I use CCleaner as a very part-time disk and registry cleaner, I have other apps for the daily primary use.
The tools I use most often -- including Windows' own disk cleanup -- know how to eradicate unnecessary files from %appdata% and other "arcane" HD locations.
I've had apps try to sneak excess storage on my data HD (D:\). *SQUASH!*
Especially annoying is the OS "restore point" junk. Several hundred MB at a whack if you turn the feature on. I don't since I have a 3rd party HD backup system that runs daily. At most if I have to restore the entire boot HD I'd lose whatever I had changed/added since that morning's backup.
That 255GB/300GB saved on each PC is app temp files and the like. Browser data, cookies, etc. It can also be files/folders previously installed apps left behind when they were updated or uninstalled. That is over several years, not all at once.
Some Windows apps can to be a bit messy about not cleaning up after themselves.
Drive letters date back to MS-DOS, and were forwarded to Windows when it was just a thin-layered shell that ran on top of DOS. Win9X/NT and later don't, though Windows' command prompt can simulate that old style DOS prompt.
Default DOS drive letters were A:\ for a floppy drive, maybe a secondary floppy at B:\, and C:\ for a hard-drive. 500MB for a hard-drive was HUUUUUGE!