Obvious connotation of Karkat’s sign I haven’t heard mentioned anywhere, although I am sure someone has thought of it before:
A cancer is what happens when an organism splits and starts attacking itself. And what does Karkat constantly do? ATTACKS HIMSELF. Present, Past and Future Karkats attack themselves. Kankri criticizes The Sufferer, and Karkat calls Kankri a windbag. Its a constant cycle of self-attacking.