The No.8, who was impressive in the two November test wins, has returned to Wasps after suffering bruising to a bone in his knee which will keep him out for three to four weeks.
Eight others, including Bath's Jonathan Joseph and Anthony Watson, who also starred alongside Hughes in England's weekend victory over Australia, will also return to club duty, with coach Eddie Jones happy to ring the changes for the Samoa test.
Tom Dunn, George Kruis, Zach Mercer, Marcus Smith, Denny Solomona and Ben Te'o are the others released, while Sam Underhill will continue to undergo the return to play protocols after suffering concussion in Saturday's match.
England are seeking to complete an unbeaten November schedule at Twickenham against the Samoans following an ordinary performance in the 21-8 victory over Argentina and the more emphatic 30-6 victory over Australia.
(Reporting by Ian Chadband; editing by Ken Ferris)
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