Risk factors and outcomes of melanoma in children and adolescents: A retrospective multicenter study.

BACKGROUND: Pediatric melanoma presents with distinct clinical features compared to adult disease. OBJECTIVE: Characterize risk factors and negative outcomes in pediatric melanoma. METHODS: Multicenter retrospective study of patients under 20 years diagnosed with melanoma between January 1, 1995 and June 30, 2015 from 11 academic medical centers. RESULTS: Melanoma was diagnosed in 317 patients, 73% of whom were diagnosed in adolescence (age ≥11). Spitzoid (31%) and superficial spreading (26%) subtypes were most common and 11% of cases arose from congenital nevi. Sentinel lymph node biopsy was performed in 68% of cases and positive in 46%. Fatality was observed in 7% of cases. Adolescent patients with melanoma were more likely to have family history of melanoma (P = .046) compared to controls. LIMITATIONS: Retrospective nature, cohort size, control selection, and potential referral bias. CONCLUSION: Pediatric melanoma has diverse clinical presentations. Better understanding of these cases and outcomes may facilitate improved risk stratification of pediatric melanoma.

Brief report: Areolar melanosis in a girl with precocious puberty.

We report a case of melanosis of the areola in a 7-year-old girl with early thelarche. Areolar melanosis is a rare condition previously only described in women over 25 years of age, often in the setting of pregnancy. This case supports a theory that hyperpigmentation may be associated with increased sensitivity to hormonal stimulation in areas with greater populations of melanocytes.

Genomic comparison of malignant melanoma and atypical Spitz tumor in the pediatric population.

BACKGROUND/OBJECTIVES: The diagnostic distinction between atypical Spitz tumor (AST) and malignant melanoma (MM) in pediatric tumors is challenging. Molecular tests are increasingly used to characterize these neoplasms; however, limited studies are available in pediatric patients. This study aimed to provide a genomic comparison of pediatric MM and AST in the context of comprehensive clinical annotation. METHODS: Pediatric patients diagnosed with MM (n=11) and AST (n=12) were compared to a cohort of 693 adult melanoma patients. DNA next-generation sequencing assessed kinase gene fusions, tumor mutational burden, sequence variants, copy number alterations, structural variants, microsatellite instability, and mutational signatures. RESULTS: Seven AST cases and eight MM cases were successfully sequenced. Kinase gene fusions were identified in both the MM and AST cohorts (NTRK1, ROS1, and MET). MM cases had TERT, BRAF, and CDKN2A alterations, which were not identified in the AST cohort. Tumor mutational burden (TMB) analysis showed pediatric ASTs had an average of 2.82 mutations/Mb, pediatric MM had an average of 5.7 mutations/Mb, and adult MM cases averaged 18.8 mut/Mb. One pediatric MM case had an elevated TMB of 15 mutations/Mb and a UV mutational signature. CONCLUSIONS: These data expand our understanding of pediatric malignant melanoma. The differences between the molecular signatures for AST and MM are not statistically significant, and histopathology remains the gold standard for the diagnosis of pediatric AST and MM at this time. With more data, molecular studies may provide additional support for diagnosis and targeted therapeutics.

Suppression of chemotherapy-induced cytokine/lipid mediator surge and ovarian cancer by a dual COX-2/sEH inhibitor.

Although chemotherapy is a conventional cancer treatment, it may induce a protumorigenic microenvironment by triggering the release of proinflammatory mediators. In this study, we demonstrate that ovarian tumor cell debris generated by first-line platinum- and taxane-based chemotherapy accelerates tumor progression by stimulating a macrophage-derived "surge" of proinflammatory cytokines and bioactive lipids. Thus, targeting a single inflammatory mediator or pathway is unlikely to prevent therapy-induced tumor progression. Here, we show that combined pharmacological abrogation of the cyclooxygenase-2 (COX-2) and soluble epoxide hydrolase (sEH) pathways prevented the debris-induced surge of both cytokines and lipid mediators by macrophages. In animal models, the dual COX-2/sEH inhibitor PTUPB delayed the onset of debris-stimulated ovarian tumor growth and ascites leading to sustained survival over 120 days postinjection. Therefore, dual inhibition of COX-2/sEH may be an approach to suppress debris-stimulated ovarian tumor growth by preventing the therapy-induced surge of cytokines and lipid mediators.

Verrucous Venous Malformation-Subcutaneous Variant.

BACKGROUND: Verrucous venous malformation (VVM), previously called "verrucous hemangioma," typically involves the dermis and the subcutaneous fat. We have encountered patients with VVM confined to the hypodermis. MATERIALS AND METHODS: During a nearly 20-year period, 13 patients, aged 2-17 years, presented with a subcutaneous mass in the limb without clinically obvious epidermal alterations. Consequently, operative excisions did not include the skin. RESULTS: Histopathologically, the specimens were composed of blood-filled channels with morphologic characteristics of capillaries and veins that infiltrated adipose tissue. Aggregates often formed nodules with variable fibrosis and a component of large and radially oriented vessels. A diagnosis of VVM was supported by endothelial immunopositivity for GLUT-1 (25%-75% immunopositive channels in 16/16 specimens); D2-40 (1%-25% channels in 14/15 specimens); and Prox-1 (1%-50% of channels in 14/16 specimens). A MAP3K3 mutation was identified by droplet digital PCR in 3 of the 6 specimens. CONCLUSIONS: Diagnosis of VVM in this uncommon location is challenging because of absence of epidermal changes and lack of dermal involvement. Imaging is not pathognomonic, and mimickers are many. Appropriate immunohistochemical stains and molecular analysis contribute to the correct diagnosis.

Antinociceptive effect of vapocoolant medium stream spray on hotplate latency in rat pups.

BACKGROUND: Heel sticks account for most blood tests performed in neonates without analgesia because topical local anesthetics are ineffective on heel glabrous skin. We investigated the antinociceptive effect of an alternative topical analgesic, a vapocoolant spray, on hind paw glabrous skin of rat pups. The spray was applied by two methods: method 1 for 4 s at a distance of 8 cm and method 2 for 10 s at a distance of 18 cm. METHODS: The rat pups were randomized to either method 1 (n = 32) or method 2 (n = 31). Vapocoolant spray was applied to one hind paw randomly, and saline spray was applied to the contralateral paw. The paws were exposed to a hotplate test to measure withdrawal latency time before and 30 s after the spray applications. Additionally, rat pups were tested for tissue toxicity in method 1 (n = 20) and method 2 (n = 20) after application of the vapocoolant spray before heel sticks three times a day for two consecutive days. Analyses of spray and method effects on hotplate withdrawal latency time were determined by nonparametric Wilcoxon tests to assess paired difference between vapocoolant spray and saline spray and to compare difference in medians between the two methods. RESULTS: Method 1 and method 2 vapocoolant spray applications significantly prolonged the withdrawal latency time compared with saline, a median difference of 0.6 s (IQR 0.1-1.2) for method 1 and 9.5 s (IQR 5.5-10.7) for method 2 (a 15-fold longer latency time with method 2). Method-2 produced significantly longer withdrawal latency time than method 1 with a difference in median time of 8.9 s (CI: 95% 7.3-10.4 s, P < .0001). No histopathological changes were detected. CONCLUSIONS: Compared with method- 1, the vapocoolant spray in method 2 produced significantly longer withdrawal latency time that is clinically applicable to collecting blood samples after a heel stick.

Solitary congenital lip pit in an infant.

Lower lip pits are infrequent, affecting fewer than 1 in 75 000 individuals. While more frequently associated with inherited syndromes, isolated lower lip pits may present sporadically as a solitary congenital anomaly. We describe an otherwise healthy 9-day-old infant who presented with a congenital lower lip lesion with unremarkable family history and testing. The appropriate workup for a solitary congenital lip nodule, differential diagnosis, and management of lip pits is described.

Infantile toxic epidermal necrolysis: Successful treatment of an 8-week-old with intravenous immunoglobulin and amniotic membrane transplant.

Stevens-Johnson syndrome and toxic epidermal necrolysis comprise a spectrum of severe mucocutaneous hypersensitivity reactions. A paucity of data limits current understanding of the etiology, treatment options, and prognosis of this entity in the infantile population compared to that in the adult and pediatric literature. We describe the case of an 8-week-old male with toxic epidermal necrolysis treated successfully with intravenous immunoglobulin and amniotic membrane transplant. This patient is the youngest surviving infant with toxic epidermal necrolysis to be reported.

Pediatric Pseudo-pseudoxanthoma Elasticum Resulting From D-Penicillamine Treatment for Wilson Disease.

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.

Pediatric facial pyoderma gangrenosum preceding the diagnosis of inflammatory bowel disease.

We describe two adolescent patients with pyoderma gangrenosum (PG) involving the face. Subsequent gastrointestinal evaluation revealed microscopic bowel inflammation suggestive of inflammatory bowel disease. While PG is rarely localized to the face, this brief report reveals two cases of pediatric facial PG and suggests a correlation between facial PG and microscopic colitis.

Pemphigus-like eruption as a complication of molluscum contagiosum treatment with imiquimod in a 5-year-old girl.

Pemphigus and pemphigus-like reactions can be triggered by a variety of medications including topical therapies, such as imiquimod. While the association between imiquimod and pemphigus-like reactions has been reported in adults, this is the first report of a generalized reaction beyond the site of imiquimod application in a child. The mechanism by which this occurs may be through a unique pathway, separate from the classic antibody-mediated pathway. Our patient had a full recovery without recurrence after cessation of the inciting drug.

Risk Factors and Outcomes of Nonmelanoma Skin Cancer in Children and Young Adults.

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.

Impact of skin biopsy on the management of acute graft-versus-host disease in a pediatric population.

BACKGROUND/OBJECTIVES: Acute graft-versus-host disease (GVHD) of the skin is a common complication of hematopoietic stem cell transplantation (HSCT) but often represents a diagnostic challenge. The adult literature suggests that histopathology rarely dictates management decisions, but the clinical utility of skin biopsies in pediatric patients with suspected acute GVHD is unknown. The objective of this study was to determine the frequency with which skin biopsy leads to a definitive diagnosis of acute GVHD and changes the management of acute GVHD in the pediatric population. METHODS: We conducted a retrospective analysis of histopathology results and the associated impact on clinical management based on chart review of pediatric patients who underwent skin biopsy for cutaneous eruptions suspicious for acute GVHD from 1995 to 2016. RESULTS: Among 27 pediatric HSCT patients, skin biopsy yielded definitive diagnoses (GVHD or otherwise) in only 15% (4/27) of cases. Overall, dermatology consultation was associated with clinical management changes in 78% (21/27) of cases. A change in management was definitively based on skin biopsy results in only 7.4% (2/27) of cases. The mean duration of time between dermatology consultation and return of biopsy results was 4.8 days (range 1-17). CONCLUSIONS: Our results suggest that skin biopsy of pediatric HSCT patients with findings concerning for acute skin GVHD rarely yields a definitive diagnosis or change in management.

Pediatric leukemia cutis: A case series.

BACKGROUND: Pediatric leukemia cutis (LC) is often difficult to diagnose due to similarity in appearance to other dermatologic diseases. Several case reports and smaller case series have been published in the medical literature, but studies on larger cohorts of children with LC are lacking. OBJECTIVE: This study aimed to better characterize the clinical features, course, and prognosis of LC in the pediatric population. METHODS: We performed a retrospective case series of 31 patients diagnosed with LC at Boston Children's Hospital and the Children's Hospital of Philadelphia. RESULTS: The number and morphology of LC lesions varied among patients, with the head and lower extremities being the most common sites of involvement. Leukemia cutis presented concomitantly with systemic leukemia in the majority of cases. Most cases of LC arose during initial leukemia episodes, rather than with relapsed leukemia. Acute myeloid leukemia was the subtype most frequently associated with LC, followed by acute lymphoblastic leukemia. Diagnosis altered treatment timing and therapeutic decisions. CONCLUSION: Children most often present concomitantly with LC and systemic leukemia. Since the morphology and distribution of LC varies, physicians must maintain a high index of suspicion for this diagnosis, as the presence of LC may change the management of systemic leukemia.

Infection regulates pro-resolving mediators that lower antibiotic requirements.

Underlying mechanisms for how bacterial infections contribute to active resolution of acute inflammation are unknown. Here, we performed exudate leukocyte trafficking and mediator-metabololipidomics of murine peritoneal Escherichia coli infections with temporal identification of pro-inflammatory (prostaglandins and leukotrienes) and specialized pro-resolving mediators (SPMs). In self-resolving E. coli exudates (10(5) colony forming units, c.f.u.), the dominant SPMs identified were resolvin (Rv) D5 and protectin D1 (PD1), which at 12 h were at significantly greater levels than in exudates from higher titre E. coli (10(7) c.f.u.)-challenged mice. Germ-free mice had endogenous RvD1 and PD1 levels higher than in conventional mice. RvD1 and RvD5 (nanograms per mouse) each reduced bacterial titres in blood and exudates, E. coli-induced hypothermia and increased survival, demonstrating the first actions of RvD5. With human polymorphonuclear neutrophils and macrophages, RvD1, RvD5 and PD1 each directly enhanced phagocytosis of E. coli, and RvD5 counter-regulated a panel of pro-inflammatory genes, including NF-κB and TNF-α. RvD5 activated the RvD1 receptor, GPR32, to enhance phagocytosis. With self-limited E. coli infections, RvD1 and the antibiotic ciprofloxacin accelerated resolution, each shortening resolution intervals (R(i)). Host-directed RvD1 actions enhanced ciprofloxacin's therapeutic actions. In 10(7) c.f.u. E. coli infections, SPMs (RvD1, RvD5, PD1) together with ciprofloxacin also heightened host antimicrobial responses. In skin infections, SPMs enhanced vancomycin clearance of Staphylococcus aureus. These results demonstrate that specific SPMs are temporally and differentially regulated during infections and that they are anti-phlogistic, enhance containment and lower antibiotic requirements for bacterial clearance.

Subcutaneous granuloma annulare involving the scalp.

Subcutaneous granuloma annulare (SGA) is an uncommon subtype of granuloma annulare. There are few reports of this entity solely affecting the scalp. We report a case of biopsy-proven SGA in a 21-month-old boy with six asymptomatic, rock-hard scalp nodules.

Eosinophilic annular erythema treated with dupilumab.

Eosinophilic annular erythema is a rare, benign, recurrent condition characterized by annular skin lesions, tissue eosinophilia, and resistance to a variety of treatments. There are fewer than 30 cases reported in the English literature, 7 of which are in children. We present a case of recurrent eosinophilic annular erythema in an adolescent that was successfully treated with dupilumab, an interleukin-4 receptor alpha antagonist.

Combined immunodeficiency with EBV positive B cell lymphoma and epidermodysplasia verruciformis due to a novel homozygous mutation in RASGRP1.

RASGRP1 is a guanine-nucleotide-exchange factor essential for MAP-kinase mediated signaling in lymphocytes. We report the second case of RASGRP1 deficiency in a patient with a homozygous nonsense mutation in the catalytic domain of the protein. The patient had epidermodysplasia verruciformis, suggesting a clinically important intrinsic T cell function defect. Like the previously described patient, our proband also presented with CD4+ T cell lymphopenia, impaired T cell proliferation to mitogens and antigens, reduced NK cell function, and EBV-associated lymphoma. The severity of the disease and the development of EBV lymphoma in both patients suggest that hematopoietic stem cell transplantation should be performed rapidly in patients with RASGRP1 deficiency.

Congenital melanocytic nevi in young children: Histopathologic features and clinical outcomes.

BACKGROUND: Although only large congenital melanocytic nevi (CMN) are associated with a significantly high risk for malignant transformation, CMN of all sizes are prone to changes in clinical appearance in early childhood and thus are often biopsied or excised. While CMNs typically exhibit benign behavior, atypical histopathologic findings might be common and may prompt additional unnecessary procedures. OBJECTIVE: To assess the prevalence and associated clinical outcomes of atypical histopathologic features in CMN in children. METHODS: A single center retrospective study was conducted with patients 0-35 months of age with CMN diagnosed by histopathology between 1993-2013. RESULTS: One hundred seventy-nine patients with a total of 197 CMNs were identified. Cytologic atypia, architectural disorder, or pagetoid spread were present in 73% of CMN. With a mean follow up of 7.3 years, no cases of melanoma or CMN-related deaths were identified. LIMITATIONS: Our findings were based on a largely Caucasian population and might not apply to darker skin types. Our findings might not apply to older children or adults with CMN. CONCLUSION: Atypical histopathologic features of cytologic atypia, architectural disorder, and pagetoid spread are common in benign CMN of young children.