Hepatoblastoma (HB) is a rare primary malignancy of the developing fetal liver. Its course is profoundly influenced by genetics, in the context of sporadic mutation or genetic syndromes. Conventionally, subtypes of HB are histologically determined based on the tissue type that is recapitulated by the tumor and the direction of its differentiation. This classification is being reevaluated based on advances on molecular pathology. The therapeutic approach comprises surgical intervention, chemotherapy (in a neoadjuvant or post-operative capacity), and in some cases, liver transplantation. Although diagnostic modalities and treatment options are evolving, some patients experience complications, including relapse, metastatic spread, and suboptimal response to chemotherapy. As yet, there is no consistent framework with which such outcomes can be predicted. N6-methyladenosine (m6A) is an RNA modification with rampant involvement in the normal processing of cell metabolism and neoplasia. It has been observed to impact the development of a variety of cancers via its governance of gene expression. M6A-associated genes appear prominently in HB. Literature data seem to underscore the role of m6A in promotion and clinical course of HB. Illuminating the pathogenetic mechanisms that drive HB are promising additions to the understanding of the clinically aggressive tumor behavior, given its potential to predict disease course and response to therapy. Implicated genes may also act as targets to facilitate the evolving personalized cancer therapy. Here, we explore the role of m6A and its genetic associates in the promotion of HB, and the impact this may have on the management of this neoplastic disease.
Hepatoblastoma (HB) is the most common malignancy within the rare cohort of pediatric primary liver tumors. It may arise sporadically or in association with germline mutations in specific genetic syndromes. Histogenesis recapitulates fetal hepatic development, however, this tumor can exhibit a markedly heterogeneous appearance both macroscopically and under the microscope. Histologic subtypes are classified based on morphologic appearance, with additional discrimination based on emerging molecular and immunohistochemical features. Numerous diagnostic pitfalls exist from clinical presentation through to ancillary testing; at all stages, the surgical pathologist must be discerning and open to collaboration with colleagues of different specialties. Problematic areas include the adequacy of tissue sampling, correlation of histology with radiologic appearance and alpha feto-protein (AFP) serology, forming a diagnostic consensus within the pediatric pathology community and choosing a shrewd immunohistochemical panel. This review discusses the sequence of events leading up to histologic assessment, and the nuances of microscopic evaluation. Along the way, pitfalls are highlighted, providing a tool for the surgical pathologists to support their individual approach.
Subnuclear vacuoles in the proximal renal tubules have been reported as a histologic sign of ketoacidosis. Originally described in diabetic ketoacidosis, renal vacuoles can be found in other ketogenic states such as alcoholic ketoacidosis (AKA), starvation, and hypothermia, underpinned by deranged fatty acid metabolism. A retrospective analysis of 133 deaths associated with alcohol use disorder (AUD) examined at autopsy between 2017 and 2020 was undertaken. This study aimed to determine the prevalence of subnuclear vacuoles in deaths of those with AUD and their specificity for deaths from AKA, and to elucidate what demographic, biochemical, and pathologic findings are associated with subnuclear vacuoles. In each case, vitreous humor biochemistry including electrolytes, glucose, and beta‐hydroxybutyrate (BHB) was analyzed alongside postmortem hemoglobin A1c and renal and liver histology. Renal histology was graded for the presence of vacuoles as absent (0), scanty (1), or easily identifiable (2). Liver histology was graded for steatosis and for fibrosis if Masson trichrome staining was available. Vacuoles were commonly seen in the deaths of those with AUD. They were seen in deaths due to AKA but were not specific to that cause of death. With vacuoles present, lower vitreous sodium (139 vs. 142 mmol/L; p = 0.005), higher vitreous BHB (1.50 vs. 1.39 mmol/L; p = 0.04), severe hepatic steatosis, and severe hepatic fibrosis were seen, compared with those without renal vacuoles.
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