The general rule for difference of two squares is that when factorised it can be written in the form (a+b)(a-b) where a is the square root of the first part of the function and b is the square root of the second part of the function.
From this we can find the square root of x² to find a and the square root of 16y² to find b.
In this case √x²=x and √16y²=4y
Therefore fully factorised it can be written as (x+4y)(x-4y)