Hematoxylin and eosin with or without acetylcholinesterase remains the criterion standard according to our PRISMA-based data. In our opinion, the number of false-positive results with potential overtreatment may limit the increasing advocacy for calretinin staining. Both the "primum non nocere" dictum and the "loss aversion heuristic" need to be satisfied harmoniously by preventing harm from unnecessary surgery.

Background: In the last decade, the proposed Cancer Stem Cell (CSC) hypothesis has steadily changed the way we are approaching cancer treatment. CSCs may be the source of the heterogeneous non-tumorigenic cell population included in a neoplasm. Intratumor and intertumoral heterogeneity is a well-known phenomenon that massively entangles the diagnosis and treatment of cancer. The literature seems to suggest that heterogeneity develops progressively as tumorinitiating stem cells. CSCs harbor genetic and/or epigenetic alterations that allow them to differentiate into multiple tumor cell types sequentially. Objective: We reviewed the CSC hypothesis, cellular therapy, and the most recent patents on CSCs. Methods: PubMed, Scopus, and Google Scholar were screened for this information. Also, we provide an analysis of the most recent data targeting CSCs in pediatric cancer developed at two Canadian institutions. We highlight the genes involved with the activation of CSCs and the drugs used to antagonize them. Results: We underline that (1) CSCs possess stem cell-like properties, including the ability for self-renewal; (2) CSCs can start carcinogenesis and are responsible for tumor recurrence after treatment; (3) Although some limitations have been raised, which may oppose the CSC hypothesis, cancer progression and metastasis have been recognized to be caused by CSCs. Conclusions: The significant roles of cell therapy may include an auto-transplant with high-dose treatment, an improvement of the immune function, the creation of chimeric antigen receptor T cells, and the recruitment of NK cellbased immunotherapy.