Scholarlink

Background <p>Congenital giant melanocytic nevi (CGMN) are rare melanocytic proliferations present at birth, associated with an increased risk of pediatric malignant melanoma (MM). Melanomas arising within CGMN are uncommon but clinically aggressive, with diagnostic challenges due to overlapping histopathological features with benign proliferations. This case series explores the clinicopathologic, molecular, and therapeutic profiles of three pediatric patients with MM arising in CGMN.</p> Methods <p>An integrated analysis—including histopathology, immunohistochemistry, mutational profiling <i>(NRAS</i>, <i>BRAF</i>, <i>PRKAR1A</i>), copy number variation (CNV) analysis, and DNA methylation profiling using the classifier developed at the German Cancer Research Center (DFKZ) in Heidelberg—was performed on tumor and matched nevus samples.</p> Results <p>All tumors harbored MAPK pathway alterations, including <i>NRAS Q61</i> mutations or <i>BRAF</i> fusions. DNA methylation profiling confirmed malignant transformation, while matched nevi clustered as melanocytoma with flat CNV profiles. Immunotherapy with checkpoint inhibitors (nivolumab ± ipilimumab) was used in all cases despite low PD-1/PD-L1 expression. However, therapeutic response was inconsistent, and two patients developed severe immune-related hepatitis requiring treatment discontinuation. Only one patient remains in remission. Epigenomic analyses revealed that benign and malignant components shared a close clustering pattern, suggesting a common cellular origin and patient-specific epigenetic imprinting.</p> Conclusion <p>MM arising within CGMN poses diagnostic and therapeutic challenges. While molecular and epigenomic profiling supports accurate classification and understanding of disease biology, the role of immunotherapy remains uncertain—marked by reduced efficacy and significant immune-related toxicity. A multidisciplinary approach is essential to guide management and improve outcomes in this rare pediatric malignancy.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Epigenomic characterization and therapeutic challenges of melanoma arising in giant nevi in pediatric patients

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月25日

查看全文
  • Evelina Miele,
  • Sabrina Rossi,
  • Alessandra Stracuzzi,
  • Sara Patrizi,
  • Sabina Barresi,
  • Marta Cajozzo,
  • Lucia Pedace,
  • Isabella Giovannoni,
  • Fabio Dell’Otto,
  • Andrea Diociaiuti,
  • Francesca Grussu,
  • Flavia Vinciarelli,
  • Alessandro Crocoli,
  • Aurora Castellano,
  • Maria Carmen Garganese,
  • Angela Mastronuzzi,
  • Franco Locatelli,
  • Rita Alaggio,
  • May El Hachem,
  • Mario Zama,
  • Maria Debora De Pasquale

摘要

Background

Congenital giant melanocytic nevi (CGMN) are rare melanocytic proliferations present at birth, associated with an increased risk of pediatric malignant melanoma (MM). Melanomas arising within CGMN are uncommon but clinically aggressive, with diagnostic challenges due to overlapping histopathological features with benign proliferations. This case series explores the clinicopathologic, molecular, and therapeutic profiles of three pediatric patients with MM arising in CGMN.

Methods

An integrated analysis—including histopathology, immunohistochemistry, mutational profiling (NRAS, BRAF, PRKAR1A), copy number variation (CNV) analysis, and DNA methylation profiling using the classifier developed at the German Cancer Research Center (DFKZ) in Heidelberg—was performed on tumor and matched nevus samples.

Results

All tumors harbored MAPK pathway alterations, including NRAS Q61 mutations or BRAF fusions. DNA methylation profiling confirmed malignant transformation, while matched nevi clustered as melanocytoma with flat CNV profiles. Immunotherapy with checkpoint inhibitors (nivolumab ± ipilimumab) was used in all cases despite low PD-1/PD-L1 expression. However, therapeutic response was inconsistent, and two patients developed severe immune-related hepatitis requiring treatment discontinuation. Only one patient remains in remission. Epigenomic analyses revealed that benign and malignant components shared a close clustering pattern, suggesting a common cellular origin and patient-specific epigenetic imprinting.

Conclusion

MM arising within CGMN poses diagnostic and therapeutic challenges. While molecular and epigenomic profiling supports accurate classification and understanding of disease biology, the role of immunotherapy remains uncertain—marked by reduced efficacy and significant immune-related toxicity. A multidisciplinary approach is essential to guide management and improve outcomes in this rare pediatric malignancy.