Characteristics of the enrolled patients

We enrolled 30 patients with ACC (15 males and 15 females; average age, 43.0 ± 12.2 years; range, 23–66 years; median, 43 years), including a primary ACC patient, 9 patients with local recurrence, 2 patients with intracranial metastasis, 8 patients with bone metastasis, 5 patients with liver metastasis, 23 patients with lung metastasis, and a patient with axillary lymph node metastasis. The characteristics of the patients are summarized in Table 1. Finally, a total of 4 patients (no. 4, 9, 10, and 11) received 177Lu-EB-PSMA-617 treatment with approximately 1.85 GBq (50 mCi). No adverse events were reported or observed in any patient during the radiopharmaceuticals administration.

Table 1 Clinical features of 30 ACC patientsDiagnostic performance of 68 Ga-PSMA-617 and 18F-FDG PET/CTComparison of tumor detectability

68 Ga-PSMA-617 exhibited PET-positive lesions as follows: 1 primary maxillary sinus neoplasm, 9 recurrent tumors, 8 intracranial lesions, 91 bone metastases, 47 liver metastases, 1 lymph node metastasis and 202 lung metastases, for a total of 359 lesions. As a contrast, 18F-FDG identified 1 primary tumor, 7 recurrent tumors, 4 intracranial metastases, 86 bone metastases, 42 liver metastases, 1 lymph node metastasis and 301 lung metastases, for a total of 442 lesions. Regarding bone metastases, there were 11 PSMA + /FDG- lesions and 6 PSMA-/FDG + lesions; the combination of two scans can detect 97 bone lesions. For lung metastases, there were 5 foci of PSMA + /FDG- and 104 PSMA-/FDG + , respectively. It is worth noting that CT can exhibit 358 pulmonary nodules, which were interpreted as tumors. The details are shown in Tables 2 and 3.

Table 2 Number of PET-positive lesions detected on 68 Ga-PSMA-617 and 18F-FDG PET/CTTable 3 Number of PET-positive lesions detected by 68 Ga-PSMA-617 PET/CT and 18F-FDG PET/CT

In short, 68 Ga-PSMA-617 exhibited more PET-positive extrapulmonary tumors (157 vs. 141, P = 0.016) than 18F-FDG. The number of PET-positive pulmonary lesions detected by 68 Ga-PSMA-617 was less than 18F-FDG (202 vs. 301, P = 0.001). The combination of 68 Ga-PSMA-617 and 18F-FDG can detect 469 PET-positive lesions, which was superior to each alone (469 vs. 359 vs. 442, P < 0.001).

Comparison of tumor uptake

68 Ga-PSMA-617 PET/CT exhibited higher tumor uptake than 18F-FDG PET/CT in a primary ACC tumor (SUVmax: 9.8 vs. 6.3) and 9 recurrent lesions (SUVmax: 10.4 ± 3.8 vs. 6.3 ± 5.9, P = 0.135), as shown in Figs. 2 and 3. For patients with distant metastases, 68 Ga-PSMA-617 PET/CT demonstrated lower tumor SUVmax than 18F-FDG PET/CT (4.1 ± 3.6 vs. 5.0 ± 3.9, P = 0.016), as shown in Fig. 4. Recurrent tumors revealed higher 68 Ga-PSMA uptake than metastatic lesions (10.4 ± 3.8 vs. 4.1 ± 3.6, P < 0.001), whereas the difference of 18F-FDG uptake in recurrent tumors and metastases was not statistically significant (6.3 ± 5.9 vs. 5.0 ± 3.9, P = 0.445).

Fig. 2

A 53-year-old female patient with primary ACC. Anterior maximum intensity projection (MIP) and axial 68 Ga-PSMA PET/CT (A–C) showed increased tracer uptake of the tumor in the left maxillary sinus (green arrow, SUVmax 9.8). 18F-FDG PET/CT (D–F) showed a lower uptake (blue arrow, SUVmax 6.3)

Fig. 3

A 62-year-old man was diagnosed with local recurrence and distant metastases 21 months after surgical removal of a right maxillary sinus ACC. 68 Ga-PSMA PET/CT (A–E) revealed a PSMA-avid tumor in the right maxillary sinus (green arrow, SUVmax 11.2), multiple bone metastases (red arrow, SUVmax 16.2), and liver metastases (blue arrow, SUVmax 8.8). 18F-FDG PET/CT (F–J) showed negative recurrent and metastatic foci

Fig. 4

A 49-year-old man was diagnosed with local recurrence and distant metastases 74 months after surgical removal of a left maxillary ACC. 68 Ga-PSMA PET/CT (A–C) showed multiple lung metastases with negligible uptake (green arrow). 18F-FDG PET/CT (D–F) revealed FDG-avid pulmonary lesions (blue arrow, SUVmax 7.1)

On lesion-based analysis, for extrapulmonary tumors, 68 Ga-PSMA-617 PET/CT depicted higher tumor uptakes (8.8 ± 3.6 vs. 6.4 ± 4.2, P = 0.027) than 18F-FDG PET/CT. Regarding pulmonary lesions, 68 Ga-PSMA-617 PET/CT illustrated significantly lower SUVmax than 18F-FDG PET/CT (3.1 ± 3.0 vs. 4.2 ± 3.9, P < 0.001).

The SUVmax of tumors, both on 68 Ga-PSMA-617 and on 18F-FDG PET/CT, was not correlated with patients age, sex, pathological type, history of treatment, or the time interval from diagnosis to PET/CT scan.

Safety of and therapeutic response to 177Lu-EB-PSMA-617 in a patient with ACC

Patient no. 11 accepted three cycles of PSMA RLT, and Patients no. 4, 9, and 10 only accepted one cycle of therapy due to the impact of COVID-19 pandemic.

Clinical Symptoms and safety evaluation

The subjective symptoms of pain reported by all 4 patients were improved, with the reduced visual analogue scale (5.0 ± 1.4 for pre-therapy vs. 2.8 ± 1.3 for post-therapy, P = 0.125).

Patient no. 11 suffered from grade 2 anemia. Patient 10 had been experiencing mild hepatic insufficiency (ALT 75 U/L; AST 68 U/L) and was treated using hepatinica before PSMA RLT. Hence, this patient had no significant liver dysfunction. Routine blood examination, liver and renal function examinations of other 2 patients demonstrated no noticeable fluctuations within therapy. Besides, patients 9, 10, and 11 experienced Grade 1 nausea and fatigue during the observation period.

Molecular imaging response

For PSMA PET response, patient 4 showed encouraging therapeutic effect and the SUVmax of meningeal metastasis decreased from 7.0 to 1.1 (equivalent to the background activity), which achieved CR, as shown in Fig. 5. Patient 11 also demonstrated positive therapeutic response, with reduced tumor uptakes (12.0 ± 3.2 for pre-therapy vs. 7.9 ± 3.5 for post-therapy, P = 0.031), which reached PR. The therapeutic responses of patients 9 and 10, however, were heterogeneous. Of them, recurrent tumors, lung metastases, and liver metastases showed reduced tumor uptakes (recurrent tumors: 10.9 vs. 9.5; lung metastases: 3.4 ± 2.3 vs. 1.8 ± 1.5, P = 0.036; liver metastases: 8.9 ± 1.3 vs. 8.0 ± 1.4, P = 0.012). Bone metastases demonstrated increased SUVmax of tumors (9.2 ± 3.3 vs. 10.6 ± 2.3, P = 0.001).

Fig. 5

A 41-year-old female patient was diagnosed with a left frontal meningeal metastasis 20 months after surgical removal of the left lacrimal gland ACC. Pre-therapy 68 Ga-PSMA-617 PET/CT (A–C) demonstrated intense PSMA uptake of tumor (green arrow, SUVmax 7.0). 68 Ga-PSMA-617 PET/CT reexamination at 9 weeks after the 1st cycle of PSMA RLT (D–F) and 8 weeks after the 3rd cycle of PSMA RLT (G–I) revealed significantly decreased tracer uptake of tumor (red arrow, SUVmax 3.5; blue arrow, SUVmax 1.1), which reached the level of CR according to modified PERSIST criteria. However, 18F-FDG PET/CT (J–L) always exhibited no positive lesions (orange arrow)

For FDG PET response, patient 11 had no FDG-positive lesions. The results of FDG PET response for others were similar to PSMA. Patient 4 depicted reduced uptake of 18F-FDG in tumors (2.5 ± 0.6 vs. 1.5 ± 0.3, P = 0.250). Patients 9 and 10 also exhibited lower SUVmax of tumors after therapy (recurrent tumors: 4.1 vs. 3.4; lung metastases: 2.2 ± 0.8 vs. 2.0 ± 0.5, P = 0.036; liver metastases: 4.7 ± 0.5 vs. 1.9 ± 0.2, P = 0.002), except for bone metastases (4.0 ± 2.2 vs. 5.6 ± 1.9, P = 0.006), as shown in Fig. 6.

Fig. 6

A 56-year-old male patient was diagnosed with local recurrence and multiple metastases 12 months after surgical removal of nasal ACC. Pre-therapy 68 Ga-PSMA-617 (A–D) and 18F-FDG PET/CT (I–L) depicted neoplasm recurrence, multiple liver, bone, and lung metastases. 68 Ga-PSMA-617 PET/CT (E–H) and 18F-FDG PET/CT (M–P) reexamination at 8 weeks after the 1st cycle of PSMA RLT revealed the decreased SUVmax of lung metastases (red arrow) and liver metastases (blue arrow); and CT showed liquefied necrosis occurred inside the lung nodule (red arrow). The uptakes of bone metastases (yellow arrow), however, were significantly increased