¹⁸F-DCFPyL PSMA PET/CT Tracheobronchial Uptake in Patients with Prostate Cancer: Incidence and Etiology

DISCUSSION

PSMA PET/CT is now considered the new standard of care in the management of PCa, with inclusion of PSMA PET/CT in the National Comprehensive Cancer Network guidelines (9). Despite the high diagnostic accuracy of PSMA-based agents in various PCa scenarios, PSMA is not specific to PCa or even to the prostatic gland. Several studies have shown a wide spectrum of nonprostatic benign and malignant PSMA uptake on PET using virtually all PSMA-based agents. We noted an unusual pattern in which physiologic uptake on PSMA PET was frequently seen in the trachea and proximal bronchi, on the left more than the right. Published examples of this pattern of PSMA tracheal uptake are limited to case reports, primarily attributed to underlying lung pathology, and do not localize the site of or determine the mechanism of PSMA expression (4–8).

In the present study, tracheal uptake was noted in 31% of patients undergoing ¹⁸F-DCFPyL PET/CT (Fig. 1). No relationship was found between tracheobronchial uptake and age, injected activity of ¹⁸F-DCFPyL, or uptake in the parotid gland, liver, spleen, kidney, small bowel, stellate or celiac ganglia, or gluteal muscle (Table 1). However, those with tracheobronchial uptake had significantly higher uptake in the lacrimal and submandibular glands but lower uptake in the blood pool and a lower PSA level. The higher uptake in the salivary glands and trachea might be related to their being secretory glands with a similar origin. Although xerostomia is one of the most common side effects of PSMA radioligand therapy, we could find no report that PSMA therapy can cause adverse airway events or respiratory symptoms. In our study, a lower PSA level was associated with higher tracheobronchial uptake. This might reflect a lower sink effect, with a low PSA level generally indicating a lower disease burden. However, lower blood pool uptake may contribute to a higher physiologic-to-background ratio, thus resulting in more noticeable tracheal uptake. Higher tracheobronchial uptake was also associated with lower uptake in the blood pool. This may reflect uptake time, as blood pool clearance and accumulation of tracer in PSMA-expressing tissues increase with time. The trachea receives its nerve supply from the pulmonary plexus, which is derived from both the sympathetic and the parasympathetic nervous systems. We hypothesized that in patients with higher autonomic tone, higher tracheal uptake may be noted more frequently in those with higher ganglia uptake, particularly stellate, since it has the same nerve supply as the trachea. In our study, tracheal uptake was associated with higher uptake in the left stellate and left celiac ganglia than in the right stellate and right celiac ganglia. Also, tracheal uptake was associated with higher lacrimal and submandibular uptake. Such a pattern might be suggestive of an underlying higher autonomic tone in the trachea, particularly on the left side. Paired t testing showed that when tracheal uptake was present, the SUV_max was significantly higher in the left main bronchus (mean, 2.7) than in the right (mean, 2.3) (P < 0.001). Anatomic differences between the narrower, longer, and more horizontal left bronchus and the wider, shorter, and more vertical right bronchus might also contribute to more PSMA PET visualization on the left side than on the right (Fig. 2).

Several studies showed differences in biodistribution between currently Food and Drug Administration–approved PSMA agents (10–12). Our data show that a relatively higher injected activity and longer uptake duration may lead to higher contrast in the image as well. In our experience, tracheobronchial uptake is seen relatively more often on ¹⁸F-DCFPyL PET/CT than on ⁶⁸Ga-PSMA-11 PET/CT (Fig. 3), but this may be because of higher contrast related to the higher positron yield and lower positron energy of ¹⁸F or because we tend to image later (90 min after injection) and inject higher activity with ¹⁸F-PSMA agents. More recently, we changed our ¹⁸F-DCFPyL imaging protocol from 90 to 60 min, which may lead to less detection of the tracheobronchial uptake. We made this change to align with Food and Drug Administration prescribing information.

Recent studies reported PSMA expression in small salivary glands in the nasopharynx (13). To localize tracheobronchial PSMA expression, immunohistochemistry was performed on tracheobronchial samples taken from 2 men who had surgical resection of lung cancer. Figure 4 shows PSMA expression in bronchial submucosal glands, suggesting that this uptake is related to tracheoglandular function. Submucosal glands are a prominent structure that lines human cartilaginous airways and contributes to respiratory defense in protecting the lung (14,15). This explains why tracheobronchial PSMA uptake is frequently seen in the absence of morphologic or metabolic changes suggestive of an inflammatory condition but more prominent uptake is noticed in the presence of underling conditions that may cause more reactive changes at the submucosal gland. In chronic obstructive pulmonary disease and asthma, hypertrophied bronchial submucosal glands are well documented (16). Such hypertrophy may lead to more prominent tracheal PSMA uptake. In general, PSMA tracheobronchial uptake is mild and relatively diffuse. It is rarely focal and is therefore not likely to represent a source of false-positive interpretation. Similar to other well-documented physiologic uptake, however, the clinical significance of tracheobronchial uptake is not yet known.

The present study was limited by the retrospective analysis. We did not assess the relationship of tracheal uptake to asthma, smoking, or occupational exposure. Furthermore, we did not evaluate the impact of switching from a 90- to 60-min uptake phase on the frequency with which tracheobronchial ¹⁸F-DCFPyL PET/CT uptake is detected, nor did we systematically compare detection with other PSMA agents.