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.

Nevo de Spitz y otros tumores spitzoides en la infancia. Parte 2: características citogenéticas y moleculares. Pronóstico y tratamiento / Spitz Nevus and Other Spitzoid Tumors in Children. Part 2: Cytogenetic and Molecular Features. Prognosis and Treatment

Las neoplasias melanocíticas con morfología spitzoide (nevo de Spitz, tumor de Spitz atípico y melanoma spitzoide) abarcan un espectro desde lesiones benignas a malignas. Debido al potencial maligno incierto de los tumores de Spitz atípicos, el abordaje terapéutico ha generado durante años controversia. El desarrollo de nuevas técnicas moleculares parece prometedor y ha contribuido a una mejor predicción del comportamiento biológico de los tumores de Spitz. Nuestro objetivo es revisar las características citogenéticas de los tumores de Spitz, el pronóstico y actualizar las últimas recomendaciones de manejo

Melanocytic neoplasms with spitzoid morphology (Spitz nevi, atypical Spitz tumors, and spitzoid melanomas) may be benign or malignant. Because the malignant potential of atypical Spitz tumors is uncertain, the proper therapeutic approach has been much debated over the years. Promising new techniques for molecular analysis have enabled better predictions of the biological behavior of these tumors. We review their cytogenetic features and prognosis and also provide an update of the most recent recommendations for management

Spitz Nevus and Other Spitzoid Tumors in Children. Part 2: Cytogenetic and Molecular Features. Prognosis and Treatment. / Nevo de Spitz y otros tumores spitzoides en la infancia. Parte 2: características citogenéticas y moleculares. Pronóstico y tratamiento.

Melanocytic neoplasms with spitzoid morphology (Spitz nevi, atypical Spitz tumors, and spitzoid melanomas) may be benign or malignant. Because the malignant potential of atypical Spitz tumors is uncertain, the proper therapeutic approach has been much debated over the years. Promising new techniques for molecular analysis have enabled better predictions of the biological behavior of these tumors. We review their cytogenetic features and prognosis and also provide an update of the most recent recommendations for management.

Filigree-like Rete Ridges, Lobulated Nests, Rosette-like Structures, and Exaggerated Maturation Characterize Spitz Tumors With NTRK1 Fusion.

Activating NTRK1 fusions have been described as oncogenic events across the spectrum of Spitz tumors. Herein we report a series of 38 Spitz tumors with NTRK1 fusion. These Spitz tumors have distinctive histopathologic features characterized by filigree-like rete ridges which are elongated, thin and branched, dermal melanocytes arranged in a rosette-like configuration, and marked diminishment of melanocyte size with descent into the dermis. These features are distinct from those of other genetically defined subtypes of Spitz tumors and can aid in microscopic diagnosis and help prioritize in case selection for molecular testing in the rare patients that need targeted therapy.

Clinical features and outcomes of spitzoid proliferations in children and adolescents.

BACKGROUND: Spitzoid proliferations range from Spitz naevi to melanomas. There are few studies describing clinical features and outcomes in the paediatric population. OBJECTIVES: To determine the clinical features and outcomes of a large paediatric cohort with histopathologically confirmed Spitz tumours. METHODS: This was a retrospective cohort study of patients seen at Boston Children's Hospital who were aged < 20 years and had a histopathological diagnosis of spitzoid proliferation from 1 January 1994 to 23 October 2012. RESULTS: In total 595 patients with 622 spitzoid proliferations were identified (median age 7·4 years, interquartile range 4·6-11·7). Overall 512 proliferations (82·3%) were typical, 107 (17·2.%) were atypical and three (0·5%) were melanomas. The median ages at biopsy were 7·4, 7·2 and 17·2 years, respectively, and there was a significant difference in age at biopsy for patients with typical or atypical proliferations vs. melanoma (P < 0·01). Among samples with positive margins (n = 153), 55% (54 of 98) of typical proliferations, 77% (41 of 53) of atypical proliferations and 100% (two of two) of melanomas were re-excised. Six patients had sentinel lymph node biopsy performed, with three patients demonstrating nodes positive for melanocytic cells. Within a median follow-up of 4·1 years for the full cohort there were no related deaths. CONCLUSIONS: Spitz tumours have strikingly benign outcomes in the paediatric population, although this study is limited by the low number of melanomas and restriction to a single paediatric institution. Aggressive management recommendations should be reconsidered for children and adolescents with banal-appearing Spitz naevi, based on the clinically indolent behaviour in this cohort.

The diagnosis and management of the Spitz nevus in the pediatric population: a systematic review and meta-analysis protocol.

BACKGROUND: Spitz nevi are uncommon melanocytic neoplasms found in children. Historically, the diagnosis and management of these tumors has lacked consensus among oncologists, pathologists, plastic surgeons, and dermatologists. Once interpreted and treated as a "juvenile melanoma", many have argued for the benignancy of such tumors in certain patient age groups, encouraging a conservative approach. The lack of consensus surrounding the diagnosis and perceived malignant potential of these tumors has led physicians to approach them on a case-by-case basis and institutional protocols. To date, no evidence-based management guideline exists. The objective of this systematic review is to both collect and appraise the evidence on the diagnosis and management of these tumors. METHODS: A comprehensive electronic literature search will be conducted in PubMed, MEDLINE, Embase, and the Cochrane Library from inception to December 2016. Our search involved collaborating with a healthcare librarian to create a strategy for the OVID/MEDLINE databases. A search of electronic databases for oncology, pathology, plastic surgery, and dermatology abstracts will be performed. Key search terms will include, among several others, "Spitz nevi," "Spitzoid melanoma," "juvenile tumor," and "pediatric". The language of publication will be restricted to English and French. Wherever data allows, meta-analyses will be used to assess differences between Spitz nevi and the tumor of comparison. Additionally, data extraction and summarization using tables will be performed. This review has been registered with PROSPERO (CRD42016034045). CONCLUSIONS: This review will systematically and comprehensively review diagnostic and management practices associated with the Spitz nevus. This overview of current literature will hopefully provide the foundation for future standardization of clinical practice. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016034045.

Update on dermoscopy of Spitz/Reed naevi and management guidelines by the International Dermoscopy Society.

Spitzoid lesions represent a challenging and controversial group of tumours, in terms of clinical recognition, biological behaviour and management strategies. Although Spitz naevi are considered benign tumours, their clinical and dermoscopic morphological overlap with spitzoid melanoma renders the management of spitzoid lesions particularly difficult. The controversy deepens because of the existence of tumours that cannot be safely histopathologically diagnosed as naevi or melanomas (atypical Spitz tumours). The dual objective of the present study was to provide an updated classification on dermoscopy of Spitz naevi, and management recommendations of spitzoid-looking lesions based on a consensus among experts in the field. After a detailed search of the literature for eligible studies, a data synthesis was performed from 15 studies on dermoscopy of Spitz naevi. Dermoscopically, Spitz naevi are typified by three main patterns: starburst pattern (51%), a pattern of regularly distributed dotted vessels (19%) and globular pattern with reticular depigmentation (17%). A consensus-based algorithm for the management of spitzoid lesions is proposed. According to it, dermoscopically asymmetric lesions with spitzoid features (both flat/raised and nodular) should be excised to rule out melanoma. Dermoscopically symmetric spitzoid nodules should also be excised or closely monitored, irrespective of age, to rule out atypical Spitz tumours. Dermoscopically symmetric, flat spitzoid lesions should be managed according to the age of the patient. Finally, the histopathological diagnosis of atypical Spitz tumour should warrant wide excision but not a sentinel lymph-node biopsy.

Spitz Nevi and Other Spitzoid Neoplasms in Children: Overview of Incidence Data and Diagnostic Criteria.

Spitz nevi are benign melanocytic neoplasms characterized by epithelioid or spindle melanocytes or both. In some rare cases their presentation overlaps with the clinical and histopathologic features of malignant melanoma, so a differential diagnosis can be difficult to make. Intermediate forms between Spitz nevi and malignant melanoma, with unpredictable behavior, have been called atypical Spitz tumors. A literature search was performed to review the clinical, dermoscopic, genetic, and histopathologic aspects of spitzoid tumors. Spitz nevi mainly occur in children, with no predilection for sex, and in young women. Common sites are the head and lower arms, where Spitz nevi present as pink nodules or hyperpigmented plaques. Spitzoid lesions may have diverse dermoscopic patterns: vascular, starburst, globular, atypical, reticular, negative homogeneous, or targetoid. The management of spitzoid lesions can be invasive or conservative; surgical excision is usually reserved for those with doubtful features, whereas clinical and dermoscopic follow-up is preferred for typical pediatric Spitz nevi. The role of sentinel lymph node biopsy in atypical Spitz tumors is debated. Immunohistochemistry and new molecular techniques such as comparative genomic hybridization, polymerase chain reaction, and fluorescence in situ hybridization offer new diagnostic perspectives, investigating genetic alterations that are specific for malignant melanoma or for Spitz nevi.

The complex management of atypical Spitz tumours.

In recent years, advances in molecular genetic characterisation have revealed that atypical Spitz tumours (ASTs) are basically heterogeneous diseases, although the clinical relevance of these findings is yet to be determined. Evidence of molecularly-defined diverse groups of lesions continues to accumulate; however, conflicting, confusing, and overlapping terminology has fostered ambiguity and lack of clarity in the field in general. The lack of fundamental diagnostic (morphological) unambiguous classification framework results in a number of challenges in the interpretation of the molecular genetic data. In this review, we discuss the main difficulties for pathologists and clinicians in the complex management of ASTs, with particular emphasis on the different genetic and biological features of recently-described entities, and offer our view of what could be medically reasonable to guide a rational approach in light of current data.

Genomic aberrations in spitzoid melanocytic tumours and their implications for diagnosis, prognosis and therapy.

Histopathological evaluation of melanocytic tumours usually allows reliable distinction of benign melanocytic naevi from melanoma. More difficult is the histopathological classification of Spitz tumours, a heterogeneous group of tumours composed of large epithelioid or spindle-shaped melanocytes. Spitz tumours are biologically distinct from conventional melanocytic naevi and melanoma, as exemplified by their distinct patterns of genetic aberrations. Whereas common acquired naevi and melanoma often harbour BRAF mutations, NRAS mutations, or inactivation of NF1, Spitz tumours show HRAS mutations, inactivation of BAP1 (often combined with BRAF mutations), or genomic rearrangements involving the kinases ALK, ROS1, NTRK1, BRAF, RET, and MET. In Spitz naevi, which lack significant histological atypia, all of these mitogenic driver aberrations trigger rapid cell proliferation, but after an initial growth phase, various tumour suppressive mechanisms stably block further growth. In some tumours, additional genomic aberrations may abrogate various tumour suppressive mechanisms, such as cell-cycle arrest, telomere shortening, or DNA damage response. The melanocytes then start to grow in a less organised fashion and may spread to regional lymph nodes, and are termed atypical Spitz tumours. Upon acquisition of even more aberrations, which often activate additional oncogenic pathways or alter cell differentiation, the neoplastic cells become entirely malignant and may colonise and take over distant organs (spitzoid melanoma). The sequential acquisition of genomic aberrations suggests that Spitz tumours represent a continuous biological spectrum, rather than a dichotomy of benign versus malignant, and that tumours with ambiguous histological features (atypical Spitz tumours) might be best classified as low-grade melanocytic tumours. The number of genetic aberrations usually correlates with the degree of histological atypia and explains why existing ancillary genetic techniques, such as array comparative genomic hybridisation (CGH) or fluorescence in situ hybridisation (FISH), are usually capable of accurately classifying histologically benign and malignant Spitz tumours, but are not very helpful in the diagnosis of ambiguous melanocytic lesions. Nevertheless, we expect that progress in our understanding of tumour progression will refine the classification of spitzoid melanocytic tumours in the near future. By integrating clinical, pathological, and genetic criteria, distinct tumour subsets will be defined within the heterogeneous group of Spitz tumours, which will eventually lead to improvements in diagnosis, prognosis and therapy.

Pediatric Melanoma and Atypical Melanocytic Neoplasms.

Melanoma is uncommon in the pediatric age range, but is increasing in frequency and often presents with atypical features compared to the classic ABCDE criteria common to adult melanoma cases. Moreover, many melanocytic neoplasms in childhood pose diagnostic challenges to the pathologist, and sometimes cannot be unequivocally classified as benign nevi or melanoma. This chapter addresses the evaluation and management of pediatric patients with melanoma and atypical melanocytic neoplasms, including the roles of and unresolved questions surrounding sentinel lymph node biopsy, completion lymphadenectomy, adjuvant therapy, and treatment of advanced disease.

Atypical Spitz Tumors: A Diagnostic Challenge.

Spitzoid melanocytic lesions encompass a spectrum from benign Spitz nevi to malignant spitzoid melanomas. Spitzoid melanocytic neoplasms have significant morphologic and molecular differences from conventional melanocytic lesions, and prediction of biologic behavior and metastatic risk may be difficult. Most challenging is the atypical Spitz tumor, a borderline spitzoid melanocytic lesion of uncertain malignant potential that has overlapping histologic features with conventional Spitz nevus and spitzoid melanoma. Atypical Spitz tumors involve the sentinel lymph nodes at a greater frequency than conventional melanoma and frequently harbor chromosomal copy number changes, yet most cases follow an indolent course. Herein we review the clinical, microscopic, and molecular features of atypical Spitz tumors, including recent molecular advances, including the potential prognostic significance of chromosomal abnormalities, such as homozygous CDKN2A loss.

Spitz nevi: defining features and management in children.

We reviewed literature data in order to better define clinical features of Spitz nevi (SNi) in children. Lots of interest has been given in the past decade to these neoplasms that due the clinical course and sometime the rapid onset, may often cause worrisome consultations. Dermoscopy has played an important role in the improved diagnostic capability of clinicians, regarding all melanocytic neoplasms and also SNi. The description of specific and typical dermoscopic patterns is largely reviewed as well as the new laboratory diagnostic tools in the field of dermatopathology.

Spitz nevi: beliefs, behaviors, and experiences of pediatric dermatologists.

IMPORTANCE: Controversy exists regarding strategies for diagnosis and management of Spitz nevi, a type of melanocytic neoplasm that most often develops in children. OBJECTIVE: To determine the beliefs, behaviors, and experiences of pediatric dermatologists with regard to Spitz nevi. DESIGN: Anonymous web-based survey. SETTING: Private and academic dermatology practices. PARTICIPANTS: Respondents included 175 pediatric dermatologists from the United States and around the world, representing a 51.1% response rate (175 of 342). Analyses were limited to the 144 respondents whose practices included at least 50% children (younger than 18 years). MAIN OUTCOME MEASURES: Assessment of the following with regard to Spitz nevi: frequency of diagnosis, general beliefs, techniques used for evaluation (eg, dermoscopy and biopsy), management strategies, and observed outcomes. RESULTS: Collectively, respondents had seen approximately 20 000 Spitz nevi; 67.6% (96 of 142) had diagnosed at least 6 Spitz nevi yearly, whereas 90.1% (128 of 142) had diagnosed no more than 2 prepubertal melanomas in the past 5 years. Ninety-six percent of respondents (95.8%; 136 of 142) categorized typical Spitz nevi as benign. Eighty percent of respondents (79.6%; 113 of 142) used dermatoscopy, and 96.5% (137 of 142) avoided partial biopsies of Spitz nevi. In children with a suspected Spitz nevus, clinical follow-up was chosen by 49.3% (69 of 140) of respondents for a small, stable nonpigmented lesion and by 29.7% (41 of 138) for a pigmented lesion with a typical starburst pattern seen via dermatoscopy. Predictors of clinical follow-up of the latter lesion included believing that Spitz nevi are not melanoma precursors (P = .04). Forty-seven percent (62 of 132) of respondents had observed involution of Spitz nevi. No deaths had resulted from the approximately 10 000 Spitz nevi or atypical spitzoid neoplasms seen by the 91 respondents with academic or hospital-based practices. CONCLUSIONS AND RELEVANCE: The results of our survey support conservative management of Spitz nevi in children, with clinical follow-up representing an option for typical lesions. This represents an important difference from strategies used for management of these lesions in adults.

Spitz nevus and Reed nevus.

Spitz and Reed nevi, also called spindle and/or epithelioid cell nevi, are a special group of melanocytic lesions due to their peculiar clinical, dermoscopic and histopathological features. The study of these nevi is of great interest because both their nomenclature and classification are still a matter of discussion. Most importantly, the difficulty to differentiate them from melanoma can lead to inadequate therapies. In this context, dermoscopy, a link between clinical and anatomopathological examinations, appears as a helpful diagnostic tool whose accuracy can reach 93%. "Borderline" lesions are still a great challenge and object of research, including molecular studies. The present study explores the relevant characteristics of these nevi, with emphasis on dermoscopic findings, aiming at understanding their natural history, as well as discussing treatment and patient follow-up.