Background:Spitz tumors (STs) are a diverse group of melanocytic lesions that range from benign to malignant. STs pose significant classification challenges due to overlapping histological and immunohistochemical (IHC) features among the STs with different malignant potential. This study aimed to assess the diagnostic value of a melanoma-specific next-generation sequencing (NGS) panel (MelArray) combined with IHC analysis to improve the assessment of diagnostically challenging ST cases.Methods:Patients with STs and available MelArray results were included in this retrospective analysis. Molecular analysis (genetic alterations, tumor mutational burden (TMB), and copy number variations (CNV)), clinical data (demographics and clinical course), and IHC data (scores for markers such as p16, Ki-67, HMB45, PRAME, and Melan A) were evaluated in conjunction and correlated with patient outcomes.Results:Atypical Spitz tumors (ASTs,n= 20) predominantly exhibited heterozygous deletions in melanoma-relevant genes, but these were not accompanied by the multiple damaging mutations commonly associated with melanoma. IHC scores were higher in ASTs compared to Spitz nevi (SN,n= 3), suggesting an intermediate biologic potential. SN exhibited minimal genetic alterations and low IHC scores, reflecting a benign profile. Genetic analysis of the Spitz melanoma (SM,n= 1) revealed a distinct molecular profile with damaging mutations affecting the key regulatory pathways involved in tumor progression, along with a high TMB, and an IHC score comparable to ASTs. During a median follow-up of 36 months (range: 6–48 months,n= 23), no recurrences, distant metastases, or tumor-related deaths were observed.Conclusions:The integration of NGS analysis with the MelArray panel, histology, and immunohistochemistry, enhances the diagnostic accuracy of challenging STs by identifying the genetic alterations linked to malignancy risk. This aids in the detection of high-risk lesions that need a more detailed work-up and more stringent follow-up, and those that will follow a benign course. Larger studies are needed to validate the clinical utility and broader applicability.
背景：斯皮茨肿瘤（STs）是一组异质性黑色素细胞病变，其生物学行为从良性到恶性不等。由于不同恶性潜能的STs在组织学和免疫组化（IHC）特征上存在重叠，其分类面临重大挑战。本研究旨在评估一种黑色素瘤特异性二代测序（NGS）检测组合（MelArray）联合IHC分析在改善诊断困难性STs评估中的诊断价值。 方法：本研究为回顾性分析，纳入具有STs诊断及可用MelArray检测结果的患者。综合评估分子分析（基因改变、肿瘤突变负荷（TMB）和拷贝数变异（CNV））、临床数据（人口统计学和临床病程）以及IHC数据（p16、Ki-67、HMB45、PRAME和Melan A等标志物的评分），并将其与患者结局相关联。 结果：非典型斯皮茨肿瘤（ASTs, n=20）主要表现为黑色素瘤相关基因的杂合性缺失，但并未伴随通常与黑色素瘤相关的多重有害突变。与斯皮茨痣（SN, n=3）相比，ASTs的IHC评分更高，提示其具有中间型生物学潜能。SN显示出极少的基因改变和较低的IHC评分，符合良性特征。对斯皮茨黑色素瘤（SM, n=1）的基因分析揭示了一个独特的分子谱，其特征是影响肿瘤进展关键调控通路的有害突变，同时伴有高TMB，其IHC评分与ASTs相当。在中位随访36个月（范围：6-48个月，n=23）期间，未观察到复发、远处转移或肿瘤相关死亡。 结论：将NGS分析（MelArray组合）与组织学和免疫组化相结合，通过识别与恶性风险相关的基因改变，提高了诊断困难性STs的诊断准确性。这有助于识别需要更详细检查和更严格随访的高风险病变，以及那些将呈良性病程的病变。需要更大规模的研究来验证其临床效用和更广泛的适用性。
A Retrospective Analysis of Ambiguous Spitz Tumors Using Next-Generation Sequencing
肿瘤(癌症)患者之家