For now, we'll have to content ourselves with piecing together what we know of the world and taking a look at the path our (hopefully) intrepid heroes will be facing. Examining future lore based on partial knowledge is a tricky thing, because there are so many different opinions and schools of thought. Follow along after the cut for a ride on the speculation train, and feel free to add your thoughts at the end!
While it's far from certain and some arguments regarding the threat from the Deep Sea Dragon can be made, the currently-inaccessible area north of Divinity Coast is generally regarded as a very likely location for Divinity's Reach. Our heroes may begin their quest here -- if not, it won't be much farther south thanks to Zhaitan. So assuming our travelers start out in this area, they'll be traveling east along Watchtower Coast to reach the Shiverpeaks. While we still don't know much about Kryta in GW2, we do know it's the last human kingdom in Tyria. While it's home to people from Tyria, Cantha, and Elona, they can probably expect minimal human resistance in their travels -- the ability for players to choose from any of those heritages for their characters is indicative of peace between the nationalities -- we can probably assume the local wildlife hasn't gotten much friendlier. Have the mergoyles evolved into something even fiercer? (As someone who favors the caster classes, I find the thought of souped-up mesmers pretty unnerving.) What about the undead? Did the tidal waves drive them north from the Black Curtain and the Cursed Lands? It's possible they headed south to join up with the undead Orrian army, but our adventurers would do well to keep a careful eye out just in case -- and maybe someone should bring Ray of Judgement.
The current standard route through Scoundrel's Rise into Griffon's Mouth is one possibility for the next leg of the journey, although another currently-inaccessible area presents a potential northern path. Traveling the southern route would come perilously close to Dredge territory. The Dredge have evolved into a fairly cranky race after years of slavery in places such as Sorrow's Furnace, and who can blame them? Whether you feel sympathy for their plight or not, however, is of little consequence to them. They're now hostile toward all other races and embroiled in a war with the Norn. The Dredge control the Southern Shiverpeaks, while the Norn control the Northern Shiverpeaks, and anyone traveling through the Griffon's Mouth/Beacon's Perch area could possibly find themselves caught in Dredge/Norn crossfire. It's not the most pleasant thought, and besides, the huge unexplored landmass to the north of Kryta presents so much more potential! Traveling north, then east through the northern part of Deldrimor Bowl would steer well clear of the Dredge and into friendlier Norn territory. However, it could be a case of "out of the frying pan and into the fire", as we have no idea what's lurking in that region.
Onward through the Northern Shiverpeaks! It's a pretty logical assumption that our heroes in Ghosts of Ascalon didn't die horribly at the hands of the Dredge (and nobody remembered to pack a rez), thus ending the novel, so our next stop is Ascalon. This is where it gets interesting. The only human settlement remaining in Ascalon is Ebonhawke, far south of where our travelers need to go. Otherwise, the former homeland of so many humans has begun regaining its Pre-Searing beauty, but is now the most hostile area to them. To begin with, they'll have to contend with the Charr.
"These Charr are relentless." They were our first enemies in Guild Wars, and remain some of our fiercest foes. The battle for Ascalon can be considered lost: Ascalon is Charr territory. Even if our travelers were holding a banner along the way that said "We are just trying to get your relic back for you, please let us pass," it's doubtful that the information would hold sway over a few hundred years of hostility and bitter fighting. The Charr think of humans as an infestation, and would like nothing more than to see them eradicated, so getting to Ascalon City is going to be a combination of stealth when possible and fighting when it's not. We know that the Iron Citadel is located upon the ruins of Rin, making a northern route possible in order to avoid a main Charr city. The Black Citadel, however, is a bit more of a mystery. It's described as a giant Charr keep constructed on the ruins of Ascalon. This leaves a lot of room for speculation, but we can assume that it'll be harder to avoid along the way, if nothing else due to sheer size. With the Iron Citadel in the area of Rin, Ascalon City occupied by the spirits of the Ascalon Guard, and Ebonhawke to the south, there aren't many places the Black Citadel will fit other than smack in the path anyone traveling to Old Ascalon needs to use. Hopefully Ghosts of Ascalon will clarify the size and location a bit.
The Charr aren't the only threat, however. Stories of the great dragon Kralkatorrik say that it flew over Ascalon, and "transformed anything that was in its flight path into a twisted caricature of its former self." Will we find mutated elementals, devourers, and gargoyles? What about the docile moa birds? Whatever they are, they're a formidable foe and one that the Charr are in a continual battle with. We can safely assume they won't be any friendlier than humans.
Here the speculation train reaches its destination, and our intrepid heroes hopefully reach theirs. Putting together the pieces of the puzzle based on current knowledge while we wait for the real thing to arrive is a fun pastime for lore fanatics. Feel free to add your own puzzle pieces in the comments below!