RESUMEN
Current knowledge on the molecular landscape of pancreatic neuroendocrine tumors (PanNETs) has advanced significantly. Still, the cellular origin of PanNETs is uncertain and the associated mechanisms remain largely unknown. DAXX/ATRX and MEN1 are the three most frequently altered genes that drive PanNETs. They are recognized as a link between genetics and epigenetics. Moreover, the acknowledged impact on DNA methylation by somatic mutations in MEN1 is a valid hallmark of epigenetic mechanism. DAXX/ATRX and MEN1 can be studied at the immunohistochemical level as a reliable surrogate for sequencing. DAXX/ATRX mutations promote alternative lengthening of telomeres (ALT) activation, determined by specific fluorescence in situ hybridization (FISH) analysis. ALT phenotype is considered a significant predictor of worse prognosis and a marker of pancreatic origin. Additionally, ARX/PDX1 expression is linked to important epigenomic alterations and can be used as lineage associated immunohistochemical marker. Herein, ARX/PDX1 association with DAXX/ATRX/MEN1 and ALT can be studied through pathological assessment, as these biomarkers may provide important clues to the mechanism underlying disease pathogenesis. In this review, we present an overview of a new approach to tumor stratification based on genetic and epigenetic characteristics as well as cellular origin, with prognostic consequences.
RESUMEN
BACKGROUND: Thyroid dysfunction (TD) was usually described in hematopoietic stem cell transplantation (HSCT) recipients who were given total body irradiation (TBI) in the conditioning regimen. Because previous studies have reported discrepant results regarding the presence of long-term thyroid complications in HSCT survivors following chemotherapy-only conditioning, we investigated the frequency of thyroid abnormalities in a series of children treated with HSCT for different disorders without TBI as part of the conditioning protocol. METHODS: We compared thyroid-stimulating hormone, free thyroxine, total triiodothyronine (TT3), anti-peroxidase (TPO Ab) and anti-thyroglobulin antibodies and thyroid volume z-score in 28 HSCT survivors and 16 healthy subjects matched for age and sex. RESULTS: HSCT recipients had a higher frequency of TD and thyroid complications in total, including TD and euthyroid Hashimoto thyroiditis, compared to the control group. Patients transplanted for Hodgkin lymphoma (HL) were more likely to develop a thyroid complication compared to patients with non-malignant hematologic diseases and leukemia patients. BEAM (carmustine, etoposide, citarabin and melphalan) conditioning compared to busulfan (Bu) and fludarabine (Flu)-based regimens and autologous compared to allogenic grafting were associated with a higher prevalence of TD in our study. HSCT survivors had higher mean serum TT3 levels. A multivariate analysis revealed that autologous (auto)-HSCT recipients had higher mean serum titers of TPO Ab compared to allogenic (allo)-HSCT recipients and controls and the mean thyroid volume z-score was significantly higher in controls compared to auto-/allo-HSCT survivors. CONCLUSIONS: We identified a 35.7% prevalence of thyroid abnormalities, emphasizing the need for a long-term surveillance of thyroid function and morphology even in this group of patients who were not exposed to TBI.
