Hyposalivation and salivary gland histopathology in graft-versus-host disease

A major long-term complication following allogeneic hematopoietic cell transplantation (HCT) is graft-versus-host disease (GVHD). Oral chronic GVHD (cGVHD) is common and affects the mucosa with diagnostic lichenoid-like manifestations. Distinctive features such as hyposalivation and inflammatory histopathology of the salivary glands have been associated with both transplant regimen and GVHD. We retrospectively explored the association of hyposalivation and minor salivary gland (MSG) histopathology with the establishment and progression of GVHD.

A total of 791 patient records were screened, and patients were included if salivary flow measurements were registered or if the biopsies contained both oral mucosal and MSG histopathology for comparison. In total, 63 unstimulated saliva and 123 stimulated saliva measurements were analyzed using the Kruskal-Wallis test with post hoc Dunn's multiple comparisons across acute, early chronic, and late chronic time phases. A total of 57 biopsies of MSG and mucosal tissue underwent histopathological grading according to NIH criteria, and 40 biopsies underwent immunohistochemical staining for CD4, CD8, CD68, and CD1a, which were analyzed using weighted kappa and Spearman's correlation.

Myeloablative conditioning had a significant impact on hyposalivation post-HCT (p < 0.0001), but no statistical difference was observed with or without acute or chronic GVHD. For all biopsies post-HCT, a moderate correlation was found between MSG and oral mucosal pathology scores (r 0.40), CD4 (r 0.69), and CD8 (r 0.51). Significant differences were observed across pathological phases. At cGVHD onset, a moderate to strong correlations were found with pathology score (r 0.73), CD4 (r 0.68), and CD8 infiltrate (r 0.84). However, at later stages, pathology score and CD8 infiltrate were non-significant.

There is limited evidence to suggest that all patients develop hyposalivation due to oral or extra-oral GVHD. MSG and oral mucosal immunopathology showed strong correlation in histopathological severity and CD8 infiltration at onset, suggesting a common initiation response. However, no correlation was found thereafter, favoring different pathophysiologies.