The Added Value of (68)Ga-FAPI PET/CT in Patients with Head and Neck Cancer of Unknown Primary with (18)F-FDG–Negative Findings

(18)F-FDG PET/CT plays an important role in locating the primary tumor for patients with head and neck cancer of unknown primary (HNCUP). Nevertheless, in some cases it can be challenging to locate the primary malignancy on (18)F-FDG PET/CT scans. Because (68)Ga-radiolabeled fibroblast activation protein inhibitor (FAPI) PET/CT has promising results in detecting different tumor entities, our study aimed to evaluate the performance of (68)Ga-FAPI PET/CT for detecting the primary tumor in HNCUP patients with negative (18)F-FDG findings. Methods: Eighteen patients (16 men and 2 women; median age, 55 y; age range, 24–72 y) with negative (18)F-FDG findings were enrolled in this study. All patients underwent (18)F-FDG and (68)Ga-FAPI PET/CT within 1 wk. Biopsy and histopathologic examinations were performed in the sites with positive (68)Ga-FAPI PET/CT findings. Results: (68)Ga-FAPI PET/CT detected the primary tumor in 7 of 18 patients (38.89%). Among these 7 patients, primary tumor sites included the nasopharynx (n = 1), palatine tonsil (n = 2), submandibular gland (n = 2), and hypopharynx (n = 2). The primary tumors showed moderate to intensive uptake of (68)Ga-FAPI (mean SUV(max), 8.79; range, 2.60–16.50) and excellent tumor–to–contralateral normal-tissue ratio (mean SUV(max) ratio, 4.50; range, 2.17–8.21). In lesion-based analysis, 65 lymph nodes and 17 bone metastatic lesions were identified. The mean SUV(max) of lymph node metastases was 9.05 ± 5.29 for (18)F-FDG and 9.08 ± 4.69 for (68)Ga-FAPI (P = 0.975); the mean SUV(max) of bone metastases was 8.11 ± 3.00 for (18)F-FDG and 6.96 ± 5.87 for (68)Ga-FAPI (P = 0.478). The mean tumor-to-background ratios of lymph node and bone metastases were 10.65 ± 6.59 versus 12.80 ± 8.11 (P = 0.100) and 9.08 ± 3.35 versus 9.14 ± 8.40 (P = 0.976), respectively. Conclusion: We present the first evidence, to our knowledge, of a diagnostic role of (68)Ga-FAPI PET/CT in HNCUP. Our study demonstrated that (68)Ga-FAPI PET/CT has the potential to improve the detection rate of primary tumor in HNCUP patients with negative (18)F-FDG findings. Moreover, (68)Ga-FAPI had a performance in assessing metastases similar to that of (18)F-FDG.