Identifying the primary tumor remains a concern for patients with HNCUP, though the development in imaging, endoscope, and pathology techniques. If without any positive findings by non-invasive procedures, invasive diagnostic operations, like tonsillectomy, are performed with a risk of bleeding or infection [5]. Thus, novel non-invasive methods may be needed for improving detection rate of primary tumor in HNCUP patients. This study took advantage of trials to investigate the performance of [68Ga]Ga-DOTA-FAPI-04 PET/CT in identifying primary tumor of FDG-negative HNCUP. Our results demonstrated that [68Ga]Ga-DOTA-FAPI-04 PET/CT can dramatically improve the detection rate of primary tumor in HNCUP patients comparing to [18F]FDG PET/CT. Furthermore, [68Ga]Ga-DOTA-FAPI-04 may compare favorably to 18F-FDG in assessing metastases.
The current study exhibited a 38.89% (7/18) detection rate of primary tumor by [68Ga]Ga-DOTA-FAPI-04 PET/CT. Notably, these patients were all with false negative [18F]FDG PET/CT findings. The sites of false negative [18F]FDG PET/CT findings in this study were nasopharynx, palatine tonsil, submandibular gland, and hypopharynx, which was different from previously reported observations that the tonsil was the most frequent false negative location [15]. Recently, S. Serfling et al [27] reported [68Ga]Ga-DOTA-FAPI-04 PET/CT showed a better visual detection of the malignant primary in Waldeyer’s tonsillar ring than [18F]FDG PET/CT. However, the representative cases could provide positive findings of primary site by [18F]FDG PET/CT alone in terms of HNCUP. Another previous research demonstrated that an SUVmax ratio of FDG uptake between tonsils of ³ 1.6 could be regarded as malignancy and used to guide biopsy [29]. In this study, two patients were diagnosed with palatine tonsil carcinoma by tonsillectomy. Puzzlingly, [18F]FDG PET/CT revealed no visual difference between right and left palatine tonsils in both two cases. Furthermore, the SUVmax ratios of FDG uptake were all approximate equivalent to 1.00 (1.07 and 1.04 for patient 2 and 3, respectively), which was mistaken as physiologic uptake. By contrast, [68Ga]Ga-DOTA-FAPI-04 PET/CT showed intensive uptake in tumor site and low uptake in the normal site, resulting in an obvious visual difference (SUVmax ratio = 3.46 and 8.21, respectively). In line with our results, M. Syed et al [26] demonstrated high FAPI avidity within tumorous lesions and low background uptake in healthy tissues of the head and neck region. In other ways, this study once again emphases the potential role of [68Ga]Ga-DOTA-FAPI-04 PET/CT in detecting palatine tonsil carcinoma, particularly in FDG-negative patients.
In addition to high grade physiologic uptake of head and neck, small size of the lesions was the major reason for the false negative FDG findings due to the partial volume effect and low tumor glucose metabolic activity [30, 31]. In this study, [18F]FDG PET/CT missed 3 of 7 primary tumors by reason of the small size (diameter < 10 mm). Encouragingly, [68Ga]Ga-DOTA-FAPI-04 PET/CT revealed mild uptake (SUVmax = 2.60, 3.20, and 3.60 for patient 1, 6, and 7, respectively) and clearly visual difference (SUVmax ratio = 2.17, 2.91, and 3.27, respectively) in these primary tumors with small size, which was consistent with previous research [24]. The uptake of FAPI is mainly based on the expression of FAP on CAFs among solid tumor microenvironment. And even small primary tumors of T1 stage could show a moderate FAP expression [27]. Thus, [68Ga]Ga-DOTA-FAPI-04 could serve as an alternative tracer for identifying primary tumor of small size to reduce the false negative results by [18F]FDG PET/CT.
Most of the researches focus on SCC, as it is the most frequent pathological type of HNCUP [3-5]. However, some other pathological types, like adenocarcinoma and neuroendocrine carcinoma, may cause diagnostic difficulties in clinical practice due to inexperience. Moreover, when it comes to cervical metastatic adenocarcinoma, diagnostic resection of salivary gland is not recommended even after thorough non-invasive investigations. Furthermore, salivary gland cancers show paucity of FDG avidity [32], which was proofed again in our study (patient 4 and 5). Some non-FDG radiopharmaceuticals, i.e., [18F]Fluorothymidine ([18F]FLT), [68Ga]Ga-DOTA-Somatostatin Analogs ([68Ga]Ga-DOTA-SSA), and [18F]Fluoromisonidazole ([18F]FMISO), are recommended to detect primary tumor of HNCUP [33]. However, these tracers are too specific to identify all types of head and neck cancers. Promisingly, recent studies have demonstrated [68Ga]Ga-DOTA-FAPI-04 can evaluate a broad spectrum of malignancies, including adenocarcinoma, neuroendocrine carcinoma, and well-differentiated carcinoma and so on [23, 24]. In this study, [68Ga]Ga-DOTA-FAPI-04 showed intensive uptake in submandibular gland (SUVmax = 16.50 and 15.80, respectively), providing sufficient information for following surgery. Notably, [68Ga]Ga-DOTA-FAPI-04 had a higher detection rate in adenocarcinoma (2/2, 100%) than SCC (5/16, 31.25%) of HNCUP, which indicated [68Ga]Ga-DOTA-FAPI-04 was more sensitive to adenocarcinoma. However, further research with larger sample size is needed to verify this result.
EBV and HPV infection strongly suggest the location (nasopharynx and oropharynx, respectively) of primary tumor of SCC HNCUP [34]. Gi Cheol Park et al [35] found that the sensitivity and accuracy of HPV were higher than those of [18F]FDG PET/CT (71.4% vs. 49.2% and 85.2% vs. 68.5%, respectively). In the current cohort, primary tumors were detected in 3 of 6 HPV-positive patients, and 2 were palatine tonsil SCC and 1 was submandibular gland salivary ductal carcinoma. Thus, HPV may offer limited information when concerning various pathologic types rather than SCC. Furthermore, virus infection status can’t provide direct anatomical information for further biopsy. With regard to the detection of regional and distant metastases, the performance of [68Ga]Ga-DOTA-FAPI-04 PET/CT varies among different researches [24, 27]. In our study, [68Ga]Ga-DOTA-FAPI-04 PET/CT showed similar performance (p > 0.05) with [18F]FDG PET/CT in detecting both lymph node and bone metastases. Considering that radiation therapy is one of the most important modalities of treating HNCUP, the advantages of [68Ga]Ga-DOTA-FAPI-04 PET/CT in both primary tumors and metastases may play a vital role in gross tumor volume delineation.
There are some limitations in this study. First, the main limitation is the relatively small number of patients, and the number of pathologic types is uneven. In the future, larger population cohort studies with more cancer types need to take into account. Second, not all the metastatic lymph nodes are confirmed by pathology. Nevertheless, imaging findings by both tracers and follow-up examinations can serve as a reference. Last, immunohistochemistry (IHC) for FAP expression of primary tumors and metastases is lacking. Hence, FAPI imaging and FAP expression control studies are also necessary in the future.