Using your own layouts for printing
The PrintingTools service included with ArcGIS for Server references a preconfigured folder with eight map layouts. These include basic designs in the 8.5 by 11 inches, 11 by 17 inches, A3, and A4 paper sizes in both portrait and landscape orientations.
If you want to use your own layouts, you can publish your own service for printing web maps. You configure this service to reference your own folder of ArcMap documents (MXDs) that you've prepared with various map layouts. It doesn't matter what data is in the MXDs or the page size of the layout (for example, such as sizes D and E); what's most important is the usage and placement of surrounding map elements in the layouts. Users of your service will be able to pick which layout they want to use.
You can find instructions for publishing your own service for web printing (and pointing it at your own layouts folder) in Tutorial: Publishing additional services for printing. The tutorial also explains what to do if you later decide you want to update your layouts. Your update approach will vary based on whether or not you registered your layouts folder with the server before publishing, and the tutorial contains instructions for both scenarios.
Including multiple data frames in the layout
The PrintingTools service can print layouts that use multiple data frames. The service only replaces the map in the active data frame; however, if the data frames have some relationship between them, such as an extent rectangle, that relationship is honored by PrintingTools.
For example, suppose you have a layout with two data frames: a main map and an overview map. The overview map includes an extent rectangle showing the current extent of the main map. Before using this layout with PrintingTools, you need to ensure that the main map data frame is the active data frame. When a web user requests a map with your layout, the main map will show the current web map view, and the overview map's extent rectangle will display the extent of the main map as expected.