Salivary Gland Histopathology in Primary Sjogren's Syndrome
In a subset of patients, lymphocyte foci may start taking on features reminiscent of secondary lymphoid organs and develop compartmentalised B-cell-rich and T-cell-rich zones. These are associated with ectopic production of lymphoid chemokines (CXCL13 and CCL21) and expression of the enzyme, activation-induced cytidine deaminase (AID). AID enables local maturation of autoimmune responses by facilitating affinity maturation and class switching of the antibody response, and is expressed in association with CD21+ follicular dendritic cell (FDC) networks.
While the presence of segregated foci with discrete B and T cell areas is relatively common, the presence of fully formed germinal centre (GC)-like structures, characterised by light and dark zones, is only present in a minority of patients. This distinction is likely to be functional since survival of high-affinity somatic-mutated B cells in the light zone is dependent upon antigen presentation and local expression of survival factors by FDC. Indeed, increased expression of autoantibodies, both in the tissue and in the periphery, has been associated with GC formation in the salivary glands.
DNA hypermutation is associated with genetic instability, and recent data have suggested that GC-like structures may provide prognostic information in relation to the risk of lymphoma, which occurs in up to 5–10% of patients over prolonged follow-up. This possibility was first suggested in 1999, but more recently, Theander et al found that 6 out of 7 lymphomas observed in a cohort of 175 patients occurred in those with GCs in baseline biopsies, giving a 99% negative predictive value in the absence of GCs. GC formation is associated with higher FS, so it is not surprising that a similar observation was made in a separate cohort, in which an FS of <3 was also associated with a negative predictive value of 98%, whereas FS ≥3 had a positive predictive value of 16%. Importantly, the median follow-up between biopsy and lymphoma was 7 years in the former study and 68 months in the latter, suggesting that biopsy characteristics might be both stable over time and capable of stratifying patients.
Light microscopy is considered sufficient to allow accurate detection of fully formed GC-like structures on H&E stained sections. However, the reported prevalence of GC-like structures is quite variable, ranging between 18% and 59% of patients with PSS. Immunohistochemical staining for FDC networks, using CD21 as a marker, might improve the reliability and consistency of GC identification. However, this remains to be tested and whether this improves prognostic value should be evaluated.
Biopsy as a Prognostic Tool?
In a subset of patients, lymphocyte foci may start taking on features reminiscent of secondary lymphoid organs and develop compartmentalised B-cell-rich and T-cell-rich zones. These are associated with ectopic production of lymphoid chemokines (CXCL13 and CCL21) and expression of the enzyme, activation-induced cytidine deaminase (AID). AID enables local maturation of autoimmune responses by facilitating affinity maturation and class switching of the antibody response, and is expressed in association with CD21+ follicular dendritic cell (FDC) networks.
While the presence of segregated foci with discrete B and T cell areas is relatively common, the presence of fully formed germinal centre (GC)-like structures, characterised by light and dark zones, is only present in a minority of patients. This distinction is likely to be functional since survival of high-affinity somatic-mutated B cells in the light zone is dependent upon antigen presentation and local expression of survival factors by FDC. Indeed, increased expression of autoantibodies, both in the tissue and in the periphery, has been associated with GC formation in the salivary glands.
DNA hypermutation is associated with genetic instability, and recent data have suggested that GC-like structures may provide prognostic information in relation to the risk of lymphoma, which occurs in up to 5–10% of patients over prolonged follow-up. This possibility was first suggested in 1999, but more recently, Theander et al found that 6 out of 7 lymphomas observed in a cohort of 175 patients occurred in those with GCs in baseline biopsies, giving a 99% negative predictive value in the absence of GCs. GC formation is associated with higher FS, so it is not surprising that a similar observation was made in a separate cohort, in which an FS of <3 was also associated with a negative predictive value of 98%, whereas FS ≥3 had a positive predictive value of 16%. Importantly, the median follow-up between biopsy and lymphoma was 7 years in the former study and 68 months in the latter, suggesting that biopsy characteristics might be both stable over time and capable of stratifying patients.
Light microscopy is considered sufficient to allow accurate detection of fully formed GC-like structures on H&E stained sections. However, the reported prevalence of GC-like structures is quite variable, ranging between 18% and 59% of patients with PSS. Immunohistochemical staining for FDC networks, using CD21 as a marker, might improve the reliability and consistency of GC identification. However, this remains to be tested and whether this improves prognostic value should be evaluated.
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