How do you approach radiation treatment of extramammary Paget's disease of vulva, diffusely involving the urothelium and the periurethral glands?

Very unusual case.

Presuming it has invasive disease, would also check HER2/neu status to see if there is any value of indication with chemo and anti-HER2/neu therapy.

Will plan definitive chemo RT treating vulva, vagina, urethra, and bladder (if involved) to 66-70 Gy to gross disease and prophylact...

I agree that there is likely invasive disease with such extensive involvement of the urothelium and periurethral gland. In addition to molecular studies, I would do a full workup to rule out GI malignancies - CT, MRI, and scope.

If no obvious other disease, but it is as extensive as described, then...