Undifferentiated Pleomorphic Sarcoma in Children and Young Adults: A Comprehensive Clinicopathologic, Genomic, and...

Undifferentiated pleomorphic sarcoma (UPS) occurs primarily in older adults and remains a diagnosis of exclusion due to its lack of differentiation and specific molecular alterations. Its occurrence in children is rare and controversial, with an unclear relationship to its adult counterpart. In this study, we aimed to investigate a cohort of 6 pediatric undifferentiated pleomorphic sarcoma (P-UPS, mean 10 years old) and 19 young-adult undifferentiated pleomorphic sarcoma (YA-UPS, mean 30 years old) cases by conducting a comprehensive comparative analysis of their clinicopathologic, genomic, and epigenetic features relative to their adult undifferentiated pleomorphic sarcoma counterparts (A-UPS, n = 100). Histologically, P-UPS and YA-UPS exhibited broad morphologic spectrum. The most frequent alterations across all groups were TP53, CDKN2A/B, and ATRX, with no significant differences among subsets. Notably, RB1 alterations were absent in P-UPS, although representing the second most common alteration in YA-UPS (32%) and A-UPS (41%). PTEN alterations were significantly more prevalent in YA-UPS (26%) compared with that in P-UPS (0%) and A-UPS (6%). Deletions in chromosomes 10, 16q, and 13q, along with amplification of 20q, were the most common across all groups. Except for a higher frequency of 17q amplification in P-UPS (33%) and YA-UPS (26%) compared with that in A-UPS (6%), no other arm-level differences were observed. P-UPS showed a lower mean fraction genome altered compared with YA-UPS and A-UPS, whereas all UPS age groups showed a low tumor mutational burden (mean <10 mut/MB). Pathogenic germline variants of high clinical significance (TP53, NF1, MLH1, CHEK2, and BARD1) were observed only in YA-UPS (31%) and A-UPS (12%) cases. By T-distributed stochastic neighborhood embedding and hierarchical clustering of DNA methylation, the majority of P-UPS and a small subset of YA-UPS grouped in a distinct cluster, characterized by a lower genomic index compared to A-UPS. In contrast, most UPS occurring in young adults genomically parallel their older adults' counterparts. P-UPS and YA-UPS cases exhibited a better disease-specific and progression-free survival, compared with A-UPS cases.