Pediatric soft tissue tumor pathology: A happy morpho-molecular union

Abstract

Since its foundation by remarkably talented and insightful individuals, prominently including Pepper Dehner, pediatric soft tissue tumor pathology has developed at an immense rate. The morphologic classification of tumoral entities has extensively been corroborated, but has also evolved with refinement or realignment of these classifications, through accruing molecular data, with many derivative ancillary diagnostic assays now already well-established. Tumors of unclear histogenesis, classically morphologically undifferentiated, are prominent amongst pediatric sarcomas, however, the classes of undifferentiated round- or spindle-cell-tumors-not-otherwise-specified are being dismantled gradually with the identification of their molecular underpinnings. Within recent years, for example, numerous subcategories of 'Ewing-like' round cell sarcoma have emerged. Such advances have provided the basis for novel diagnostic and prognostic sub-classifications. Efforts at defining cell- or lineage-of-origin for several tumor types have produced interesting insights especially for rhabdomyosarcoma. The remarkably early onset of pediatric sarcomas defies the theory necessitating stochastic accumulation of several somatic mutations for cancer development and indeed, these tumors may be remarkably genomically stable, often belying their aggressive nature. Much is coming to light recently regarding the role of epigenetic modifications in the evolution of these sarcomas. Indeed the morphologic features of embryonal tumors generally (not just sarcomas) may be highly reminiscent of arrested differentiation, and given the tight epigenetic regulation of cell fate determination and cell identity maintenance, a theory of epigenetically-driven oncogenesis sits easily with these tumors. The age-delimited distinct biologies of 'pediatric' and adult GIST are intriguing, particularly, the SDH-deficient 'pediatric' form, driven by a metabolic defect, but resulting in epigenetic dysregulation with genome-wide DNA methylation changes. There is little doubt that many of the gaps in our understanding of pediatric sarcoma biology will be filled by a deeper appreciation of the role of dysregulated epigenetics including chromatin biology, perhaps best exemplified in malignant rhabdoid tumor. The field of pediatric soft tissue tumor pathology grows ever more interesting. Importantly though, it must be emphasized, that none of this progress could have occurred, or indeed continue, without the initial step of accurate diagnosis, founded solidly on morphology - thank you Pepper for your unparalleled contributions to this field! The opportunity to be your apprentice for five years has been a bigger and more positive influence than words can express.