Welll Hokage-IV, that's a good question.

The way I see it, there is a difference between a knife, and fire. One is physical, being the knife, and fire is not. Now before anyone starts going all science on my ass (yes I know fire is also physical), let me exlain. A knife will always have the same mass, while a fire will roar up, sink, be blown in all directions, etc. It can also die out in a moment. The knife will always go in the direction you throw it and affected very little by wind. When there is wind combined with fire, you have a big-ass problem on your hands.

To answer your question, yes, Orochimaru could certinally be killed by a standard weapon. He may be one of the strongest ninjas alive, but he is still only human. I base this simply on the "physical" theory in the above paragraph. For one, if Orochimaru didn't bring up his defenses against a fire jutsu, he would most likely be burned alive. If he got a knife stab in the heart, he'd still die. The reason? Using a weapon is not a ninja technique, so to speak. There is no way to build up resistance to a weapon. Sure, you can deflect weapons with other techniques, but there is no way you have a jutsu defense for something that is not a jutsu.

That is also the reason I think ninjas use weapon. The options for countering them are few. You can either, catch them, dodge them, or be hit by them. The last being the least prefferrable.