But it can't work if the data direction is from C to Perl (return value of a C function, @_ value coming into a Perl callback from C).

I'd just always return quads to perl as strings. As soon as the programmer attempts to use it in a numeric context it'll get converted to whatever makes sense for the platform he is running on, or return an appropriate error message.

Just note in the pod that is what will happen and suggest that if the user needs ints that will range outside +-2**52 on platforms that does support them natively, then they should consider creating Math::Int64 objects from the strings returned.

Most of the time, they'll get converted to NVs and just work.