**3. Histopathology of the Salivary Gland**

For decades, salivary gland histopathology has played a major role in diagnosing pSS. The characteristic finding within labial and parotid gland biopsies is the presence of infiltrates around striated ducts, mainly consisting of B- and T-lymphocytes. From the number of periductal foci (clusters of >50 lymphocytes) per 4 mm2, the focus score can be calculated, which is used in classification criteria sets for pSS [2,14]. Another scoring system is the grading system by Chisholm and Mason. In this grading system, stage 0, 1, and 2 indicate no, slight, or moderate infiltration with less than one focus per 4 mm2, respectively. Stage 3 and 4 correspond with a positive focus score (≥1 focus per 4 mm2) [17]. Besides the presence of periductal foci, other characteristic features can be found within the salivary glands of pSS patients, such as influx of IgG plasma cells and the presence of lymphoepithelial lesions (LELs) and germinal centers [18–20]. LELs are defined as hyperplastic ductal epithelial cells with infiltrating lymphocytes. LELs can eventually lead to complete obstruction of ducts (Figure 1). In addition to these characteristic features, proportions of fibrosis and acinar atrophy within salivary gland tissue are higher in pSS patients compared to controls [21,22]. There is no agreement yet whether fatty infiltration is age-associated or specific for pSS [23,24]. Besides their role in the diagnostic work-up of pSS, biopsies may also be used to assess prognosis (Table 2). Higher focus score is associated with higher European League Against Rheumatism (EULAR) Sjögren's syndrome disease activity index (ESSDAI) scores, severe serological profiles, and an increased risk of lymphoma development [25,26]. PSS-associated salivary gland MALT lymphomas are diagnosed on histomorphological appearance (Figure 1) in combination with clonal analysis of immunoglobulin heavy chain (IGH) variable(V)-diversity(D)-joining(J) (VDJ) gene segments [27]. The following sections will discuss whether the characteristic histopathological findings correspond with imaging findings found in pSS patients.

**Figure 1.** Histopathological features in parotid salivary glands of primary Sjögren's syndrome patients (**A**) Lymphocytic infiltrate located around a hyperplastic striated duct (lymphoepithelial lesion: LEL) without obstructed lumen. Both (**B**) CD3+ T-lymphocytes and (**C**) CD20+ B-lymphocytes are present in the periductal infiltrate and within the ductal epithelium. (**D**) Presence of a germinal center, which was revealed by the presence of a cluster of ≥5 adjacent Bcl6-positive cells within a focus [28]. (**E**) Immunoglobulin A (IgA) (red) and immunoglobulin G (IgG) (brown) staining shows a plasma cell shift towards IgG plasma cells. (**F**) Salivary gland mucosa associated lymphoid tissue (MALT) lymphoma biopsy, which shows a diffuse CD20+ B-lymphocytic infiltrate around lymphoepithelial lesions in the absence of normal salivary gland parenchyma.


*J. Clin. Med.* **2020**, *9*, 2492

contradictive

 data, and (−) in case there is no evidence for contribution of the imaging technique to the specific item.
