Background: Papillary thyroid carcinoma (PTC) is a rare malignancy in children and young adults (CAYA). It often presents with aggressive disease patterns and advanced stages, which are clinically distinct from those in adult patients. In this study, we sought to characterize and better understand the clinical variants of PTC in CAYA and explore the underlying mechanisms. Methods: CAYA patients (age ≤18 years) diagnosed with PTC between June 2006 and June 2018 were retrospectively recruited from five hospitals. Demographic information, pathological data, and follow-up status were recorded. Tumor samples obtained from 20 children (mean age 15.15 years) and 10 adults (mean age 38.80 years) underwent comprehensive whole transcriptome sequencing. Differentially expressed genes (DEGs), mutational landscape, and immune infiltration were analyzed. Results: A total of 217 CAYA-PTC patients (162 females and 55 males) with an average age of 14.38 ± 3.53 years (range 2-18) were included. Lymph node metastasis (LNM) was observed in 85.71%, of which 57.60% were in the lateral cervical compartment. Disease recurred in 28 of 217 (12.90%) patients with a median follow-up of 4.76 years. Multivariate logistic regression analysis revealed that age, bilateral disease, extrathyroidal extension, and coexisting Hashimoto's thyroiditis (co-HT) were independent risk factors for LNM, while co-HT was the only risk factor for recurrence. Using whole transcriptome sequencing of PTC tissues, we identified 301 DEGs. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses showed that differences in immune mediators played important roles, based on the distributions of mutation frequencies, types, and expression levels between CAYA and adult patients. Based on the integrated data sets, we identified significantly mutated immune genes, cluster of differentiation 24 (CD24), coagulation factor 12 (F12), coagulation factor 5 (F5), integrin subunit alpha 3 (ITGA3), and retinoic acid early transcript 1L (RAET1L), which were then verified by immunohistochemistry. Furthermore, resting mast cells, resting natural killer cells, plasma cells, and regulatory T cells were different in the CAYA-PTC group and correlated with the expression of immune checkpoints. Conclusions: There are considerable variabilities that may contribute to the different clinical presentations between CAYA and adult PTC patients, among which the decrease in protective immune cells may be a factor. Collectively, our results add to the possible biological mechanisms involved in CAYA-PTC.

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