Sjögren's syndrome (SS) is a chronic autoimmune inflammatory disease in which lymphocytic infiltration of the lacrimal and salivary glands is the hallmark of disease diagnosis. The present study was conducted to identify developmental features of labial salivary gland histopathology to permit earlier diagnosis of SS patients with borderline biopsies. Control subjects were chosen on the basis of clinical presentation consistent with SS, but whose biopsies did not meet current focus score criteria. Intraglandular connective tissue and diffuse cellular infiltration were significantly greater in SS patients than in controls. Glands in both groups had small cellular aggregates (10 to 50 cells/100 microns2), but those in SS patients were more numerous, larger, and contained more lymphocytes, plasma cells, and active fibroblasts. The large inflammatory foci characteristic of SS appeared to be formed by the enlargement and merging of these aggregates. This suggested aggregate formation was the earliest stage of pathology. Therefore, a comprehensive analysis of these cellular aggregates in borderline or negative biopsies could identify at-risk patients and lead to earlier diagnosis and intervention in the disease.