rituximab, who ultimately noted resolution of symptoms with tacrolimus, a T-cell-directed immunosuppressant., Case Presentation: This 72-year-old Caucasian man with Waldenstrom's macroglobulinemia and myelin-associated glycoprotein (MAG) immunoglobulin M (IgM) antibody-associated neuropathy was being treated with maintenance rituximab and intravenous immunoglobulin when he was started on pembrolizumab (2.26 mg/kg) for metastatic urothelial cancer 31 months after surgery and adjuvant chemotherapy. After his third dose of pembrolizumab, he developed a painful blistering papular rash of the distal extremities. He received two more doses of pembrolizumab before he also developed diarrhea, and it was held; he was initiated on 1 mg/kg prednisone for presumed ICI-induced dermatitis and colitis. Skin biopsy 10 weeks after cessation of pembrolizumab and taper of steroids to 20  mg daily revealed a unique bullous erythema multiforme. He was then admitted with dyspnea and imaging concerning for necrotizing pneumonia, but did not respond to antibiotic therapy. Bronchoscopy and biopsy revealed acute fibrinous organizing pneumonia. His symptoms failed to fully respond to multiple courses of high-dose systemic corticosteroids and a trial of azathioprine, but pneumonia, diarrhea, and skin rash all improved markedly with tacrolimus. The patient has since completed his therapy for tacrolimus, continues off of ICI, and has not experienced a recurrence of any irAEs, though has more recently experienced progression of his cancer., Conclusion: Despite immunosuppression with rituximab and intravenous immunoglobulin, two immunomodulators targeting B cells, ICI cessation, and systemic corticosteroid therapy, our patient developed two high-grade unusual irAEs, bullous erythema multiforme and acute fibrinous organizing pneumonia. Our patient's improvement with tacrolimus can offer critical insight into the pathophysiology of steroid-refractory irAEs.

Background: Dermatofibroma (DF) is a common benign skin neoplasm. Induction above DF lesions, including follicular unit induction, is a frequently observed phenomenon. Wnt signaling is known to be critical in hair follicle morphogenesis. Our study assesses the role of Wnt signaling in DF induction by evaluating intracellular localization of β-catenin in various types of DF induction., Methods: Archived tissue collected between 1 October 1980 and 1 October 2013 was stained per protocol using hematoxylin and eosin and anti-β-catenin monoclonal antibody. Specimens were grouped into categories based on the presence or absence and type of induction. All specimens were scored for nuclear β-catenin localization., Results: Of 62 specimens, 42 (68%) showed induction while 20 (32%) showed none. Nuclear β-catenin staining was detected in 23 (55%) of the induction and in none of the no-induction specimens (P-value < 0.001). Types of induction included: 15 (24%) follicular induction, 31 (50%) acanthosis, and 4 (6%) sebaceous induction. For follicular induction, 13 (87%) showed positive nuclear β-catenin staining compared to 11 (35%) for acanthosis and 1 (25%) for sebaceous induction (P-value = 0.002)., Conclusion: Our findings support the hypothesis that DFs promote an ectopic activation of Wnt pathway signaling in follicular induction phenomenon., (© 2020 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

Introduction: Mucosal melanoma is rare and associated with poorer prognosis in comparison to conventional melanoma subtypes. Little is known about the prognostic significance as well as possible associations between PARP1 and immunologic response in mucosal melanoma., Methods: PARP1, PD-L1 and IDO1 immunostains were performed on 192 mucosal melanomas including 86 vulvar, 89 sinonasal, and 17 anorectal melanomas., Results: By Kaplan-Meier analyses, high PARP1 expression correlated with worse overall and melanoma-specific survival (log-rank p values = 0.026 and 0.047, respectively). Tumors with combined PARP1 and IDO1 high expression correlated with worse overall and melanoma-specific survival ( p = 0.015, 0.0034 respectively). By multivariate analyses, high PARP1 expression remained a predictor of worse survival independent of stage. By Fisher's exact test, high PARP1 expression correlated with highly mitogenic tumors ( p = 0.02). High tumoral PD-L1 and IDO1 expression were associated with ulcerated primary tumors ( p = 0.019, 0.0019, respectively). By linear regression analyses, correlations between PARP1 expression versus IDO1 expression ( p = 0.0001) and mitotic index ( p = 0.0052) were observed., Conclusion: Increased expression of PARP1 is an independent negative prognostic marker in mucosal melanomas. The association between PARP1 and IDO1 and their combined adverse prognostic role raise the potential of combined therapy in mucosal melanoma.

Lichen sclerosus (LS) is a chronic inflammatory dermatosis that classically presents as sclerotic, atrophic plaques in the genital region. We present a case of acrochordon with histological features of LS, clinically mimicking intradermal nevus, in a 53-year-old man with no prior history of LS. Our case highlights an unusual morphologic variant of acrochordon and illustrates the role of chronic pressure and occlusion in the development of secondary features of LS.

The prognostic role of PDL1 expression, CD8+ and FoxP3+ lymphocytes in vulvar melanomas has not been studied. We correlated PDL1 expression and CD8+ and FoxP3+ immune infiltrates with clinicopathologic variables and patient outcomes in a series of 75 vulvar melanomas. Tumoral PDL1 expression (>5%) was seen in 23% of cases. By Fisher exact test, PDL1 expression and peritumoral FoxP3+ lymphocytes significantly correlated with less disease-specific death. By linear regression analysis, correlations between tumoral PDL1 expression with the density of tumoral CD8+ and peritumoral CD8+ lymphocytes, tumoral FoxP3+ with tumoral CD8+ lymphocytes, and peritumoral FoxP3+ with peritumoral CD8+ lymphocytes were observed. By univariate analyses, tumor thickness >4 mm predicted poorer progression-free survival, melanoma-specific survival, and overall survival. PDL1 expression >5% and peritumoral CD8+, peritumoral FoxP3+, and tumoral FoxP3+ lymphocytes correlated with better overall survival. By multivariate analyses, high peritumoral FoxP3+ lymphocytes independently predicted better melanoma-specific survival (P = .023), and tumor thickness independently predicted poorer progression-free survival (P = .05) and overall survival (P = .039). In conclusion, our study shows that, independent from tumor thickness, an increased density of peritumoral FoxP3+ lymphocytes may positively impact survival in a subset of vulvar melanomas. Tumoral PDL1 expression correlated with tumoral as well as peritumoral CD8+ and FoxP3+ lymphocytes, supportive of an adaptive immune response. Although the frequency of PDL1 expression is low in vulvar melanoma, its expression may identify a subset of vulvar melanoma that might respond to immunotherapy., (Copyright © 2018. Published by Elsevier Inc.)

Background: Few studies have addressed prognostic markers and none has correlated molecular status and prognosis in vulvar melanomas., Objectives: To evaluate the clinicopathological features of 95 cases of vulvar melanoma., Methods: p53, CD117, Ki-67, neurofibromin, brafv600e and nrasq61r immunostains, and molecular analyses by either targeted next-generation or direct sequencing, were performed on available archival materials., Results: Molecular testing detected mutations in KIT (44%), BRAF (25%), NF1 (22%), TP53 (17%), NRAS (9%) and TERT promoter (9%). Co-mutation of KIT and NF1 and of KIT and NRAS were identified in two and one cases, respectively. KIT mutations were significantly associated with better progression-free survival in univariate analyses. In multivariate analyses CD117 expression was significantly associated with better progression-free survival. Tumour thickness was significantly associated with worse progression-free and overall survival, and perineural invasion significantly correlated with reduced melanoma-specific survival and reduced overall survival. Cases were from multiple centres and only a subset of samples was available for molecular testing., Conclusions: KIT mutations and CD117 overexpression are markers of better progression-free survival. In addition to its prognostic value, molecular testing may identify cases that might respond to targeted agents or immunotherapeutic approaches., (© 2017 British Association of Dermatologists.)

Importance: Patients with germline mutations in BAP1 may develop several flesh-colored melanocytic BAP1-mutated atypical intradermal tumors (MBAITs). These tumors generally develop earlier than other BAP1-associated tumors, highlighting an important role for dermatologists in identifying and screening patients with a history suggestive of a germline mutation., Objective: To describe 8 new families with germline mutations in BAP1 and provide a comprehensive review of reported cases., Design, Settings and Participants: Patients were identified in an outpatient dermatology clinical setting over a 6-month period (10 mutation carriers from 8 families) and through a literature review using PubMed (205 patients)., Exposures: Mutations were identified through next-generation sequencing of saliva or blood samples, and RNA was extracted from fibroblasts cultured from a patient with an intronic variant to determine the impact of the mutation on the coding sequence., Main Outcomes and Measures: All 215 patients were assessed for personal and/or family history and genotype. These findings were compiled and assessed for any association between genotype and phenotype., Results: Overall, this study included 215 patients (108 women, 91 men, and 16 gender unspecified; median [range] age, 46.5 [10.0-79.0] years). Nine of the 10 patients who were identified in the outpatient dermatology setting were found to have MBAITs on clinical examination. Forty of 53 patients (75%) identified in the literature review who underwent total-body skin examinations (TBSE) were found to have MBAITs, suggesting a high penetrance in patients who have undergone TBSE. The most prevalent malignancies among BAP1 mutation carriers were uveal melanoma (n =  60 [28%]), mesothelioma (n = 48 [22%]), cutaneous melanoma (n = 38 [18%]), and renal cell carcinoma (n = 20 [9%]). A total of 71 unique mutations in BAP1 have been reported., Conclusions and Relevance: Our results indicate that germline mutations in both coding and noncoding regions throughout the BAP1 gene can impair protein function, leading to an increased risk for several associated malignancies. Four of the 8 probands we present had no history of BAP1-associated malignancies and were assessed for germline mutations when found to have MBAITs on dermatologic examination. Dermatologists can identify patients with a high likelihood of the BAP1 cancer syndrome through personal and family history and TBSE for the presence of possible MBAITs.

Macroautophagy (hereafter autophagy) is a cellular "self-eating" process that is implicated in many human cancers, where it can act to either promote or suppress tumorigenesis. However, the role of autophagy in regulation of inflammation during tumorigenesis remains unclear. Here we show that autophagy is induced in the epidermis by ultraviolet (UV) irradiation and autophagy gene Atg7 promoted UV-induced inflammation and skin tumorigenesis. Atg7 regulated UV-induced cytokine expression and secretion, and promoted Ptgs2/Cox-2 expression through both a CREB1/CREB-dependent cell autonomous mechanism and an IL1B/IL1β-dependent non-cell autonomous mechanism. Adding PGE 2 increased UV-induced skin inflammation and tumorigenesis, reversing the epidermal phenotype in mice with Atg7 deletion in keratinocytes. Similar to ATG7 knockdown in human keratinocytes, ATG5 knockdown inhibited UVB-induced expression of PTGS2 and cytokines. Furthermore, ATG7 loss increased the activation of the AMPK pathway and the phosphorylation of CRTC1, and led to endoplasmic reticulum (ER) accumulation and reduction of ER stress. Inducing ER stress and inhibiting calcium influx into the ER by thapsigargin reverses the inflammation and tumorigenesis phenotype in mice with epidermal Atg7 deletion. Taken together, these findings demonstrate that deleting autophagy gene Atg7 leads to a suppression of carcinogen-induced protumorigenic inflammatory microenvironment and tumorigenesis of the epithelium.

Background: Pathologists use diverse terminology when interpreting melanocytic neoplasms, potentially compromising quality of care., Objective: We sought to evaluate the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) scheme, a 5-category classification system for melanocytic lesions., Methods: Participants (n = 16) of the 2013 International Melanoma Pathology Study Group Workshop provided independent case-level diagnoses and treatment suggestions for 48 melanocytic lesions. Individual diagnoses (including, when necessary, least and most severe diagnoses) were mapped to corresponding MPATH-Dx classes. Interrater agreement and correlation between MPATH-Dx categorization and treatment suggestions were evaluated., Results: Most participants were board-certified dermatopathologists (n = 15), age 50 years or older (n = 12), male (n = 9), based in the United States (n = 11), and primary academic faculty (n = 14). Overall, participants generated 634 case-level diagnoses with treatment suggestions. Mean weighted kappa coefficients for diagnostic agreement after MPATH-Dx mapping (assuming least and most severe diagnoses, when necessary) were 0.70 (95% confidence interval 0.68-0.71) and 0.72 (95% confidence interval 0.71-0.73), respectively, whereas correlation between MPATH-Dx categorization and treatment suggestions was 0.91., Limitations: This was a small sample size of experienced pathologists in a testing situation., Conclusion: Varying diagnostic nomenclature can be classified into a concise hierarchy using the MPATH-Dx scheme. Further research is needed to determine whether this classification system can facilitate diagnostic concordance in general pathology practice and improve patient care., (Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Cellular blue nevomelanocytic lesions (CBNLs) frequently pose diagnostic problems to pathologists, and their biological potential may be difficult to establish. In this study, the authors have analyzed the clinical, histological, and outcome data of 37 cellular blue nevomelanocytic lesions and the molecular characteristics of 4 lesions. The cohort of cases comprised 8 cellular blue nevi (CBNs), 17 atypical cellular blue nevi (ACBNs), and 12 blue-nevus-like melanomas (BNLMs) with a mean follow-up of 5 years. The average age at diagnosis was 25.9 years for patients with ACBN, versus 30.4 years for CBN, and 44.6 years for BNLM. Both CBN and ACBN occurred most frequently on the trunk or extremities, whereas BNLM primarily involved the scalp. Histologically, CBN and ACBN were characterized by a mean diameter of <1 cm, absence of necrosis, low mitotic rate (mean: 1-2 mitotic figures/mm), little or no infiltrative properties, and usually low-grade cytologic atypia. In contrast, BNLM had a mean diameter of 1.6 cm, necrosis, tissue infiltration, greater mitotic activity (mean: 6 mitotic figures/mm), and high-grade cytologic atypia. ACBNs often were larger, more densely cellular, exhibited higher mitotic counts, and were cytologically more atypical than CBN. Seven CBN cases with follow-up had a benign clinical course (average follow-up of 4.7 years). Among 6 patients with ACBN who underwent sentinel lymph node (SLN) biopsy, 3 were positive, and a single additional case had 1 positive non-SLN (this patient did not have a SLN biopsy performed). All 14 cases of ACBN with follow-up were alive and without recurrence with mean follow-up of 5 years. Of the 9 melanoma cases with follow-up, 3 patients with SLN and non-SLN involvement died from their disease (average follow-up of 4.8 years). Array comparative genomic hybridization was performed on 2 ACBNs and 1 BNLM: One of the 2 ACBNs showed chromosomal aberrations and 1 BNLM showed multiple chromosomal gains and losses. Multiplex polymerase chain reaction was performed on 1 ACBN, and no mutations were found. From these results, the authors conclude that ACBN occupy an intermediate position within the spectrum of CBN and BNLM, yet many lesions cannot be reliably distinguished from either CBN or BNLM because of overlapping histologic features. However, in general, ACBNs seem to aggregate more closely with CBN in terms of clinical, histological, molecular profile (limited data), and biological behavior.

Dermal melanophages are frequently encountered in both benign melanocytic nevi and malignant melanoma. In contrast, intraepidermal melanophages (IEM) are under-recognized in melanocytic lesions and their biologic significance is not understood. Herein, we report the clinical and histopathologic features of five melanocytic lesions featuring IEM encountered prospectively in our dermatopathology practice at the University of Chicago. Two hundred and thirty-one (231) archived skin primary melanocytic proliferations were also investigated retrospectively in a de-identified, archival teaching set collection. Nineteen of 231 of the archived cases were positive for IEM. Among the total 24 IEM-positive cases (5 prospective and 19 archived cases), 13 were categorized as Spitz nevi (p < 0.0001) and 3 as atypical Spitz tumors (p = 0.0152). Fourteen of 24 cases with IEM also exhibited intracorneal melanocytes (p < 0.0001). IEM are evidently not rare, especially in spitzoid melanocytic neoplasms. IEM in our series were significantly correlated with intracorneal melanocytosis, possibly indicating an association between IEM and suprabasal melanocytosis and/or transepidermal elimination of melanocytes., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Morphea is a rare fibrosing condition of the skin and underlying tissues characterized histopathologically by thickened collagen bundles throughout the dermis, loss of adnexal structures, and "fat trapping." In the early stages of morphea, the absence of the fully developed characteristic findings may cause diagnostic confusion for the practicing pathologist. The authors report an unusual case of early morphea misdiagnosed as patch-stage poikilodermatous mycosis fungoides (MF) based on the initial clinical, histopathologic, and molecular findings. However, as time elapsed, well-developed lesions revealed clinical and histopathologic features diagnostic of morphea. The authors report this case to illustrate that lesions of early morphea may simulate MF. Given the similarities in clinicopathologic presentation, dermatologists and dermatopathologists should be cautious not to inadvertently misinterpret early morphea as MF.

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., (© 2015 The Authors. Journal of Cutaneous Pathology published by John Wiley & Sons Ltd.)

Background: Skin barrier integrity requires a highly coordinated molecular system involving the structural protein filaggrin (FLG). Mutational loss of the skin barrier protein FLG predisposes subjects to the development of atopic dermatitis (AD)., Objective: We sought to determine the role of sirtuin 1 (SIRT1) in skin barrier function, FLG expression, and development of AD., Methods: Skin histology of mice with skin-specific SIRT1 deletion and wild-type control animals was examined by using hematoxylin and eosin staining. Protein and mRNA abundance was analyzed by means of immunoblotting, immunohistochemistry, immunofluorescence, and RT-PCR. Serum antibody levels were assessed by means of ELISA., Results: Here we show that FLG is regulated by the protein deacetylase SIRT1 and that SIRT1 is critical for skin barrier integrity. Epidermis-specific SIRT1 ablation causes AD-like skin lesions in mice, and mice with epidermal SIRT1 deletion are sensitive to percutaneous challenge by the protein allergen ovalbumin. In normal human keratinocytes and mouse skin SIRT1 knockdown or genetic deletion downregulates FLG, and regulation of FLG expression by SIRT1 requires the deacetylase activity of SIRT1. SIRT1 also promotes activation of the aryl hydrocarbon receptor, and the aryl hydrocarbon receptor ligand restores FLG expression in SIRT1-inhibited cells. Compared with normal human skin, SIRT1 is downregulated in both AD and non-AD lesions., Conclusion: Our findings demonstrate a critical role of SIRT1 in skin barrier maintenance, open up new opportunities to use SIRT1 as a pharmacologic target, and might facilitate the development of mechanism-based agents for AD prevention and therapy., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The protein deacetylase SIRT1 regulates various pathways in metabolism, aging and cancer. However, the role of SIRT1 in skin cancer remains unclear. Here, using mice with targeted deletions of SIRT1 in their epidermis in both resistant B6 and sensitive SKH1 hairless backgrounds, we show that the role of SIRT1 in skin cancer development induced by ultraviolet B (UVB) radiation is dependent on its gene dose. Keratinocyte-specific heterozygous deletion of SIRT1 promotes UVB-induced skin tumorigenesis, whereas homozygous deletion of SIRT1 suppresses skin tumor development but sensitizes the B6 mice to chronic solar injury. In mouse skin, SIRT1 is haploinsufficient for UVB-induced DNA damage repair and expression of xeroderma pigmentosum C (XPC), a protein critical for repairing UVB-induced DNA damage. As compared with normal human skin, downregulation of SIRT1 is in parallel with downregulation of XPC in human cutaneous squamous cell carcinoma at both the protein and mRNA levels. In contrast, homozygous SIRT1 deletion in mouse skin augments p53 acetylation and expression of its transcriptional target Noxa, and sensitizes the epidermis to UVB-induced apoptosis in vivo, while heterozygous SIRT1 deletion has no such effect. The gene dosage-dependent function of SIRT1 in DNA repair and cell survival is consistent with the dual roles of SIRT1 in UVB-induced skin tumorigenesis. Our results reveal the gene dosage-dependent in vivo functions of SIRT1 in skin tumorigenesis and may shed light on the role of SIRT1 in epithelial cancer induced by DNA damage.

Cutaneous squamous cell carcinomas (CSCCs) comprise 20-30% of nonmelanoma skin cancers (NMSCs), and continue to increase in incidence. We report a case of a patient with severe psoriasis who had recurrent and eruptive CSCCs on her leg, which were successfully treated with cetuximab and radiotherapy. The patient had successful long-term clearance of her skin tumours, with the additional finding of resolution of psoriasis while on cetuximab therapy., (© 2014 British Association of Dermatologists.)

Background: Epidemiologic research suggests that increased cancer risk due to chronic arsenic exposure persists for several decades even after the exposure has terminated. Observational studies suggest that antioxidants exert a protective effect on arsenical skin lesions and cancers among those chronically exposed to arsenic through drinking water. This study reports on the design, methods and baseline analyses from the Bangladesh Vitamin E and Selenium Trial (BEST), a population-based chemoprevention study conducted among adults in Bangladesh with visible arsenic toxicity., Materials and Methods: Bangladesh Vitamin E and Selenium Trial is a 2 × 2 full factorial, double-blind, randomized controlled trial of 7000 adults having manifest arsenical skin lesions evaluating the efficacy of 6-year supplementation with alpha-tocopherol (100 mg daily) and L-selenomethionine (200 μg daily) for the prevention of nonmelanoma skin cancer., Results: In cross-sectional analyses, we observed significant associations of skin lesion severity with male gender (female prevalence odds ratio (POR) = 0.87; 95% CI = 0.79-0.96), older age (aged 36-45 years, POR = 1.27; 95% CI = 1.13-1.42; aged 46-55 years, POR = 1.44; 95% CI = 1.27-1.64 and aged 56-65 years, POR = 1.50; 95% CI = 1.26-1.78 compared with aged 25-35 years), hypertension (POR = 1.29; 95% CI = 1.08-1.55), diabetes (POR = 2.13; 95% CI = 1.32-3.46), asthma (POR = 1.55; 95% CI = 1.03-2.32) and peptic ulcer disease (POR = 1.20; 95% CI = 1.07-1.35)., Conclusions: We report novel associations between arsenical skin lesions with several common chronic diseases. With the rapidly increasing burden of preventable cancers in developing countries, efficient and feasible chemoprevention study designs and approaches, such as employed in BEST, may prove both timely and potentially beneficial in conceiving cancer chemoprevention trials in Bangladesh and beyond., (© 2013 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Borderline sebaceous neoplasms are rare tumors that can be challenging to diagnose because of their admixture of histopathologic features. Most such tumors have been described in patients with Muir-Torre syndrome (MTS). We report the case of an immunosuppressed, 82-year-old African-American woman without MTS who developed a rapidly growing lesion on the left cheek. Histopathology revealed a borderline sebaceous neoplasm with predominant features of sebaceous adenoma and with focal features raising concern for the possibility of an evolving, well-differentiated, low-grade sebaceous carcinoma with a high mitotic index. In the setting of immunosuppression, borderline sebaceous neoplasms may occur outside of MTS; careful evaluation and conservative treatment are recommended in managing such tumors., (© 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.)

Melanocyte stem cells differ greatly from melanoma stem cells; the former provide pigmented cells during normal tissue homeostasis and repair, and the latter play an active role in a lethal form of cancer. These 2 cell types share several features and can be studied by similar methods. Aspects held in common by both melanocyte stem cells and melanoma stem cells include their expression of shared biochemical markers, a system of similar molecular signals necessary for their maintenance, and a requirement for an ideal niche microenvironment for providing these factors. This review provides a perspective of both these cell types and discusses potential models of stem cell growth and propagation. Recent findings provide a strong foundation for the development of new therapeutics directed at isolating and manipulating melanocyte stem cells for tissue engineering or at targeting and eradicating melanoma specifically, while sparing nontumor cells., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Context: Pemphigus is a group of autoimmune vesiculobullous diseases characterized by immunoglobulin G (IgG) antibodies directed against desmosomal adhesion proteins, with IgG4 being the predominant subclass in active diseases. Direct immunofluorescence for IgG performed on fresh-frozen tissue plays a crucial role in diagnosing pemphigus. However, the diagnosis might be hindered when frozen tissue is not available., Objective: To evaluate the usefulness of immunohistochemistry for IgG4 performed on paraffin sections as a diagnostic test for pemphigus., Design: Eighteen immunofluorescence-proven pemphigus cases (12 pemphigus vulgaris, 6 pemphigus foliaceus) were studied. Four normal skin specimens and 32 nonpemphigus vesiculobullous disease specimens served as controls. Paraffin sections of all cases were examined immunohistochemically for IgG4 expression. Positivity was defined as distinct, condensed, continuous immunoreactivity localized to the intercellular junctions of keratinocytes., Results: The immunostains were independently evaluated in a masked manner by 3 pathologists, with a 100% interobserver agreement. Nine of 12 pemphigus vulgaris cases (sensitivity 75.0%), and 4 of 6 pemphigus foliaceus cases (sensitivity 66.7%), were positive for IgG4 immunostain. The overall sensitivity was 72.2%. One control specimen (bullous pemphigoid) showed IgG4 positivity (specificity 97.2%). In specimens demonstrating acantholysis, 8 of 10 pemphigus vulgaris cases (sensitivity 80.0%) and 4 of 4 pemphigus foliaceus cases (sensitivity 100.0%) were positive for IgG4. The overall sensitivity for specimens with acantholytic lesions was 85.7%., Conclusion: Immunohistochemistry for IgG4 provides a reasonably sensitive and highly specific test for diagnosing pemphigus, especially when frozen tissue is not available, and active acantholytic lesions are examined.

Background: Overlapping histopathologic features of cellular neurothekeoma (CNT) and plexiform fibrohistiocytic tumor (PFHT), when both are predominantly composed of histiocytoid cells, make distinction between these entities challenging. Some have suggested that CNT and PFHT are related entities. No prior study has demonstrated a reliable immunohistochemical panel to differentiate these entities., Methods: Skin biopsies diagnosed as CNT and PFHT, from 2004 to 2010 were retrieved with accompanying pathology reports. Each case was reviewed by at least 2 dermatopathologists and 2 soft tissue pathologists for confirmation of diagnosis. All cases were then evaluated for immunohistochemical expression of PAX2, NKIC3, CD10, and microphthalmia transcription factor (MiTF)., Results: Histopathologically, the histiocytoid areas of each tumor shared similar architecture, demonstrating nests and fascicles of histiocytoid to spindled cells, with some separation of nests by collagen bands. Both CNT and PFHT were uniformly positive for NKIC3 and CD10, and both were frequently PAX2 positive. MiTF was strongly and diffusely positive in CNT and was consistently negative in the PFHT., Conclusions: CNT and PFHT share many histopathologic features and immunohistochemical staining patterns. Of the stains we evaluated, we found that expression of MiTF may be a reliable marker for distinguishing CNT from histiocytoid-predominant PFHT, especially in instances where only a small part of the tumor is sampled for evaluation.

Background: Taxane drugs block cell-cycle progression via centrosomal impairment, induction of abnormal spindles, and suppression of spindle microtubule dynamics. Affected cells experience aberrant mitosis or mitotic slippage, which may trigger apoptosis., Objective: The aim was to characterize the histopathologic changes due to taxane therapy in skin biopsy specimens., Methods: Three examples were identified of benign skin biopsy specimens of patients receiving paclitaxel or docetaxel therapy for breast carcinoma or leiomyosarcoma. All specimens were studied by light microscopy after routine histopathologic processing., Results: All cases exhibited numerous apoptotic and mitotic figures including atypical forms, changes consistent with cytotoxic effects of taxane. The first case had been provisionally considered by the referring pathologist to be a malignant melanoma; however, when reviewed in consultation, it was ultimately diagnosed as an atypical nevus; the second and third cases were diagnosed as reactive epidermal hyperplasia and ecthyma, respectively, in addition to showing background taxane effects., Limitations: This study is limited by the relatively small number of cases examined., Conclusion: Taxane therapy has profound cytopathic effects in skin biopsy specimens, and in difficult cases these changes may raise consideration of possible malignancy. Dermatopathologists should use caution when interpreting biopsy specimens of patients receiving taxane therapy., (Copyright © 2010 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)