RESUMEN
Calcinosis cutis (CC) is characterized by the deposition of calcium salts in the skin and subcutaneous tissues. CC involving the vulva or foreskin (prepuce) is uncommon. We present a 9-year-old female with vulvar CC and a 15-year-old male with preputial CC. Microscopic review of excisional specimens revealed calcification associated with follicular cysts in the vulvar case and lichen sclerosus in the preputial case, suggesting a dystrophic origin to a subset of cases of genital CC that might otherwise be classified as idiopathic. The clinical implication of these findings is the need for close histopathologic scrutiny and ongoing clinical surveillance of patients with genital CC initially deemed idiopathic.
RESUMEN
We describe the first cases of pediatric melanoma with ALK fusion gene arising within giant congenital melanocytic nevi. Two newborn boys presented with large pigmented nodular plaques and numerous smaller satellite nevi. Additional expansile nodules developed within both nevi and invasive melanomas were diagnosed before 10 months of age in both boys. Oncogenic driver mutations in NRAS and BRAF were absent in both cases. Instead, oncogenic ZEB2::ALK fusion genes were identified in both the nevus and melanoma developing within the nevus. In both cases, tumors were noted by ultrasound in utero, demonstrated significant nodularity at birth, and progressed to melanoma in the first year of life suggesting that congenital nevi with ALK fusion genes may behave more aggressively than those with other mutations. As ALK kinase inhibitors are effective against a range of tumors with similar ALK fusion kinases, identifying ALK fusion genes in congenital melanocytic nevi may provide an opportunity for targeted therapy.
Asunto(s)
Melanoma , Nevo de Células Epitelioides y Fusiformes , Nevo Pigmentado , Neoplasias Cutáneas , Niño , Humanos , Lactante , Recién Nacido , Masculino , Quinasa de Linfoma Anaplásico/genética , Fusión Génica/genética , Melanoma/genética , Melanoma/patología , Nevo Pigmentado/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patologíaRESUMEN
BACKGROUND: Schwannomas are common peripheral nerve sheath tumors that can cause severe morbidity given their stereotypic intracranial and paraspinal locations. Similar to many solid tumors, schwannomas and other nerve sheath tumors are primarily thought to arise due to aberrant hyperactivation of the RAS growth factor signaling pathway. Here, we sought to further define the molecular pathogenesis of schwannomas. METHODS: We performed comprehensive genomic profiling on a cohort of 96 human schwannomas, as well as DNA methylation profiling on a subset. Functional studies including RNA sequencing, chromatin immunoprecipitation-DNA sequencing, electrophoretic mobility shift assay, and luciferase reporter assays were performed in a fetal glial cell model following transduction with wildtype and tumor-derived mutant isoforms of SOX10. RESULTS: We identified that nearly one-third of sporadic schwannomas lack alterations in known nerve sheath tumor genes and instead harbor novel recurrent in-frame insertion/deletion mutations in SOX10, which encodes a transcription factor responsible for controlling Schwann cell differentiation and myelination. SOX10 indel mutations were highly enriched in schwannomas arising from nonvestibular cranial nerves (eg facial, trigeminal, vagus) and were absent from vestibular nerve schwannomas driven by NF2 mutation. Functional studies revealed these SOX10 indel mutations have retained DNA binding capacity but impaired transactivation of glial differentiation and myelination gene programs. CONCLUSIONS: We thus speculate that SOX10 indel mutations drive a unique subtype of schwannomas by impeding proper differentiation of immature Schwann cells.
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Neoplasias de la Vaina del Nervio , Neurilemoma , Neuroma Acústico , Humanos , Mutación INDEL , Activación Transcripcional , Neurilemoma/genética , Neurilemoma/patología , Neuroma Acústico/patología , Mutación , Factores de Transcripción SOXE/genética , Factores de Transcripción SOXE/metabolismoRESUMEN
Spiny keratoderma (SK) was first described by Brown in 1871 and is characterized by numerous 1-2 mm spines of keratin on the palms and soles, usually sparing the dorsal surfaces, or disseminated over the trunk. Histologically, the "spine" represents a column of hyperkeratosis. Several different forms are known, including familial, sporadic, post-inflammatory and paraneoplastic. Although an association of SK with melanoma has been reported, the significance of such co-occurrence remains unclear due to the limited number of cases. To increase the body of knowledge and shed further light on this rare condition, we present a case of SK in a patient with a recent history of melanoma in situ.
RESUMEN
Infantile myofibroma (IM) commonly presents as a benign cutaneous fibrous tumor in infancy. Although the majority of solitary IM regress without any morbidity, some cases have underlying bone or visceral involvement that can lead to both morbidity and mortality. In this report with review of the literature, we present two cases of solitary cutaneous IM with internal involvement and discuss screening cases of solitary IM with full body imaging.
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Miofibroma , Miofibromatosis , Neoplasias Cutáneas , Neoplasias de los Tejidos Blandos , Huesos , Humanos , Miofibroma/diagnóstico , Miofibroma/patología , Miofibromatosis/diagnóstico , Miofibromatosis/patología , Neoplasias Cutáneas/diagnósticoRESUMEN
OBJECTIVES: To describe consecutive vulvar biopsy cases and to create an educational template for pathology trainees and practicing pathologists. METHODS: We reviewed 189 consecutive biopsies from the female genital area skin and mucosa. We classified them based on etiologies and examined limited clinical information. RESULTS: We classified diagnoses as squamous intraepithelial neoplasia (21.5%), melanocytic neoplasia (17.9%), lichenoid dermatoses (15.9%), nonlichenoid dermatoses (11.3%), infectious (6.2%), reparative (4.6%), or miscellaneous (22.6%). The miscellaneous diagnoses included common entities (polyps and cysts) and rarer entities (calcinosis cutis, adnexal neoplasms, or basal cell carcinoma) and nonspecific descriptive diagnoses. Clinicians most often included the actual diagnosis in their differential for melanocytic lesions (83%) and least often for inflammatory lesions (32%). However, some cases included a clinical description without a differential diagnosis (14%) or no helpful clinical information (4%). The distribution of whether correct diagnoses were included in the clinical differential was similar between submitting physicians and midlevel providers. CONCLUSIONS: Understanding squamous and melanocytic pathology and the various lichenoid and other inflammatory diagnoses is critical for signing out female genital tract skin pathology. The cases examined in this report can serve as an educational template for trainees and practicing pathologists.
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Curriculum , Enfermedades de los Genitales Femeninos/diagnóstico , Enfermedades de los Genitales Femeninos/patología , Patólogos/educación , Patología Clínica/educación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Niño , Educación Médica Continua/métodos , Femenino , Humanos , Persona de Mediana Edad , Membrana Mucosa/patología , Piel/patología , Adulto JovenRESUMEN
Melanocytic tumors with inactivation of protein kinase A regulatory subunit-α (PRKAR1A) have large oval nuclei and intense pigmentation. Historically, these tumors have been categorized under various names, including epithelioid blue nevus, pigmented epithelioid melanocytoma (PEM) and animal-type melanoma. Although a subset of PEM harbor BRAF activating mutations and biallelic inactivation of PRKAR1A, there are only a few reports of melanomas, or of tumors with genomic alterations beyond those of PEMs. Herein, we describe the clinicopathologic and genetic features of 8 melanomas and tumors that lack PRKAR1α expression by immunohistochemistry but do not fit with conventional PRKAR1A-inactivated melanocytomas. These tumors tended to affect younger patients than conventional melanomas (median age=38 y) and presented as dark brown/black papules and nodules. Histopathologically, they demonstrated nodularity, sometimes in a background of conventional melanoma, and large vesicular nuclei with prominent nucleoli. With the exception of 1 case, the mitotic index was not significantly elevated. Immunohistochemically, all cases showed loss of PRKAR1α and of p16 expression. Seven tumors underwent massively parallel short read (next-generation) sequencing of a panel of 480 cancer-associated genes. Five tumors demonstrated truncating mutations of PRKAR1A and the 2 in which such mutations were not identified demonstrated loss of heterozygosity of the PRKAR1A locus. Four of the tumors harbored BRAF V600E mutations, and 1 harbored a FAM39B-BRAF gene fusion. Another harbored a GNA11 activating mutation. A MAP kinase activating mutation was not identified in the remaining case. Four tumors displayed TERT promoter mutations and chromosomal copy number changes supporting the diagnosis of melanoma. Two cases without these alterations and were classified as "high-grade PRKAR1A-inactivated melanocytomas". The 1 case with widespread metastases demonstrated mutations in TP53 and RB1. Overall, we provide the first genetic characterization of PRKAR1A-inactivated melanomas, discuss the differential diagnosis of heavily pigmented epithelioid melanocytic neoplasms, and propose a new nomenclature for such tumors.
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Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/genética , Melanoma/genética , Melanoma/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Adolescente , Adulto , Anciano , Niño , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , MutaciónRESUMEN
Melanomas that have histopathologic features that overlap with those of Spitz nevus are referred to as spitzoid melanomas. However, the diagnostic concept is used inconsistently and genomic analyses suggest it is a heterogeneous category. Spitz tumors, the spectrum of melanocytic neoplasms extending from Spitz nevi to their malignant counterpart Spitz melanoma, are defined in the 2018 WHO classification of skin tumors by the presence of specific genetic alterations, such as kinase fusions or HRAS mutations. It is unclear what fraction of "spitzoid melanomas" defined solely by their histopathologic features belong to the category of Spitz melanoma or to other melanoma subtypes. We assembled a cohort of 25 spitzoid melanomas diagnosed at a single institution over an 8-year period and performed high-coverage DNA sequencing of 480 cancer related genes. Transcriptome wide RNA sequencing was performed for select cases. Only nine cases (36%) had genetic alterations characteristic of Spitz melanoma, including HRAS mutation or fusion involving BRAF, ALK, NTRK1, or MAP3K8. The remaining cases were divided into those with an MAPK activating mutation and those without an MAPK activating mutation. Both Spitz melanoma and spitzoid melanomas in which an MAPK-activating mutation could not be identified tended to occur in younger patients on skin with little solar elastosis, infrequently harbored TERT promoter mutations, and had a lower burden of pathogenic mutations than spitzoid melanomas with non-Spitz MAPK-activating mutations. The MAPK-activating mutations identified affected non-V600 residues of BRAF as well as NRAS, MAP2K1/2, NF1, and KIT, while BRAF V600 mutations, the most common mutations in melanomas of the WHO low-CSD category, were entirely absent. While the "spitzoid melanomas" comprising our cohort were enriched for bona fide Spitz melanomas, the majority of melanomas fell outside of the genetically defined category of Spitz melanomas, indicating that histomorphology is an unreliable predictor of Spitz lineage.
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Melanoma/patología , Nevo de Células Epitelioides y Fusiformes/patología , Neoplasias Cutáneas/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Melanoma/genética , Melanoma/metabolismo , Persona de Mediana Edad , Mutación , Nevo de Células Epitelioides y Fusiformes/genética , Nevo de Células Epitelioides y Fusiformes/metabolismo , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Piel/metabolismo , Piel/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismo , Adulto JovenAsunto(s)
Compuestos de Bencidrilo/efectos adversos , Glucósidos/efectos adversos , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Síndrome de Sweet/inducido químicamente , Anciano , Compuestos de Bencidrilo/administración & dosificación , Femenino , Glucósidos/administración & dosificación , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/administración & dosificación , Síndrome de Sweet/diagnósticoRESUMEN
Genetic variation in the NF-κB inhibitors, ABIN1 and A20, increase risk for psoriasis. While critical for hematopoietic immune cell function, these genes are believed to additionally inhibit psoriasis by dampening inflammatory signaling in keratinocytes. We dissected ABIN1 and A20's regulatory role in human keratinocyte inflammation using an RNA sequencing-based comparative genomic approach. Here we show subsets of the IL-17 and tumor necrosis factor-α signaling pathways are robustly restricted by A20 overexpression. In contrast, ABIN1 overexpression inhibits these genes more modestly for IL-17, and weakly for tumor necrosis factor-α. Our genome-scale analysis also indicates that inflammatory program suppression appears to be the major transcriptional influence of A20/ABIN1 overexpression, without obvious influence on keratinocyte viability genes. Our findings thus enable dissection of the differing anti-inflammatory mechanisms of two distinct psoriasis modifiers, which may be directly exploited for therapeutic purposes. Importantly, we report that IL-17-induced targets of A20 show similar aberrant epidermal layer-specific transcriptional upregulation in keratinocytes from diseases as diverse as psoriasis, atopic dermatitis, and erythrokeratodermia variabilis, suggesting a contributory role for epidermal inflammation in a broad spectrum of rashes.
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Proteínas de Unión al ADN/metabolismo , Exantema/inmunología , Queratinocitos/inmunología , Transducción de Señal/inmunología , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/metabolismo , Células Cultivadas , Proteínas de Unión al ADN/inmunología , Dermatitis Atópica/inmunología , Dermatitis Atópica/patología , Eritroqueratodermia Variable/inmunología , Eritroqueratodermia Variable/patología , Exantema/patología , Genómica , Humanos , Interleucina-17/inmunología , Interleucina-17/metabolismo , Queratinocitos/patología , Cultivo Primario de Células , Psoriasis/inmunología , Psoriasis/patología , RNA-Seq , Análisis de la Célula Individual , Piel/citología , Piel/inmunología , Piel/patología , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia ArribaRESUMEN
Perturbations in the transcriptional programs specifying epidermal differentiation cause diverse skin pathologies ranging from impaired barrier function to inflammatory skin disease. However, the global scope and organization of this complex cellular program remain undefined. Here we report single-cell RNA sequencing profiles of 92,889 human epidermal cells from 9 normal and 3 inflamed skin samples. Transcriptomics-derived keratinocyte subpopulations reflect classic epidermal strata but also sharply compartmentalize epithelial functions such as cell-cell communication, inflammation, and WNT pathway modulation. In keratinocytes, â¼12% of assessed transcript expression varies in coordinate patterns, revealing undescribed gene expression programs governing epidermal homeostasis. We also identify molecular fingerprints of inflammatory skin states, including S100 activation in the interfollicular epidermis of normal scalp, enrichment of a CD1C+CD301A+ myeloid dendritic cell population in psoriatic epidermis, and IL1ßhiCCL3hiCD14+ monocyte-derived macrophages enriched in foreskin. This compendium of RNA profiles provides a critical step toward elucidating epidermal diseases of development, differentiation, and inflammation.
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Epidermis/metabolismo , Epidermis/patología , Inflamación/genética , Inflamación/patología , Análisis de la Célula Individual , Transcripción Genética , Anfirregulina/farmacología , Biomarcadores/metabolismo , Agregación Celular/genética , Comunicación Celular , Diferenciación Celular , Proliferación Celular , Prepucio/citología , Folículo Piloso/metabolismo , Humanos , Inflamación/inmunología , Queratinocitos/metabolismo , Cinética , Masculino , Psoriasis/genética , Psoriasis/inmunología , Psoriasis/patología , Proteínas S100/metabolismo , Factores de Tiempo , Transcriptoma/genética , Proteínas Wnt/metabolismoRESUMEN
BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) encompasses rare neoplasms that can arise either in the dermis or in the subfascial soft tissue. The behavior of UPS ranges from indolent to aggressive, but data predicting outcomes are limited. OBJECTIVE: Identify predictors of poor outcomes by analyzing a large collection of UPS cases. METHODS: We evaluated all available cases of UPS (including those termed atypical fibroxanthoma, malignant fibrous histiocytoma, pleomorphic dermal sarcoma, and subfascial UPS) across 3 tertiary care centers. RESULTS: Among the 319 patients, 45 experienced recurrence, 33 experienced metastasis, and 96 died of any cause. Risk factors for recurrence were clinical tumor size larger than 5 cm and invasion beyond subcutaneous fat. Risk factors for distant metastases were tumor site, tumor size larger than 2 cm, invasion beyond subcutaneous fat, and lymphovascular invasion. Risk factors for overall mortality were age, immunosuppression, tumor size larger than 2 cm, and lymphovascular invasion. History of skin cancer was associated with a lower risk of recurrence and metastasis. LIMITATIONS: This was a retrospective study. CONCLUSIONS: Using the unbiased approach of pooling all UPS cases regardless of terminology, we identified clinical and histologic factors predicting poor outcomes. We propose subcategorization of UPS (into superficial versus deep UPS), which is consistent with the American Joint Committee on Cancer staging of soft-tissue sarcoma.
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Histiocitoma Fibroso Maligno/patología , Cirugía de Mohs/métodos , Recurrencia Local de Neoplasia/patología , Sarcoma/patología , Neoplasias Cutáneas/patología , Neoplasias de los Tejidos Blandos/patología , Adulto , Anciano , Análisis de Varianza , Biopsia con Aguja , Carcinoma/mortalidad , Carcinoma/patología , Carcinoma/cirugía , Estudios de Cohortes , Supervivencia sin Enfermedad , Femenino , Histiocitoma Fibroso Maligno/mortalidad , Histiocitoma Fibroso Maligno/cirugía , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Análisis Multivariante , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/cirugía , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Sistema de Registros , Estudios Retrospectivos , Medición de Riesgo , Sarcoma/mortalidad , Sarcoma/cirugía , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/cirugía , Neoplasias de los Tejidos Blandos/mortalidad , Neoplasias de los Tejidos Blandos/cirugía , Análisis de Supervivencia , Estados UnidosRESUMEN
Atypical fibroxanthoma (AFX), is a rare type of skin cancer affecting older individuals with sun damaged skin. Since there is limited genomic information about AFX, our study seeks to improve the understanding of AFX through whole-exome and RNA sequencing of 8 matched tumor-normal samples. AFX is a highly mutated malignancy with recurrent mutations in a number of genes, including COL11A1, ERBB4, CSMD3, and FAT1. The majority of mutations identified were UV signature (C>T in dipyrimidines). We observed deletion of chromosomal segments on chr9p and chr13q, including tumor suppressor genes such as KANK1 and CDKN2A, but no gene fusions were found. Gene expression profiling revealed several biological pathways that are upregulated in AFX, including tumor associated macrophage response, GPCR signaling, and epithelial to mesenchymal transition (EMT). To further investigate the presence of EMT in AFX, we conducted a gene expression meta-analysis that incorporated RNA-seq data from dermal fibroblasts and keratinocytes. Ours is the first study to employ high throughput sequencing for molecular profiling of AFX. These data provide valuable insights to inform models of carcinogenesis and additional research towards tumor-directed therapy.
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Genoma Humano , Neoplasias Cutáneas/genética , Regiones no Traducidas 3' , Cadherinas/genética , Colágeno Tipo XI/genética , Transición Epitelial-Mesenquimal , Humanos , Proteínas de la Membrana/genética , Mutación , Receptor ErbB-4/genética , Análisis de Secuencia de ARN , Neoplasias Cutáneas/patología , Transcriptoma , Secuenciación del ExomaRESUMEN
Hair re-pigmentation in adults is a rare phenomenon. We describe a 58-year-old woman who developed hair re-pigmentation on her vertex scalp as a marker of underlying melanoma. Histopathology revealed a nodular melanoma that was surrounding but not invading follicular epithelium. To our knowledge, there have only been 4 other previously published cases describing hair re-pigmentation in the setting of scalp melanoma. Focal hair re-pigmentation in adults should prompt a thorough evaluation for an underlying melanoma.
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Cabello , Hiperpigmentación/patología , Melanoma/patología , Neoplasias Cutáneas/patología , Biopsia con Aguja , Diagnóstico Diferencial , Femenino , Folículo Piloso/patología , Humanos , Hiperpigmentación/diagnóstico , Inmunohistoquímica , Melanoma/diagnóstico , Persona de Mediana Edad , Enfermedades Raras , Cuero Cabelludo , Neoplasias Cutáneas/diagnósticoRESUMEN
Oncogenic gene fusions have been identified in many cancers and many serve as biomarkers or targets for therapy. Here we identify six different melanocytic tumours with genomic rearrangements of MET fusing the kinase domain of MET in-frame to six different N-terminal partners. These tumours lack activating mutations in other established melanoma oncogenes. We functionally characterize two of the identified fusion proteins (TRIM4-MET and ZKSCAN1-MET) and find that they constitutively activate the mitogen-activated protein kinase (MAPK), phosphoinositol-3 kinase (PI3K) and phospholipase C gamma 1 (PLCγ1) pathways. The MET inhibitors cabozantinib (FDA-approved for progressive medullary thyroid cancer) and PF-04217903 block their activity at nanomolar concentrations. MET fusion kinases thus provide a potential therapeutic target for a rare subset of melanoma for which currently no targeted therapeutic options currently exist.
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Reordenamiento Génico , Melanoma Experimental/genética , Nevo de Células Epitelioides y Fusiformes/genética , Fusión de Oncogenes , Proteínas Proto-Oncogénicas c-met/genética , Adulto , Animales , Línea Celular , Femenino , Humanos , Masculino , Ratones , Persona de Mediana EdadRESUMEN
Skin infections are not uncommon after cosmetic laser procedures. Infection rates following ablative laser resurfacing procedures are reported to be as high as 7.6%, compared to 1.9% for fractional ablation. An infrequent yet important infectious complication of ablative laser treatment is that caused by non-tuberculous mycobacteria (NTM).