Clinical features and outcomes of paediatric Spitz-type lesions.

INTRODUCTION AND OBJECTIVES: No definitive management guidelines exist for Spitz-type lesions; recommendations in the UK favour a 'safe' approach with a low threshold for excision. We aimed to describe Spitz-type lesions in children to further clarify the clinical features and outcomes. METHODS: We conducted a retrospective cohort study in Addenbrooke's Hospital, Cambridge, UK, and reviewed all patients aged ≤18 years with histologically confirmed Spitz-type lesions from November 2014 to September 2020. Information collected included patient demographics, lesion details, follow-up, outcomes and recurrence. RESULTS: Ninety-one children (male: female 42: 49; mean age at diagnosis: 9.4 years, SD: 4.6 years) were identified. Among them, 64 (70.3%) had classic Spitz or spitzoid naevi, 26 (28.6%) atypical Spitz tumours and 1 (1.1%) had spitzoid malignant melanoma based on histological features. On assessing the clinical features, where documented, we found that 22.0% (20/91) had amelanosis, 44.0% (40/91) had a raised bump, 12.1% (11/91) displayed bleeding, 25.0% (20/80) had non-uniform colour, 96.7% (88/91) were de novo lesions, 55.1% (43/78) were evolving in size and 35.9% (28/78) were evolving in colour. Fifty-nine patients (64.8%) were discharged without the need for follow-up, and the other 32 had a median follow-up time of 4 months. After confirmed excision, no incidences of local recurrence, distant metastases or mortality have been reported to date in all patients. CONCLUSIONS: The outcomes for paediatric Spitz-type lesions continue to be exceptionally good, remaining a low-risk lesion, which is more likely to be benign in children. Hence, we do not advocate aggressive management strategies for paediatric patients with clinically banal Spitz-type lesions.

[ALK rearranged Spitz melanocytoma: a clinicopathological and molecular genetic analysis of two cases].

Objective: To investigate the clinicopathological, immunohistochemical and molecular characteristics of cutaneous ALK-rearranged Spitz melanocytoma. Methods: Two cases of cutaneous ALK-rearranged Spitz melanocytoma from outside hospital consultations in Department of Pathology, Affiliated Cancer Hospital of Fudan University in August 2020 and in Shanghai Ackermann Medical Laboratory in June 2022 were collected. The clinicopathological features, immunophenotypes and molecular profiles of two patients with cutaneous Spitzoid melanocytic tumor harboring ALK-rearrangement were analyzed. The literatures were reviewed. Results: The study included an 8-year-old boy and an 11-year-old girl, who presented with a polypoid lesion in the skin of right thigh and left auricle measuring 1.0 cm and 1.2 cm, respectively. Histologically, they were composed of medium to large-sized epithelioid to plump spindle cells, arranged in nested, plexiform or fascicular patterns in the superficial dermis. The neoplastic cells had abundant eosinophilic cytoplasm with round to ovoid vesicular nuclei containing prominent eosinophilic nucleoli. One case showed mild to moderate nuclear pleomorphism and mitotic activity (average, 2/mm2). Immunohistochemically, the epithelioid and plump spindle cells showed diffuse and strong staining of S-100 protein, SOX10, and ALK (D5F3 and 1A4), but did not express HMB45, PNL2 and MiTF. ALK-rearrangement was detected by fuorescence in situ hybridization in both cases. Subsequent next generation sequence (NGS) analysis identified KANK1::ALK and TPM3:ALK fusions. At 34 and 14 months after surgical resection, both patients remained well with no signs of recurrence or metastasis. Conclusions: ALK-rearranged Spitz melanocytoma represents a morphologically and genetically distinct subset of Spitz melanocytoma, characterized clinically by predilection in children and adolescents, with Spitzoid morphology in plexiform pattern, positive immunohistochemical stains, and rearrangement of ALK. As some cases show atypical features and high mitotic activity, a distinction from Spitz melanoma is warranted.

Spitz Melanoma With SLC20A1::ALK Fusion: A Novel Fusion Previously Undescribed in Spitz Melanocytic Neoplasm.

ABSTRACT: Spitz melanocytic neoplasms exhibit frequent chromosomal rearrangements leading to recurring gene fusions, such as ALK fusions. TPM3 and DCTN1 emerge as the predominant fusion partners of ALK , although less common partners such as NPM1 , TPR , CLIP1 , GTF3C2 , MLPH , EEF2 , MYO5A , and KANK1 have also been documented. Although ALK fusions are primarily associated with Spitz nevi or atypical Spitz tumors, instances of Spitz melanoma with ALK fusions documented in the English literature are exceedingly rare. Here, we present a case of Spitz melanoma harboring SLC20A1::ALK fusion, highlighting a novel fusion transcript not previously reported in Spitz melanocytic neoplasms, including Spitz melanomas. In addition, the tumor exhibits multiple aberrant chromosomal alterations characteristic of melanoma, along with a somatic mutation in GRM3 .

Comparative Performance Analysis of Idylla and Archer in the Detection of Gene Fusions in Spitzoid Melanocytic Tumors.

Melanocytic neoplasms with spitzoid histomorphology are often difficult to classify without identifying genetic drivers such as kinase fusions. Traditional diagnostic methods, such as immunohistochemistry, can yield inconclusive results, and advanced techniques such as the Archer fusion assay are often inaccessible and costly. The Idylla GeneFusion Assay might offer a rapid and cost-effective alternative. This study compared Idylla and Archer in identifying ALK, pan-NTRK, RET, and ROS1 gene fusions. Of the 147 samples where next-generation sequencing did not detect genetic drivers, 89 (60.5%) meeting the tissue requirements were further analyzed using Idylla (Cohort A). Idylla demonstrated a sensitivity of 75% and a specificity of 100% in detecting these fusions. Additionally, among 27 randomly selected cases (Cohort B) that failed to meet the inclusion criteria, Idylla maintained the same levels of sensitivity and specificity. Our findings also show that Idylla can be effectively conducted with isolated RNA, broadening its applicability beyond tissue samples. Although the Idylla assay may not replace more comprehensive molecular assays such as Archer, it could serve as a valuable initial screening tool in diagnosing spitzoid melanocytic tumors.

Clinical, Morphological and Molecular Features of Spitz tumors.

Spitz tumors represent a heterogeneous group of challenging melanocytic neoplasms, displaying a range of biological behaviors, spanning from benign lesions, Spitz nevi (SN) to Spitz melanomas (SM), with intermediate lesions in between known as atypical Spitz tumors (AST). They are histologically characterized by large epithelioid and/or spindled melanocytes arranged in fascicles or nests, often associated with characteristic epidermal hyperplasia and fibrovascular stromal changes. In the last decade, the detection of mutually exclusive structural rearrangements involving receptor tyrosine kinases ROS1, ALK, NTRK1, NTRK2, NTRK3, RET, MET, serine threonine kinases BRAF and MAP3K8, or HRAS mutation, led to a clinical, morphological and molecular based classification of Spitz tumors. The recognition of some reproducible histological features can help dermatopathologist in assessing these lesions and can provide clues to predict the underlying molecular driver. In this review, we will focus on clinical and morphological findings in molecular Spitz tumor subgroups.

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.

Spitz tumour with ALK rearrangement: A case report and literature review.

Spitz tumour with ALK rearrangement is a recently described entity and a rare tumour. The incidence of Spitz tumour was estimated at 3.63 per 100,000 persons in American paediatric population; while there is no data in Asian population. Here we reported a case of an eleven-year-old Asian boy who presented with a left shin nodule of two months' duration. The skin biopsy revealed a Spitz tumour with predominantly spindle cell morphology arranged in fascicles, vertically orientated nests and radial growth pattern. Junctional component, melanin pigment or Kamino bodies were not identified. Immunohistochemical study displayed homogenous cytoplasmic staining for ALK. Fluorescence in-situ hybridisation (FISH) analysis confirmed ALK rearrangement. Review of the literatures demonstrated that positive ALK immunohistochemistry may not correlate with ALK rearrangement. ALK-rearranged Spitz tumour confirmed with FISH analysis favour clinically benign behaviour despite atypical histomorphology or positive sentinel lymph node. Therefore, correlation of histomorphology, immunohistochemical stain and molecular study are important for the definitive diagnosis of this entity.

Histological interpretation of spitzoid tumours: an extensive machine learning-based concordance analysis for improving decision making.

The histopathological classification of melanocytic tumours with spitzoid features remains a challenging task. We confront the complexities involved in the histological classification of these tumours by proposing machine learning (ML) algorithms that objectively categorise the most relevant features in order of importance. The data set comprises 122 tumours (39 benign, 44 atypical and 39 malignant) from four different countries. BRAF and NRAS mutation status was evaluated in 51. Analysis of variance score was performed to rank 22 clinicopathological variables. The Gaussian naive Bayes algorithm achieved in distinguishing Spitz naevus from malignant spitzoid tumours with an accuracy of 0.95 and kappa score of 0.87, utilising the 12 most important variables. For benign versus non-benign Spitz tumours, the test reached a kappa score of 0.88 using the 13 highest-scored features. Furthermore, for the atypical Spitz tumours (AST) versus Spitz melanoma comparison, the logistic regression algorithm achieved a kappa value of 0.66 and an accuracy rate of 0.85. When the three categories were compared most AST were classified as melanoma, because of the similarities on histological features between the two groups. Our results show promise in supporting the histological classification of these tumours in clinical practice, and provide valuable insight into the use of ML to improve the accuracy and objectivity of this process while minimising interobserver variability. These proposed algorithms represent a potential solution to the lack of a clear threshold for the Spitz/spitzoid tumour classification, and its high accuracy supports its usefulness as a helpful tool to improve diagnostic decision-making.

Spitz melanocytic neoplasms with MLPH::ALK fusions: Report of two cases with previously unreported features and literature review.

ALK-fused Spitz melanocytic neoplasms are a distinct subgroup of melanocytic lesions exhibiting unique histopathologic characteristics. These lesions often manifest as exophytic or polypoid tumors, characterized by fusiform-to-epithelioid melanocytes arranged in a nested, fascicular, or plexiform growth pattern. Several fusion partners of the ALK gene have been identified in spitzoid melanocytic neoplasms, with TPM3 and DCTN1 being the most prevalent. Less common fusion partners include NPM1, TPR, CLIP1, GTF3C2, EEF2, MYO5A, KANK1, and EHBP1. The MLPH gene, which encodes melanophilin (MLPH), playing a crucial role in regulating skin pigmentation by acting as a linker between RAB27A and myosin Va during melanosome transport, has also recently been recognized as a rare fusion partner of ALK in Spitz melanocytic neoplasms. Currently, there exists a sparse documentation within English literature, illustrating a limited number of cases featuring MLPH::ALK fusion in Spitz melanocytic neoplasms. In this report, we present two additional cases, including a previously unreported instance of Spitz melanoma, contributing to the expanding knowledge on ALK-fused Spitz melanocytic neoplasms. In addition, we provide a comprehensive review of the clinical, histopathologic, and molecular features observed in documented cases with this novel fusion.

Novel MED15::ATF1 fusion in a pediatric melanoma with spitzoid features and aggressive presentation.

Childhood melanoma is a rare and biologically heterogeneous pediatric malignancy. The differential diagnosis of pediatric melanoma is usually broad, including a wide variety of spindle cell or epithelioid neoplasms. Different molecular alterations affecting the MAPK and PI3K/AKT/mTOR pathways, tumor suppressor genes, and telomerase reactivation have been implicated in melanoma tumorigenesis and progression. Here, we report a novel MED15::ATF1 fusion in a pediatric melanoma with spitzoid features and an aggressive clinical course.

Amplification of Mutant NRAS in Melanocytic Tumors With Features of Spitz Tumors.

NRAS activating mutations are prevalent in melanocytic neoplasia, occurring in a subset of common acquired melanocytic nevi and ∼30% of cutaneous melanomas. In this study, we described a cohort of 7 distinctive melanocytic tumors characterized by activating point mutations in codon 61 of NRAS with amplification of the mutant NRAS allele and shared clinicopathologic features. These tumors occurred predominantly in younger patients, with a median age of 20 years (range, 6-56 years). They presented as papules on the helix of the ear (4 cases) or extremities (3 cases). Microscopically, the tumors were cellular, relatively well-circumscribed, compound, or intradermal proliferations. The tumor cells often extended into the deep reticular dermis and involved the superficial subcutaneous fat in some cases. The melanocytes were epithelioid to spindled with moderate amounts of cytoplasm and conspicuous nucleoli. They were arranged in short plexiform fascicles, nests, and cords. Some cases had occasional pleomorphic and multinucleated melanocytes. Rare dermal mitotic figures were present in all cases. The dermis contained thick collagen bundles and minimal solar elastosis. Follow-up data were available for 5 patients, with a median period of 4.2 years (range, 1-9 years), during which no recurrences or metastases were reported. Our series highlights a clinicopathologically and molecularly distinctive subset of NRAS-mutated tumors with amplification of the mutant NRAS allele.

BRAF Mutated and Morphologically Spitzoid Tumors, a Subgroup of Melanocytic Neoplasms Difficult to Distinguish From True Spitz Neoplasms.

Drivers of Spitz neoplasms include activating point mutations in HRAS and Spitz-associated genomic fusions. It has become evident that some BRAF -mutated melanocytic neoplasms can morphologically mimic Spitz tumors (STs). These have been termed BRAF mutated and morphologically spitzoid (BAMS). In this study, 17 experts from the International Melanoma Pathology Study Group assessed 54 cases which included 40 BAMS and 14 true STs. The participants reviewed the cases blinded to the genomic data and selected among several diagnostic options, including BAMS, ST, melanoma, and other. A total of 38% of all diagnostic selections in the BAMS cases were for BAMS, whereas 32% were for ST. In 22 of the BAMS cases, the favored diagnosis was BAMS, whereas in 17 of the BAMS cases, the favored diagnosis was ST. Among the 20 cases in the total group of 54 with the highest number of votes for ST, half were BAMS. Of BAMS, 75% had a number of votes for ST that was within the SD of votes for ST seen among true ST cases. There was poor interobserver agreement for the precise diagnosis of the BAMS (kappa = 0.16) but good agreement that these cases were not melanoma (kappa = 0.7). BAMS nevi/tumors can closely mimic Spitz neoplasms. Expert melanoma pathologists in this study favored a diagnosis of ST in nearly half of the BAMS cases. There are BAMS cases that even experts cannot morphologically distinguish from true Spitz neoplasms.

Melanoma on congenital melanocytic nevi.

Among nevus-associated melanomas, which overall account for 20%-30% of all melanomas, those arising specifically in congenital melanocytic nevi are infrequent, but can be disproportionately frequent in childhood and adolescence. Congenital melanocytic nevi (CMNi) are common benign melanocytic tumors that are present at birth or become apparent in early childhood. They are classified based on the projected adult size. Small and medium-sized CMNi are frequent, whereas large/giant CMNi (over 20 cm in diameter) are rare, but can be associated with high morbidity due to marked aesthetic impairment and the risk of neurocutaneous syndrome or melanoma development. In this setting, melanomas can appear in early childhood and are very aggressive, while the risk of small-medium CMNi of developing melanoma is low and similar to non-congenital melanocytic nevi. Histologically, most melanomas on CMNi initiate their growth at the epidermal-dermal junction, but in large/giant CMNi they can develop entirely in the dermis, in deeper tissues, or in extracutaneous sites (especially in the central nervous system). Most CMNi harbour an NRAS mutation, but other genes are rarely involved, and gene translocations have recently been described. However, no prognostic implications have been associated with the CMN genotype. Melanomas developed on CMNi harbour additional molecular alterations to which the aggressive clinical course of these tumors has been attributed. This review covers the distinctive clinical and pathological aspects of melanomas on CMNi, and includes the epidemiology, etiopathogenesis, clinical and dermoscopic presentation, histological and molecular characteristics, as well as tumour behaviour.

Spitz Melanocytic Tumors: A Fascinating 75-Year Journey.

Over the last 75 years, our understanding of Spitz lesions has undergone substantial evolution. Initially considered a specific type of melanoma, the perception has shifted towards recognizing Spitz lesions as a spectrum comprising Spitz nevi, Spitz melanocytomas, and Spitz melanomas. Spitz lesions are known for posing a significant diagnostic challenge regarding the distinction between benign neoplasms displaying atypical traits and melanomas. A comprehensive understanding of their molecular basis and genomic aberrations has significantly improved precision in classifying and diagnosing these challenging lesions. The primary aim of this review is to encapsulate the current understanding of the molecular pathogenesis and distinct clinicopathologic characteristics defining this intriguing set of tumors.

Assessment of RAS-RAF-MAPK Pathway Mutation Status in Healthy Skin, Benign Nevi, and Cutaneous Melanomas: Pilot Study Using Droplet Digital PCR.

In the present study, we employed the ddPCR and IHC techniques to assess the prevalence and roles of RAS and RAF mutations in a small batch of melanoma (n = 22), benign moles (n = 15), and normal skin samples (n = 15). Mutational screening revealed the coexistence of BRAF and NRAS mutations in melanomas and nevi and the occurrence of NRAS G12/G13 variants in healthy skin. All investigated nevi had driver mutations in the BRAF or NRAS genes and elevated p16 protein expression, indicating cell cycle arrest despite an increased mutational burden. BRAF V600 mutations were identified in 54% of melanomas, and NRAS G12/G13 mutations in 50%. The BRAF mutations were associated with the Breslow index (BI) (p = 0.029) and TIL infiltration (p = 0.027), whereas the NRAS mutations correlated with the BI (p = 0.01) and the mitotic index (p = 0.04). Here, we demonstrate that the "young" ddPCR technology is as effective as a CE-IVD marked real-time PCR method for detecting BRAF V600 hotspot mutations in tumor biopsies and recommend it for extended use in clinical settings. Moreover, ddPCR was able to detect low-frequency hotspot mutations, such as NRAS G12/G13, in our tissue specimens, which makes it a promising tool for investigating the mutational landscape of sun-damaged skin, benign nevi, and melanomas in more extensive clinical studies.

Restrospective reappraisal of the prognostic classification of spitzoid melanocytic neoplasms after BRAF and NRAS mutation characterisation: a single institution experience.

AIMS: The current WHO classification of melanocytic tumours excludes neoplasms showing BRAF or NRAS mutations from the Spitz category. This study aimed to review and reclassify atypical melanocytic tumours with spitzoid morphological features diagnosed between 2009 and 2021 in our hospital after expanding the molecular profile, including BRAF and NRAS mutations in all cases. METHODS AND RESULTS: A total of 71 neoplasms showing spitzoid features (Spitz-like) and atypia were included. The risk of progression of tumours was first studied by integrating the morphology, immunohistochemistry (p16, Ki67, HMB45 and PRAME) and fluorescence in-situ hybridisation (FISH) results (melanoma multiprobe and 9p21). In a second step, after expanding the molecular study, including BRAF and NRAS mutational status, the neoplasms were finally classified into four subgroups: atypical Spitz tumour (AST, n = 45); BRAF-mutated naevus/low-grade melanocytoma with spitzoid morphology (BAMS, n = 2); Spitz melanoma (SM, n = 14); and BRAF or NRAS mutated melanoma with spitzoid features (MSF, n = 10). Follow-up of patients revealed uneventful results for AST and BAMS. Only one SM presented lymph node metastasis after 134 months. Conversely, patients with MSF showed an unfavourable outcome: three developed lymph node metastases after a mean time of 22 months, with one patient presenting distant metastasis and dying of the disease 64 months from diagnosis. The progression-free survival showed significant differences between the four groups of spitzoid tumours (P < 0.001) and between both melanoma subtypes (P = 0.012). CONCLUSIONS: The classification and prognostication of atypical neoplasms with spitzoid features requires the integration of histomorphology with the molecular investigation of tumours, which should include BRAF and NRAS mutational status.