Morphologic and genomic changes in clinical relapse of young onset tongue cancer.

e18133 Background: The morphological and genomic changes associated with relapse in young-onset tongue cancer remain unclear. Methods: Medical records of 107 patients aged <40 years with tongue squamous cell carcinoma were reviewed, and the patient characteristics, therapies, and clinical outcomes were analyzed. The pathological features of biopsied/resected specimens were characterized based on the tumor differentiation status, fibrosis, and immunostaining of p16. We performed next-generation sequencing on 16 paired primary and recurrent tumor samples from patients whose relapse was pathologically confirmed. Results: The age of the patients was 20–29 years in 33 patients and 30–39 years in 74 patients. The clinical stage was AJCC, stages 0–II in 68 patients (64%), and the well-differentiated pathological subtype was present in 74% of the cases. The 3-year overall survival (OS) rate in 107 young patients and the relapse-free survival (RFS) rate in 106 patients who underwent initial surgery were 80% and 71%, respectively. Patients with stages III to IV had worse OS and RFS than those with stages 0-II (3-year OS rate: 60% vs. 92%, P <0.001; 3-year RFS rate: 57% vs. 79%, P = 0.004). Thirty-three of the 106 patients (31%) experienced clinical relapse (with 25 with localized relapse and eight with metastatic relapse). Among the 33 patients with clinical relapse, 16 pairs were subjected to histopathological assessment and whole-exome sequencing. Twelve of the 16 paired specimens showed consistent tumor differentiation status between initial and relapsed samples (9 well-, 2 moderately-, and 1 poorly- differentiated tumors). Meanwhile, four pairs (25%) had altered differentiation status at relapse: two changed to differentiation, and two changed to dedifferentiation, including one case that relapsed as the scirrhous type. Immunostaining for p16, which suggests the involvement of human papillomavirus, was negative in all 16 pairs. Thirteen of the 16 pairs harbored mutations in either the initial or relapsed specimen. Concordant mutations were found in seven pairs (44%), including four with TP53 , one with concurrent TP53 and CDKN2A , one with CDKN2A , and one with PIK3CA . Discordant mutations were detected in five pairs (31%) as follows: two with TP53 , one with NOTCH1 , AJUBA and MAP4K3, one with PIK3CA and IPO7 , and one with FAT1 . At clinical relapse, out of eight discordant mutations, two mutations in TP53 and AJUB A emerged, while the other six mutations disappeared. No cases were found to harbor pathogenic germline variants associated with hereditary genetic syndromes. Conclusions: This analysis indicates that, in the context of clinical relapse, some cases exhibit unique morphological changes and clonal alterations in driver genes. TP53 -mutated clones were preserved in one-third of the cases. These findings provide insight into the molecular mechanisms underlying tumor relapse.