Historically, cGVHD has been understood and classified based on its common presentations; however, it is almost certain that there are other alloimmune manifestations that may go unrecognized due to their relative rarity and/or the lack of consistent association with cGVHD. The National Institutes of Health Consensus Project Task Force has recently attempted to codify some of these manifestations, building on our collective experience. The new report by Cuvelier et al reflects this effort and gives a very nice overview of some of the more uncommon manifestations of cGVHD.

For example, there are clearly renal manifestations, such as minimal change disease or glomerulonephritis, that are associated with cGVHD. Although these manifestations are not formally recognized as cGVHD, they are immune phenomena and are characterized as autoimmune diseases when they occur outside of transplantation. There are also manifestations within both the central and the peripheral nervous systems that are likely manifestations of cGVHD. For example, there are several small fiber neuropathies that most of us see but usually do not classify as cGVHD.

While cGVHD must always be considered as a possible cause of these atypical manifestations, it is also important to explore the full differential diagnosis before attributing a condition to an atypical manifestation of cGVHD. Additionally, the publication by Cuvelier and colleagues notes that a connection between cGVHD and some manifestations is still speculative, outlining some of the steps that can be taken to further this research.

As relates to potential mimics of atypical cGVHD in the renal sphere, we know that there is a late form of microangiopathy that is more often associated with radiation and could present as glomerulonephritis or nephrotic syndrome, so that must be ruled out. We also use many treatments such as tacrolimus or vinca alkaloids that have neuropathic side effects that should not be confused with neuropathy from cGVHD. Finally, infections have the potential to mimic manifestations of cGVHD. There are several seasonal endemic viruses that can cause pericarditis, and, unless we look for echovirus or enterovirus in pericardial fluid, we might erroneously ascribe the pericarditis to cGVHD. Thus, it is good clinical practice to perform a differential diagnosis, since clearly not everything is an alloimmune phenomenon and is related to cGVHD. In general, I would say that atypical cGVHD is a diagnosis of exclusion.