6.2.1. 18F-FDG-PET/CT

The most commonly used PET tracer is 18F-fluorodeoxyglucose (FDG). Uptake of this tracer is relatively higher in cells that are metabolically active, such as inflammatory cells. FDG is indicated in several infectious and inflammatory diseases and is useful for the diagnosis and follow-up of various autoimmune diseases [4,101,102]. In pSS patients, several case reports showed abnormal FDG uptake in salivary glands [103–105] (Figure 5). However, physiological FDG accumulation in salivary glands is highly variable, and subjects without known head and neck pathology frequently show increased FDG uptake in the salivary glands [106,107]. A possible explanation for the wide range in physiological uptake is that salivary glands of different subjects utilize different amounts of glucose for metabolism [108,109]. Which human salivary gland cells have the highest glucose uptake is not known, but in rodent salivary glands, both acinar and ductal cells seem to play a role in glucose uptake [110,111].

**Figure 5.** FDG-PET uptake patterns within the parotid glands. FDG-PET/CT showing (**A**) no increased uptake in the parotid glands of a subject without pathology in the head/neck region, (**B**) increased uptake in both parotid glands in a pSS patient, and (**C**) intense uptake in both parotid glands of a pSS patients with histologically confirmed parotid salivary gland MALT lymphoma.

Whether pSS patients show increased FDG uptake in inflamed salivary and lacrimal glands is not yet clear. Although Cohen et al. [112] reported increased FDG uptake in salivary glands of pSS patients compared to a control group of patients who underwent PET for an isolated pulmonary nodule, another study could not confirm this finding [36]. However, both studies used different scoring methods and camera settings, and standardized guidelines and EANM Research Ltd. (EARL) reconstructions were not applied in these studies.

Besides visualizing salivary gland inflammation, several authors reported the ability of FDG-PET/CT to detect systemic disease activity in pSS [104,105,112–115]. Abnormal FDG uptake was observed in 75–85% of pSS patients, mainly within salivary glands, lymph nodes, and lungs [112,113]. However, not all organ involvement in pSS can be visualized by FDG-PET/CT, such as neuropathies, cutaneous vasculitis, and other skin abnormalities, which is mainly due to limited spatial resolution of PET cameras. Since the optimal spatial resolution is around 3-4 mm in newer PET/CT systems, it would be of interest to use these newer systems to study the effectiveness of FDG-PET/CT in assessing systemic disease activity in representative pSS cohorts.

The applicability of FDG-PET/CT in MALT lymphomas is still controversial due to variable FDG avidity at different MALT locations. Pulmonary and head/neck MALT lymphomas seem to be most FDG avid, and FDG-PET/CT shows higher sensitivities at these regions [116,117]. Since pSS-associated MALT lymphomas frequently develop in the salivary glands and/or lungs, there may be a role for this technique in the detection of lymphomas associated with pSS [113,118,119] (Figure 3). Cohen et al. [112] reported a higher maximum standardized uptake value (SUVmax) in lymphoma patients compared to pSS patients without lymphoma. Since only four lymphoma patients were included in this retrospective cohort, the study was not powered to affirm the usefulness of FDG-PET/CT in the diagnosis of pSS-associated MALT lymphoma. In another retrospective study by Kerean et al. [113], 8 out of 15 pSS patients had confirmed salivary gland or pulmonary MALT lymphoma. They found that a SUVmax of ≥4.7 in the parotid glands and presence of focal lung lesions were associated with lymphoma. An important advantage of FDG-PET/CT is the possibility to detect extraglandular lymphoma locations by using whole-body imaging. In addition, Kerean et al. [113] showed that FDG-PET/CT is useful for biopsy guiding and for treatment response monitoring [113]. However, the mentioned SUVmax threshold found in this study cannot directly be used by others, as different nonstandardized camera systems were used in this multicenter study. Importantly, both retrospective studies state that the frequent presence of benign lymph node uptake in pSS patients can be misleading and should be taken into account when using FDG-PET/CT for the diagnosis of lymphoma in pSS patients [112,113].
