In the present study, we found enhanced non-tumor pulmonary FES uptake in a subset of patients, most frequently after radiation therapy in the thoracic area. Uptake of FES is considered to be ER specific, and the cause of this non-tumor uptake is not fully elucidated yet. However, this study supports a possible fibrosis-related origin. This aspect of non-tumor FES uptake on FES-PET has not been described before, and this is the largest series so far to allow hypothesis generation with regard to this aspect.
One possible cause of the enhanced tracer uptake is that the tracer binds to inflammation-related ERβ expression. Two isoforms of ER exist, α and β, and despite the fact that 18F-FES has a 6.3 times higher affinity for ERα compared to ERβ [12], uptake can be seen in ERβ-driven pathology [17]. Under normal conditions, low levels of ERβ are present in ovaries, the kidney, the brain, bone, the heart, the lungs, intestinal mucosa, the prostate, the immune system, and endothelial cells [18]. Also, in patients with interstitial pneumonia and cystic fibrosis, ERβ expression is higher than in healthy lung tissue [19, 20]. Both cystic fibrosis and interstitial pneumonia are marked by lung fibrosis and inflammation.
Both ERβ and ERα play a role in inflammation and fibrosis. Estrogen-dependent ERα activation is required for normal development of the dendritic cells [21] and high levels of dendritic cells are present in patients with lung fibrosis [22]. During inflammation, dendritic cells are activated to initiate and coordinate immune responses. We observed fibrosis or post-radiation inflammation in most patients with enhanced non-tumor FES uptake, but not in all. This could be explained by the timing of the CT scans. Fibrosis may not yet be detectable on a CT scan in an early stage of the formation of fibrosis. Exposure to radiation therapy could lead to side effects, largely depending on the anatomic site and dose received [23].
The pathogenesis of radiation-induced side effects is not fully understood but seems mostly related to extended inflammatory effects. As part of the inflammatory process, fibrosis may occur several weeks after radiation therapy [24]. The late phase typically occurs between 6 and 12 months and can continue to progress up to several years [25]. In 23 out of the 48 patients, enhanced uptake was seen bilaterally, which was beyond the boundaries of the radiation field. It has been reported, both preclinically and clinically, that bilateral radiation therapy toxicity may occur [26,27,28,29]. This suggests that enhanced FES uptake may be associated with a (late) inflammatory event caused by irradiation, also outside the irradiation field. Not in all patients, a contrast-enhanced CT scan was available, and due to the lower image quality of the low-dose CT, small areas of fibrosis could be missed.
Not all fibrosis in patients is related to radiation therapy. Extensive literature exists on lung toxicity due to several systemic treatments. With the wide time interval between irradiation and FES-PET treatment types, as well as treatment regimens and doses have changed over the years. With the retrospective design of the current study, we were unable to establish other correlations between fibrosis and FES uptake.
Another explanation for enhanced uptake in irradiated lungs is that radiation results into leakage of the blood vessels, possibly leading to extravasation of FES. In a preclinical rat model, radiation of the lungs showed vascular damage early after irradiation and remodeling leading to increased permeability, perivascular edema, and vascular remodeling [29, 30]. As a compensatory effect, the blood pressure, blood flow, and thereby shear stress may increase in the vasculature in the non-irradiated part of the lungs. This increase of shear stress may then lead to damage to the non-irradiated vasculature [30] and potentially explain leakage of the tracer in surrounding tissue. Though unbound FES can readily permeate the endothelium, most FES is bound to the sex hormone-binding globulin (SHBG) which, in case of leaky vessels, may also leak out.
FES-PET scans are increasingly used, both in a research and a clinical setting. The scans are often qualitatively assessed and lesions are identified as ER-positive if the tracer uptake is above the background signal. Therefore, it is important for the analysis of the scans to know that non-tumor uptake in the lungs may occur and that this finding should not be interpreted as pathological uptake. Also, existing lesions in the radiation field may potentially be non-evaluable in cases where the background signal is increased due to the uptake after radiation treatment. Furthermore, to facilitate the interpretation of FES-PET scans, semi-quantitative analysis can be performed and correction for physiologic background uptake is often applied when calculating SUV using the unaffected contralateral site or surrounding tissue of the same origin. In such cases, one should keep in mind that background activity in the reference region can be influenced by radiation therapy and consequently background correction may cause an underestimation of the tracer uptake in the lesion.
Despite the limitations of being a retrospective study over a long period of time, this is the most comprehensive series of patients receiving FES PET scans after radiation therapy described so far. The clinical significance of these findings has to be further investigated, e.g., the relation between the lung function of the patients and enhanced uptake. These data were not available in our patient charts. As such, the findings described here should be regarded as hypothesis generating and should preferably be confirmed in larger, prospective studies.