Introduction
Oral cancer is a prevalent malignancy globally, with an estimated 354,864 new cases and 177,384 deaths in 2018 [
1]. Oral squamous cell carcinoma (OSCC), accounting for > 90% of oral malignancies, is mainly treated by surgery, radiotherapy, and adjuvant chemotherapy. The early-stage OSCC can be successfully controlled by curative treatment, with good treatment outcomes and high survival rates. In contrast, the prognosis of patients with advanced OSCC has not significantly improved during the past four decades [
2]. Crucial factors remain unknown even at present despite many efforts to identify the prognostic factors of patients with OSCC. Improving the prognosis of patients with OSCC requires a treatment strategy following reliable prognostic factors.
Positron emission tomography (PET) imaging allows clinicians to view and assess the metabolic activities of tumor cells, not the anatomical or structural changes in affected sites, by the uptake of radioactive tracers [
3].
18F-fluorodeoxyglucose (FDG)-PET is widely used clinically for tumor imaging due to increased glucose metabolism in many tumor types, including OSCC [
3,
4]. In theory, cancer with a high uptake of FDG indicates more aggressive behavior, resulting in poor prognosis of patients [
5]. However, whether or not FDG-uptake parameters, including the maximum standardized uptakes value (SUV
max), can predict the prognosis of OSCC patients remains controversial [
4]. FDG uptake in oral malignancy is likely to overlap with FDG accumulation in dental inflammation or physiological uptake [
3,
6]. These artifacts frequently make the evaluation of true FDG uptake by the primary OSCC tumor difficult. Therefore, another metabolic imaging, which can correctly assess tumor malignancy without these artifacts and predict the prognosis of patients with OSCC, is required.
An amino acid PET tracer,
11C-methionine (MET), is used to evaluate several tumor types [
6‐
16]. MET-uptake reflects increased amino acid transport and protein synthesis [
10,
17,
18]. MET-PET is mostly used for brain tumors, and its usefulness has been reported in terms of tumor detection, tumor grading, biopsy and radiotherapy planning, tumor extent and therapeutic response assessment, differentiation between tumor recurrence and radiation necrosis, and patient prognosis [
10]. Some studies are conducted on MET-PET for head and neck malignancies [
11‐
14]. MET-PET imaging has been reported to be useful in detecting lesions [
11‐
14] and assessing response to radiotherapy in head and neck cancer [
12,
14]. To the best of our knowledge, only one study evaluated MET uptake as a prognostic factor in patients with head and neck cancer. Lindholm et al. have revealed no association in the amount of MET uptake by the tumor with clinical outcomes in patients with head and neck cancer [
13]. However, some limitations may have influenced this result. First, the study included patients who underwent various types of curative treatment: surgery and definitive radiotherapy with or without chemotherapy. Second, they used SUV
mean as a parameter. The reproducibility of measurement of SUV
mean may be insufficient compared with that of SUV
max because the regions of interest were placed manually on the tumor areas. Additionally, they included a limited number of patients with OSCC. Taken together, whether or not MET uptake by the tumor is predictive for the prognosis of patients with OSCC remains unclear.
Therefore, the present study aimed to elucidate the correlation between SUVmax of MET of primary tumor and survival of patients with OSCC.
Materials and methods
Patients
This study enrolled 46 patients with OSCC who were treated in the Department of Oral Medicine and Surgery, Hokkaido University Hospital from 2005 to 2008. All patients underwent pretreatment MET-PET scanning. This study excluded 2 patients who received brachytherapy for tongue cancer, 7 patients with recurrent tumors, and six patients who received palliative treatment. Finally, the analysis included 31 patients who underwent curative surgery. This study complied with the Declaration of Helsinki and was approved (approval no. CT2022-0233) by the Ethical Committee of the Hokkaido University Hospital. Each patient signed informed consent for this study.
The present study included 22 males and 9 females (Table
1). The median age was 69.0 years, ranging from 24 to 84 years. The primary sites of OSCC were the tongue (
n = 14), upper gingiva (
n = 7), lower gingiva (
n = 4), floor of the mouth (
n = 3), palate (
n = 2), and buccal mucosa (
n = 1). The clinical T-classification was T1, T2, T3, and T4 in 2, 13, 6, and 10 patients, respectively. The clinical N-classification was N0, N1, and N2 in 19, 7, and 5 patients, respectively. The clinical staging was stages I, II, III, and IV in 2, 10, 7, and 12 patients, respectively. OSCC was staged according to the 7th edition of the American Joint Committee on Cancer TNM staging system [
19].
Table 1
Patient and tumor characteristics
1 | 31 | M | Tongue | 3 | 2 | 5.7 | 2 | pre-R | + | − | DOD |
2 | 69 | F | Tongue | 3 | 2 | 8.3 | 0 | pre-CR | − | − | NED |
3 | 76 | F | Tongue | 2 | 0 | 3.1 | | | − | − | NED |
4 | 76 | F | Floor of the mouth | 3 | 0 | 3.9 | 0 | | − | − | NED |
5 | 69 | M | Tongue | 2 | 0 | 2.0 | | | − | − | DOC |
6 | 79 | M | Upper gingiva | 4a | 0 | 5.6 | | | − | − | NED |
7 | 65 | M | Lower gingiva | 4a | 1 | 4.9 | 1 | pre-CR | + | + | DOD |
8 | 75 | M | Tongue | 3 | 1 | 4.1 | 1 | | − | − | NED |
9 | 59 | M | Tongue | 2 | 0 | 1.0 | | | − | − | NED |
10 | 73 | M | Upper gingiva | 2 | 0 | 4.4 | | | − | − | NED |
11 | 48 | M | Floor of the mouth | 4a | 1 | 5.2 | 0 | | − | − | NED |
12 | 84 | M | Palate | 3 | 1 | 5.0 | 2 | | − | − | NED |
13 | 78 | M | Lower gingiva | 2 | 1 | 2.7 | 1 | | − | − | NED |
14 | 63 | M | Tongue | 1 | 0 | 3.5 | | | − | − | DOC |
15 | 69 | M | Tongue | 2 | 1 | 3.2 | 2 | pre-R | − | − | NED |
16 | 62 | M | Tongue | 3 | 0 | 9.0 | 0 | pre-R | − | − | NED |
17 | 60 | F | Upper gingiva | 4a | 0 | 3.0 | | | − | − | NED |
18 | 77 | F | Lower gingiva | 2 | 0 | 10.2 | | | − | − | NED |
19 | 58 | F | Upper gingiva | 4a | 0 | 6.6 | | post-R | + | + | DOD |
20 | 69 | F | Upper gingiva | 1 | 0 | 2.4 | | | − | − | NED |
21 | 53 | M | Palate | 4a | 2 | 7.1 | 0 | post-R | − | − | NED |
22 | 45 | M | Tongue | 2 | 0 | 3.4 | | | − | − | NED |
23 | 69 | M | Tongue | 2 | 0 | 6.1 | | | − | − | NED |
24 | 72 | F | Upper gingiva | 4a | 0 | 8.1 | | pre-CR | − | − | NED |
25 | 74 | M | Lower gingiva | 2 | 1 | 3.7 | 0 | | − | − | NED |
26 | 54 | M | Tongue | 4a | 2 | 6.1 | 2 | | − | − | DOC |
27 | 24 | M | Tongue | 2 | 0 | 3.4 | 1 | | − | − | NED |
28 | 63 | M | Floor of the mouth | 4a | 2 | 4.4 | 2 | | + | + | DOD |
29 | 74 | M | Upper gingiva | 2 | 0 | 2.7 | | | − | − | NED |
30 | 70 | F | Buccal | 4a | 0 | 6.8 | | pre-CR | + | + | DOD |
31 | 79 | M | Tongue | 2 | 0 | 3.7 | | | − | − | NED |
Treatment and prognosis
The treatment for 31 patients with OSCC included surgery alone (22 patients), surgery with preoperative radiotherapy (16–50 Gy; 3 patients: cases 1, 15, and 16), surgery with preoperative chemo-radiotherapy (cisplatin of 4 mg/m2 and docetaxel of 10 mg/m2; 26–30 Gy; 4 patients: cases 2, 7, 24, and 30), and surgery with postoperative radiotherapy (60 Gy; 2 patients: cases 19 and 21). The patients with clinical stage III or IV with a long waiting time for surgery received preoperative radiotherapy with concurrent chemotherapy. The primary tumor was resected with surgical margins of > 10 mm. Twelve patients with clinically metastatic cervical lymph nodes received neck dissection. Three patients with N0 tumors underwent elective neck dissection along with the reconstruction using a vascularized-free flap. A total of nine patients had pathological positive nodes. The patients who had pathological close margins in the primary tumor, more than three pathological metastatic nodes, or pathological extra-nodal extension received postoperative radiotherapy.
All 31 patients were followed up for over five years postoperative. Five patients experienced loco-regional recurrence in the follow-up periods. Five patients died of loco-regional and/or distant failure and three died of other causes.
PET study
Whole-body emission images were obtained 15–20 min after injecting 395.6 ± 44.4 MBq (mean ± standard deviation, range 334–512 MBq) of MET using the three-dimensional acquisition method. A day before the PET studies, the patients were requested to fast for at least 3 h before the scheduled MET injection. All patients were requested to remain resting and quiet and to void just before scanning. Whole-body PET acquisitions were performed from the skull base to the pelvis with an axial field of view of 15.5 cm (spatial resolution, 4.5 mm full width at half maximum) using a PET scanner (ECAT EXACT HR + ; Siemens/CTI, Knoxville, TN, USA). Attenuation correction was performed using rotating
68Ge–
68Ga rod sources. The attenuation-corrected images were reconstructed with the ordered subsets expectation maximization algorithm. Two experienced nuclear medicine physicians (KH and SW), who were blinded to the clinical data and the results of other imaging studies, evaluated all PET scans. MET uptake was evaluated by visual analysis and using the maximum standardized uptake value (SUV
max), as reported earlier [
20,
21]. The MET-PET imaging results have not affected the treatment of the patients with OSCC.
Statistical analyses
To analyze an association between SUVmax of MET-PET and clinicopathological features, we used the Mann-Whitney U test for comparison of two groups and the Kruskal-Wallis test for comparison of more than three groups. Overall survival (OS) was measured from the date of surgery to death of any cause. Disease-specific survival (DSS) was measured from the date of surgery to death of uncontrolled OSCC. Loco-regional recurrence (LRR) was measured from the date of surgery to loco-regional relapse. The ability of SUVmax of MET-PET to predict prognosis or loco-regional recurrence were evaluated by a receiver operating characteristic curve analysis. Based on maximizing Youden index, the optimal cut-off value of SUVmax was determined as follows: 4.4 (sensitivity: 0.75; AUC 0.58) for OS, 4.4 (sensitivity: 1.0; AUC 0.71) for DSS, and 4.4 (sensitivity: 1.0; AUC 0.71) for LRR. Therefore, we divided the patients into two groups according to SUVmax of primary tumor: SUVmax of ≥ 4.4 and < 4.4. Survival and recurrence rates were analyzed using the Kaplan–Meier method and compared between two groups using the log-rank test. All statistical analyses were performed using JMP14 and JMP17 (SAS Institute Inc., Cary, NC, USA). P-values of < 0.05 indicated statistical significance in all analyses.
Discussion
This is the first study to reveal the prognostic impact of MET uptake by the primary tumor in patients with OSCC. The present study demonstrated significantly higher LRR rate and poor DSS rate in the patients with SUVmax of MET-PET of ≥ 4.4 than those with SUVmax of MET-PET of < 4.4. Notably, advanced primary tumors exhibited higher uptake of MET in comparison to early tumors. These results indicate that the SUVmax of MET-PET may correctly reflect the malignancy of the tumor and be predictive for the prognosis of patients with OSCC.
FDG is widely used as a PET tracer for tumor imaging. One of the limitations in FDG-PET imaging is most likely caused by increased FDG accumulation in the physiological structures and benign lesions such as infection and inflammation [
3,
6]. Almost all patients with OSCC have multiple FDG uptakes in the oral cavity, such as the muscle, salivary gland, tonsil, and dental inflammations, on FDG-PET/CT imaging; therefore, the SUV
max of the primary tumor frequently overlaps with that of these areas [
22]. Moreover, FDG uptake in the whole tumor has been reported to be accentuated by the macrophages and granulation tissues, in animal models [
23]. Hence, FDG accumulation by oral cancer might not correctly reflect the biological activity and malignancy of its cancer cells. Recent studies have revealed that SUV
max of FDG-PET is not significantly associated with prognosis in most patients with OSCC or nasopharyngeal cancer [
24,
25].
Its uptake reflects increased amino acid transport, protein synthesis, and cellular proliferation activity in MET-PET imaging [
17,
18,
26]. MET and FDG have been reported to show different distributions in tumor tissue of the animal models [
27]. A high MET uptake by the tumor was mostly observed by the viable cancer cells, and its uptake by macrophages and granulation tissues was lower than that of FDG [
27]. Clinical studies of lung cancer have demonstrated that MET-PET may reduce the false-positive findings in inflammatory lung diseases when compared with FDG-PET [
6,
9,
28]. Hsieh et al. studied 14 cases of solitary lung nodules using MET-PET and FDG-PET to differentiate between malignant and benign diseases [
6]. Their results revealed that MET-PET accurately diagnosed 7 cases of inflammatory and infectious nodules with true negative results, despite false positives of FDG-PET [
6]. This result indicates that MET uptake by the tumor might be less under the influence of inflammation and be likely to reflect the true activity of cancer cells.
It is unclear whether metabolic assessment of the primary tumor can predict regional lymph node metastasis. Goksel et al. reported that metabolic tumor volume of the primary tumor on FDG-PET/CT was a significant predictor of cervical lymph node metastasis in patients with head and neck cancer [
29]. Meanwhile, Yamada et al. demonstrated that SUV
max in OSCC primary tumor was not associated with cervical lymph node metastasis [
30]. The results of MET-PET investigation by Lindholm et al. showed that the proportion of patients with cervical lymph node metastasis was not different in the low and high SUV groups in patients with head and neck cancer [
13]. In the present study, higher MET uptake of the primary tumor was significantly correlated with advanced T-classification, locoregional recurrence, and prognosis. However, there was no association between N-classification and SUV
max of MET. These results suggest that higher MET uptake by the primary tumor may be a potential predictor of locoregional recurrence, but does not appear to be a predictor of cervical lymph node metastasis in patients with OSCC.
The present study has some limitations. (1) This study included a relatively small number of patients. Therefore, the statistical power to draw firm conclusions was insufficient. (2) Preoperative radiotherapy and chemo-radiotherapy are currently not standard treatments for patients with OSCC; however, seven patients received these treatments in the present study.
In conclusion, the present study revealed that SUVmax of MET-PET may predict clinical outcomes and prognosis in patients with OSCC who underwent curative surgery. Additional prospective studies with a large cohort of patients are necessary to verify and further extend our study results.
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