Agminated presentation of fusion-driven melanocytic neoplasms.

BACKGROUND: The conventionally understood pathogenesis of agminated Spitz nevi includes a mosaic HRAS mutation followed by copy number gains in 11p. However, we have recently observed agminated presentations of fusion-driven melanocytic neoplasms. METHODS: We retrieved cases from our database of benign fusion-induced melanocytic neoplasms with an agminated presentation. Both the primary lesion and the secondary lesion were sequenced. TERT-promoter mutational testing and the melanoma fluorescence in situ hybridization assay were also performed. RESULTS: Three cases were included. Two had a PRKCA fusion (partners ATP2B4 and MPZL1) and one had a ZCCHC8::ROS1 fusion. None of the cases met morphologic or molecular criteria for malignancy. There was no evidence of tumor progression in secondary lesions. The same fusion was identified in the primary and secondary lesions. None of the patients developed evidence of nodal or systemic metastasis. CONCLUSIONS: We present accumulating evidence that fusion-driven melanocytic neoplasms can present with an agminated presentation. The differential diagnosis of an agminated presentation versus a locally recurrent or potentially locally metastatic tumor is critical, and accurate diagnosis has significant prognostic and therapeutic consequences for the patient. As with HRAS mutations, fusion-driven melanocytic tumors may have an agminated presentation.

Idiopathic facial aseptic granuloma: case series and review of histological findings.

Idiopathic facial aseptic granuloma (IFG) is a benign condition that typically presents as asymptomatic nodules on the cheeks of pediatric patients. The underlying etiology of IFG remains unknown; however, increasing evidence supports the theory that IFG may lie on a spectrum with childhood rosacea. Typically, biopsy and excision are deferred due to the benign nature, high spontaneous resolution rates, and cosmetically sensitive location. As biopsy is infrequently used to diagnose IFG, a limited library of histopathologic findings exists to characterize the lesions. We present a single-center retrospective review of five cases of IFG diagnosed by histology after surgical excision.

Rubella Virus Infected Macrophages and Neutrophils Define Patterns of Granulomatous Inflammation in Inborn and Acquired Errors of Immunity.

Rubella virus (RuV) has recently been found in association with granulomatous inflammation of the skin and several internal organs in patients with inborn errors of immunity (IEI). The cellular tropism and molecular mechanisms of RuV persistence and pathogenesis in select immunocompromised hosts are not clear. We provide clinical, immunological, virological, and histological data on a cohort of 28 patients with a broad spectrum of IEI and RuV-associated granulomas in skin and nine extracutaneous tissues to further delineate this relationship. Combined immunodeficiency was the most frequent diagnosis (67.8%) among patients. Patients with previously undocumented conditions, i.e., humoral immunodeficiencies, a secondary immunodeficiency, and a defect of innate immunity were identified as being susceptible to RuV-associated granulomas. Hematopoietic cell transplantation was the most successful treatment in this case series resulting in granuloma resolution; steroids, and TNF-α and IL-1R inhibitors were moderately effective. In addition to M2 macrophages, neutrophils were identified by immunohistochemical analysis as a novel cell type infected with RuV. Four patterns of RuV-associated granulomatous inflammation were classified based on the structural organization of granulomas and identity and location of cell types harboring RuV antigen. Identification of conditions that increase susceptibility to RuV-associated granulomas combined with structural characterization of the granulomas may lead to a better understanding of the pathogenesis of RuV-associated granulomas and discover new targets for therapeutic interventions.

What's New in Genetic Skin Diseases.

The discoveries of new genes underlying genetic skin diseases have occurred at a rapid pace, supported by advances in DNA sequencing technologies. These discoveries have translated to an improved understanding of disease mechanisms at a molecular level and identified new therapeutic options based on molecular targets. This article highlights just a few of these recent discoveries for a diverse group of skin diseases, including tuberous sclerosis complex, ichthyoses, overgrowth syndromes, interferonopathies, and basal cell nevus syndrome, and how this has translated into novel targeted therapies and improved patient care.

Cutaneous neurofibromas in Neurofibromatosis type I: a quantitative natural history study.

BACKGROUND: Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by a predisposition to develop multiple benign tumors. A major feature of NF1 is the development of localized cutaneous neurofibromas. Cutaneous neurofibromas manifest in > 99% of adults with NF1 and are responsible for major negative effects on quality of life. Previous reports have correlated increased burden of cutaneous neurofibromas with age and pregnancy, but longitudinal data are not available to establish a quantitative natural history of these lesions. The purpose of this study is to conduct a prospective natural history study of 22 adults with NF1 over an 8-year period to quantify cutaneous neurofibroma number and size. RESULTS: The average monthly increase in volume for cutaneous neurofibromas was 0.37 mm3 in the back region (95% CI (0.23, 0.51), p < 0.0001), 0.28 mm3 in the abdominal region (95% CI (0.16, 0.41), p < 0.0001), and 0.21 mm3 in the arm/leg region (95% CI (0.08, 0.34), p = 0.0022). The number of cutaneous neurofibromas significantly increased in the back (slope = 0.032, p = 0.011) and abdominal (slope = 0.018, p = 0.026) regions, while the leg/arm regions retained a positive trend (slope = 0.004, p = 0.055). CONCLUSIONS: The number and volume of cutaneous neurofibromas significantly increased over an 8-year timespan; however, the rate of increase is variable by individual and body region. These findings may provide insight into cutaneous neurofibroma development and benefit researchers considering clinical trials targeting cutaneous neurofibromas.

Utility of Wood's light in margin determination of melanoma in situ after excisional biopsy.

BACKGROUND: Margin evaluation of melanoma in situ (MIS) is difficult because of its ill-defined clinical borders. Wood's light examination is commonly used to help delineate MIS margin before excision. OBJECTIVE: To prospectively study the accuracy of preoperative Wood's light examination for margin assessment of MIS. MATERIALS AND METHODS: The authors evaluated 60 patients before excision of MIS under white light and Wood's light. Staged excision was performed using the square procedure technique. After achieving clear margins, they compared final wound size with expected wound size if surgical margins had been based on Wood's light examination. RESULTS: Seven patients (11.7%) had Wood's light enhancement beyond the visible margin of the biopsy site. In all 7, increased wounding would have occurred if the surgical margins had been based on Wood's light examination. In 1 of the 7, use of the Wood's light examination would have reduced the surgical stages needed by 1 stage but would have increased the wound size by 83.3%. CONCLUSION: Wood's light examination has limited utility if complete excisional biopsy of MIS is performed before treatment. In this study, surgical margin based on the Wood's light examination would have resulted in an increased average wound size and would not have reduced the number of stages needed when performing the square procedure.

Validity and interexaminer reliability of a new method to quantify skin neurofibromas of neurofibromatosis 1 using paper frames.

BACKGROUND: Skin neurofibromas represent one of the main clinical manifestations of neurofibromatosis 1, and their number varies greatly between individuals. Quantifying their number is an important step in the methodology of many clinical studies, but counting neurofibromas one by one in individuals with thousands of tumors is arduous, time-consuming, and subject to intra and interexaminer variability. We aimed to evaluate the efficacy of a new methodology for skin neurofibromas quantification using paper frames. METHODS: The sample comprised 92 individuals with NF1. Paper frames, with a central square measuring 100 cm2, were placed on the back, abdomen and thigh. Images were taken, transferred to a computer and two independent examiners counted the neurofibromas. The average number of neurofibromas/100 cm2 of skin was obtained from the mean of the three values. The differences in the quantity of neurofibromas counted by two examiners were evaluated with Intraclass correlation coefficient (ICC), paired t-test, Bland-Altman and survival-agreement plots. To evaluate the predictive value of the method in obtaining the total number of neurofibromas, 49 participants also had their tumors counted one by one. Reproducibility was assessed with Pearson's correlation coefficients and simple linear regression model. RESULTS: There was excellent agreement between examiners (ICC range 0.992-0.997) and the total number of skin neurofibromas could be predicted by the adhesive frames technique using a specific formula (P < 0.0001). CONCLUSIONS: In this article we describe a reliable, easy and rapid technique using paper frames to quantify skin neurofibromas that accurately predicts the total number of these tumors in patients with NF1. This method may be a useful tool in clinical practice and clinical research to help achieve an accurate quantitative phenotype of NF1.

Epidermolysis bullosa nevus in a patient with recessive dystrophic epidermolysis bullosa: a case report.

We present a case of a 6-year-old girl with recessive dystrophic epidermolysis bullosa (EB) who presented with a large pigmented lesion clinically concerning for melanoma. After histological examination and fluorescent in situ hybridization analysis, diagnosis of EB nevus was performed. EB nevi are benign melanocytic neoplasms with histological findings similar to recurrent nevi occurring in all types of EB. They often mimic melanoma clinically, dermatoscopically, and histopathologically. The ability to recognize an EB nevus is essential for appropriate management of the patient. Unnecessary surgical excision in patients with already high-risk EB should be avoided. Close monitoring of these lesions is recommended because no cases of transformation to melanoma have been described.

Mitotically active proliferative nodule arising in a giant congenital melanocytic nevus: a diagnostic pitfall.

Proliferative (cellular) nodules (PN) which mimic malignant melanoma clinically and histologically are described in congenital melanocytic nevi (CMN) and may pose significant diagnostic challenges. We report the case of a 10-day-old male with a giant congenital nevus involving the neck, upper chest, back, and left shoulder containing several nodular lesions, some crusted. Biopsy of a nodule revealed densely packed nevus cells with hyperchromatic round to oval and occasionally irregularly shaped nuclei. There was no necrosis or pushing border, and the nodule blended with the adjacent nevus; however, the lesion demonstrated a significant number of mitoses (27 per mm2) and a 60% labeling index with Ki-67. Further analysis by fluorescence in situ hybridization (FISH) with a 4-color probe set targeting 6p25, 6q23, 11q13, and centromere 6 revealed increased chromosomal copy numbers of all 4 probes, which was interpreted as evidence of polyploidy. In addition, analysis of DNA copy number changes using a single nucleotide polymorphism microarray (Affymetrix, Santa Clara, CA) showed no chromosomal aberrations. The diagnosis of PN in a giant congenital nevus was eventually rendered. At 13-month follow-up, the nodules showed no evidence of growth. Our case illustrates that PNs in the neonatal period might demonstrate extreme mitotic activity. This feature is worrisome when encountered in melanocytic lesions; however, it should not trigger by itself a diagnosis of melanoma in the absence of other histologic criteria of malignancy. In addition, we document polyploidy by FISH in PN, which can potentially be misinterpreted as a FISH-positive result.

Genotype-phenotype correlations emerging from the identification of missense mutations in MBTPS2.

Missense mutations affecting membrane-bound transcription factor protease site 2 (MBTPS2) have been associated with Ichthyosis Follicularis with Atrichia and Photophobia (IFAP) syndrome with or without BRESHECK syndrome, with keratosis follicularis spinulosa decalvans, and Olmsted syndrome. This metalloprotease activates, by intramembranous trimming in conjunction with the protease MBTPS1, regulatory factors involved in sterol control of transcription and in cellular stress response. In this study, 11 different MBTPS2 missense mutations detected in patients from 13 unrelated families were correlated with the clinical phenotype, with their effect on cellular growth in media without lipids, and their potential role for sterol control of transcription. Seven variants were novel [c.774C>G (p.I258M); c.758G>C (p.G253A); c.686T>C (p.F229S); c.1427T>C (p.L476S); c.1430A>T (p.D477V); c.1499G>A (p.G500D); c.1538T>C (p.L513P)], four had previously been reported in unrelated sibships [c.261G>A (p.M87I); c.1286G>A (p.R429H); c.1424T>C (p.F475S); c.1523A>G (p.N508S)]. In the enzyme, the mutations cluster in transmembrane domains. Amino-acid exchanges near the active site are more detrimental to functionality of the enzyme and, clinically, associated with more severe phenotypes. In male patients, a genotype-phenotype correlation begins to emerge, linking the site of the mutation in MBTPS2 with the clinical outcome described as IFAP syndrome with or without BRESHECK syndrome, keratosis follicularis spinulosa decalvans, X-linked, Olmsted syndrome, or possibly further X-linked traits with an oculocutaneous component.

Treatment of infantile hemangiomas with sirolimus in a patient with PHACE syndrome.

Infantile hemangiomas (IHs) are common benign tumors of childhood. IHs often regress satisfactorily without intervention, but a subset of IHs may lead to functional or cosmetic morbidity necessitating therapy. PHACE syndrome is characterized by a variety of neurocutaneous and vascular anomalies that typically include segmental hemangiomas. We present an infant with PHACE syndrome and segmental IH that failed conventional first-line therapies. Treatment with sirolimus provided benefit with regression of the cutaneous IH. As an inhibitor of the mammalian target of rapamycin (mTOR) pathway, the effective use of sirolimus may shed light on the emerging role of mTOR signaling in the development and pathogenesis of IHs.

Superficial granulomatous pyoderma: a case in an 11-year-old girl and review of the literature.

Superficial granulomatous pyoderma is a rare entity thought to be a variant of pyoderma gangrenosum and is often mistaken for classic pyoderma gangrenosum. Superficial granulomatous pyoderma has mainly been described in adults. We describe a case of Superficial granulomatous pyoderma in an 11-year-old girl and present a review of the literature. Superficial granulomatous pyoderma maintains clinical and histopathologic characteristics distinct from classic pyoderma gangrenosum and has a more favorable prognosis. It is often responsive to conservative treatment.

Phenotypic variability among café-au-lait macules in neurofibromatosis type 1.

BACKGROUND: Café-au-lait macules (CALMs) in neurofibromatosis type 1 (NF1) are an early and accessible phenotype in NF1, but have not been extensively studied. OBJECTIVE: We sought to more fully characterize the phenotype of CALMs in patients with NF1. METHODS: In all, 24 patients with a diagnosis of NF1 confirmed through clinical diagnosis or molecular genetic testing were recruited from patients seen in the genetics department at the University of Alabama at Birmingham. CALM locations were mapped using standard digital photography. Pigment intensity was measured with a narrowband spectrophotometer, which estimates the relative amount of melanin based on its absorption of visible light. The major response was defined as the difference between the mean melanin from the CALM and the mean melanin from the surrounding skin. The major response for each spot was compared with spots within an individual and across individuals in the study population. RESULTS: There was significant variability of the major response, primarily attributable to intrapersonal variability (48.4%, P < .0001) and secondly to interpersonal variability (33.0%, P < .0094). Subsequent analysis based on genetic mutation type showed significantly darker spots in individuals with germline mutations leading to haploinsufficiency. LIMITATIONS: The study was performed on a small population of patients and the method has not yet been used extensively for this purpose. CONCLUSIONS: CALMs vary in pigment intensity not only across individuals, but also within individuals and this variability was unrelated to sun exposure. Further studies may help elucidate the molecular basis of this finding, leading to an increased understanding of the pathogenesis of CALMs in NF1.

Neurofibromatosis type 1.

UNLABELLED: Neurofibromatosis type 1 (NF1) is an autosomal dominant, multisystem disorder affecting approximately 1 in 3500 people. Significant advances in the understanding of the pathophysiology of NF1 have been made in the last decade. While no medical therapies for NF1 are currently available, trials are ongoing to discover and test medical treatments for the various manifestations of NF1, primarily plexiform neurofibromas, learning disabilities, and optic pathway gliomas. In addition, mutational analysis has become available on a clinical basis and is useful for diagnostic confirmation in individuals who do not fulfill diagnostic criteria or when a prenatal diagnosis is desired. There are several disorders that may share overlapping features with NF1; in 2007, a disorder with cutaneous findings similar to NF1 was described. This paper addresses the dermatologist's role in diagnosis and management of NF1 and describes the variety of cutaneous and extracutaneous findings in NF1 to which the dermatologist may be exposed. LEARNING OBJECTIVES: After completing this learning activity, participants should be able to discuss the indications and limitations of genetic testing in neurofibromatosis type 1, distinguish common and uncommon cutaneous findings, and recognize the dermatologist's role in diagnosis and management.

Adult T-cell leukemia/lymphoma in an adolescent presenting with skin lesions.

Adult T-cell leukemia/lymphoma is a T-cell malignancy caused by the human T-cell lymphotropic virus-I. Adult T-cell leukemia/lymphoma is primarily a disease of adults due to the long latency period between initial infection and development of leukemia. We present a case of acute adult T-cell leukemia/lymphoma in an adolescent. Skin lesions had appeared 3 years earlier and were the initial sign of human T-cell lymphotropic virus-I infection and T-cell malignancy. Her disease failed to respond to both intensive chemotherapy and antiviral therapy. Cutaneous lesions are sometimes the initial sign of adult T-cell leukemia/lymphoma and early recognition is imperative.