Perspectives on oral chronic graft-versus-host disease from immunobiology to morbid diagnoses.

Chronic Graft-versus-Host Disease (cGVHD) is a major long-term complication, associated with morbidity and mortality in patients following allogenic hematopoietic cell transplantation (HCT) for immune hematopoietic disorders. The mouth is one of the most frequently affected organs after HCT (45-83%) and oral cGVHD, which may appear as the first visible sign. Manifestations present with mucosal lichenoid lesions, salivary gland dysfunction and limited oral aperture. Diagnosis of oral cGVHD severity is based on mucosal lesions with symptoms of sensitivity and pain and reduced oral intake. However, diagnostic difficulties arise due to subjective definitions and low specificity to cover the spectrum of oral cGVHD. In recent years there have been significant improvements in our understanding of the underlying oral cGVHD disease mechanisms. Drawing upon the current knowledge on the pathophysiology and biological phases of oral cGVHD, we address oral mucosa lichenoid and Sjogren's Syndrome-like sicca syndromes. We consider the response of alloreactive T-cells and macrophages to recipient tissues to drive the pathophysiological reactions and biological phases of acute inflammation (phase 1), chronic inflammation and dysregulated immunity (phase 2), and subsequent aberrant fibrotic healing (phase 3), which in time may be associated with an increased malignant transformation rate. When formulating treatment strategies, the pathophysiological spectrum of cGVHD is patient dependent and not every patient may progress chronologically through the biological stages. As such there remains a need to address and clarify personalized diagnostics and management to improve treatment descriptions. Within this review, we highlight the current state of the art knowledge on oral cGVHD pathophysiology and biological phases. We address knowledge gaps of oral cGVHD, with a view to facilitate clinical management and improve research quality on lichenoid biology and morbid forms of oral cGVHD.

Immunohistopathology of oral mucosal chronic graft-versus-host disease severity and duration.

OBJECTIVE: Chronic graft-versus-host disease (cGVHD) is the main cause of late non-relapse mortality following hematopoietic cell transplantation. Oral mucosal (om-) cGVHD is common, but diagnosis and assessment rely on clinical interpretation and patient-reported symptoms. We investigated immunohistopathological profiles with respect to om-cGVHD severity disease duration. MATERIAL AND METHODS: Ninety-four transplant patients and 15 healthy controls (n = 212 biopsies) were investigated by quantitative immunohistochemistry for T cells (CD4, CD8, and CD5), B cells (CD19 and CD20), macrophages (CD68), and Langerhans cells (CD1a). RESULTS: We found significant increases in T (CD4, CD8) and monocytic (CD68) cells in om-cGVHD, and a notable absence of B (CD19 and CD20) cells. Histopathological activity correlated with increased CD4, CD8 and CD68. However, CD4 was associated with mild om-cGVHD, whereas CD8 and CD68 were found to be elevated in severe om-cGVHD. CD8 and CD68 levels were raised at disease onset, but during late phase, the predominant CD68 population was accompanied by CD4. CONCLUSION: Oral cGVHD is a heterogenous clinical disorder, but our knowledge of the underlying biology remains limited. We highlight the importance of CD4, CD8 and CD68 immune profiling, together with histological grading for the staging of oral cGVHD, to broaden our understanding of the biology and individual disease course.

Histopathological Grading of Oral Mucosal Chronic Graft-versus-Host Disease: Large Cohort Analysis.

Graft-versus-host disease (GVHD) can manifest as acute or chronic complications in patients after hematopoietic cell transplantation (HCT). Oral chronic GVHD (cGVHD) occurs in approximately 70% of HCT recipients and includes lichenoid-like mucosal reactions, restricted mouth opening, and salivary gland dysfunction. However, the underlying histopathological presentation remains to be validated in large cohorts. We characterized the histopathological features of oral mucosal cGVHD and devised a scoring model in a large patient cohort (n = 112). Oral mucosal biopsy sections (n = 303) with and without oral cGVHD were identified from archived and current HCT recipients with additional healthy controls. Histological screening was performed on hematoxylin and eosin-stained and periodic acid-Schiff-stained sections. A points-based grading tool (0 to 19, grade 0 to IV) was established based on intraepithelial lymphocytes and band-like inflammatory infiltrate, atrophic epithelium with basal cell liquefaction degeneration, including apoptosis, as well as separation of epithelium and pseudo-rete ridges. Validation involved 62 biopsy specimens, including post-HCT (n = 47) and healthy (n = 15) specimens. Remaining biopsy specimens (n = 199) were blindly graded by 3 observers. Histological severity was correlated with clinical diagnostic and distinctive features, demonstrating a spectrum of individual patient severity, including frequent signs of subclinical GVHD in healthy mucosa. However, oral cGVHD presented with significantly higher (P < .001) scores compared with HCT controls, with moderate to high positive likelihood ratios for inflammatory infiltrate, exocytosis, and basal membrane alterations. The grade II-IV biopsy specimens demonstrated a histopathological diagnosis of active mucosal lichenoid-like cGVHD, highlighting the importance of correlating clinical presentation with the dynamic histopathological processes for improved patient stratification. In addition, this tool could be used for assessing treatments, pathological processes, and immune cellular content to provide further insight into this debilitating disease.