I have not had time to deeply read everything in this post, so I apologize if I repeat anything that has been said before, but here is a bit on my perspective.
First of all I have one client that has 1,600 portals on the site, this has been a nightmare due to the complexity of management, and issues with needed third party modules.
I typically will rely on multi-portal functionality only for light load, similar featured sites as they prevent little risk to the other sites. You must also consider that when working multi-portal all other domains as ailased, and depending on server configurations, handing e-mail can proove to be a bit complicated. Granted that is easy to overcome.
Also, careful consideration must be taken when working with third party modules, as some modules for reporting and other functionalities can provide users exposure into the whole database without issue.
Lastly with multi-portal, usernames MUST be unique across all portals, on larger implementations this can become a major issue.