Background:Sarcomatoid variant of UTUC (S-UTUC) is a rare and aggressive malignancy. Due to the paucity of reported literature, the molecular landscape and potentially targetable alterations harbored by these tumors are not well described. We aimed to comprehensively compare the clinical, pathological, and genomic profiles of S-UTUC and conventional UTUC.

Methods:We leveraged the Tempus LENS genomic dataset to extract clinical, pathologic, and somatic genomic alteration data from patients with UTUC and S-UTUC. Patients with any-stage disease who underwent either blood- or tissue-based next-generation sequencing were included. Baseline clinical and demographic characteristics were summarized using descriptive statistics. Comparisons between groups were performed using Chi-square or Fisher’s exact tests for categorical variables, and Student’s t-test or ANOVA for continuous variables, as appropriate. Mutational frequencies and pairwise comparisons were performed to assess significant differences between histological groups.

Results:In total, 1721 patients were included, of which 1600 (93%) had UTUC and 121 (7%) had S-UTUC. Patients with S-UTUC were younger at diagnosis, 61 years (IQR 54, 69), compared to UTUC (71 years, IQR 64, 77) (p < 0.001). Compared to UTUC, patients with S-UTUC were more likely to have node-positive (24% vs 10%), pT4 (13% vs 11%), and stage 4 disease (37% vs 0.5%) (all p < 0.05). Patients with S-UTUC were more likely to have visceral metastasis to the lung (44% vs 30%), bone (19% vs 10%), and brain (7% vs 1%) compared to patients with UTUC (all p < 0.05). Among patients with S-UTUC, the most common genomic alterations were TERT (30%), TP53 (29%), NF2 (19%), PTEN (13%), SETD2 (12%), PBRM1 (12%), and BAP1 (8%). Among patients with UTUC, the most common genomic alterations were TERT (52%), TP53 (52%), KMT2D (30%), FGFR3 (25%), ARID1A (20%), and KDM6A (18%). S-UTUC group was significantly enriched with NF2, SETD2, PBRM1, PTEN, and BAP1 (all p < 0.05), with lower prevalence of FGFR3 (0% vs 8%) and FGFR4 (0% vs 8%) mutations compared to UTUC (both p < 0.05). Alterations in genes with potentially actionable targets were observed in S-UTUC, including NF2 (19%), SETD2 (12%), PTEN (13%), and PI3KCA (2%).

Conclusions:Compared to UTUC, S-UTUC demonstrated a more aggressive clinical and genomic profile, characterized by a younger age at onset, more aggressive metastatic tropism, relative enrichment in NF2, SETD2, PTEN and PI3KCA alterations, and an absence of FGFR-family mutations. These findings underscore the divergent molecular landscape of S-UTUC and highlight potentially targetable genomic alterations to guide precision oncology strategies for this rare disease.

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