I have a 2004 (2003 chassis) with the 4R100, and a 2013 van with the 4R70 (same gear ratios, with 5.4 V8 rather than 6.8 V-10). I've driven the 5R110 with 6,8 V-10 E-450 (rental trucks) about 800 miles in moderate mountain country, and have found it really performs no differently above about 30 mph (top three gear ratios are the same on all three transmissions, final drive will differ with GCWR).
Ford split the first gear into two ratios to accommodate the torque characteristics of the 6.0 Powerstroke, providing a "granny" first gear to raise GCWR for the smaller diesel. The V-10 gas engine in E-450 got a 2000 pound boost in GCWR, that could be relevant if you want to tow heavy.
The gear ratios in the 4-speed worked well for the V-10 for more than ten years, and same ratios on the predecessor transmission paired with a 7.5 V-8 that liked to run a lot slower.
I have no experience with the 6 speed. If the transmission splits the same overall range into six more closely spaced gears, that might help the diesel with its more narrow power band, but for the V10 I might prefer another level of overdrive, for those days when I have tailwinds.
If you are buying what you can afford, what you can afford is functional and adequate. Something newer might be a little better.