Tsunade has no real durability feats to her name. She has damage soak sure, but normal blades cut her up just fine. Kabuto had no problems cutting through her.
Has Tsunade ever healed from having her brain punctured or destroyed?
Kakashi loses. Without Sharingan at all, and Tsunade with mitotic regen, he can't use any of his best attacks, including his copied jutsu, and lightning blade.
He has no lightning blade, hardly any justsu other than a few fire styles, can't use Taijutsu as effectively by reading her movements, and can't use any genjutsu or mangekyo.
Tsunade's got Katsuyu, ridiculous taijutsu, and speed to keep up with Jiraiya and Orochimaru.
She wins easily if he doesn't have sharingan.
True.
It was implied that she could. She did have her heart punctured by Madara's Susano'o.
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