RESUMEN
BACKGROUND/OBJECTIVES: The principal environmental risk factor for conventional nevi and melanomas is ultraviolet exposure. However, little is known about genetic or environmental risk factors for developing Spitz tumors. This study investigates risk factors associated with Spitz neoplasms. METHODS: Patients with Spitz tumors seen at Northwestern Memorial Hospital and Lurie Children's Hospital were surveyed with a 16-item questionnaire about environmental and inherited factors. Spitz tumor patients were compared to a pediatric control cohort from a similar clinical setting. This was supplemented with a meta-analysis of genetic and environmental causes of Spitz neoplasms. RESULTS: One hundred and six Spitz and 58 control surveys were obtained and no statistically significant differences in genetic or environmental risk factors were found between Spitz and control groups. CONCLUSION: Our data and meta-analysis suggest that typical risk factors associated with melanoma are not significantly associated with Spitz tumors. Identification of relevant genetic or environmental risk factors will likely require larger and population-based studies.
Asunto(s)
Melanoma , Nevo de Células Epitelioides y Fusiformes , Nevo , Neoplasias Cutáneas , Niño , Diagnóstico Diferencial , Humanos , Melanoma/etiología , Melanoma/genética , Nevo de Células Epitelioides y Fusiformes/epidemiología , Nevo de Células Epitelioides y Fusiformes/genética , Factores de Riesgo , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/genéticaRESUMEN
The presence of a characteristic chimeric fusion as the initiating genomic event is one defining feature of Spitz neoplasms. Characterization of specific subtypes of Spitz neoplasms allows for better recognition facilitating diagnosis. Data on clinical outcomes of the specific tumor types may help in predicting behavior. In this study we present the largest series to date on ROS1 fusion Spitz neoplasms. We present the clinical, morphologic, and genomic features of 17 cases. We compared the morphologic features of these 17 cases to a cohort of 99 other non-ROS1 Spitz neoplasms to assess for features that may have high specificity for ROS1 fusions. These tumors consisted of ten Spitz nevi and seven Spitz tumors. None of the cases met criteria for a diagnosis of Spitz melanoma. Morphologically, the ROS1 fusion tumors of this series were characterized by a plaque-like or nodular silhouette, often densely cellular intraepidermal melanocyte proliferation, frequent pagetosis, tendency toward spindle cell cytomorphology, low grade nuclear atypia, and floating nests with occasional transepidermal elimination. However, there was a significant range in microscopic appearances, including two cases with morphologic features of a desmoplastic Spitz nevus. Different binding partners to ROS1 were identified with PWWP2A and TPM3 being the most common. No case had a recurrence or metastasis. Our findings document that most ROS1 fusion Spitz neoplasms have some typical characteristic microscopic features, while a small proportion will have features overlapping with other genomic subtypes of Spitz neoplasms. Preliminary evidence suggests that they tend to be indolent or low grade neoplasms.
Asunto(s)
Nevo de Células Epitelioides y Fusiformes/genética , Nevo de Células Epitelioides y Fusiformes/patología , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fusión de Oncogenes/genética , Proteínas de Fusión Oncogénica/genéticaRESUMEN
ABSTRACT: Two distinct studies have shown that RET fusions are found in 3%-4% of Spitz neoplasms. RET fusions have been well described in papillary thyroid cancer, non-small-cell lung cancer, breast cancer, and soft-tissue mesenchymal tumors as well as some other neoplasms. However, there are no comprehensive descriptions to date of the characteristic morphologic, clinical, or genomic findings in RET fusion Spitz neoplasms. In this study, we identified 5 cases of RET fusion Spitz neoplasms. These tumors showed characteristic morphologic features which included plaque-like silhouette and monotonous epithelioid cytology with expansile and dyscohesive nesting. Four of 5 patients including 1 diagnosed as Spitz melanoma had clinical follow-up all of which was uneventful. Furthermore, we describe the genomic sequences in 4 of these cases, 2 of which have previously described KIF5B-RET fusion and 2 of which had a novel LMNA-RET fusion. We believe this report significantly contributes to our current knowledge regarding Spitz neoplasms and describes characteristics features which can help with recognition of the RET subgroup of Spitz.
Asunto(s)
Biomarcadores de Tumor/genética , Fusión Génica , Melanocitos/patología , Melanoma/genética , Nevo de Células Epitelioides y Fusiformes/genética , Proteínas Proto-Oncogénicas c-ret/genética , Neoplasias Cutáneas/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Hibridación Genómica Comparativa , Bases de Datos Factuales , Femenino , Predisposición Genética a la Enfermedad , Humanos , Hibridación Fluorescente in Situ , Lactante , Masculino , Melanoma/patología , Persona de Mediana Edad , Nevo de Células Epitelioides y Fusiformes/patología , Fenotipo , Estudios Retrospectivos , Neoplasias Cutáneas/patología , Adulto JovenRESUMEN
BACKGROUND: Atypical network encompasses several patterns. Few studies assess the sensitivity, specificity, and positive and negative predictive values of network subtypes. OBJECTIVE: We assessed the diagnostic value of atypical network subtypes and their histopathologic correlates in cutaneous melanocytic lesions. METHODS: A retrospective search (2014-2018) from a high-risk melanoma clinic for cases scored for atypical network with accompanying dermoscopic photographs yielded 120 lesions (15 melanoma; 30 severely, 38 moderately, and 32 mildly atypical nevi; 4 compound nevi; and 1 junctional nevus). A dermatopathologist blinded to diagnosis assessed dermoscopic and histologic features. Network abnormality correlates with histopathology and clinical diagnoses were assessed with sensitivity, specificity, positive and negative predictive values, and odds ratios. RESULTS: A multivariable model with shiny white streaks (odds ratio 3.02) and inverse network (OR 4.46) was most predictive of melanoma or severe atypia. Positive predictive value for melanoma or severe atypia in decreasing order was inverse network (73.9%), shiny white streaks (71.4%), loss of network (46%), branched streaks (29.4%), and thick brown lines (28.4%). LIMITATIONS: Cases were retrospectively found from a pigmented lesion clinic and evaluated by a single dermatopathologist. CONCLUSION: Shiny white streaks and inverse network are most predictive of melanoma or severe atypia and warrant biopsy if found on dermoscopy.
Asunto(s)
Síndrome del Nevo Displásico/diagnóstico por imagen , Melanoma/diagnóstico por imagen , Nevo Pigmentado/diagnóstico por imagen , Neoplasias Cutáneas/diagnóstico por imagen , Adulto , Anciano , Dermoscopía , Síndrome del Nevo Displásico/patología , Femenino , Humanos , Masculino , Melanoma/patología , Persona de Mediana Edad , Nevo Pigmentado/patología , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Neoplasias Cutáneas/patología , Adulto JovenRESUMEN
Deep penetrating nevi (DPN) are dermal-based, heavily pigmented melanocytic proliferations primarily resulting from mutations in B-catenin and BRAF or, less commonly, NRAS. DPNs are considered to be intermediate grade tumors which are stable with low risk of malignant transformation. The precise risk for transformation is unknown. Only rare cases of DPN progressing to melanoma have been described. We present a case of a 53-year-old female with a blue-black thigh lesion, on histopathology illustrating a melanocytic proliferation with morphology most consistent with a DPN progressing to melanoma. Targeted next generation sequencing performed on both the atypical melanocytic proliferation and melanoma components showed NRAS and CTNNB1 mutations but no evidence of TERT promoter mutation or chromosomal copy number aberrations. The melanoma had additional mutations including a hotspot TERT promoter mutation as well as unbalanced chromosomal copy number aberrations. This report details the progression of DPN to melanoma through a prominent ultraviolet signature and acquisition of genetic aberrations. While the vast majority of DPNs are benign stable nevi, there are rare examples, which may progress to melanoma. This report documents a case and shows the molecular evolution by which the tumor transformed to melanoma.
Asunto(s)
Dermis/patología , Melanoma/diagnóstico , Melanoma/metabolismo , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Proliferación Celular , Transformación Celular Neoplásica/metabolismo , Síndrome del Nevo Displásico/metabolismo , Síndrome del Nevo Displásico/patología , Femenino , GTP Fosfohidrolasas/metabolismo , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Melanocitos/patología , Melanoma/tratamiento farmacológico , Melanoma/patología , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Mutación , Nevo Pigmentado/metabolismo , Nevo Pigmentado/patología , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/ultraestructura , Muslo/patología , Resultado del Tratamiento , beta Catenina/metabolismoRESUMEN
BACKGROUND: Fusions involving the BRAF gene are responsible for 5% of Spitz neoplasms. To better characterize them, we report the clinical, morphological, and genomic findings of six BRAF fusion Spitz tumors. METHODS: The morphological, clinical, and molecular findings of six BRAF fusion Spitz neoplasms assessed by next generation sequencing (NGS) were compared to a control set of Spitz without BRAF fusions. RESULTS: BRAF fusion Spitz tumors had frequent predominance of epithelioid morphology (4/6 cases), frequent high-grade nuclear atypia and pleomorphism (5/6 cases), and a frequent desmoplastic base (3/6 cases). Five of six cases were diagnosed as atypical Spitz tumor and one as Spitz nevus. All cases had uneventful clinical follow-up. There were five different fusion partners, with CLIP2 being the most frequent. Secondary pathogenic mutations were frequent and chromosomal copy number changes were seen in three of six cases by an NGS platform. CONCLUSIONS: BRAF fusions Spitz usually have epithelioid morphology, high-grade nuclear atypia, and desmoplasia. Chromosomal copy number changes are not infrequent. While our cases had uneventful follow-up, a meta-analysis of the literature suggests that among the fusion subtypes associated with Spitz tumors, they are among the subgroups more likely to develop distant metastasis.
Asunto(s)
Síndrome del Nevo Displásico/genética , Nevo de Células Epitelioides y Fusiformes/genética , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Cutáneas/patología , Adulto , Anciano , Estudios de Casos y Controles , Niño , Síndrome del Nevo Displásico/diagnóstico , Síndrome del Nevo Displásico/patología , Femenino , Genómica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Masculino , Proteínas Asociadas a Microtúbulos/genética , Mutación , Nevo de Células Epitelioides y Fusiformes/diagnóstico , Nevo de Células Epitelioides y Fusiformes/patología , Proteínas de Fusión Oncogénica/genética , Estudios Retrospectivos , Neoplasias Cutáneas/ultraestructuraRESUMEN
With the advent of better molecular characterization of Spitz melanocytic neoplasms, there has been increasing effort to better understand and describe the relationships between specific driver fusion and/or mutations with the clinical and histomorphological characteristics of the lesions. Structural rearrangements in mitogen activated protein kinase genes have recently been noted to be important in Spitz neoplasms. Only very few reports, however, have described in detail melanocytic tumors with in frame deletions in MAP2K1. Cases in the literature with this aberration have been described as having a diagnosis of Spitz, deep penetrating nevi, or pigmented epithelioid melanocytoma. In this study, we describe a cohort of 6 cases with MAP2K1 activating in frame deletions. The morphologic spectrum of the cases was broad. Common features of these cases include Spitzoid cytomorphology (5/6) cases, prominent melanin pigmentation (4/6) cases, and deep penetrating nevi-like plexiform architecture (3/6) cases. The diagnoses at the time of clinical care of these cases included nevus of Reed (1/6), desmoplastic Spitz tumor (1/6), BAPoma (1/6), deep penetrating melanocytic nevus (2/6), and melanoma (1/6). Clinical follow-up was available in 3 of the 6 cases. None of the patients had a tumor recurrence. This builds on the growing literature to help expand the spectrum of changes associated with Spitzoid melanocytic neoplasms.
Asunto(s)
Mutación del Sistema de Lectura , MAP Quinasa Quinasa 1/genética , Nevo de Células Epitelioides y Fusiformes/genética , Neoplasias Cutáneas/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Análisis Mutacional de ADN , Bases de Datos Factuales , Femenino , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Nevo de Células Epitelioides y Fusiformes/enzimología , Nevo de Células Epitelioides y Fusiformes/patología , Nevo de Células Epitelioides y Fusiformes/cirugía , Fenotipo , Estudios Retrospectivos , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/cirugía , Resultado del Tratamiento , Adulto JovenRESUMEN
Desmoplastic melanoma can be difficult to diagnose and on average have a significantly higher T stage at the time of diagnosis compared with conventional melanomas. Histologically, these tumors typically consist of spindle cells in a fibrous matrix. The spindle cells may display fibroblast and/or Schwann cell-like features. In this study, we describe the features of 12 cases of desmoplastic melanoma closely simulating neurofibroma. Although the spindle cells in these tumors may be indistinguishable from those of neurofibroma, features such as prominent fibroplasia (12/12), poor lateral circumscription (8/9), diffuse infiltration of subcutaneous tissue (7/9), and lymphoid aggregates (10/12) may be helpful clues to the diagnosis. No immunohistochemical markers were reliable in distinguishing neurofibroma-like desmoplastic melanomas from neurofibroma. Clinical follow-up was available in 8 cases, of which 4 were initially misdiagnosed as benign neoplasms and given no further re-excision. All 4 of these cases recurred; 2 of which showed transformation to a more aggressive phenotype.
Asunto(s)
Melanoma/patología , Neurofibroma/patología , Neoplasias Cutáneas/patología , Adulto , Anciano , Anciano de 80 o más Años , Antígenos de Neoplasias/análisis , Biomarcadores de Tumor/análisis , Biopsia , Diagnóstico Diferencial , Errores Diagnósticos , Femenino , Humanos , Illinois , Inmunohistoquímica , Filamentos Intermedios/patología , Masculino , Melanoma/química , Melanoma/cirugía , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Neurofibroma/química , Neurofibroma/cirugía , Ciudad de Nueva York , Fenotipo , Valor Predictivo de las Pruebas , Neoplasias Cutáneas/química , Neoplasias Cutáneas/cirugía , Factores de Tiempo , Resultado del Tratamiento , Proteína p53 Supresora de Tumor/análisisRESUMEN
BACKGROUND: Some melanomas closely resemble pigmented spindle cell nevi (PSCN) of Reed histologically. The distinction of these entities is important for clinical management. A recent study showed most PSCN (78%) are fusion-driven, commonly involving NTRK3 (57%). Conversely, BRAF V600E mutations are not characteristic of PSCN but are frequent in melanoma. OBJECTIVE: In this study, we assessed clinical, histologic and genomic differences between PSCN of Reed and Reed-like melanomas (RLMs). METHODS: We performed BRAF V600E immunohistochemistry (IHC) for 18 PSCN and 20 RLM cases. All 23 benign PSCN cases previously underwent whole transcriptome and targeted DNA sequencing with a 1711 gene panel. RESULTS: We previously demonstrated the majority of PSCN (18 of 23) has chimeric fusions. Among PSCN without a chimeric fusion, BRAF mutations were common. Noncanonical BRAF mutations were identified in 2 of 5 nonfusion cases, and 1 case had a canonical BRAF mutation. Alternatively, 70% of RLM demonstrated a BRAF V600E mutation. RLM also occurred more frequently in older patients. LIMITATIONS: The overall sample size was small. CONCLUSIONS: In diagnostically challenging cases, ancillary IHC studies can assist in distinguishing PSCN from RLM. Our study suggests positive staining by IHC for BRAF V600E and older age strongly favors a diagnosis of RLM.
Asunto(s)
Biomarcadores de Tumor/genética , Melanoma/genética , Mutación , Nevo de Células Epitelioides y Fusiformes/genética , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Cutáneas/genética , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Diagnóstico Diferencial , Femenino , Predisposición Genética a la Enfermedad , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Lactante , Masculino , Melanoma/patología , Persona de Mediana Edad , Nevo de Células Epitelioides y Fusiformes/patología , Fenotipo , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Neoplasias Cutáneas/patología , Secuenciación del Exoma , Adulto JovenRESUMEN
While having a thin melanoma (defined as AJCC 8 T1 stage tumor ≤ 1.0 mm) with negative sentinel lymph node biopsy (SLNB) provides an excellent prognosis, some patients still develop recurrence and die. To determine risk factors for any recurrence (local/in-transit, nodal, distant) in thin melanoma patients with negative SLNB and assess survival outcomes. Retrospective review of thin melanomas with negative SLNB from 1999 to 2018 was performed. Two hundred and nine patients were identified. Clinicopathologic characteristics of the primary melanoma were collected. Patterns of recurrence for local/in-transit, nodal or distant recurrence and survival outcomes were analyzed. Eighteen patients (8.6%) developed recurrence: 3 (1.9%) local/in-transit, 4 (2.9%) regional/nodal, and 11 (5.3%) distant recurrence during a median follow-up time of 62 months. A multivariate Cox regression model showed that head and neck site (HR 3.52), ulceration (HR 10.8), and mitotic rate (HR 1.39) were significant risk factors for recurrence. Median time to first recurrence was 49 months. Patients with recurrence had a significantly worse 5 year overall survival than those without recurrence (82.2 vs 99.2%). A retrospective single center study and limited sample size. Did not factor in possible false negative SLNBs when calculating hazard ratios. For thin melanoma patients with negative SLNB, heightened surveillance is warranted for those with ulceration, primary tumor location on the head or neck, and elevated mitotic rate.