The code in libs/class.FileSystem.php function imageThumbnail(…) assumes that wp-content/uploads is located beneath ABSPATH, which is not necessarily the case if WP_CONTENT_DIR is defined otherwise.
In particular, line #386 (v5.0.7):
$path = str_replace(site_url('/'), $abspath, $path);
This creates a filesystem path to the thumbnail beneath ABSPATH which may not be the case. This assumption breaks the code and results in a 404 image since the thumbnail file will not be found.
-Russ
