Well, let's see.
With the release of nightfall, some fundamental changes did occur - you get some permanent henchmen - i.e. heroes. In Prophecies, there's Olias. A necromancer you gain at lion's arch. Any skill you have unlocked on any character on the account, will be available to him (assuming appropriate secondary). There's an assassin hero in factions, and quite a few in Nightfall.
In terms of area, Nightfall is pretty huge. Not as big as the original, but much bigger than factions. The ramp up to level 20 is also longer - factions was a bit ridiculous with getting players to 20 in 2 days, though it's nice to do so when you're starting up and don't want to go through it all again.
Nightfall ties Shiro and the Lich together, serving a demon god, Abaddon, who has usurped the gods (the fictional pantheon you hear about from the first - Balthazar, Melandru, Lyssa... etc). It starts off with giant claws, demons (from underworld) and rifts turning up (in your original area, say lion's arch, take the quest), eventually you end up in Elona's docks (their version of lions arch). The antagonist is a new face - warmarshal Varesh, who's demons are preparing the world for the coming of Abaddon.
Playing the story involves doing quests to build up an encampment - you have a base, and side quests add armorers, merchants etc. You'll pick up numerous hero's - they level like pets, and you configure the skills, attributes, runes on the armor, weapons etc.
There's a cool feature where in the sulfurous wastes, you and your party, can call upon wurms, and just wreak havok on the enemies there (3k health each party member, siege attacks, all skills become wurm skills).
It's not hard though it CAN get difficult late game. The late game torment areas features foes from underworld - terrorweb dryders, grasping horrors, the shadow army. Evasion and interruption are necessities.
I LOVE the new item system. Weapons found in Nightfall are COMPLETELY modable. you can normally change the suffix and prefix, but if the beautiful fellblade fell with a native mod you didn't care for - say "spells have a 6% chance half recharge time" you can replace it with a better inscription say "damage +14% if health > 50%". When salvaging, you choose not only the suffix and prefix, but you can also choose to salvage the inscription. It makes personalizing you character using a weapon skin you like with the mods you want easier.
Cinematics are nice - they added lip movement, which makes it a hundred times better.
Paragon and dervish enemies are frequent, as it's the new class to show off. There's a few assassins and ritualists though.
Of course there's new skills and synergies. Paragons use a spear, but their most impressive effect is through echos. My warrior build using an "echo" skill for a near permanent 3 pip regen. Echo's effects take place at the end of a shout or chant - some echo's are refreshed when the shout or chant ends. Chants are just like shouts really, cept they're usually triggered on use of a skill, and then end.
The Dervish's scythe has the highest top end damage in the game - 9-41. So critical hits with a scythe can do some damage. They have some interesting skills - such as forms. They can choose a form of the gods (elite skill) and gain benefits of it. e.g. form of lyssa adds damage to any enemy activating skills. A lot of their skills rely on use of enchantments, often losing them.
I like it more then the bulk of factions. Factions has you crawling over trashy looking sewers for more than half the game, though it did have some beautiful areas. This game if full of lots of open areas - more open than most areas of prophecies or factions. In fact you don't have to fight a lot of mobs if you're careful.
As far as skills, I wish all skills were available to you
from the builds I've tried, skills from all 3 can make an awesome powerful character.