Basically there’s the main area with Thrall (Org) or Alleria (SW). There are 4 additional areas that scale in difficulty (i.e. sanity drain, mechanics) that you’ll eventually get to once your cloak allows you to survive that long. On top of that, each area gets a random ‘madness’ mechanic that is basically a subzone affix (i.e. scorched feet causes flames to spawn at your feet randomly, dot dmg). Leave the subzone and the madness changes.
So at first you’ll only do the main kill, because your sanity won’t allow you to do much more. Two of the subzones will be slightly more difficult as they have a higher sanity-drain rate, and then the last two subzones will be even more difficult as they have an even higher sanity-drain rate.
As you progress you’ll pick up corrupted mementos which you can use on the titanic research, giving you additional benefits (i.e. higher total sanity, dmg reduction, sanity buffs when killing elites) and these all make the runs more productive/successful. So there’s a hint of efficiency built in over time as you get these additional benefits. But the enemies you encounter will always do the same things, so strategy-wise things don’t change.
Using the masks offers scaling challenges. There are 5 masks you can find in the HVs, and once you collect them you offer them to their respective altars, and can always activate them if you choose before starting the run. I don’t remember what all of them do, I do know that one of them activates a fog of war effect, limiting your vision/sight significantly – makes it particularly difficult to move out of bad things on the ground. You can also run as many masks as you want, and the challenge goes up significantly the more masks you activate. So there are ways to make these more challenging for the player who so chooses – I guess you can call that variability.