Spitzoid

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...

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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...

NRAS activating mutations are prevalent in melanocytic neoplasia, occurring in a subset of common acquired melanocytic nevi and approximately 30% of cutaneous melanomas. In this study, we describe a cohort of seven 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 (ranging from 6 to 56). They presented as papules on the helix of the ear (four cases) or extremities (three cases)...

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...

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...

Spitz tumors are a subset of melanocytic neoplasms characterized by epithelioid or spindled melanocytes(1). The benign nature of the "Spitz nevus" has since been clarified, but the debate regarding Spitzoidtumors (STs) is still ongoing. Spitzoid tumors encompass a wide spectrum of cutaneous lesions ranging from benign Spitz nevus (SN) to Spitzoid melanoma (SM), the latter displaying capacity for widespread metastasis and a potentially lethal outcome (2). The term atypical Spitz tumors (ASTs) refers to melanocytic tumors exhibiting the morphological features of SN, as well as some features associated with malignancy, but not sufficient to classify them as SMs...

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...

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...

In recent years, particular interest has developed in molecular biology applied to the field of dermatopathology, with a focus on nevi of the Spitz spectrum. From 2014 onwards, an increasing number of papers have been published to classify, stratify, and correctly frame molecular alterations, including kinase fusions. In this paper, we try to synthesize the knowledge gained in this area so far. In December 2023, we searched Medline and Scopus for case reports and case series, narrative and systematic reviews, meta-analyses, observational studies-either longitudinal or historical, case series, and case reports published in English in the last 15 years using the keywords spitzoid neoplasms, kinase fusions, ALK, ROS1, NTRK (1-2-3), MET, RET, MAP3K8, and RAF1...

Preferentially Expressed Antigen in Melanoma (PRAME), a member of the cancer/testis antigen family, is central to the field of skin cancer diagnostics and therapeutics. As a nuclear receptor and transcriptional regulator, PRAME plays a critical role in inhibiting retinoic acid signalling, which is essential for cell differentiation and proliferation. Its aberrant overexpression in various malignancies, particularly cutaneous melanoma, is associated with more aggressive tumour phenotypes, positioning PRAME as both a diagnostic and prognostic marker...

Current diagnostic algorithms are insufficient for the optimal clinical and therapeutic management of cutaneous spitzoid tumors, particularly atypical spitzoid tumors (AST). Therefore, it is crucial to identify new markers that allow for reliable and reproducible diagnostic assessment and can also be used as a predictive tool to anticipate the individual malignant potential of each patient, leading to tailored individual therapy. Using Reduced Representation Bisulfite Sequencing (RRBS), we studied genome-wide methylation profiles of a series of Spitz nevi (SN), spitzoid melanoma (SM), and AST...

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...

Pediatric melanoma of the scalp has the highest mortality of any anatomic location. We describe five pediatric patients with a diagnosis of scalp melanoma receiving care at Massachusetts General Hospital and/or Boston Children's Hospital from 2018 through 2022. Melanoma presented in diverse contexts: cellular blue nevus-associated, compound nevus-associated, spitzoid, nodular, and superficial spreading subtypes. This study describes a range of melanoma presentations and emphasizes the need for additional compilation of data on pediatric scalp melanomas to promote their recognition and improve patient care...

Ancillary tests such as immunohistochemistry (IHC) and gene expression profile (GEP) testing may be needed to arrive at a definitive diagnosis for some atypical melanocytic neoplasms. A 34-year-old male with a family history of melanoma presented with a large, heterogeneous melanocytic lesion on the cheek. Histopathological review of two biopsies revealed an atypical intradermal melanocytic proliferation with spitzoid features without ulceration or regression. Scattered mitotic figures were identified. In addition to performing SOX10 IHC, PRAME and HMB45 staining highlighted weak, patchy positivity that was stronger in superficial, pleomorphic melanocytes (Ki-67, 5-7% mitotic rate)...

BACKGROUND: Pediatric melanoma presents with distinct clinical features compared to adult disease. OBJECTIVE: Characterize risk factors and negative outcomes in pediatric melanoma. METHODS: Multicenter retrospective study of patients under 20 years diagnosed with melanoma between 1/1/1995 - 6/30/2015 from 11 academic medical centers. RESULTS: Melanoma was diagnosed in 317 patients, 73% of whom were diagnosed in adolescence (age ≥11)...

BACKGROUND: A subset of melanocytic tumors with spitzoid morphology may lead to potential inaccurate diagnosis and lack of assessment of malignancy potential. In this study, we aimed to evaluate melanocytic tumors with spitzoid morphology using conventional melanoma FISH (RREB-1, CCND1, MYB and CEP6) and 9p21 FISH (CDKN2A) probes and compare the probe results with clinical and histopathological features. METHODS: This study is a multicentric retrospective study including three centers, İstanbul University-Cerrahpaşa, Cerrahpaşa School of Medicine, Department of Pathology, Acıbadem University, School of Medicine, Department of Pathology and ETA Pathology Laboratory...

PRAME (PReferentially expressed Antigen in Melanoma) is a gene first identified in melanoma. It has been proposed as a useful marker to differentiate melanoma from benign melanocytic neoplasms. Recently genomic testing using fluorescence in situ hybridization has been used to aid in the diagnosis of difficult melanocytic neoplasms. We have compared PRAME staining to FISH testing results in 83 difficult to classify melanocytic neoplasms which showed spitzoid histologic features. A relatively low sensitivity of 29...

Spitz tumors are melanocytic neoplasms morphologically characterized by spindled and/or epithelioid cells and specific stromal and epidermal changes associated with mutually exclusive fusion kinases involving ALK, ROS1, NTRK1, NTRK2, NTRK3, MET and RET, BRAF and MAP3K8 genes or, less commonly, HRAS mutation. RAF1 fusions have been recently detected in cutaneous melanocytic neoplasms, including conventional melanoma, congenital nevus and BAP-1 inactivated tumors. We report herewith three Spitz neoplasms with a RAF1 fusion, including a previously reported CTDSPL::RAF1 fusion and two novel PPAP2B::RAF1 and ATP2B4::RAF1 fusions...

Spitzoid tumors (ST) are a group of melanocytic tumors of high diagnostic complexity. Since 1948, when Sophie Spitz first described them, the diagnostic uncertainty remains until now, especially in the intermediate category known as Spitz tumor of unknown malignant potential (STUMP) or atypical Spitz tumor. Studies developing deep learning (DL) models to diagnose melanocytic tumors using whole slide imaging (WSI) are scarce, and few used ST for analysis, excluding STUMP. To address this gap, we introduce SOPHIE: the first ST dataset with WSIs, including labels as benign, malignant, and atypical tumors, along with the clinical information of each patient...