The accumulations of driver mutations in a single stem cell may be analogous to an evolutionary poker game. The rarity of SI cancer may reflect that SI crypts are smaller and have fewer stem cells than the colon, which reduces the numbers of cells at risk for mutation and perhaps selection efficiency. Tissue microarchitecture may physically modulate cancer evolution by controlling the numbers of directly competing neighboring cells. A better understanding of the SI cancer paradox may illuminate how tissues naturally avoid cancers when mutations are unavoidable.