The genetic signature in this cohort was remarkably different than that observed in adults. Although observed at a lower prevalence, the spectrum of mutations was quite similar to that described in radiation-exposed pediatric PTCs. As mutations were unidentifiable in over 40% of the PTC cases, more comprehensive studies conducted in these patients will help to decipher the genetic landscape of sporadic pediatric PTCs.

Data from the National Cancer Institute and from the literature have disclosed an increasing incidence of thyroid cancer in children, adolescents and adults. Although children and adolescents with thyroid cancer tend to present with more advanced disease than adults, their overall survival rate is excellent; however, there is no clear explanation for the differences observed in the clinicopathological outcomes in these age groups. There has been an ongoing debate regarding whether the clinicopathological differences may be due to the existence of distinct genetic alterations. Efforts have been made to identify these acquired genetic abnormalities that will determine the tumor's biological behavior and ultimately allow molecular prognostication. However, most of the studies have been performed in radiation-exposed pediatric thyroid carcinoma. Therefore, our understanding of the role of these driver mutations in sporadic pediatric differentiated thyroid cancer development is far from complete, and additionally, there is a strong need for studies in both children and adolescents. The aim of this review is to present an extensive literature review with emphasis on the molecular differences between pediatric sporadic and radiation-exposed differentiated thyroid carcinomas and adult population. Key Words" sporadic pediatric papillary thyroid carcinomas " radiation-exposed papillary thyroid carcinomas " RET/PTC

Background The incidence of thyroid carcinoma has increased in most populations, including pediatric patients. The increase is almost exclusively due to an increase in the incidence of papillary thyroid carcinoma (PTC). Genetic alterations leading to mitogen‐activated protein kinase (MAPK) pathway activation are highly prevalent in PTC, with BRAF V600E mutation being the most common event in adult PTC. Although a lower prevalence of BRAF V600E had been reported among pediatric patients, a higher prevalence of BRAF fusion has been identified in both radiation‐exposed and sporadic pediatric PTC. However, little is known about the prognostic implications of BRAF fusions in pediatric PTC. Procedure In this study, we investigated the prevalence of BRAF alterations (AGK‐BRAF fusion and BRAF V600E mutation) in a large set of predominantly sporadic pediatric PTC cases and correlate with clinicopathological features. Somatic AGK‐BRAF fusion was investigated by RT‐PCR and confirmed by FISH break‐apart. The BRAF V600E mutation was screened using Sanger sequencing. Results AGK‐BRAF fusion, found in 19% of pediatric PTC patients, was associated with distant metastasis and younger age. Conversely, the BRAF V600E, found in 15% of pediatric PTC patients, was correlated with older age and larger tumor size. Conclusion Collectively, our results advance knowledge concerning genetic bases of pediatric thyroid carcinoma, with potential implications for diagnosis, prognosis, and therapeutic approaches.

Thyroid cancer is the fastest increasing cancer worldwide in all age groups. Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer in both adults and children. PTC genomic landscape has been extensively studied in adults, but information regarding sporadic pediatric patients is lacking. Although BRAF V600E mutation is highly prevalent in adults, this mutation is uncommon in pediatric cases. As adult and pediatric PTC is a mitogen‐activated protein kinase‐driven cancer, this altered pathway might be activated by different genetic events. The aim of this study was to investigate the occurrence of AGK‐BRAF fusion gene, recently described in radiation‐exposed pediatric PTC, in a cohort of exclusively sporadic pediatric PTC. The series consisted of 30 pediatric PTC younger than 18 years of age at the time of diagnosis and 15 matched lymph node metastases (LNM). Primary tumors and matched LNM were screened for the presence of the AGK‐BRAF fusion transcript by RT‐PCR. To confirm the identity of the amplified products, randomly selected samples positive for the presence of the fusion transcripts were sequenced. Moreover, BRAF dual‐color, break‐apart probes confirmed BRAF rearrangement. Overall, the AGK‐BRAF fusion gene was detected in 10% (3/30) of primary tumors. For one of these cases, paired LNM was also available, which also shows the presence of AGK‐BRAF fusion gene. This study described, for the first time, the presence of AGK‐BRAF in sporadic pediatric PTC. Understanding the molecular events underlying pediatric PTC may improve preoperative diagnosis, allow molecular prognostication and define a therapeutic approach toward sporadic PTC patients.

Lymph node (LN) is a secondary lymphoid organ with highly organized and compartmentalized structure. LNs harbor B, T, and other cells among fibroblastic reticular cells (FRCs). FRCs are characterized by both podoplanin (PDPN/gp38) expression and by the lack of CD31 expression. FRCs are involved in several immune response processes but mechanisms underlying their function are still under investigation. Double-negative cells (DNCs), another cell population within LNs, are even less understood. They do not express PDPN or CD31, their localization within the LN is unknown, and their phenotype and function remain to be elucidated. This study evaluates the gene expression and cytokines and chemokines profile of human LN-derived FRCs and DNCs during homeostasis and following inflammatory stimuli. Cytokines and chemokines secreted by human FRCs and DNCs partially diverged from those identified in murine models that used similar stimulation. Cytokine and chemokine secretion and their receptors expression levels differed between stimulated DNCs and FRCs, with FRCs expressing a broader range of chemokines. Additionally, dendritic cells demonstrated increased migration toward FRCs, possibly due to chemokine-induced chemotaxis since migration was significantly decreased upon neutralization of secreted CCL2 and CCL20. Our study contributes to the understanding of the biology and functions of FRCs and DNCs and, accordingly, of the mechanisms involving them in immune cells activation and migration.