Melanoma in Pediatric and Young Adult Patients.

PURPOSE OF REVIEW: Melanoma in younger individuals has different clinical presentations, histologic characteristics and prognosis from older patients. This review summarizes key differences and important new insights into pediatric and young adult melanoma, as well as recent evolutions in treatment. RECENT FINDINGS: Molecular techniques have improved the classification of melanocytic neoplasms, and are especially useful in the workup of the diagnostically challenging lesions frequent in this age group. Molecular evaluation highlights differences between melanoma and atypical lesions with Spitz-like morphology, and should routinely be incorporated for diagnosing and classifying Spitzoid melanocytic to guide prognostication and treatment. Once diagnosed, the management of bona fide melanoma in children and young adults is largely similar to older patients, while the optimal management of lesions such as atypical Spitz tumors remains uncertain. Increased awareness of the presentation and diagnostic characteristics of melanoma in young individuals will allow earlier detection, and improved diagnostic techniques will allow optimum management without over- or under-treatment.

Atypical Presentation of Spitz Nevus: A Case Report.

Introduction: The Spitz nevus (SN) is an acquired melanocytic neoplasm composed of epithelioid and/or spindle cells, which tends to develop in childhood. In pediatric patients, it is usually located on the face and neck. Unusual locations have been found in the literature, such as the penis, mouth, and tongue, as well as 2 cases of ungual SN. Case Report: A 15-year-old male evaluated for dark brown-black longitudinal melanonychia that covered 40% of the nail, with pseudo-Hutchinson's sign, of 1 year of evolution. Discussion: The SN accounts for 1% of the melanocytic neoplasms. In the present paper, we show the third case of ungual SN never previously disclosed, which presents a zigzag pattern reported in the literature for its association with the pediatric population.

Spitz Tumors and Melanoma in the Genomic Age: A Retrospective Look at Ackerman's Conundrum.

After 25 years, "Ackerman's conundrum", namely, the distinction of benign from malignant Spitz neoplasms, remains challenging. Genomic studies have shown that most Spitz tumors harbor tyrosine and serine/threonine kinase fusions, including ALK, ROS1, NTRK1, NTRK2, NTRK3, BRAF and MAP3K8, or some mutations, such as HRAS and MAP3K8. These chromosomal abnormalities act as drivers, initiating the oncogenetic process and conferring basic bio-morphological features. Most Spitz tumors show no additional genomic alterations or few ones; others harbor a variable number of mutations, capable of conferring characteristics related to clinical behavior, including CDKN2A deletion and TERT-p mutation. Since the accumulation of mutations is gradual and progressive, tumors appear to form a bio-morphologic spectrum, in which they show a progressive increase of clinical risk and histological atypia. In this context, a binary classification Spitz nevus-melanoma appears as no longer adequate, not corresponding to the real genomic substrate of lesions. A ternary classification Spitz nevus-Spitz melanocytoma-Spitz melanoma is more adherent to the real neoplastic pathway, but some cases with intermediate ambiguous features remain difficult to diagnose. A prognostic stratification of Spitz tumors, based on the morphologic and genomic characteristics, as a complement to the diagnosis, may contribute to better treatment plans for patients.

Novel gene fusion discovery in Spitz tumours and its relevance in diagnostics.

In addition to morphologic analysis, molecular diagnostic work up of Spitz tumours is often of great value for their accurate diagnosis/classification. Nowadays, next-generation sequencing (NGS) is the predominant screening method in molecular diagnostics. Up to 80% of these melanocytic neoplasms comprise gene fusions as genetic anomalies for which the driver codes for a protein harbouring a kinase domain. However, because of the variety of fusion partners the use of PCR-based targeted enrichment NGS methods is not recommended. We describe a series of four Spitz tumour samples in which distinct gene fusions were detected by hybridisation-based capture NGS (TPM3::ALK, LIMA1::ROS1, LRRFIP2::ROS1 and MYO5A::RET). Two of these fusions are not previously described. All 4 fusions were confirmed by reverse transcription-PCR. These findings demonstrate the need for molecular analysis that can detect unknown fusions in Spitz neoplasms for optimal diagnosis.

Pediatric spitzoid lesions of the ear: a single-center experience and review of the literature.

Spitzoid lesions are challenging melanocytic lesions comprising benign, intermediate, and malignant lesions. In this study, we aimed to analyze the diagnostic accuracy of clinical and dermatoscopical evaluations of pediatric spitzoid ear lesions. We collected and analyzed, clinically, dermatoscopically, and histologically, pediatric spitzoid ear lesions. We also conducted a systematic review of the literature. At the Pediatric Hospital Gaslini, excision and histopathological evaluation were performed on eight cases: 87.5% of the lesions were consistent with Spitz nevus (SN), and 12.5% with atypical Spitz tumor (AST). Notably, multiple (≥2) dermatoscopical irregularities were present in 5 of 7 SN (71%), yet none were found in AST (0%, 0/1) (Fisher's exact test, P=0.375). From systematic research in the literature, 9 patients were included in this review. At histology, 88.9% were SN and 11% AST. Remarkably, also in the literature, multiple dermatoscopical irregularities were present in most SN (75%, 6/8), but not in the identified AST (0%, 0/1) (P=0.3333). We present a monocentric study on pediatric spitzoid ear lesions. Importantly, dermatoscopical irregularities were not significantly associated with AST, neither in our series nor in the reviewed literature (respectively P=0.375 and P=0.3333), supporting the fact that relying only on the dermatoscopical aspect of spitzoid lesions is not accurate enough for the special site of the ear, where dermatoscopy could actually be misleading.

Spitz nevus and melanoma: evaluation with dermoscopy and reflectance confocal microscopy.

Introduction: Spitz nevi (SN) include a wide range of benign melanocytic nevi, which are controversial due to their morphologic resemblance to melanoma (MM). Aim: To describe dermoscopic and reflectance confocal microscopic (RCM) features of SN compared to MM and assess the RCM utility in the differential diagnosis. Material and methods: We performed a multicentre retrospective analysis of MM and SN evaluated with dermoscopy and reflectance confocal microscopy. Three RCM mosaics were obtained for each lesion. Nine dermoscopic and twenty-one microscopic features were assessed for each lesion. Results: A total of 26 lesions (15 SN and 11 MM) were included. Dermoscopically, most SN showed a "starburst" pattern. Asymmetry was marked in 8 MM. There were 6 dermoscopic features significantly more prevalent in MM than in SN. RCM showed that an atypical honeycomb pattern, atypical infiltration, and disarray of the epidermis were significant for MM. SN mostly revealed a typical honeycomb pattern. At the DEJ, most of SN had a meshwork pattern; MM revealed an atypical meshwork pattern. Atypical cells and sheet-like structures were observed in most MM. Conclusions: A combined approach using dermoscopy and RCM supports the differential diagnosis of SN and MM. Although our study showed some significant differences between SN and MM in RCM, further research on a larger group should be considered.

MAP2K1-mutated melanocytic tumors have reproducible histopathologic features and share similarities with melanocytic tumors with BRAF V600E mutations.

BACKGROUND: Melanocytic tumors driven by MAP2K1 in-frame deletions are among the most recently described class of melanocytic neoplasms. The reported range of diagnoses and associated genomic aberrations in these neoplasms is wide and includes melanomas, deep penetrating melanocytomas, and pigmented epithelioid melanocytoma. However, little is known about the characteristics of these tumors, especially in the absence of well-known second molecular "hits." Moreover, despite their frequent spitzoid cytomorphology, their potential categorization among the Spitz tumors is debatable. MATERIALS AND METHODS: We conducted a retrospective search through our molecular archives to identify sequenced melanocytic tumors with MAP2K1 in-frame deletions. We reviewed the clinical and histomorphological features of these tumors and compared them to similar neoplasms reported to date. In addition, we performed single-nucleotide polymorphism (SNP) array testing to identify structural chromosomal aberrations. RESULTS: Of 27 sequenced tumors, 6 (22%) showed a pathogenic MAP2K1 in-frame deletion (with or without insertion) and were included in this series. Five (83%) were females with lesions involving the upper limb. Histopathologically, all neoplasms were compounded with plaque-like or wedge-shaped silhouettes, spitzoid cytomorphology, and impaired cytologic maturation. All cases showed background actinic damage with sclerotic stroma replacing solar elastosis, variable pagetoid scatter, and occasional dermal mitotic figures (range 1-2/mm2 ). Five cases (83%) had a small component of nevic-looking melanocytes. Biologically, these tumors likely fall within the spectrum of unusual nevi. Five cases (83%) had a relatively high mutational burden and four (67%) showed an ultraviolet radiation signature. Four cases (67%) showed in-frame deletion involving the p.I103_K104del locus while two cases (33%) showed in-frame deletion involving the p.Q58_E62del locus. SNP array testing showed structural abnormalities ranging from 1 to 5 per case. Five of these cases showed a gain of chromosome 15 spanning the MAP2K1 gene locus. DISCUSSION AND CONCLUSION: Melanocytic tumors with MAP2K1 in-frame deletion could represent another spectrum of melanocytic tumors with close genotypic-phenotypic correlation. They are largely characterized by a spectrum that encompasses desmoplastic Spitz nevus as shown in our series and Spitz and Clark nevus as shown by others. Evolutionary, they share many similarities with tumors with BRAF V600E mutations, suggesting they are better classified along the conventional pathway rather than the Spitz pathway despite the frequent spitzoid morphology.

Paediatric Spitzoid Neoplasms: 10-Year Retrospective Study Characterizing Histological, Clinical, Dermoscopic Presentation and FISH Test Results.

INTRODUCTION: Spitzoid lesions are a wide tumour class comprising Spitz nevus (SN), atypical Spitz tumour (AST) and Spitz melanoma (SM). MATERIALS AND METHODS: We conducted a single-centre-based retrospective survey on all histologically diagnosed spitzoid lesions of paediatric patients (1-18 years) of the last 10 years (2012-2022). Histopathological reports and electronic records of patients were used to retrieve relevant data regarding patients' features, clinical and dermatoscopical aspects of lesions when recorded, and FISH tests when present. RESULTS: Of 255 lesions, 82% were histologically benign, 17% atypical, 1% malignant. Clinically, 100% of SM were large (≥6 mm) and raised; AST were mainly large (63%), raised (98%), pink (95%). Small (≤5 mm), pigmented, flat lesions correlated with benign histology (respectively 90%, 97%, 98% SN) (p < 0.0001). Dermatoscopical patterns were analysed in 100 patients: starburst pattern correlated with benign histology (26% SN (p = 0.004)), while multicomponent pattern correlated with atypical/malignant lesions (56% AST, 50% SM (p = 0.0052)). Eighty-five lesions were subjected to fluorescence in situ hybridization (FISH): 34 (71% AST; 29% SN) were FISH-positive; 51 (63% SN; 37% AST) were FISH-negative (p = 0.0038). DISCUSSION: This study confirmed predominant benign histology (82%) of paediatric spitzoid lesions, thus detecting 17% AST and 1% SM, highlighting the need for caution in handling spitzoid lesions. CONCLUSION: Until AST are considered potentially malignant proliferations and no reliable criteria are identified to distinguish them, the authors suggest a prudent approach, especially in children.

Optical coherence tomography confirms non-malignant pigmented lesions in phacomatosis pigmentokeratotica using a support vector machine learning algorithm.

INTRODUCTION: Phacomatosis pigmentokeratotica (PPK), an epidermal nevus syndrome, is characterized by the coexistence of nevus spilus and nevus sebaceus. Within the nevus spilus, an extensive range of atypical nevi of different morphologies may manifest. Pigmented lesions may fulfill the ABCDE criteria for melanoma, which may prompt a physician to perform a full-thickness biopsy. MOTIVATION: Excisions result in pain, mental distress, and physical disfigurement. For patients with a significant number of nevi with morphologic atypia, it may not be physically feasible to biopsy a large number of lesions. Optical coherence tomography (OCT) is a non-invasive imaging modality that may be used to visualize non-melanoma and melanoma skin cancers. MATERIALS AND METHOD: In this study, we used OCT to image pigmented lesions with morphologic atypia in a patient with PPK and assessed their quantitative optical properties compared to OCT cases of melanoma. We implement a support vector machine learning algorithm with Gabor wavelet transformation algorithm during post-image processing to extract optical properties and calculate attenuation coefficients. RESULTS: The algorithm was trained and tested to extract and classify textural data. CONCLUSION: We conclude that implementing this post-imaging machine learning algorithm to OCT images of pigmented lesions in PPK has been able to successfully confirm benign optical properties. Additionally, we identified remarkable differences in attenuation coefficient values and tissue optical characteristics, further defining separating benign features of pigmented lesions in PPK from malignant features.

Nevus de Spitz / Nevus of Spitz

El nevus de Spitz es una neoplasia de naturaleza benigna que aparece en la infancia con mayor frecuencia que en cualquier otro periodo de la vida. Algunas lesiones, especialmente aquellas localizadas en extremidades, presentan un aspecto similar al melanoma, por lo que debe establecerse el diagnóstico diferencial con esta patología. El manejo de este tipo de nevus depende de las características clínicas, así como de la edad del paciente (AU)

Spitz's nevus is a relatively frequent lesion that appears in children, it is usually a benign lesion and completely asymptomatic. Some lesions, especially those located in the extremities, have an appearance similar to melanoma, so the differential diagnosis with this pathology must be established. The management of this type of nevus depends on the clinical characteristics, as well as the age of the patient. (AU)

Expression of TFE3 in Cellular and Myxoid Type of Neurothekeoma: Four Cases in Young Children and Adolescents.

Introduction: Cellular neurothekeoma is a benign tumor that mainly occurs in young children and adolescents. The aberrant expression of transcription factor E3 (TFE3) has not been reported in cellular neurothekeoma previously. Case report: We report four cellular neurothekeoma with aberrant immunohistochemical expression of TFE3 protein. The fluorescence in situ hybridization (FISH) showed no TFE3 gene rearrangement or amplification. Discussion/Conclusion: TEF3 protein expression may not be related to TFE3 gene translocation in cellular neurothekeoma. TFE3 may be a potential pitfall in diagnosis, for several malignant tumors in children also express TFE3. The aberrant expression of TFE3 may offer insights into cellular neurothekeoma etiology, and associated molecular mechanisms.

Reflectance confocal microscopy in paediatric patients: Applications and limits.

Reflectance confocal microscopy (RCM) is a non-invasive diagnostic tool extensively studied for adult patients. In this retrospective case series conducted at the Dermatology Unit of the University of Campania, Naples, Italy, all patients under 19 years old who were submitted to RCM from January 2011 to December 2021 where evaluated. The aim of the study was to review the most usual indications and possible benefits that it might add for children. Data collection included 215 patients (86 males and 129 females, mean age: 12). Most of the exams (n = 85; 39.5%) were performed for lesions clinically compatible with Spitz nevi, congenital nevi (n = 50 23,2%) and atypical melanocytic lesions (n = 46; 21%) among which two melanomas were detected. RCM can be an useful instrument when evaluating paediatric patients and may help avoid unnecessary biopsy in most cases, representing an additional instrument to improve diagnostic accuracy.

Spitzoid melanocytic tumors / 中华皮肤科杂志

Clinical and histological features of Spitz nevi, atypical Spitz tumors and spitzoid melanoma overlap each other, making their identification challenging. Combined with clinical and histological features of spitzoid melanocytic tumors, this review summarizes research progress in their immunohistochemical features and application of fluorescence in situ hybridization in their identification.

Ungual Spitz Nevus: Description of Dermoscopic Data.

Introduction: Spitz nevus is an uncommon, benign melanocytic proliferation that primarily appears on face, trunk or lower extremities of children. This lesion may share clinical and microscopical characteristics with melanoma, making it a diagnostic and management challenge. Case Report: A 13-year old male presented with an asymptomatic chronic dermatosis located on the third left-hand nail. Cutaneous examination revealed a homogeneous dark brown melanonychia which extended up to the cuticle. Upon dermoscopy, longitudinal bands measuring less than 3 mm wide of heterogeneous colors ranging from light to dark brown, and positive Hutchinson's sign were observed. Discussion/Conclusion: We report the second case of a Spitz nevus ungually localized which strongly resembled an ungual melanoma with a positive Hutchinson's sign upon dermoscopy. Describing the infrequent presentation and location of the Spitz nevus poses an opportunity to establish diagnostic and management criteria in the near future.

Nipple adenoma with ipsilateral Spitz nevus in a 26-year-old female: a case report.

A 26-year-old female with a palpable mass and progressively darker itchy area in her left nipple was admitted to hospital. The left nipple surface showed furfuraceous desquamation and bloody discharge, with a 1.0×0.7×0.4 cm area of grayish-brown pigmentation in the ipsilateral nipple and areola. Surgical resection of the primary skin tumor and biopsy of the partial mass in the middle of the nipple were undertaken since color Doppler ultrasonography and dermoscopy were unable to make a differential diagnosis. We thus report the first case of a nipple adenoma with concomitant ipsilateral nipple areola Spitz nevus.

Conceptual Evolution and Current Approach to Spitz Tumors.

Over the past several decades, the study of Spitz neoplasms has flourished, with expanded conceptualization and refined terminology, providing a framework for the assessment and classification of Spitz nevi, atypical Spitz Tumors, and Spitz melanoma. Cancer genomics have generated concepts such as driver and passenger genes and clonal evolution, which can be applied to Spitz tumors. Herein, we provide a historical perspective, followed by a summary of current knowledge and clinical approaches for these challenging tumors.

The Spectrum of Spitz Melanocytic Lesions: From Morphologic Diagnosis to Molecular Classification.

Spitz tumors represent a distinct subtype of melanocytic lesions with characteristic histopathologic features, some of which are overlapping with melanoma. More common in the pediatric and younger population, they can be clinically suspected by recognizing specific patterns on dermatoscopic examination, and several subtypes have been described. We now classify these lesions into benign Spitz nevi, intermediate lesions identified as "atypical Spitz tumors" (or Spitz melanocytoma) and malignant Spitz melanoma. More recently a large body of work has uncovered the molecular underpinning of Spitz tumors, including mutations in the HRAS gene and several gene fusions involving several protein kinases. Here we present an overarching view of our current knowledge and understanding of Spitz tumors, detailing clinical, histopathological and molecular features characteristic of these lesions.