Francesca Signorini

The 2022 WHO classification gives more importance to the integration of morphological and molecular characteristics of tumors, introducing new diagnostic criteria for papillary thyroid carcinoma (PTC). The invasive encapsulated follicular variant of PTC (IEFVPTC) is now considered a separate entity and no longer a subtype of PTC, while the infiltrative follicular variant (IFVPTC) is still considered a PTC subtype. The separation of invasive encapsulated follicular variants from PTCs implies that differential diagnosis between IEFVPTC and IFVPTC can be difficult. We performed a gene expression analysis by NanoString technology on 23 PTCs, divided into 11 IEFVPTCs and 12 IFVPTCs. We focused our attention on the possible role of the tumor microenvironment (TME) and, in particular, the role of the extracellular matrix (ECM). IFVPTC, compared to IEFVPTC, showed a statistically significant downregulation of 2 genes and an upregulation of 45. Among these genes, we focused our attention on TIMP2 and COL1A2, whose high upregulation was statistically significant in IFVPTC. TIMP2 and COL1A2 are involved in ECM degradation and synthesis and in collagen biosynthesis and modification. The ECM and collagen alterations in IFVPTC could reflect the different tumor behavior of FVPTCs, allowing the identification of new biomarkers to distinguish IEFVPTC from IFVPTC.

Papillary thyroid cancer (PTC) is linked to obesity, but the biological mechanisms that may explain this connection have been only partially described. Potential factors that combine overweight/obesity with this cancer should be searched for in the immune pathways and chronic inflammation onset. In this study, we evaluated the role of the immune system in patients affected by PTC and stratified them according to Body Mass Index (BMI). An analysis of the expression profiles of >700 immune-related genes was performed in 36 PTCs, subdivided into four categories: underweight (A), normal weight (B), overweight (C), and subjects living with obesity (D). B was considered a reference category. In our study, the immune microenvironment of PTCs did not seem strongly influenced by BMI. However, based on the interaction from in silico protein–protein analysis, we found that the dysregulation profiles of groups A or D were similar as concerns pathways involved in T-cell differentiation, macrophage activation, regulation of the cell cycle, and senescence processes. Furthermore, we found significant downregulation of HMGB1 in the A and D categories, with upregulation of ARG2 in the D category. Although further studies are necessary, these genes may provide an opportunity to better understand immunometabolism in thyroid cancer.

The tall-cell variant of papillary thyroid carcinoma (TCPTC) is the most common aggressive variant of papillary thyroid carcinoma (PTC) and typically occurs in older patients. In this study, we analyzed retrospectively the largest mono-institutional series of PTCs with tall-cell features (989 patients) over a 17-year period, re-evaluating tumors based on age at presentation and outcomes in different age groups. We divided patients into three age groups following different criteria (the criterion from the American Joint Committee on Cancer Tumor Node Metastasis (AJCC TNM) guidelines, criterion for the statistical division into tertiles and adolescent/post-adolescent criterion) to analyze the clinicopathological characteristics in different age groups, especially in terms of recurrence-free survival (RFS) and distant recurrence-free survival (DRFS). We obtained three main results: 1. the population is distributed among the different age groups, and therefore, this type of cancer is not exclusively found among those of an older age; 2. in the RFS analysis, we can see a higher probability of local recurrence in the younger and older groups and, unexpectedly, a lower probability of local recurrence in the “median age” group; and 3. in the DRFS analysis, we can observe a higher probability of distant recurrence in older patients. From a molecular perspective, no significant differences in the mutational status of BRAF were detected according to different age groups, while mutations in the TERT promoter were exclusively present in older patients of all age groups, highlighting the potential prognostic implications of TERT promoter mutations in PTCs. In conclusion, the results of this series confirm that TC morphology alone in PTCs does not have the same negative prognostic significance in the younger population as in the older population. The reason for these different outcomes remains unclear and needs further studies.

Introduction: In recent years, there has been a growing development of molecularly targeted therapies for various types of solid tumors—in particular, in non-small-cell lung cancer (NSCLC). This has required the need for greater quantities of tissue that is able to support ancillary studies, alongside cyto-histological diagnoses for the assessment of molecular targets. Conventional TBNA (cTBNA) and EBUS-guided TBNA (EBUS-TBNA) have shown a high diagnostic yield for malignant mediastinal and/or hilar lymph node enlargement and peribronchial masses; however, few studies have compared these two procedures. We retrospectively compared TBNA patients (EBUS-TBNA and cTBNA) in order to determine the diagnostic yield and material adequacy for subsequent ancillary analyses. Materials and Methods: We retrospectively evaluated 318 patients with clinical suspicion of lung cancer or with disease recurrence. All of the patients underwent TBNA (either EBUS-TBNA or cTBNA) on enlarged mediastinal and/or hilar lymph nodes and peribronchial masses between January 2017 and June 2021 at the University Hospital of Pisa, Italy. After a definitive diagnosis, molecular analyses and an evaluation of PD-L1 expression were performed in the cases of adenocarcinoma, squamous cell carcinoma, and NSCLC, not otherwise specified (NOS). Results: EBUS-TBNA was performed in 199 patients and cTBNA was performed in 119 patients with 374 and 142 lymph nodes, respectively. The overall diagnostic yield for positive diagnoses was 59% (diagnostic rate of 61% in EBUS-TBNA, and 55% in cTBNA). Adenocarcinoma (ADC) was the most frequent diagnosis in both methods. EBUS-TBNA diagnostic adequacy was 72% for molecular analysis, while it was 55.5% for cTBNA, showing a statistical trend (p = 0.08) towards the significance of EBUS. The average percentage of neoplastic cells was also statistically different between the two methods (p = 0.05), reaching 51.19 ± 22.14 in EBUS-TBNA and 45.25 ± 22.84 in cTBNA. With regard to the PD-L1 protein expression, the percentage of positivity was similar in both procedures (86% in EBUS-TBNA, 85% in cTBNA). Conclusions: Conventional TBNA (cTBNA) and EBUS-guided TBNA (EBUS-TBNA) are minimally invasive diagnostic methods that are associated with a high diagnostic yield. However, EBUS-TBNA has an improved diagnostic adequacy for molecular analysis compared to cTBNA, and is associated with a higher average percentage of neoplastic cells.