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.

A case of neonatal sweet syndrome associated with mevalonate kinase deficiency.

BACKGROUND: Sweet syndrome (SS), also known as acute febrile neutrophilic dermatosis, is an immunologic syndrome characterized by widespread neutrophilic infiltration. Histiocytoid Sweet syndrome (H-SS) is a histopathologic variant of SS. While SS most commonly occurs in adults, this case report discusses an infant patient who presented with H-SS. CASE PRESENTATION: Through a multidisciplinary approach, this patient was also found to have very early onset inflammatory bowel disease (VEO-IBD) and Mevalonate kinase-associated disease (MKAD). While prior case studies have characterized an association between VEO-IBD and MKAD, there is no literature describing the association of all three diagnoses this case: H-SS, VEO-IBD and MKAD. Initiation of canakinumab in this patient resulted in successful control of the disease. CONCLUSIONS: This case highlights the importance of a multidisciplinary approach to rare diagnoses, and collaboration during cases with significant diagnostic uncertainty.

Revision of the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis Classification Schema for Melanocytic Lesions: A Consensus Statement.

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.

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.

Pediatric Lichen Myxedematosus: A Diagnostic and Management Challenge.

Localized lichen myxedematosus (LM) is a rare, idiopathic mucinosis characterized by dermal mucin deposition and variable fibroblast proliferation. Nodular lichen myxedematosus, a clinicopathologic subtype of localized LM, is exceedingly rare in pediatric patients with only three prior cases reported. Understanding of LM in pediatric patients is limited by the rarity of the disease, and diagnosis is complicated by overlapping clinical and histopathologic features. There is no standardized treatment for localized LM and treatment is largely dictated by a patient's desire to minimize cosmetic disfigurement. This case series reports two additional patients with juvenile nodular lichen myxedematosus, highlights the limitations of existing diagnostic criteria, and describes successful treatment of one patient with intralesional triamcinolone.

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.

Impact of Next-generation Sequencing on Interobserver Agreement and Diagnosis of Spitzoid Neoplasms.

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.

Combined immunodeficiency with autoimmunity caused by a homozygous missense mutation in inhibitor of nuclear factor 𝛋B kinase alpha (IKKα).

Inhibitor of nuclear factor kappa B kinase alpha (IKKα) is critical for p100/NF-κB2 phosphorylation and processing into p52 and activation of the noncanonical NF-κB pathway. A patient with recurrent infections, skeletal abnormalities, absent secondary lymphoid structures, reduced B cell numbers, hypogammaglobulinemia, and lymphocytic infiltration of intestine and liver was found to have a homozygous p.Y580C mutation in the helix-loop-helix domain of IKKα. The mutation preserves IKKα kinase activity but abolishes the interaction of IKKα with its activator NF-κB­inducing kinase and impairs lymphotoxin-ß­driven p100/NF-κB2 processing and VCAM1 expression. Homozygous IKKαY580C/Y580C mutant mice phenocopy the patient findings; lack marginal zone B cells, germinal centers, and antigen-specific T cell response to cutaneous immunization; have impaired Il17a expression; and are susceptible to cutaneous Staphylococcus aureus infection. In addition, these mice demonstrate a severe reduction in medullary thymic epithelial cells, impaired thymocyte negative selection, a restricted TCRVß repertoire, a selective expansion of potentially autoreactive T cell clones, a decreased frequency of regulatory T cells, and infiltration of liver, pancreas, and lung by activated T cells coinciding with organ damage. Hence, this study identifies IKKα deficiency as a previously undescribed cause of primary immunodeficiency with associated autoimmunity.

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.

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.

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.

Management of Residual Spitz Nevus in Surgical Specimens following Biopsy and Excision.

Proper management of Spitz nevi continues to be debated, with treatment ranging from observation to surgery. To better characterize the outcome of surgical procedures performed for incomplete initial excision or biopsy, we sought to ascertain the histopathological presence of residual Spitz nevi in a set of surgical specimens. METHODS: We retrospectively reviewed 123 records with histologically-confirmed Spitz nevus. Data concerning treatment, clinical features, histopathological margin involvement, and presence of residual lesion on subsequent procedural specimens were collected. RESULTS: Fifty-three percent of lesions (n = 65) were initially sampled by shave or punch biopsy, and the remainder (n = 58) were formally excised without initial biopsy. The rates of re-excision for involved margins were: shave biopsy (92.2%), punch biopsy (78.6%), and formal excision (13.8%). In total, 61.0% of patients who underwent an initial procedure of any kind had involved margins, but only half of those re-excised for involved margins (57.6%) had histologically residual lesion on repeated excision. A significantly higher proportion of initial punch biopsies (90.9%) resulted in residual lesion (in secondary excision specimens) when compared with shave biopsy (48.9%) and formal excision (62.5%; P < 0.05). CONCLUSIONS: Findings suggest that clinicians may consider shave biopsy over punch biopsy for diagnosing suspected lesions, when indicated and appropriate. Given the rarity of malignant transformation and the frequency of residual nevus, observation may be reasonable for managing pediatric patients with histologically-confirmed Spitz nevi, who are post initial biopsy or excision despite known histopathological margin involvement.

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.