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We describe a 14-year-old boy with Wilson disease (WD) who first developed pseudo-pseudoxanthoma elasticum (PPXE) after 4.5 years of treatment with D-penicillamine. Although previously reported cases have occurred in adults following at least a decade of high-dose D-penicillamine use, this case demonstrates that D-penicillamine-induced PPXE can present in children with shorter treatment courses. Upon this diagnosis, the patient was switched from D-penicillamine to trientine, with adequate cupriuresis and stabilization of the skin lesion. Prompt diagnosis and management of PPXE in children can limit systemic progression and prevent long-term complications.

Background: Pediatric melanoma is rare and diagnostically challenging., Objective: To characterize clinical and histopathologic features of fatal pediatric melanomas., Methods: Multicenter retrospective study of fatal melanoma cases in patients younger than 20 years diagnosed between 1994 and 2017., Results: Of 38 cases of fatal pediatric melanoma identified, 57% presented in white patients and 19% in Hispanic patients. The average age at diagnosis was 12.7 years (range, 0.0-19.9 y), and the average age at death was 15.6 years (range, 1.2-26.2 y). Among cases with known identifiable subtypes, 50% were nodular (8/16), 31% were superficial spreading (5/16), and 19% were spitzoid melanoma (3/16). One fourth (10/38) of melanomas arose in association with congenital melanocytic nevi., Limitations: Retrospective nature, cohort size, and potential referral bias., Conclusions: Pediatric melanoma can be fatal in diverse clinical presentations, including a striking prevalence of Hispanic patients compared to adult disease, and with a range of clinical subtypes, although no fatal cases of spitzoid melanoma were diagnosed during childhood., (Copyright © 2020 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background/objectives: Store-and-forward teledermatology provides pediatricians with specialist guidance in managing skin disease. This study evaluates wait times and face-to-face (FTF) dermatology visit avoidance associated with a pediatric dermatology eConsult program at an urban academic medical center., Methods: In this retrospective cohort study, electronic medical records were reviewed for patients under age 18 for whom a dermatology eConsult was completed between November 1, 2014, and December 31, 2017. Wait times for eConsult completion and initial FTF dermatology appointments were calculated and compared to average wait times for new patient dermatology office appointments from 2016 to 2017. Recommendations for FTF dermatology visits were assessed, along with FTF visit attendance and potential cost savings., Results: One hundred eighty pediatric patients with 188 unrelated skin conditions ("cases") were referred to the program. Of 188 cases, FTF dermatology visits were recommended for 60 (31.9%). Actual FTF dermatology visit avoidance was 53.7% of total cases (n = 101 for whom FTF visit was not recommended and no dermatology visit occurred within 90 days after eConsult submission). The program generated potential savings of $24 059 ($9840 out-of-pocket) in 2016 dollars. Average turnaround for eConsult completion was 1.8 calendar days (median: 1 calendar day, target: 2 business days). Average wait time to initial FTF dermatology evaluation was 37.3 calendar days (versus 54.1 days for pediatric patients referred directly to dermatology clinic between 2016 and 2017)., Conclusion: Pediatric dermatology eConsults reduce wait times for specialist care, triage cases for in-office evaluation, reduce need for FTF dermatology visits, and offer potential cost savings for payers and patients., (© 2020 Wiley Periodicals LLC.)

Purpose of Review: To update pediatric providers on new developments in our understanding of the clinical presentation, genetics, and systemic risks associated with congenital melanocytic nevi (CMN)., Recent Findings: CMN are primarily caused by sporadic postzygotic somatic mutations, most frequently in NRAS, and studies of the genetic underpinnings of CMN have demonstrated a diverse array of genetic drivers. The primary complications of large and giant CMN include neurocutaneous melanocytosis and malignant melanoma. Abnormalities in CNS MRI may predict a worse clinical course for patients and increased risk of melanoma. Targeted therapies of the MEK pathway have begun to be studied for the treatment of CMN and prevention of associated complications., Summary: Patients with large and giant CMN should be managed by an interdisciplinary care team for the monitoring of dermatologic, neurologic, and psychosocial concerns. Ongoing research is underway to better characterize the genetic drivers of CMN and to better guide development of targeted therapeutics.

Purpose of Review: To inform pediatric providers of the clinical characteristics, underlying genetic drivers, and therapeutic options for skin cancer arising in childhood and adolescence., Recent Findings: The incidence of melanoma in pediatric patients has been declining in the past decades. Pediatric-specific diagnostic criteria should be utilized when assessing lesions concerning for melanoma to better account for the different presentations seen in pediatric disease compared with adults, such as an increased prevalence of amelanotic melanoma or frequent mimic of benign pediatric lesions. Pediatric melanoma often presents with a higher histopathologic stage and a higher Breslow depth as compared with adult melanoma. Pediatric nonmelanoma skin cancer including basal cell carcinoma and squamous cell carcinoma are associated with genetic conditions and immunosuppression, both iatrogenic and inherited., Summary: Melanoma in pediatric patients often presents differently from conventional adult melanoma, including Spitz melanoma and melanoma associated with congenital melanocytic nevi. Pediatric patients with nonmelanoma skin cancers should be evaluated for predisposing risk factors. More research on therapeutic options for pediatric skin cancer is vital to understanding the tolerance and response of our pediatric patients to therapies that are more frequently utilized in adult disease.

Background/objective: Pediatric hematopoietic stem cell transplantation (HSCT) patients are at an increased risk for skin cancers. Sun exposure is a significant modifiable environmental risk factor. While patient education on sun protection and avoidance behaviors with regular dermatology evaluations are crucial for pediatric HSCT patients, the real-life practice of these sun-protection recommendations in this patient population compared to their peers is unknown., Methods: A survey-based cross-sectional cohort study was performed in pediatric HSCT patients seen at the Dana-Farber Cancer Institute and Boston Children's Hospital over a 1.5-year period compared with age/sex/Fitzpatrick skin phototype-matched healthy controls. Study participants were surveyed using the validated Glanz survey for pediatric sun protection behavioral research., Results: Eighty-five pediatric HSCT patients and 85 controls completed the study. Pediatric HSCT patients more frequently used sunscreen, hats, umbrellas, and sunglasses and obtained full-body skin exams compared to controls. No difference was observed in sun exposure during hours of peak sun intensity, frequency of purposeful tanning, tanning bed use, and the number of painful sunburns received between pediatric HSCT patients and controls., Conclusions: Although pediatric HSCT patients practice more sun protection behaviors, they experienced harmful sunburns and intentional tanning behaviors at the same rate as their peers. Patient-directed counseling and strategies to improve patient adherence to optimal sun protection behaviors could have a significant impact on the dermatology quality of life in pediatric HSCT patients., (© 2019 Wiley Periodicals, Inc.)

Background: Spitzoid proliferations range from Spitz naevi to melanomas. There are few studies describing clinical features and outcomes in the paediatric population., Objectives: To determine the clinical features and outcomes of a large paediatric cohort with histopathologically confirmed Spitz tumours., Methods: This was a retrospective cohort study of patients seen at Boston Children's Hospital who were aged < 20 years and had a histopathological diagnosis of spitzoid proliferation from 1 January 1994 to 23 October 2012., Results: In total 595 patients with 622 spitzoid proliferations were identified (median age 7·4 years, interquartile range 4·6-11·7). Overall 512 proliferations (82·3%) were typical, 107 (17·2.%) were atypical and three (0·5%) were melanomas. The median ages at biopsy were 7·4, 7·2 and 17·2 years, respectively, and there was a significant difference in age at biopsy for patients with typical or atypical proliferations vs. melanoma (P < 0·01). Among samples with positive margins (n = 153), 55% (54 of 98) of typical proliferations, 77% (41 of 53) of atypical proliferations and 100% (two of two) of melanomas were re-excised. Six patients had sentinel lymph node biopsy performed, with three patients demonstrating nodes positive for melanocytic cells. Within a median follow-up of 4·1 years for the full cohort there were no related deaths., Conclusions: Spitz tumours have strikingly benign outcomes in the paediatric population, although this study is limited by the low number of melanomas and restriction to a single paediatric institution. Aggressive management recommendations should be reconsidered for children and adolescents with banal-appearing Spitz naevi, based on the clinically indolent behaviour in this cohort., (© 2018 British Association of Dermatologists.)

Objective: To identify risk factors associated with nonmelanoma skin cancer (NMSC) occurrence and survival in children., Study Design: This was a multicenter, retrospective, case-control study of patients <20 years of age diagnosed with NMSC between 1995 and 2015 from 11 academic medical centers. The primary outcome measure was frequency of cases and controls with predisposing genetic conditions and/or iatrogenic exposures, including chemotherapy, radiation, systemic immunosuppression, and voriconazole., Results: Of the 124 children with NMSC (40 with basal cell carcinoma, 90 with squamous cell carcinoma), 70% had at least 1 identifiable risk factor. Forty-four percent of the cases had a predisposing genetic condition or skin lesion, and 29% had 1 or more iatrogenic exposures of prolonged immunosuppression, radiation therapy, chemotherapy, and/or voriconazole use. Prolonged immunosuppression and voriconazole use were associated with squamous cell carcinoma occurrence (cases vs controls; 30% vs 0%, P = .0002, and 15% vs 0%, P = .03, respectively), and radiation therapy and chemotherapy were associated with basal cell carcinoma occurrence (both 20% vs 1%, P < .0001). Forty-eight percent of initial skin cancers had been present for >12 months prior to diagnosis and 49% of patients were diagnosed with ≥2 skin cancers. At last follow-up, 5% (6 of 124) of patients with NMSC died. Voriconazole exposure was noted in 7 cases and associated with worse 3-year overall survival (P = .001)., Conclusions: NMSC in children and young adults is often associated with a predisposing condition or iatrogenic exposure. High-risk patients should be identified early to provide appropriate counseling and management., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Although melanoma is a rare diagnosis in the pediatric population, advances in the management of adults with melanoma offer the prospect of promising therapeutic options for children. At this time, medical management is not considered curative but may reduce the risk of recurrence or prolong survival. Surgical management remains the mainstay of treatment. Medical therapy of pediatric melanoma is not thought to have a role for in situ, early-stage, or localized disease, but adjuvant therapy may have a role in improving the prognosis of patients with positive sentinel lymph node biopsy (SLNB), spread beyond the regional lymph node basin, metastatic disease, or recurrent disease. Medical treatment options include immunotherapies, particularly checkpoint inhibitors, and targeted therapies, which have provided improved toxicity profiles compared with traditional chemotherapy regimens in the setting of advanced disease. There is a growing body of pediatric-specific data relevant to the use of adjuvant therapies for advanced melanoma in children.

Background: Melanoma can mimic other cutaneous lesions, but the full spectrum and prevalence of these morphologic variants remain largely unknown., Objective: To classify nonacral cutaneous melanomas into distinct morphologic clusters and characterize clusters' clinicopathologic features., Methods: All pathologic melanoma diagnoses (occurring during 2011-2016) were reviewed for routine prebiopsy digital photographs (n = 400). Six dermatologists independently assigned lesions into 1 of 14 diagnostic classes on the basis of morphology. Image consensus clusters were generated by K-means; clinicopathologic features were compared with analysis of variance and χ 2 ., Results: Five morphologic clusters were identified: typical (n = 136), nevus-like (n = 81), amelanotic/nonmelanoma skin cancer (NMSC)-like (n = 70), seborrheic keratosis (SK)-like (n = 68), and lentigo/lentigo maligna (LM)-like (n = 45) melanomas. Nevus-like melanomas were found in younger patients. Nevus-like and lentigo/LM-like melanomas tended to be thinner and more likely identified on routine dermatologic examinations. NMSC-like melanomas were tender, thicker, more mitotically active, and associated with prior NMSC. Typical and SK-like melanomas had similar clinicopathologic features., Limitations: Cluster subdivision yielded diminished sample sizes. Visual assignment was performed without clinical context., Conclusion: When primary cutaneous melanomas were assigned into diagnostic groups and subjected to novel consensus clustering, recurrent morphologic patterns emerged. The spectrum of these morphologies was unexpectedly diverse, which might have implications for visual training and possibly clinical diagnosis., (Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

We investigated factors associated with quality of life (QOL) in children with eczema. We conducted a cross-sectional analysis of survey data from 224 parents of children with eczema attending a large, hospital-based pediatric clinic. Parents completed a validated eczema severity scale (Patient-Oriented Eczema Measure), a QOL scale (Infants' Dermatitis QOL Index or Children's Dermatology Life Quality Index), and a knowledge and understanding questionnaire. In adjusted multivariate analyses, worse eczema severity was associated with worse overall QOL (β = 0.5; 95% confidence interval [CI] = [0.5, 0.6]), while a higher knowledge score was associated with better QOL (β = -3.4; 95% CI = [-6.6, -0.2]). Similarly, even after adjustment for eczema severity, greater understanding of a child's individual treatment plan was associated with better QOL (β = -0.7; 95% CI = [-1.4, -0.08]), while increased frequency of worrying about a child's eczema was associated with worse QOL (β = 0.7; 95% CI = [0.03, 1.1]). These results suggest primary care providers may be able to influence QOL through optimal eczema management and family education.

Pediatric melanoma is a rare disease that affects approximately 6 out of every one million children and accounts for 1-4% of all melanomas. This article reviews the epidemiology, etiology, diagnosis, treatment and prognosis of pediatric melanoma - with particular attention to recent updates in the literature. While awareness of melanoma increases among the general population, recent data suggest stable and even declining incidence rates among certain pediatric populations. Studies have examined clinical features and presentations of melanoma among the pediatric population and the conventional ABCDE criteria (asymmetrical shape, border, color, diameter, evolving lesion) used to diagnosis adult melanoma may not be entirely appropriate for pediatric melanoma; as such, additional pediatric-ABCD and CUP criteria (color changing, ulceration, pyogenic granuloma-like lesions) have been proposed. Dermoscopy serves as a valuable tool to detect suggestive patterns among pediatric skin lesions, and aids in the monitoring of skin lesions and detection of melanoma among children and adolescents. The etiology and pathogenesis of the pediatric melanoma is currently being investigated; studies have examined the genetic alterations that may be involved with the development of pediatric melanomas including TERT promoter, BRAF, and NRAS among others. While genetic testing using molecular techniques such as comparative genomic hybridization and fluorescence in-situ hybridization is helpful for diagnosis in certain contexts, molecular workup is not considered standard of care among pediatric melanoma cases, and in fact has not been proven to reliably distinguish between benign and malignant spitzoid tumors in children. Our growing understanding of melanoma has informed treatment decisions regarding management of positive sentinel lymph nodes, use of adjuvant therapy, and use of immunotherapy in treatment plans.

Objective: To test whether an eczema care plan (ECP) would improve provider documentation and management, decrease eczema severity, and increase patient quality of life (QOL) in the pediatric primary care setting., Methods: We conducted a randomized controlled trial from June 2015 to September 2016 at a large hospital-based pediatric primary care clinic. Participants included children from 1 month to 16 years of age with a diagnosis of eczema. The intervention group received the ECP and the control group received usual care. Both groups completed a validated eczema severity scale (Patient-Oriented Eczema Measure [POEM]) and a QOL scale (Infant's Dermatitis Quality of Life Index [IDQOL]) or Children's Dermatology Life Quality Index [CDLQI]) before the visit and again ~1 month later., Results: A total of 211 caregivers completed both the pre- and postintervention surveys (100 control group and 111 intervention group [94% completion]). Intervention group providers were more likely to recommend a comprehensive "step-up" plan (88%) vs 28%; P < .001, bleach baths (45%) vs 9%; P < .001, and wet wraps (50%) vs 7%; P < .001. They were also more likely to document providing a written plan to families (80%) vs 2%; P < .001. In the intervention and control groups, eczema severity and QOL improved between the pre- and postintervention periods. However, there was not a significant difference between the groups on either measure: POEM difference -0.8, 95% confidence interval (CI) -3.2 to 1.7; IDQOL difference -0.1, 95% CI -1.8 to 1.6; CDLQI difference 0.8, 95% CI -0.9 to 2.6., Conclusions: Intervention group providers documented more comprehensive eczema care than control group providers. Although patients improved on all measures in the postintervention period, the ECP did not augment that improvement., (Copyright © 2018 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Background: There are limited pediatric data on nonmalignant cutaneous changes, including autoimmune conditions and permanent alopecia, after hematopoietic stem cell transplantation (HSCT)., Objective: We sought to characterize late cutaneous changes and associated risk factors after allogeneic HSCT in children., Methods: A cross-sectional cohort study of pediatric HSCT recipients was performed at a single institution. All participants underwent a full skin examination., Results: The median visit age was 13.8 years, with a median time post-HSCT of 3.6 years. Of 85 patients, 14% (n = 12) had vitiligo, 16% (n = 14) had psoriasis/sebopsoriasis, 25% (n = 21) had alopecia, and 6% (n = 5) had nail changes. Factors significantly associated with vitiligo included a history of chronic graft-versus-host disease (cGVHD), transplant indication of primary immunodeficiency, and younger age at transplant (<10 years of age). Fifty-two percent of patients with alopecia had androgenetic alopecia patterns. Factors significantly associated with alopecia included cGVHD, busulfan conditioning, and family history of early male pattern alopecia. All patients with nail changes had cGVHD., Limitations: The cross-sectional design did not allow time of onset identification. Histopathologic correlation was not performed., Conclusion: Pediatric HSCT recipients, particularly those with cGVHD, are at risk for developing nonmalignant late cutaneous changes., (Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background/objectives: Melanoma in children and adolescents is uncommon, and there are limited data on pediatric outcomes. Several studies have shown comparable survival rates in children and adults, but other research demonstrates that prepubescent children have more favorable outcomes. This study aims to compare childhood and adolescent melanoma., Methods: Retrospective cohort study of children who received a melanoma diagnosis at the Massachusetts General Hospital between January 1, 1995, and December 21, 2016. Childhood melanoma is defined as disease occurring in patients younger than 11 years old, and adolescent melanoma is defined as disease occurring in patients 11 to 19 years old. Patients diagnosed with ocular melanoma and borderline tumors of uncertain malignant potential were excluded. This analysis compares clinical, histopathologic, and outcome characteristics of childhood and adolescent melanoma., Results: Thirty-two children with melanoma were identified (12 children, 20 adolescents). The spitzoid melanoma subtype was significantly more common in children (6/12) than adolescents (2/20) (P = .01). Four adolescents and no children with melanoma died from melanoma, and survival was significantly different between the age groups (P = .04). Median follow-up time for survivors was 3.6 years., Conclusions: These results suggest that children and adolescents present with different melanoma subtypes and that adolescents have a more aggressive disease course than children., (© 2018 Wiley Periodicals, Inc.)

A 3-year-old girl presented with a 7-month history of a waxing and waning left thigh mass associated with pruritus and erythema at the site of two previous DTaP-HepB-IPV vaccinations. Patch testing was positive to aluminum chloride, supporting a diagnosis of vaccine granuloma secondary to aluminum allergy; her symptoms had been well controlled with antihistamines and topical steroids. Injection site granulomas are a benign but potentially bothersome reaction to aluminum-containing immunizations that can be supportively managed, and we encourage strict adherence to the recommended vaccine schedule in this setting. Patch testing is a sensitive, noninvasive diagnostic tool for patients presenting with this clinical finding, and dermatologist awareness can prevent unnecessary medical examination and provide reassurance., (© 2018 Wiley Periodicals, Inc.)

Competing Interests: Competing interests: None declared.

There is a known increased risk of skin cancer in the adult population after hematopoietic stem cell transplantation (HSCT). However, late dermatologic effects that children may experience after HSCT have not been well described. The primary objective of this study was to characterize nevi and skin cancers affecting children after allogeneic HSCT. A cross-sectional cohort study of 85 pediatric HSCT recipients and 85 controls matched for age, sex and skin phototype was performed at a single institution. All participants underwent a full skin examination. Median age at study visit was 13.8 years in HSCT patients with median time post-HSCT of 3.6 years. HSCT patients had significantly more nevi than control patients (median (range): 44 (0-150) vs 11 (0-94), P<0.0001). HSCT patients also had significantly more nevi >5 mm in diameter and atypical nevi than controls. Factors associated with increased nevus count included malignant indication for HSCT, pretransplant chemotherapy, TBI exposure and myeloablative conditioning. A total of 16.5% of HSCT patients developed cancerous, precancerous lesions and/or lentigines. Our study suggests that pediatric HSCT recipients have an increased risk of benign and atypical melanocytic proliferations and nonmelanoma skin cancer that can manifest even during childhood.

Atopic dermatitis (AD) is the most common pediatric skin disease. AD has a significant effect on patient and family quality of life caused by intense pruritus, sleep disruption, dietary and nutritional concerns, and psychological stress associated with the disease and its management. Multidisciplinary approaches to AD care have been developed in appreciation of the complex interplay among biological, psychological, behavioral, and dietary factors that affect disease control and the wide range of knowledge, skills, and support that patients and families require to effectively manage and cope with this condition. Common components of multidisciplinary treatment approaches include medical evaluation and management by an AD specialist, education and nursing care, psychological and behavioral support, and nutritional assessment and guidance. Models of care include both clinical programs and structured educational groups provided as adjuncts to standard clinical care. Available evidence suggests beneficial effects of multidisciplinary interventions in improving disease severity and quality of life, particularly for patients with moderate-to-severe disease. Additional research is needed to identify the best candidates for the various multidisciplinary approaches and evaluate the cost-effectiveness of these programs., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Eccrine angiomatous hamartoma (EAH) is a rare, benign hamartoma of eccrine and vascular components that predominantly affects children. Growth is typically commensurate with the child's growth. Herein we report an additional case of this rare entity that enlarged after trauma in a 7-year-old girl., (© 2015 Wiley Periodicals, Inc.)

Background: Voriconazole, an antifungal agent, is associated with various cutaneous reactions, including phototoxicity, accelerated photoaging, and skin cancer. Incidence and risk factors for these reactions in children have not been well described., Objective: We sought to determine the incidence of and factors associated with phototoxic reactions and nonmelanoma skin cancer in pediatric patients treated with voriconazole., Methods: This was a retrospective analysis of 430 pediatric patients treated with voriconazole between 2003 and 2013 at Boston Children's Hospital., Results: Incidence of phototoxicity was 20% in all children treated with voriconazole and 47% in children treated for 6 months or longer. Factors associated with phototoxicity included white race, cystic fibrosis, cumulative treatment time, and cumulative dose. Four patients (1%) had nonmelanoma skin cancer; all experienced a phototoxic reaction during voriconazole treatment. Of those with phototoxicity, 5% were discontinued on voriconazole, 6% were referred to dermatology, and 26% received counseling about sun protection from their primary physician., Limitations: Our study is limited by its retrospective design and potential referral bias associated with a tertiary-care center., Conclusions: Voriconazole-associated phototoxicity is relatively common in children and may lead to nonmelanoma skin cancer. However, those with phototoxic reactions are often continued on therapy, rarely referred to dermatology, and infrequently counseled on sun protection., (Copyright © 2014 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Recent efforts in genomic research have enabled the characterization of molecular mechanisms underlying many types of cancers, ushering novel approaches for diagnosis and therapeutics. Melanoma is a molecularly heterogeneous disease, as many genetic alterations have been identified and the clinical features can vary. Although discoveries of frequent mutations including BRAF have already made clinically significant impact on patient care, there is a growing body of literature suggesting a role for additional mutations, driver and passenger types, in disease pathophysiology. Although some mutations have been strongly associated with clinical phenotypes of melanomas (such as physical distribution or morphologic subtype), the function or implications of many of the recently identified mutations remains less clear. The phenotypic and clinical impact of genomic mutations in melanoma remains a promising opportunity for progress in the care of melanoma patients., (Copyright © 2014 Cold Spring Harbor Laboratory Press; all rights reserved.)

Although pediatric melanoma is a rare disease, diagnosis and management of pigmented lesions in the pediatric population, particularly dysplastic nevi and Spitz nevi, can be challenging. In this article, we provide an overview of pigmented lesions in children, including melanoma and management of melanoma risk factors and melanocytic nevi in the pediatric population. Congenital melanocytic nevi, Spitz nevi, dysplastic and acquired nevi, and changes over time are reviewed. We discuss considerations for excision and management of pigmented lesions in children., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Importance: Targeted BRAF inhibitor therapy (vemurafenib, dabrafenib) is an effective, novel treatment for patients with metastatic melanoma with the V600E BRAF mutation. This therapy is associated with squamous cell carcinomas and keratoacanthomas. Granulomatous eruptions have not been previously reported., Observations: Two patients with melanoma developed cutaneous granulomatous eruptions during targeted BRAF inhibitor therapy. In case 1, after 2 months of treatment with dabrafenib and trametinib (MEK inhibitor), a papular eruption concerning for progression of disease prompted cessation of treatment. After the histopathologic diagnosis of granulomas, the patient was treated with clobetasol ointment with resolution within days and resumption of therapy. In case 2, after 5 months of vemurafenib treatment, the patient developed a granulomatous eruption, which resolved 3 weeks after cessation of therapy., Conclusions and Relevance: We report 2 cases of cutaneous granulomatous eruptions on treatment with targeted BRAF inhibitors, a previously unreported association. Although additional investigations are necessary to better elucidate the pathogenic mechanisms, our report includes a treatment plan that prevents unnecessary discontinuation of therapy. Given the Food and Drug Administration approval of vemurafenib for metastatic melanoma, clinicians should be aware of this possible cutaneous reaction and treatment option to optimize patient management.

Background: Merkel cell carcinoma (MCC) is a rare and lethal cutaneous neuroendocrine carcinoma. Imaging is crucial for accurate staging, which remains a strong predictor of survival, as well as earlier detection of recurrence and progression, which are common despite aggressive management. There is no consensus on the role of initial and subsequent imaging for MCC., Objective: We sought to evaluate the use of 2-fluoro-[(18)F]-deoxy-2-D-glucose (FDG)-positron emission tomography (PET)/computed tomography (CT) in the management of MCC., Methods: In all, 270 FDG-PET/CT studies were performed in 97 patients with pathology-proven MCC at the Dana-Farber/Brigham and Women's Cancer Center, Boston, Mass, from August 2003 to December 2010., Results: FDG-PET/CT scans were obtained as part of the initial (61 scans in 61 patients) and subsequent (209 scans in 79 patients) treatment strategies. MCCs were FDG-avid with a mean maximum standardized uptake value of primary lesions of 6.5 (range 1.3-12.9) and a mean maximum standardized uptake value of regional and distant metastases of 7.2 (range 1.5-9.9). FDG-PET/CT upstaged 16% of patients who underwent baseline scans. FDG-PET/CT studies showed that bone and bone-marrow metastases were more common than previously reported, and were often undetected by CT., Limitations: Our study is limited by its retrospective design, and potential referral bias associated with a tertiary care center., Conclusions: FDG-PET/CT performed as part of the initial management strategy tended to upstage patients with more advanced disease. FDG-PET/CT performed as part of the subsequent treatment strategy identified metastatic disease, particularly in bone/bone marrow, which was not seen on CT. FDG-PET/CT imaging is a valuable staging and restaging tool in MCC management., (Copyright © 2012 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

Although targeting oncogenic mutations in the BRAF serine/threonine kinase with small molecule inhibitors can lead to significant clinical responses in melanoma, it fails to eradicate tumors in nearly all patients. Successful therapy will be aided by identification of intrinsic mechanisms that protect tumor cells from death. Here, we used a bioinformatics approach to identify drug-able, "driver" oncogenes restricted to tumor versus normal tissues. Applying this method to 88 short-term melanoma cell cultures, we show that the antiapoptotic BCL2 family member BCL2A1 is recurrently amplified in ∼30% of melanomas and is necessary for melanoma growth. BCL2A1 overexpression also promotes melanomagenesis of BRAF-immortalized melanocytes. We find that high-level expression of BCL2A1 is restricted to melanoma due to direct transcriptional control by the melanoma oncogene MITF. Although BRAF inhibitors lead to cell cycle arrest and modest apoptosis, we find that apoptosis is significantly enhanced by suppression of BCL2A1 in melanomas with BCL2A1 or MITF amplification. Moreover, we find that BCL2A1 expression is associated with poorer clinical responses to BRAF pathway inhibitors in melanoma patients. Cotreatment of melanomas with BRAF inhibitors and obatoclax, an inhibitor of BCL2A1 and other BCL2 family members, overcomes intrinsic resistance to BRAF inhibitors in BCL2A1-amplified cells in vitro and in vivo. These studies identify MITF-BCL2A1 as a lineage-specific oncogenic pathway in melanoma and underscore its role for improved response to BRAF-directed therapy.

Markedly pleomorphic epithelioid cells with high mitotic activity, giant cell formation, very large atypical nuclei, multiple nucleoli and abundant cytoplasm characterize 'monster' cells and may indicate aggressive tumor behavior. Very rare reports of melanomas comprised of 'monster cells' or cells with comparable histomorphological features, found in tissue samples from skin, lymph nodes, CNS, oral cavity and ileum have been published in the literature. This case is the first such description in the lung, and it is characterized with a battery of immunohistochemical stains; BRAF mutation status was negative, and fluorescence in situ hybridization analysis revealed increased copy number gains in 11q (cyclin D1), which is associated with poor prognosis in melanoma. The presence of monster cells in melanoma was associated with aggressive behavior in the reported patient., (Copyright © 2012 John Wiley & Sons A/S.)

Background: The histopathologic diagnosis of some melanocytic tumors is extraordinarily difficult. With this in mind, melanocytic tumors from patients referred to the Massachusetts General Hospital (MGH) Pigmented Lesion Clinic (PLC) are routinely reviewed in the MGH Dermatopathology Unit., Objective: We sought to determine the frequency of diagnostically challenging cases from patients treated at the MGH PLC, as measured by a change in the diagnosis upon review of the referral materials., Methods: We retrospectively reviewed the MGH and referral pathology reports for 478 consecutive cutaneous melanocytic tumors: 126 from 1996-1997 and 352 from 2010-2011. Differences in diagnosis and in therapeutic impact were evaluated., Results: Changes in diagnosis occurred in 168 of 478 cases (35%), more frequently when the original diagnostician was a general pathologist (P = .003). A similar fraction of diagnoses were changed from malignant to benign or vice versa, in both historic and contemporary cohorts. In 64 patients (13%), changes in diagnosis led to a change in therapy. Changes in stage or grading led to the most changes in therapy (78%; 50/64) versus changes from benign to malignant or vice versa (22%; 14/64)., Limitations: This is a retrospective study with the bias of a tertiary-care referral center., Conclusions: These findings demonstrate the diagnostic difficulty of a subset of melanocytic tumors and highlight the utility of review by more than one pathologist; patient treatment is affected in more than 10% of cases. Identification of melanoma prognostic factors and melanocytic nevus grading led to clinically significant changes in diagnosis leading to a change in patient management., (Copyright © 2012 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

Little is known about the maintenance of intestinal stem cells (ISCs) and progenitors during immune-mediated tissue damage or about the susceptibility of transplant recipients to tissue damage mediated by the donor immune system during graft versus host disease (GVHD). We demonstrate here that deficiency of recipient-derived IL-22 increased acute GVHD tissue damage and mortality, that ISCs were eliminated during GVHD, and that ISCs as well as their downstream progenitors expressed the IL-22 receptor. Intestinal IL-22 was produced after bone marrow transplant by IL-23-responsive innate lymphoid cells (ILCs) from the transplant recipients, and intestinal IL-22 increased in response to pretransplant conditioning. However, ILC frequency and IL-22 amounts were decreased by GVHD. Recipient IL-22 deficiency led to increased crypt apoptosis, depletion of ISCs, and loss of epithelial integrity. Our findings reveal IL-22 as a critical regulator of tissue sensitivity to GVHD and a protective factor for ISCs during inflammatory intestinal damage., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Biologic therapies targeting tumor necrosis factor (TNF)-alpha have become a mainstay in the management of a number of autoimmune diseases. We report a series of adverse skin eruptions in six patients (four females, two males, age: 21-58 years, mean: 39) receiving 4 months to 10 years (mean 3.1 years) of anti-TNF-alpha therapies (infliximab, n = 4; adalimumab, n = 1 or etanercept, n = 1). The following drug-associated diagnoses were made in eight skin biopsies performed at Massachusetts General Hospital between 3/2007 and 10/2010: pustular folliculitis, psoriasis, interface dermatitis, neutrophilic eccrine hidradenitis, Sweet's syndrome, lupus, vasculitis and palmoplantar pustulosis. The descriptions of neutrophilic eccrine hidradenitis-like and Sweet's-like hypersensitivity eruptions induced by anti-TNF-alpha therapies are the first such cases described in the literature. Each cutaneous eruption improved or resolved with switching to a different TNF-alpha inhibitor, discontinuation of the anti-TNF-alpha agent, and/or topical or systemic steroids. There was a clear chronologic relationship with, and clinical remission upon withdrawal or steroid suppression of the anti-TNF-alpha agents. The mechanism for such diverse cutaneous eruptions among this class of medications remains poorly understood. The cutaneous adverse reaction profile of TNF-alpha inhibitors is broad and should be considered in the histopathologic differential in this clinical setting., (Copyright © 2012 John Wiley & Sons A/S.)

Pyoderma gangrenosum is a rare disease characterized by chronic, nonhealing, noninfectious ulcers that can become exacerbated by trauma or manipulation, including surgical treatment. We describe the case of a 30-year-old woman who presented with a large ulcer at the site of an excisional cervical lymph node biopsy; she also had a smaller ulcer at the site of an earlier biopsy that had been previously well healed. The ulcers persisted despite local care, and the larger ulcer was exacerbated by surgical debridement. Histopathology revealed the presence of intense neutrophilic infiltrates with sterile microabscesses-a finding consistent with pyoderma gangrenosum. With 9 weeks of treatment with a high-potency topical steroid, both ulcers gradually healed.

Hair abnormalities can have tremendous psychosocial impacts on adolescents and young adults, and may cause a great amount of anxiety regarding physical appearance, associated illnesses, and potential clinical course. The pathophysiology of such disorders may vary,with potential congenital, infectious, autoimmune, nutritional, or environmental causes. Hair abnormalities may present as changes in hair appearance or quality, becoming weathered or fractured.An abnormal increase in hair is present in hypertrichosis and hirsutism, whereas a thinning or shedding of hair is evident in patients with telogen effluviumand alopecia areata. Diagnosis is focused on a detailed clinical history and physical exam, in addition to laboratory testing, a variety of clinical diagnostic tests, and scalp biopsy, which may be necessary to confirm some diagnoses. Many hair disorders have no cure, but clinicians can have a positive impact on their patients by identifying the abnormality and educating the patient regarding disease course. However, some conditions such as infectious hair disorders or scarring alopecia should be identified promptly to initiate treatment and ensure clinical improvement or optimal outcome.