Spitzoid Melanoma Across the Age Spectrum: A Review of Diagnostic Criteria, Molecular Markers, and Clinical Outcomes Volume 62- Issue 1

Calista Persson¹*, Alisa Nguyen¹ and Akhil Gupta²

• ¹Nova Southeastern University Kiran Patel College of Osteopathic Medicine, United States
• ²Skin Center of Florida, North Palm Beach, United States

Received: May 13, 2025; Published: May 23, 2025

*Corresponding author: Calista Persson, Nova Southeastern University Kiran Patel College of Osteopathic Medicine, Davie, FL, United States

DOI: 10.26717/BJSTR.2025.62.009688

Abstract PDF

Background: Spitzoid melanoma is a rare melanoma subtype that mimics Spitz nevi, creating diagnostic challenges, especially in children and adolescents. This review synthesizes evidence from 2015–2025 on diagnostic criteria, molecular markers, and outcomes across age groups, with clinical practice implications.
Methods: A comprehensive literature search identified studies from 2015–2025 focused on spitzoid melanocytic neoplasms. Data from case series, cohorts, and clinical trials were analyzed, with review articles providing context. Diagnostic features, molecular alterations, and outcomes were compared across pediatric, adolescent, and adult populations.
Results: Spitzoid melanoma remains uncommon but diagnostically complex. Histologically, it overlaps with Spitz nevi, with features like epithelioid or spindle melanocytes and mitotic activity. Dermoscopy aids in evaluation— multicomponent patterns suggest malignancy, while starburst patterns are more typical of benign lesions. Ancillary tools such as FISH and PRAME immunohistochemistry improve diagnostic accuracy. Molecularly, spitzoid melanomas often show kinase fusions (e.g., ALK, NTRK, MAP3K8) rather than BRAF/NRAS mutations. MAP3K8 fusions appear in ~30% of pediatric cases; MC1R variants and UV signatures may also contribute. Clinically, most cases have favorable outcomes. Pediatric cases show frequent lymph node involvement but low mortality, while adult cases rarely metastasize. Prognostic indicators include tumor thickness, ulceration, anatomic site, and high-risk mutations (e.g., TERT).
Conclusions: Accurate distinction between spitzoid melanoma and benign Spitz lesions is essential. An integrated approach—incorporating morphology, dermoscopy, molecular testing, and immunohistochemistry—enhances diagnosis and risk stratification. Although most tumors follow an indolent course, some behave aggressively, warranting long-term follow-up and potential for targeted therapy.

Keywords: Spitzoid Melanoma; Spitz Nevus; Atypical Spitz Tumor; Pediatric Melanoma; Dermoscopy; Molecular Diagnostics; Clinical Outcomes

Abbreviations: SM: Spitzoid Melanoma; SN: Spitz Nevi/Nevus; AST: Atypical Spitz Tumor; FISH: Fluorescence in Situ Hybridization; IHC: Immunohistochemistry; SLNB: Sentinel Lymph Node Biopsy; PFS: Progression-Free Survival; (PFS): PRAME: Preferentially Expressed Antigen in Melanoma; MSF: Melanoma with Spitzoid Features; SSM: Superficial Spreading Melanoma; BAMS: BRAF-Mutated Atypical Spitz tumors; MSF: Mutated Spitzoid Melanoma

Spitzoid melanoma (SM) is a unique cutaneous melanoma subtype with significant diagnostic and management difficulties because it shows clinical and histological similarities to benign Spitz nevi. Spitz nevi (SN) were initially identified as “juvenile melanoma” in children by Sophie Spitz but are now understood to represent benign melanocytic neoplasms formed by epithelioid and spindle-shaped melanocytes. In contrast, SM defines the malignant spectrum of these lesions [1]. Spitzoid lesions manifest in all age demographics but show a higher incidence among children and adolescent populations compared to older adults [1,2]. Spitzoid melanomas usually emerge as dome-shaped papules or nodules that grow quickly and display varying pigmentation, including pink and red colors, appearing mainly on the extremities or face. The typical presentation of SM does not match the “ABCDE” melanoma criteria due to its symmetric shape and consistent coloration, which resembles non-cancerous lesions [3]. The uncertain clinical presentation necessitates thorough examination and additional diagnostic testing (Figure 1). Spitzoid melanocytic neoplasms include benign Spitz nevus and atypical Spitz tumor (AST), which is also known as Spitz tumor of uncertain malignant potential, progressing to frank malignant SM [1]. Expert dermatopathologists encounter substantial difficulty when attempting to differentiate between an AST and a true spitzoid melanoma based solely on morphological characteristics, which results in only moderate interobserver agreement without supplemental information [4]. The stakes of accurate diagnosis are high: Diagnosing a benign SN as melanoma can result in unnecessary aggressive treatments for young patients, while failing to detect spitzoid melanoma presents a potentially fatal risk. Recent discoveries indicate that SMs demonstrate unique biological patterns compared to adult melanomas [5]. Pediatric SMs tend to display intermediate clinical behavior because they frequently spread to regional lymph nodes but seldom advance to fatal disease [5]. This review seeks to extensively examine spitzoid melanoma throughout different age groups despite existing complexities. This paper outlines the key diagnostic criteria, including histopathological features and dermoscopic patterns, together with adjunctive diagnostic tests, while detailing the molecular markers for classification and prognostication of SM and presenting clinical outcomes and prognostic factors for patients across pediatric to adult age ranges. The analysis highlights developments from 2015 through 2025 that have enhanced both our knowledge and treatment approaches for SM. Our review of the latest studies aims to establish evidence-based diagnostic and treatment methods for SM while identifying areas that require consensus and more research.

Figure 1

Search Strategy and Selection Criteria

Our research team performed an exhaustive literature search to find studies published from January 2015 through April 2025 that analyzed spitzoid melanocytic lesions, including Spitz nevi, atypical Spitz tumors, and spitzoid melanomas in terms of diagnostic techniques, molecular features, and clinical results. We searched PubMed, Embase, and Web of Science with terms including “Spitz nevus”, “atypical Spitz tumor”, “spitzoid melanoma”, “pediatric melanoma”, “molecular”, “genomics”, “clinical outcomes”, and “survival” and conducted manual reviews of key article reference lists to identify more relevant studies. The criteria for eligible sources required primary research studies such as case reports, case series, cohort studies, clinical trials, and other observational designs that provided original data about diagnosis, molecular profiling, or outcomes for pediatric, adolescent, or adult patients. The research incorporated extensive systematic reviews and meta-analyses to establish foundational knowledge about epidemiology and prognosis. The main analysis excluded narrative reviews and expert opinions to concentrate on primary data. Articles had to be published in English. For overlapping or duplicate cohorts, researchers chose the most recent publication or offered the most comprehensive information for inclusion.

Data Extraction and Synthesis

Researchers used a standardized form to extract information from studies that met eligibility requirements. Our research included data collection from each study about patient demographics (age distribution), diagnostic techniques (clinical features and histopathology with dermoscopy and ancillary tests such as Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC)), molecular analysis (mutations and fusions plus other genetic data), and patient outcomes. The study retrieved clinical outcome data, including sentinel lymph node biopsy (SLNB) results, metastasis rates, and disease-specific and overall survival statistics. We recorded particular details separately for pediatric and adult groups to enable comparison. Due to the diverse study designs and results, we analyzed the findings through qualitative synthesis. The research findings are divided into three thematic areas, including diagnostic criteria, molecular markers, and clinical outcomes, with special attention given to age-related variations and consistencies. The review remains narrative- based, avoiding meta-analysis of numerical results yet including summary statistics from primary studies and pooled analyses to demonstrate trends. The quality and bias of the included studies were considered through evaluations, such as the duration of follow-up periods and diagnostic verification methods. Relevant comments about these aspects are included in the discussion section.

Clinical and Pathological Definitions

The terms “Spitz nevus”, “atypical Spitz tumor”, and “spitzoid melanoma” represent benign Spitz tumors, spitzoid lesions with uncertain malignant potential (also known as Spitz melanocytoma or Spitz tumor of unknown potential), and histologically malignant spitzoid lesions, respectively. We recognize that research studies sometimes utilize different definitions or terminologies, which we have attempted to reconcile with our standardized definitions during the summary process. The definition of pediatric patients usually encompasses individuals up to 18 years of age, but varies according to specific study definitions, while some datasets identify adolescents as those aged between 10 and 20 years. The original studies define progression-free survival (PFS) and melanoma-specific survival.

Diagnostic Criteria for Spitzoid Melanocytic Lesions

Histopathological Features: The diagnosis of spitzoid melanoma depends mainly on histopathology, yet its microscopic characteristics share similarities with both benign and atypical Spitz nevi. Classic SN exhibit symmetric, well-defined wedge shapes with large epithelioid and spindle melanocytes that mature as they move deeper into the dermis. SN mitoses remain superficial and typical while the cells maintain their monomorphic nature without demonstrating notable cytologic atypia. In contrast, SM usually displays architectural and cytologic derangement: Spitzoid melanoma demonstrates asymmetric expansion and irregular boundaries while extending past the normal wedge shape [6,7]. SM contains melanocytes that exhibit pleomorphism with enlarged hyperchromatic nuclei and develop sheet-like or confluent nests instead of the benign Spitz nevus’s orderly “raining down” arrangement. The dermis shows deep mitotic figures, which frequently appear atypical, and certain cases exhibit epidermal ulceration (Figure 2) [6]. Histopathologic clues increase the likelihood of diagnosing spitzoid melanoma. SMs in adolescents and adults demonstrate ulceration and a higher mitotic index in the dermis while lacking Spitz nevi’s typical clefted nests or Kamino bodies [1]. A single-institution study discovered that atypical Spitz tumors with BRAF or NRAS mutations, which resemble conventional melanoma genetic profiles, demonstrated significantly more severe histologic and clinical characteristics, including increased mitoses and metastasis, leading to their reclassification as true melanomas [8]. The analysis of molecular markers alongside histological evaluation proves essential for accurate diagnosis. Expert dermatopathologists do not always agree when making diagnoses solely from morphological observations. In a 2021 study by Benton et al., twenty expert pathologists reviewed 70 challenging spitzoid lesions and initially showed fair agreement between benign and malignant diagnoses, but achieved nearly perfect agreement after genomic data were added [9]. Histologic criteria remain the primary diagnostic standard, but ancillary tests have become more helpful in enhancing diagnostic precision in ambiguous cases.

Figure 2

Dermoscopy: Dermoscopic examination serves as a crucial non-invasive diagnostic approach to identify potential SM before surgical removal. Children’s benign SN demonstrate a typical “starburst” dermoscopic pattern consisting of symmetric radial streaking or pseudopod patterns at the edges with a uniform central area indicating benign regular growth. Spitzoid atypical or malignant lesions display irregular multicomponent patterns with asymmetrical colors and structures more frequently [3]. Herzum, et al. [10] conducted a decade-long pediatric study and recently systematically reviewed dermoscopic patterns in 100 children with Spitzoid neoplasms: Histologically benign SN displayed a strong correlation with the starburst pattern, which was present in approximately 26% of cases and was significantly rarer in AST or SM (p = 0.004). At the same time, a multicomponent pattern (combining irregular pigmented globules, network, and streaks) was seen in over half of spitzoid melanomas and atypical Spitz tumors (56% of AST, 50% of SM, vs. only 18% of Spitz nevi, p = 0.0052). Spitz nevi might develop from an initial starburst pattern to a homogeneous “stardust” pattern, but remain non-malignant if their other characteristics are benign. Adult spitzoid lesions show pigmentation that resembles ordinary acquired nevi in dermoscopic examination but require further investigation if they present irregular streaks, non-typical network patterns, or blue-white veiling [10]. While dermoscopy alone cannot diagnose SM, clinicians use specific patterns to determine when to perform excision and histological examinations. The primary suspect in dermoscopy for Spitz nevi is the unusual mix of structures when the lesion looks like a Spitz nevus clinically, which necessitates a pathological examination.

Ancillary Diagnostic Techniques: The limitations of morphology require ancillary tests to become standard diagnostic components for spitzoid lesions in resource-rich practice settings. Among adjunct tests, fluorescence in situ hybridization (FISH) is one of the first techniques implemented. The standard FISH test for melanocytic lesions targets specific chromosome 6 and 11 locations, which show frequent gains or losses in melanoma cases (including RREB1 at 6p25, MYB at 6q23, CCND1 at 11q13, and centromere six as a control) [11,12]. When FISH analysis identifies specific copy number aberrations at target loci, it supports a diagnosis of melanoma. While FISH offers potential for identifying malignancy-indicating chromosomal aberrations in spitzoid neoplasms, its sensitivity and specificity remain imperfect [11,13]. Dika, et al. [12] assessed FISH results against histopathology findings for 15 spitzoid tumors in five children and eight adults. They reported that most results matched diagnoses, but five lesions showed discrepancies between the two tests (two children and three adults). A number of pediatric SMs exhibited no typical FISH abnormalities (false-negative FISH) while some SN in children showed FISH positivity even though they behaved benignly [12]. Researchers found that the standard melanoma FISH probe set demonstrates greater reliability in adult patients than pediatric patients because spitzoid tumors in children can possess alternative genomic changes like kinase fusions that escape detection by conventional probes [12].

The interpretation of FISH results requires consideration of both morphology and patient age. Recent advancements have introduced new FISH probes and genomic copy number arrays to target 9p21 (CDKN2A/p16) because homozygous deletion of 9p21 appears more frequently in melanomas than nevi. Immunohistochemistry has developed into an essential supplementary diagnostic technique. The traditional melanoma markers S100, MART-1, and HMB-45 cannot be used to differentiate SN from SM because they show positive results in both conditions. The immunomarkers p16 (CDKN2A) and PRAME (Preferentially Expressed Antigen in Melanoma) display different expression patterns. When an atypical spitzoid lesion shows patchy or total loss of p16 expression compared to normal surrounding keratinocytes, it may point to CDKN2A gene deletion, which correlates with aggressive behavior in ASTs [1]. The binary immunohistochemical marker PRAME has recently become prominent for melanoma detection. The cancer-testis antigen PRAME shows no expression in benign nevi, yet appears in numerous melanoma cases. Gerami, et al. [14] evaluated PRAME immunohistochemistry in 59 spitzoid melanocytic neoplasms with known outcomes. After establishing nuclear PRAME staining in ≥75% of tumor cells as positive, they discovered 33.3% of lesions histologically diagnosed as SM tested positive for PRAME. In comparison, only 2.6% of benign SN showed any PRAME positivity [14]. Furthermore, PRAME tended to correlate with aggressive behavior: The primary lesions of two out of three patients who developed metastases displayed diffuse PRAME expression according to reference 14. The statistical analysis showed that PRAME positivity strongly correlated with both final malignant diagnosis outcomes and TERT promoter mutations, which serve as another marker of tumor aggressiveness. Diffuse PRAME staining in spitzoid lesions indicates a higher likelihood of spitzoid melanoma rather than Spitz nevus. PRAME expression is unreliable because some SN show weak PRAME expression, whereas certain true SMs do not express PRAME [15]. PRAME IHC functions as additional evidence in diagnostic evaluations. Determining malignancy in challenging AST cases relies on combining a panel of markers such as p16, PRAME, and Ki-67 index with FISH or CGH to gather evidence. The process of diagnosing SM now requires multiple assessment modes. Any lesion that looks suspicious clinically and under dermoscopy must be removed for histopathological examination. When pathology results between AST and melanoma remain unclear, doctors use ancillary studies like FISH and IHC for PRAME/p16 or molecular genetic testing to gain clarity. The integration of these modalities has led to better diagnostic certainty and enhanced agreement between observers [4]. An experienced dermatopathologist must synthesize all data to reach a final diagnosis, yet some lesions may remain classified as having “uncertain malignant potential,” which calls for cautious clinical management.

Germline and Environmental Factors

Molecular Markers and Genetic Characteristics: The past decade has seen significant progress in understanding the molecular genetics of spitzoid neoplasms. Mutations in BRAF and NRAS, which drive conventional adult melanomas in 40–50% and 20% of cases, respectively, occur less frequently in spitzoid melanomas. Initial research found that BRAF^V600E mutations appeared in less than 3% of SMs in one series, and NRAS mutations were almost nonexistent [2]. The genetic alterations in spitzoid tumors frequently involve kinase fusions or different oncogenic drivers rather than the mutations common in typical cutaneous melanoma.

Kinase Fusions and HRAS Mutations: Spitz tumors display characteristic chromosomal rearrangements that produce gene fusions, often involving receptor tyrosine kinases. Studies have identified fusions with ALK, NTRK1, NTRK3, ROS1, MET, BRAF (specifically its kinase domain rather than V600 point mutation), RET, and MAP3K8 within Spitz lesions [2]. Gene fusions lead to permanent MAP-kinase signaling activation, which results in melanocytic proliferation, like the effect of BRAF/NRAS mutations in typical melanoma. Notably, these gene fusions can occur in lesions across the spectrum: ALK or NTRK1/3 fusions drive many benign Spitz nevi in children, which include ALK-rearranged SN that present characteristic epidermal changes; meanwhile, spitzoid melanomas may contain similar gene fusions but likely require additional genetic events to become malignant. HRAS stands out as a notable exception because mutations in HRAS, specifically Q61L or Q61R, appear in certain SN and ASTs that display distinctive histological features, including extensive telangiectasia and fibrosis, which is sometimes identified as desmoplastic SN. HRAS-mutated Spitz tumors remain benign or low-grade but lose p16 expression, demonstrating that HRAS activation and CDKN2A inactivation can result in an AST-like presentation [1]. Identifying HRAS mutations or kinase gene fusions supports the classification of ambiguous spitzoid lesions into the Spitz spectrum group rather than conventional melanoma [1]. This principle is now enshrined in the WHO Classification (2018) criteria: Spitz tumors include lesions that are BRAF/NRAS wild-type but contain Spitz-associated fusions or HRAS mutations, while conventional melanomas encompass those lesions with BRAF^V600 or NRAS mutations.

Genomic sequencing studies have revealed that MAP3K8, encoding the serine-threonine kinase COT, is a frequently mutated gene in SM. Newman, et al. [16] discovered that MAP3K8 fusions or truncating rearrangements appeared in about 33% of pediatric SMs but were found to be very uncommon in adult conventional melanomas [16]. The MAP3K8 mutations present possible targets because COT participates in the MAPK pathway, which implies MEK inhibitors could be used therapeutically. The MAP3K8 fusion in one adolescent SM case led to a remarkable response to MEK inhibitor therapy, according to a case report emphasizing the clinical value of detecting these fusions [12]. Other fusions also carry therapeutic significance: ALK fusions found in some ASTs and rare spitzoid melanomas might be treated with ALK inhibitors, while NTRK fusions found in Spitz nevi and rare SMs become targetable by TRK inhibitors like larotrectinib and entrectinib during metastasis. For example, Frederico, et al. [17] identified a pediatric Spitz melanoma that presented a new C2orf42-ALK fusion, showing that ALK rearrangements, which generally appear in benign SN, can also feature in malignant lesions [17].

Conventional Melanoma Mutations in Spitzoid Lesions: The majority of spitzoid melanomas do not exhibit BRAF^V600E or NRAS mutations. The existence of these mutations indicates a potential for more aggressive lesions. A 2024 study by Moysset et al. reclassified atypical spitzoid neoplasms through expanded molecular testing and discovered 10 lesions that exhibited BRAF or NRAS mutations in combination with spitzoid morphology. These were labeled “melanoma with spitzoid features” (MSF) as opposed to true “Spitz melanoma.” Clinically, the MSF group had a significantly worse outcome: Among the 10 lesions with BRAF or NRAS mutations and spitzoid features, three developed lymph node metastases, and one patient died from their disease. Among Spitz melanomas with either Spitz-type fusions or wild-type status, only one patient (7%) experienced nodal recurrence, and none succumbed during follow-up. The study showed a distinct difference in PFS rates between the groups with statistical significance (p < 0.01) [8]. The findings support the WHO position that spitzoid tumors with BRAF/NRAS mutations function as regular melanomas instead of low-grade atypical Spitz tumors. The occurrence of TERT promoter mutations, which remain rare in spitzoid lesions, indicates aggressive behavior when they manifest [14,18]. Research revealed that within spitzoid neoplasms, those containing TERT promoter mutations demonstrated higher rates of PRAME positivity and metastasis [14]. TERT promoter mutations serve as an adverse prognostic indicator in typical melanoma cases, and this pattern persists in SMs despite the mutation’s rare occurrence. The study of molecular markers highlights both germline predispositions and mutation signatures in melanoma research. Recent genomic studies have challenged previous assumptions that UV radiation does not contribute to melanomas in children, particularly in cases of pediatric spitzoid melanoma. For instance, exome sequencing conducted by Liebmann, et al. [2] found that specific pediatric SMs exhibited UV mutation signatures, identifiable by C>T mutations at dipyrimidine sites. While the research indicated some degree of UV radiation involvement in the formation of SM in children, it suggested that this involvement is less significant compared to UV’s impact on conventional melanoma [2]. As part of their investigation, the researchers also examined germline variants in genes associated with melanoma susceptibility. They found that high-penetrance germline mutations, such as those in the CDKN2A or CDK4 genes, were rare in their pediatric cohort. However, moderate-risk alleles were more common: genetic tests revealed that each of the ten pediatric patients with conventional melanoma carried one or more germline mutations in melanoma or pigmentation genes, such as MC1R (associated with red hair), MITF, BRCA2, or PTEN. Notably, 41.7% of patients with SM carried an MC1R variant [2]. The MC1R gene affects skin pigmentation and UV sensitivity, and this research suggests its potential role in SM when combined with specific somatic events. Children or adolescents with SM often present genetic predispositions, such as fair skin and MC1R gene variants, alongside some UV exposure, which interacts with unique oncogenic drivers found in Spitz tumors. Benign SN typically develop in healthy young children who have not had significant UV exposure [2,19]. In contrast, conventional melanoma presents a strong UV signature and features primary mutations in BRAF and NRAS [20]. Spitzoid melanomas exhibit distinct molecular characteristics that differentiate them from conventional melanomas. These tumors commonly show kinase fusion occurrences alongside unusual changes in the MAPK pathway, which present specific histologic features—such as dermal sclerosis and spindle cell morphology in ALK-fused lesions, plexiform growth in NTRK-fused tumors, and intense cytologic atypia in cases involving MAP3K8 rearrangements [1]. The use of targeted next-generation sequencing has greatly enhanced the diagnostic precision for ambiguous melanocytic neoplasms through the identification of these characteristic genetic changes. Diagnosing atypical Spitz tumors can be supported by the detection of an ALK fusion without the presence of a BRAF mutation. Conversely, conventional melanoma is more likely to be classified when mutations such as BRAF^V600E or TERT promoter mutations are present [4,20]. Molecular testing plays a crucial role in diagnosing conditions and predicting patient outcomes. A summary of the essential genetic distinctions and their clinical relevance is provided in Table 1 [21,22]. Spitz-associated fusions or isolated HRAS mutations typically indicate a less aggressive tumor behavior, while mutations associated with conventional melanoma, like BRAF, NRAS, and TERT in spitzoid lesions, suggest a higher risk of malignancy. Diagnostic procedures and treatment options now regularly incorporate these molecular distinctions.

Table 1: Key Molecular Features of Spitzoid Melanomas vs. Conventional Melanomas.

Clinical Outcomes and Prognosis Across Age Groups

Pediatric and Adolescent Patients: Spitzoid melanoma in childhood is considered sporadic. The majority of spitzoid lesions in pediatric patients are usually benign SN or ASTs, with only a small fraction meeting the criteria for melanoma. In a large pediatric dermatopathology study conducted by Herzum, et al. [10] involving 255 spitzoid lesions in patients under 18, 82% were classified as Spitz nevi, 17% as atypical Spitz tumors, and only 1% (three cases) were identified as spitzoid melanomas [10]. This finding reflects the true rarity of pediatric melanoma and a potential bias in terminology, as pathologists often classify many ambiguous pediatric lesions as AST rather than outright melanoma. Nonetheless, SMs do occur in children and adolescents, making it essential to understand their behavior. A key observation is that pediatric spitzoid melanomas often exhibit an intermediate prognosis compared to other melanoma subtypes. A systematic review and meta-analysis by Pampena, et al. [5] pooled data from 1,002 pediatric melanoma cases across 213 studies [5]. They found that among histologic subtypes, SMs had a significantly higher risk of progression (recurrence or metastasis) compared to the more common superficial spreading melanoma (SSM). However, they also showed a trend toward lower mortality than SSM [5]. This means that children with SM are more likely to experience disease relapse, often in regional lymph nodes, but less likely to succumb to the disease compared to children with conventional melanomas. The behavior of SM appears to be intermediate between that of SSM (which typically has lower nodal involvement) and nodular melanoma (which has the worst survival rates) [5]. Indeed, spitzoid melanomas are often diagnosed at a greater thickness but are rarely fatal. For example, Batra, et al. [23] reported a series of pediatric melanomas where tumors of the spitzoid subtype frequently had positive sentinel lymph node biopsies, yet none of the children died from their disease [23]. This pattern has led some experts to question whether certain pediatric “metastatic” Spitz tumors are being overdiagnosed as melanoma, given their indolent course despite regional node involvement [5]. Several clinical and pathological factors have been identified as unfavorable prognostic indicators in pediatric SM. El Sharouni, et al. [24] analyzed a multi-center cohort of melanomas in patients ≤20 years old and found that ulceration, a primary lesion on the head or neck, and Breslow thickness greater than 4 mm were independent predictors of worse MSS in this young population [24]. These factors are similar to those affecting prognosis in adult melanoma, suggesting that extremely thick or ulcerated spitzoid melanomas behave more like conventional melanoma, even in children [24]. Additionally, specific molecular changes can negatively impact prognosis. For instance, the presence of a TERT promoter mutation or loss of 9p21 (p16) in a pediatric Spitz tumor indicates a high-risk lesion that may be prone to metastasis [14]. Sentinel lymph node status is a unique factor in pediatric spitzoid lesions. SLN biopsy positivity is common in pediatric SM and even in AST, with reports indicating this occurs in 40–50% of cases in some series. However, unlike in adult melanoma, a positive node in a child does not carry the same severe prognostic implications. Many children with positive nodes can be cured with surgery alone and do not experience further progression [5]. Consequently, managing node-positive Spitz tumors in children remains controversial; there are arguments for a more conservative treatment approach than would typically be taken for conventional melanoma, given the overall excellent survival rates. Current practices often involve complete lymph node dissection for melanoma, but clinical trials are assessing whether observation might be sufficient for minimal nodal disease in pediatric AST/SM. In adolescents (generally defined as ages 10–19) and young adults, outcomes for SM also appear promising. In the meta-analysis by Pampena et al., including adolescent patients, the spitzoid subtype demonstrated low rates of melanoma-specific mortality [5]. A separate analysis based on SEER data previously indicated that patients under 20 with SM have over 90% 5-year survival rates, confirming the generally favorable prognosis with appropriate treatment. However, caution is warranted because adolescence is also the period when conventional melanoma subtypes frequently emerge, often associated with large congenital nevi or significant UV exposure. Distinguishing these from true spitzoid melanoma is crucial for accurate outcome prediction [25].

Adult Patients: Spitzoid lesions in adults are uncommon. Most melanocytic lesions that exhibit Spitz-like characteristics and arise de novo in adults are typically found to be atypical or melanoma upon thorough examination. Classic Spitz nevi do occur in adults, but they are far less frequent than in children. Adults can also develop what is known as “Spitz melanoma.” In older literature, the term “atypical Spitz tumor” was sometimes applied to adult cases that today might be classified as melanoma. Historically, spitzoid melanoma in adults was thought to be more aggressive than in children [26]. However, recent evidence suggests that many adult Spitz tumors also follow an indolent course. Chintapalli et al. (2023) performed a long-term retrospective cohort study involving 126 adults with Spitz-type lesions (including SN, ASTs, and SMs) with a median follow-up of about 5 years. Their findings were reassuring: Spitz-type lesions in adults were only very rarely associated with distant metastasis or death [22]. In fact, in that series, only a single patient (out of 126) developed distant metastatic disease from a SM, and there were no melanoma-specific deaths reported [22]. This aligns with earlier smaller studies and case series that noted that while adult SMs can metastasize to lymph nodes, progression to Stage IV or fatal outcomes is uncommon [27]. Chintapalli et al. did observe, however, that patients with a history of a Spitz lesion—particularly those with so-called “classic Spitz nevi” in adulthood—had an increased incidence of developing a second, unrelated melanoma of conventional type later on [22].

This may be due to underlying genetic susceptibility (fair skin, UV exposure patterns) or could reflect heightened surveillance. In any case, this suggests that adults diagnosed with even benign Spitz tumors should be followed similarly to other melanoma patients, as they may be at risk for new primary melanomas over time. Prognostic factors in adult spitzoid melanoma are again similar to those in conventional melanoma. Tumor thickness remains important: adults with truly malignant Spitz tumors that are very thick or ulcerated have a higher chance of recurrence or metastasis. In older adults (specifically those over 50 years) who present with a Spitz-like melanoma, it is essential to consider the possibility that it is a conventional melanoma with spitzoid morphology (which pathology reports might refer to as “melanoma with spitzoid features”), which tends to behave as aggressively as comparably staged ordinary melanoma [28]. For instance, in the Moysset, et al [8]. study, their category of “melanoma with spitzoid features” that harbored BRAF/NRAS mutations included several adult patients, and those tumors led to metastasis and one death, as noted earlier [8]. Thus, molecular analysis in adults is also valuable to discern true Spitz melanoma (which often has fusions and possibly a better outlook) from melanoma not otherwise specified that histologically resembles Spitz (which often carries conventional mutations and a typical melanoma prognosis). From a management standpoint, adult patients with ASTs or SM are generally treated following melanoma guidelines. Wide local excision with appropriate margins is indicated for any Spitz lesion diagnosed as melanoma or deemed uncertain but high-risk. SLNB is often recommended for spitzoid melanomas greater than 1 mm thick in adults, as it would be for any melanoma, with about 20–30% showing a positive node (though numbers are smaller than in children) [29]. If nodes are positive, adjuvant therapy decisions (such as immunotherapy) are made on a case-by-case basis due to the indolent nature in many cases; there is no consensus, and while some patients are observed, others with multiple positive nodes or extracapsular spread might receive interferon or checkpoint inhibitors, similar to conventional melanoma protocols [30].

Implications for Follow-up and Therapy

The generally favorable outcomes for both pediatric and adult patients with SM, compared to those with conventional melanoma at similar stages, are encouraging. However, this presents a complex challenge in management. It raises important questions: Do all patients require complete lymph node dissection or adjuvant therapy if their only sign of spread is a positive sentinel node? Should children with AST or SM be spared aggressive therapies, given their excellent survival rates? These questions remain under investigation. Current practices tend to be conservative, leaning towards treatment, because criteria for reliably distinguishing which spitzoid melanomas will exhibit aggressive behavior are still being refined. However, risk stratification is improving with the use of molecular markers. For instance, an AST in a child that is FISH-negative, p16-positive, PRAME-negative, and carries an isolated ALK fusion could be considered to have minimal malignant potential—such a patient might be treated with surgery alone and observed. In contrast, an AST in an adult that is FISH-positive for 6p25 gain and harbors a TERT mutation should likely be treated as melanoma, with complete staging and consideration of adjuvant therapy [8,14].

No discussion of outcomes is complete without acknowledging the role of targeted therapy in advanced cases of SM. While most cases do not progress to this stage, a subset of patients, particularly those with high-risk molecular alterations, have been treated with targeted agents. Case reports have shown that children with meta static ALK-fused Spitz melanoma responded favorably to ALK inhibitors, and tumor regression has been observed in a teenager with MAP3K8-rearranged melanoma who was treated with a MEK inhibitor [16]. Immunotherapy, such as anti-PD-1 checkpoint inhibitors, has demonstrated a 30–60% survival rate at 1.5 years in patients with advanced stage IV melanoma [31]. Although specific data on the use of immunotherapy for SM are limited due to its rarity, it shows promise in metastatic cases. Fortunately, the need for systemic therapy in SM is uncommon. For long-term follow-up, experts recommend that patients with AST or spitzoid melanoma undergo regular skin examinations for life, similar to other melanoma survivors [22]. Pediatric patients should transition to adult melanoma clinics when they reach adulthood, since their initial tumor is unlikely to recur after a long disease-free interval. However, their risk of developing new melanomas (whether Spitz or conventional) may be elevated, particularly if they carry germline risk factors like MC1R variants or have high sun exposure.

This literature review consolidates ten years of insights into spitzoid melanoma, emphasizing how our understanding of these complex tumors has become more nuanced and multidisciplinary. Several major themes emerge from the data. First, the accurate diagnosis of SM remains challenging, although it has improved with the use of adjunctive tools. Traditional diagnostic criteria—symmetry, cell morphology, maturation, and mitotic activity—are still fundamental. However, we now recognize that some spitzoid melanomas can deviate from these expected “rules.” For instance, certain lesions may appear symmetric and deceptively bland-looking [32]. Incorporating dermoscopic evaluation has significantly aided clinicians in identifying lesions that warrant excision. Additionally, ancillary tests like FISH and IHC, particularly using PRAME, provide objective data to either support or challenge a malignant diagnosis. The finding that PRAME expression strongly correlates with malignant behavior in Spitzoid neoplasms is especially important; many pathology laboratories have incorporated PRAME IHC for routine evaluation of atypical Spitz tumors. For instance, a PRAME-negative result can reassure clinicians that a lesion is likely benign (or at least low risk), while a positive PRAME result would suggest a need for more aggressive treatment and follow-up [14]. Similarly, the routine incorporation of a 9p21 FISH probe to detect CDKN2A deletions in ambiguous Spitz tumors can reveal cases with a higher likelihood of melanoma that may have been overlooked by the original 4-probe FISH assay [8].

Moreover, next-generation sequencing (NGS) has revolutionized the classification of Spitz tumors. Our review indicates that pathologists achieve much higher agreement when genomic data is available in diagnosing spitzoid lesions [4]. This was convincingly demonstrated in studies involving both expert groups and general pathologists [4]. Therefore, a practical recommendation is that any Spitz lesion exhibiting atypical features, especially in an older patient, should be considered for molecular sequencing. Many academic centers now utilize targeted NGS panels that cover hotspots in BRAF, NRAS, HRAS, NF1, TERT, and fusion detection through RNA sequencing as part of their evaluation for challenging melanocytic lesions [4]. The information obtained not only aids in diagnosis but also informs prognosis and potential treatment strategies Table 2 [33]. Recent advancements in the molecular understanding of spitzoid melanoma have significant clinical implications. The discovery of recurrent kinase fusions in Spitz neoplasms helps explain why many of these tumors behave less aggressively; some of these fusions drive proliferative lesions that do not possess the full malignant potential of UV-mutated melanomas. In contrast, the identification of conventional melanoma mutations in a spitzoid tumor flags it as high risk. Our review highlighted how the presence or absence of BRAF and NRAS mutations is now used to stratify patients in certain centers [8]. The most exciting aspect of these developments is their therapeutic potential.

Table 2: Summary of Evolving Concepts in Spitzoid Melanoma.

As precision oncology continues to evolve, even rare melanoma subtypes can benefit. For instance, a child diagnosed with metastatic SM in 2025 might undergo comprehensive genomic profiling. If an ALK fusion is found, the child could receive ALK inhibitor therapy instead of, or in addition to, standard immunotherapy. Such scenarios were merely hypothetical a decade ago, but advancements in case reports and small series have made them more feasible [16]. Our review also pointed out MAP3K8 as a targetable event unique to Spitz tumors—an insight that emerged from sequencing efforts [16]. While clinical trials specifically for pediatric melanoma are still exceedingly rare, as more molecular data accumulates, there may be justification for enrolling pediatric spitzoid melanoma patients in basket trials— for example, trials of NTRK inhibitors for any tumor with an NTRK fusion, etc. Regarding clinical outcomes, the evidence presents an overall positive message: patients with spitzoid melanoma, particularly children and young adults, tend to do very well with appropriate surgical management. The low melanoma-specific mortality rate in this group is notable [22]. This suggests that historically treating all SMs as one would a similarly thick conventional melanoma may result in overtreatment in many cases. For example, many pediatric oncology centers have shifted away from automatically administering adjuvant interferon or targeted therapy to children with metastatic Spitz tumors, opting instead for careful observation following surgical clearance. The data we reviewed (e.g., Pampena, et al. [5,22]) support a more cautious approach for low-risk cases [5,22].

However, caution is warranted: some SMs behave aggressively and can be fatal, and our ability to predict which cases will be is not perfect. Features like ulceration and TERT mutations are useful red flags, but not all lethal cases exhibit these features, nor do all cases with these features result in death [34]. Therefore, clinical judgment and patient preferences should guide management on a case-by-case basis. It is also important to note that long-term outcomes beyond 10 to 15 years for these tumors are not well documented in the literature. A child with an atypical Spitz tumor who is disease-free at five years could still, in theory, develop a recurrence or a new melanoma later in adulthood [20]. Ongoing surveillance into adulthood is therefore recommended. From a clinical practice perspective, this review emphasizes the necessity of a multidisciplinary approach to spitzoid melanocytic lesions. Collaboration among dermatologists, dermatopathologists, pediatric oncologists, and surgical oncologists is often needed. Discussions at a tumor board are frequently beneficial for specific cases, as they weigh pathology results (along with any ancillary studies) against the clinical context. Integrating molecular pathology into these discussions is a relatively new development; molecular results should be clearly communicated in pathology reports so clinicians can understand their significance [35]. For instance, a report might state: “Mutation analysis: HRAS Q61R mutation detected; no BRAF, NRAS, or TERT mutations; supports classification as atypical Spitz tumor.”

This reassures regarding the prognosis. Conversely, a report stating: “Mutation analysis: BRAF V600E detected; this finding, along with homozygous 9p21 loss by FISH, supports a diagnosis of spitzoid melanoma,” conveys a high-risk assessment, which indicates the need for more aggressive treatment [18,36]. Our review also identifies several gaps and controversies in this field. One significant controversy is the management of sentinel lymph node-positive Spitz tumors. Sentinel node biopsy is routinely performed for melanomas thicker than 1 mm in adults and often in pediatric melanoma as well. However, a positive node in SM does not carry the same prognostic weight as it does in typical melanoma. Some experts argue that SLNB may not be necessary for certain Spitz tumors to avoid subjecting children to unnecessary surgery [5]. Others argue that SLNB remains valuable for staging and later preventing regional recurrences. There is currently no consensus on this issue, and practices vary. The MSLT trials that established the prognostic value of SLNB in melanoma did not specifically analyze Spitz subtypes due to their rarity [37]. Therefore, clinicians must make individualized decisions in these cases. Given the high rate of nodal positivity alongside low mortality, some propose that completion lymph node dissection can be avoided even if the sentinel lymph node is positive (a strategy now common in adult melanoma, based on MSLT-II trial results), with close ultrasound surveillance of the lymphatic basin deemed sufficient.

This approach has already been implemented in some pediatric centers, with reportedly positive outcomes, though data on its effectiveness remain limited. One significant gap in our understanding is establishing an optimal definition and nomenclature for borderline cases. The term “atypical Spitz tumor” is a convenient descriptor but does not accurately convey specific biological characteristics or necessary treatment protocols. Some authors have proposed a grading system for ASTs based on histologic and molecular features, categorizing them as low, intermediate, or high risk. For instance, a lowrisk AST might be treated similarly to a SN, which typically involves simple excision. In contrast, a high-risk AST would require treatment akin to that for melanoma. Developing and validating such a grading system is a research priority and will likely require international collaboration due to the rarity of these cases. The work by Moysset et al. is a step toward this goal by classifying “BAMS” (BRAF-mutated atypical Spitz tumors, biologically benign) and “MSF” (mutated spitzoid melanomas, biologically malignant) apart from other cases [8]. Future studies incorporating gene expression profiling or other genome-wide techniques may help identify signatures predictive of metastasis, thus refining our risk stratification [20]. Additionally, the role of genetic predisposition warrants further investigation. We have learned that moderate-risk alleles, such as MC1R, are common in pediatric cases [2]. A recent epidemiological review by Hagstrom, et al. [38] suggested that while Spitz neoplasms have not decreased in the molecular era, our ability to identify truly dangerous cases has improved [38]. This raises the question of whether certain patients, such as those with multiple atypical nevi or a family history of melanoma, might benefit from closer dermatologic monitoring after being diagnosed with a benign Spitz nevus. Conversely, children without any risk factors who develop a solitary SN may have virtually no chance of developing melanoma. These hypotheses require data to validate. Finally, we must consider the psychosocial impact on patients and their families. Informing parents that their young child has “melanoma” can be distressing, given the profound implications associated with the term. It can be challenging to explain that “this type of melanoma (Spitz) is unlike typical melanoma and is unlikely to be fatal.” Some families may opt for aggressive treatment due to understandable anxiety. In contrast, others might feel confused if, after further expert review or molecular testing, a diagnosis is downgraded to “Spitz tumor, probably benign.” This situation underscores the need for clear communication and perhaps a distinct terminology when discussing these cases with patients, one that conveys both the uncertainty and a generally favorable prognosis. For instance, explicitly using the term “Spitz tumor” when appropriate, rather than “melanoma,” could aid in this communication. A multidisciplinary approach with psychosocial support can help families navigate these complex decisions.

Spitzoid melanocytic neoplasms include conditions ranging from benign Spitz nevi to malignant spitzoid melanomas. The last ten years have brought substantial progress in diagnostic standardization and molecular research, enhancing our understanding of lesion behavior across different age populations. Spitzoid melanomas demonstrate significant regional lymph node involvement despite having low mortality rates among children and adolescents who rarely develop this condition. This paradox challenges conventional melanoma management strategies. Adult SMs occur rarely yet usually result in positive clinical outcomes. Doctors must perform comprehensive evaluations to distinguish conventional melanomas that display comparable characteristics from other types. The contemporary optimal diagnostic method combines histopathological examination with dermoscopic observations alongside additional molecular testing. By implementing a multifaceted approach, clinicians achieve better accuracy in differentiating atypical Spitz tumors from true melanomas, enabling them to reassure and monitor patients or initiate aggressive treatments. The routine use of next-generation sequencing and advanced IHC techniques like PRAME testing marks a step forward in dermatopathology that enhances patient care by minimizing overdiagnosis and underdiagnosis risks. Molecular pathology research has established spitzoid melanoma as a separate genetic entity. The disease stands apart from adult melanoma because of its common kinase fusions and lack of UV signature mutations, which enable targeted treatments in exceptional cases of progression.

The biological differences of SMs explain why they tend to grow more slowly than other types. Identifying high-risk molecular features like TERT promoter mutations or BRAF/NRAS mutations remains essential because these features correlate with aggressive disease progression and demand intensive treatment. Most patients with spitzoid melanoma achieve excellent long-term outcomes, which reassures clinicians. Nonetheless, ongoing vigilance is important. Patients and their parents require education about sun protection and melanoma symptoms. Patients need lifelong skin examination follow- ups because they may develop new melanomas later in life. Centralized expert review of Spitz tumors should be conducted, especially for pediatric cases, since expert consensus coupled with molecular analyses can dramatically change treatment approaches in specific cases. Prospective research studies must focus on atypical Spitz tumors to test risk-stratification models that combine histological analysis with immunohistochemical and genetic data. Using collaborative registries will allow researchers to collect adequate cases for generating statistically valid treatment strategy conclusions regarding SLNB necessity and adjuvant therapy benefits in specific cases. Investigating new targeted and immune-based treatments for SM especially in advanced cases shows promise because patients with this rare cancer could benefit from clinical trials that target their unique tumor mutations or fusions. Spitzoid melanoma demonstrates how modern dermatology and oncology benefit from multidisciplinary expertise and personalized tumor evaluation to improve patient outcomes. Using rigorous diagnostic standards and molecular diagnostic methods enables clinicians to prevent unnecessary treatment for young patients and sustain high survival outcomes. Our growing knowledge base on SM will drive the development of more effective treatment strategies that aim to cure patients while reducing unnecessary side effects efficiently. Research findings from spitzoid melanoma show potential applicability to other uncommon melanoma types, which demonstrates why personalized treatment plans are crucial in cancer treatment.

The authors declare no conflicts of interest.

Conceptualization, C.P.; methodology, C.P.; software, C.P.; validation, C.P., A.E., and A.G.; formal analysis, C.P. and A.E.; investigation, C.P. and A.E.; resources, C.P.; data curation, C.P.; writing—original draft preparation, C.P. and A.E.; writing—review and editing, A.G. and C.P..; visualization, C.P.; supervision, A.G.; project administration, C.P. All authors have read and agreed to the published version of the manuscript.

This research received no external funding.

Not applicable.

Not applicable.

Not applicable.

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