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Clinical usefulness of 2-deoxy-2-[18F] fluoro-d-glucose-positron emission tomography/computed tomography for assessing early oral squamous cell carcinoma (cT1-2N0M0)

Clinical usefulness of 2-deoxy-2-[18F] fluoro-d-glucose-positron emission tomography/computed... Abstract Background Positron emission tomography with 2-deoxy-2-[18F] fluoro-d-glucose integrated with computed tomography (FDG-PET/CT) is a useful method to evaluate patients with oral squamous cell carcinoma (OSCC). However, the prognostic significance of FDG-PET/CT for assessing early OSCC remains unclear. Methods Pretreatment FDG-PET/CT of 205 consecutive patients (125 men, 80 women, mean age 59.7 year old) with early OSCC (cT1-2N0M0) between June 2010 and December 2014 were retrospectively analyzed. FDG avidity in primary lesions was assessed by visual interpretation. Thereafter, maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were measured in primary lesions. The relationship between each parameter and recurrence free survival (RFS) was assessed using the log-rank test. The performance of FDG-PET/CT for diagnosing metastatic lesions and synchronous cancer was also assessed. Results During the follow-up period (mean 32.9 months), 43 patients developed recurrences (21.0%). Patients with visually positive FDG uptake in primary lesions showed significantly shorter RFS than the others (63.0 months vs. 52.9 months, P = 0.005). In those patients, greater SUVmax, MTV, and TLG did not significantly predict shorter RFS. The sensitivity and specificity of FDG-PET/CT for cervical nodal metastases detection were 32.3% and 77.6%, respectively. FDG-PET/CT detected eight synchronous cancers (3.9%) and overlooked six synchronous cancers (2.9%). Conclusions Although its utility for detecting cervical nodal metastases and synchronous cancers is limited, FDG-PET/CT is a potentially prognostic indicator in early OSCC. oral squamous cell carcinoma, FDG-PET/CT, staging, synchronous cancer, prognosis Introduction A previously published report estimates that 32 670 cases of oral cancer will be newly diagnosed and 6650 patients will die from the disease in the United States in 2017 (1). 2-deoxy-2-[18F] fluoro-d-glucose-positron emission tomography/computed tomography (FDG-PET/CT) is a useful method to evaluate patients with oral squamous cell carcinoma (OSCC). A review article has revealed the utility of FDG-PET/CT for staging, screening of recurrent lesions, monitoring therapy and predicting prognosis (2). The National Comprehensive Cancer Network (NCCN) guideline for cancer of the oral cavity refers to the consideration of performing FDG-PET/CT for patients with Stage III–IV disease because it may change their therapeutic strategy (3). On the other hand, there is no statement referring to FDG-PET/CT for Stage I–II disease in this guideline. Some studies have shown the limited potential of FDG-PET/CT for detecting nodal metastases in patients of clinical N0 (cN0) (4–6) and detecting synchronous primary cancers, particularly esophageal cancer and gastric cancer (7,8). However, many OSCC patients enrolled in previous studies investigating the utility of FDG-PET/CT for prognosis prediction had advanced disease (9,10). To the best of our knowledge, one investigator has evaluated the clinical usefulness of FDG-PET/CT in patients with early lingual cancer (11). Thus, it is unclear whether FDG-PET/CT has potential of predicting prognosis of early OSCC. The purpose of this study was to assess the clinical usefulness of FDG-PET/CT for determining prognosis and for staging of early OSCC (cT1-2N0M0) in a large cohort. Patients and methods Our ethics committee approved this retrospective study (approval number: M2016-215). Written informed consent was waived. Subjects From June 2010 to December 2014, a total of 252 consecutive patients with early OSCC (cT1-2N0M0) underwent FDG-PET/CT prior to treatment in our hospital. Diagnosis of OSCC was confirmed histopathologically in all patients. Staging was performed by clinical examination, CT of the head and neck and chest, magnetic resonance imaging (MRI), and cervical ultrasonography (US). Although actual therapeutic strategy was decided on the basis of findings from conventional and FDG-PET/CT examinations, the patient population in this study was assessed without FDG-PET/CT findings, because one aim of this study was to confirm that additional FDG-PET/CT could enhance detection of unexpected metastatic lesions in early OSCC patients. We excluded 47 patients using the following criteria: (a) previous history of other malignant tumors in the past 5 years, (b) previous history of other head and neck cancers at any time, (c) previous history of neck dissection or radiotherapy for head and neck region, (d) hyperglycemia (>150 mg/dl), (e) age (<20 years), (f) complete resection by biopsy before FDG-PET/CT and (g) having multiple OSCC lesions at the time of FDG-PET/CT. Finally, 205 patients (125 men, 80 women, mean age 59.7 ± 14.9 years) were enrolled in this study (Fig. 1). Table 1 shows clinical characteristics of the enrolled patients. Figure 1. View largeDownload slide Flow chart of the patient selection process. Figure 1. View largeDownload slide Flow chart of the patient selection process. Table 1. Clinical characteristics of the patients Characteristic n (%) Sex  Men 125 (61.0)  Women 80 (39.0) Primary site  Oral tongue 135 (65.9)  Upper alveolus and gingiva 23 (11.2)  Lower alveolus and gingiva 32 (15.6)  Buccal mucosa 9 (4.4)  Floor of mouth 5 (2.4)  Hard palate 1 (0.5) Clinical T category  T1 88 (42.9)  T2 117 (57.1) Treatment  Surgery 188 (91.7)   Partial glossectomy 120 (58.5)   Partial glossectomy + cervical node biopsy 7 (3.4)   Partial glossectomy + neck dissection 61 (29.8)    Surgery alone 154 (75.1)    Surgery + radiotherapy 5 (2.4)    Surgery + chemoradiotherapy 7 (3.4)    Surgery + chemotherapy 22 (10.7)  Brachytherapy 16 (7.8)  Photon beam therapy + intra-arterial chemotherapy 1 (0.5) Smoking  No 97 (47.3)  Yes 102 (48.8)  Unknown 6 (2.9) Alcohol drinking  No 77 (37.6)  Yes 108 (52.7)  Unknown 20 (9.8) Characteristic n (%) Sex  Men 125 (61.0)  Women 80 (39.0) Primary site  Oral tongue 135 (65.9)  Upper alveolus and gingiva 23 (11.2)  Lower alveolus and gingiva 32 (15.6)  Buccal mucosa 9 (4.4)  Floor of mouth 5 (2.4)  Hard palate 1 (0.5) Clinical T category  T1 88 (42.9)  T2 117 (57.1) Treatment  Surgery 188 (91.7)   Partial glossectomy 120 (58.5)   Partial glossectomy + cervical node biopsy 7 (3.4)   Partial glossectomy + neck dissection 61 (29.8)    Surgery alone 154 (75.1)    Surgery + radiotherapy 5 (2.4)    Surgery + chemoradiotherapy 7 (3.4)    Surgery + chemotherapy 22 (10.7)  Brachytherapy 16 (7.8)  Photon beam therapy + intra-arterial chemotherapy 1 (0.5) Smoking  No 97 (47.3)  Yes 102 (48.8)  Unknown 6 (2.9) Alcohol drinking  No 77 (37.6)  Yes 108 (52.7)  Unknown 20 (9.8) Table 1. Clinical characteristics of the patients Characteristic n (%) Sex  Men 125 (61.0)  Women 80 (39.0) Primary site  Oral tongue 135 (65.9)  Upper alveolus and gingiva 23 (11.2)  Lower alveolus and gingiva 32 (15.6)  Buccal mucosa 9 (4.4)  Floor of mouth 5 (2.4)  Hard palate 1 (0.5) Clinical T category  T1 88 (42.9)  T2 117 (57.1) Treatment  Surgery 188 (91.7)   Partial glossectomy 120 (58.5)   Partial glossectomy + cervical node biopsy 7 (3.4)   Partial glossectomy + neck dissection 61 (29.8)    Surgery alone 154 (75.1)    Surgery + radiotherapy 5 (2.4)    Surgery + chemoradiotherapy 7 (3.4)    Surgery + chemotherapy 22 (10.7)  Brachytherapy 16 (7.8)  Photon beam therapy + intra-arterial chemotherapy 1 (0.5) Smoking  No 97 (47.3)  Yes 102 (48.8)  Unknown 6 (2.9) Alcohol drinking  No 77 (37.6)  Yes 108 (52.7)  Unknown 20 (9.8) Characteristic n (%) Sex  Men 125 (61.0)  Women 80 (39.0) Primary site  Oral tongue 135 (65.9)  Upper alveolus and gingiva 23 (11.2)  Lower alveolus and gingiva 32 (15.6)  Buccal mucosa 9 (4.4)  Floor of mouth 5 (2.4)  Hard palate 1 (0.5) Clinical T category  T1 88 (42.9)  T2 117 (57.1) Treatment  Surgery 188 (91.7)   Partial glossectomy 120 (58.5)   Partial glossectomy + cervical node biopsy 7 (3.4)   Partial glossectomy + neck dissection 61 (29.8)    Surgery alone 154 (75.1)    Surgery + radiotherapy 5 (2.4)    Surgery + chemoradiotherapy 7 (3.4)    Surgery + chemotherapy 22 (10.7)  Brachytherapy 16 (7.8)  Photon beam therapy + intra-arterial chemotherapy 1 (0.5) Smoking  No 97 (47.3)  Yes 102 (48.8)  Unknown 6 (2.9) Alcohol drinking  No 77 (37.6)  Yes 108 (52.7)  Unknown 20 (9.8) FDG-PET/CT protocol Prior to scanning, the patients were instructed to fast for at least 4 h before receiving an injection of FDG (3.7 MBq/kg). At 60 min (early phase) and 120 min (delayed phase) after the injection, PET/CT images of the head and neck (from the skull base to subclavicular area) were obtained, without breath holding, using a PET/CT system (Aquiduo, Toshiba Medical Systems, Japan). CT images for attenuation correction were acquired using a 16-row MDCT scanner with the following parameters: 120 kV, 150 mA, an FOV of 500 mm, a pitch of 15.0, and a 2.0-mm slice thickness. PET emission data were acquired in 3D mode using a full-ring PET scanner utilizing lutetium oxyorthosilicate crystals. The parameters of PET were as follows: 4 min per bed position (for 8 min total), matrix size of 256 × 256, and a gaussian filter size of 5 mm. Patients also underwent whole-body scanning at 75 min after FDG injection. Contrast medium was not used in all patients. Image evaluation Two nuclear medicine physicians, experienced in FDG-PET/CT assessment of head and neck cancers for 11 and 10 years, respectively, evaluated the FDG-PET/CT images of all enrolled patients. First, they visually determined whether the primary lesion had elevated FDG uptake. Generally, evaluators judged asymmetrical nodular FDG uptake in the oral cavity as positive FDG uptake. On the other hand, unclearly bound, low-to-moderate uptake matching that of a tooth was regarded as physiological or caries-related FDG uptake and judged to be negative. The evaluators were allowed to refer to non-attenuation corrected PET images to exclude dental metallic artifacts. If the lesions were judged positive for FDG uptake, their sites were identified on the fused PET/CT images. When the judgments of two evaluators were discordant, the third independent nuclear medicine physician, who had experience of FDG-PET/CT evaluation for 7 years, was asked to evaluate the FDG-PET/CT images under the same conditions and reach a consensus opinion. Thereafter, if FDG uptake was not concordant with the primary tumor site, the tumor was considered as negative for FDG uptake. For primary tumors with positive FDG uptake, maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were measured on the head and neck PET/CT images in the delayed phase (12,13). To calculate MTV and TLG, we used the previously published cutoff SUV of 2.5 (14,15). The evaluators also judged whether cervical nodal metastasis, distant metastasis and synchronous cancer in other organs were detected by FDG-PET/CT. For evaluating cervical lymph nodes, head and neck PET/CT images were obtained during the delayed phase and judged positive for nodal metastases using the following criteria: (a) visually asymmetrical FDG uptake exceeding background, and (b) lymphadenopathy with short axis greater than 10 mm on CT. Whole-body PET/CT images were used for screening of distant metastasis and synchronous cancer. Prognostic prediction Recurrence free survival (RFS) was defined as the number of months from the start of treatment to recurrence confirmation and used as the clinical endpoint. The cutoff value of each PET/CT parameter in tumors with visually positive FDG uptake was determined by time-dependent receiver operating characteristics (ROC) curve analysis using the free software R (version 3.4.0). Diagnostic performance of FDG-PET/CT for detection of metastatic lesions and synchronous cancers As the secondary purpose, we evaluated the diagnostic performance of FDG-PET/CT in early OSCC patients. The sensitivity, specificity and accuracy of detecting cervical nodal metastasis were calculated. The definite diagnosis was confirmed by pathological examination or clinical follow-up. If the cervical nodes did not increase in size or number after at least 6 months of clinical follow-up, they were considered negative for metastasis at the time of the FDG-PET/CT study. On the other hand, if cervical nodes increased in size or number within 6 months after the treatment, they were judged as positive when pathological examination confirmed metastasis, or decrease in size was observed following anticancer treatment. We calculated the frequency of distant metastasis or synchronous cancers from clinical or follow-up data. Statistical analyses We used SPSS version 22 (IBM, Armonk, New York) for the following statistical analyses. We used the Kaplan–Meier method to estimate RFS, followed by univariate analysis using the log-rank test to compare the difference in RFS between two groups in each category. A population for log-rank test based on semi-quantitative PET/CT parameters included only the patients with visually positive FDG uptake in primary tumors. Fisher’s exact test was performed to evaluate the relationship between FDG uptake and some clinical or available pathological factors as shown in Table 2. A P < 0.05 was considered as significant. Table 2. Relationship between FDG uptake and patients’ characteristics Characteristics Total FDG–a FDG+ a P n (%) n (%) n (%) Clinical factors  Sex   Men 125 (61.0) 36 (17.6) 89 (43.4) 0.284   Women 80 (39.0) 29 (14.1) 51 (24.9)  Ageb   ≤62 105 (51.2) 36 (17.6) 69 (33.7) 0.455   >62 100 (48.8) 29 (14.1) 71 (34.6)  Clinical T category   T1 95 (46.3) 37 (18.0) 58 (28.3) 0.050   T2 110 (53.7) 28 (13.7) 82 (40.0)  Clinical N category   N0 156 (76.1) 53 (25.9) 103 (50.2) 0.291   ≥N1c 49 (23.9) 12 (5.9) 37 (18.0)  Smoking   No 97 (47.3) 34 (16.6) 63 (30.7) 0.369   Yes or unknown 108 (52.7) 31 (15.1) 77 (37.6)  Alcohol drinking   No 77 (37.6) 23 (11.2) 54 (26.3) 0.757   Yes or unknown 128 (62.4) 42 (20.5) 86 (42.0) Pathological factors  Pathological T category   T1 84 (58.7) 42 (29.4) 42 (29.4) <0.001   ≥T2 59 (41.3) 10 (7.0) 49 (34.3)  Tumor thicknessb   ≤3 mm 74 (52.9) 41 (29.3) 33 (23.6) <0.001   >3 mm 66 (47.1) 9 (6.4) 57 (40.7)  YK classification   1–2 42 (29.6) 25 (17.6) 17 (12.0) <0.001   3-4D 100 (70.4) 27 (19.0) 73 (51.4)  Lymphatic invasion   Negative 115 (86.5) 43 (32.3) 72 (54.1) 0.112   Positive 18 (13.5) 3 (2.3) 15 (11.3)  Vascular invasion   Negative 94 (70.7) 39 (29.3) 55 (41.4) 0.010   Positive 39 (29.3) 7 (5.3) 32 (24.1) Characteristics Total FDG–a FDG+ a P n (%) n (%) n (%) Clinical factors  Sex   Men 125 (61.0) 36 (17.6) 89 (43.4) 0.284   Women 80 (39.0) 29 (14.1) 51 (24.9)  Ageb   ≤62 105 (51.2) 36 (17.6) 69 (33.7) 0.455   >62 100 (48.8) 29 (14.1) 71 (34.6)  Clinical T category   T1 95 (46.3) 37 (18.0) 58 (28.3) 0.050   T2 110 (53.7) 28 (13.7) 82 (40.0)  Clinical N category   N0 156 (76.1) 53 (25.9) 103 (50.2) 0.291   ≥N1c 49 (23.9) 12 (5.9) 37 (18.0)  Smoking   No 97 (47.3) 34 (16.6) 63 (30.7) 0.369   Yes or unknown 108 (52.7) 31 (15.1) 77 (37.6)  Alcohol drinking   No 77 (37.6) 23 (11.2) 54 (26.3) 0.757   Yes or unknown 128 (62.4) 42 (20.5) 86 (42.0) Pathological factors  Pathological T category   T1 84 (58.7) 42 (29.4) 42 (29.4) <0.001   ≥T2 59 (41.3) 10 (7.0) 49 (34.3)  Tumor thicknessb   ≤3 mm 74 (52.9) 41 (29.3) 33 (23.6) <0.001   >3 mm 66 (47.1) 9 (6.4) 57 (40.7)  YK classification   1–2 42 (29.6) 25 (17.6) 17 (12.0) <0.001   3-4D 100 (70.4) 27 (19.0) 73 (51.4)  Lymphatic invasion   Negative 115 (86.5) 43 (32.3) 72 (54.1) 0.112   Positive 18 (13.5) 3 (2.3) 15 (11.3)  Vascular invasion   Negative 94 (70.7) 39 (29.3) 55 (41.4) 0.010   Positive 39 (29.3) 7 (5.3) 32 (24.1) FDG-PET/CT, 2-deoxy-2-[18F] fluoro-d-glucose-positron emission tomography/computed tomography; YK, Yamamoto-Kohama. aWhether FDG uptake is negative or positive in visual interpretation. bMedian value was used as the cutoff. cNodal metastases were suggested only by FDG-PET/CT. Table 2. Relationship between FDG uptake and patients’ characteristics Characteristics Total FDG–a FDG+ a P n (%) n (%) n (%) Clinical factors  Sex   Men 125 (61.0) 36 (17.6) 89 (43.4) 0.284   Women 80 (39.0) 29 (14.1) 51 (24.9)  Ageb   ≤62 105 (51.2) 36 (17.6) 69 (33.7) 0.455   >62 100 (48.8) 29 (14.1) 71 (34.6)  Clinical T category   T1 95 (46.3) 37 (18.0) 58 (28.3) 0.050   T2 110 (53.7) 28 (13.7) 82 (40.0)  Clinical N category   N0 156 (76.1) 53 (25.9) 103 (50.2) 0.291   ≥N1c 49 (23.9) 12 (5.9) 37 (18.0)  Smoking   No 97 (47.3) 34 (16.6) 63 (30.7) 0.369   Yes or unknown 108 (52.7) 31 (15.1) 77 (37.6)  Alcohol drinking   No 77 (37.6) 23 (11.2) 54 (26.3) 0.757   Yes or unknown 128 (62.4) 42 (20.5) 86 (42.0) Pathological factors  Pathological T category   T1 84 (58.7) 42 (29.4) 42 (29.4) <0.001   ≥T2 59 (41.3) 10 (7.0) 49 (34.3)  Tumor thicknessb   ≤3 mm 74 (52.9) 41 (29.3) 33 (23.6) <0.001   >3 mm 66 (47.1) 9 (6.4) 57 (40.7)  YK classification   1–2 42 (29.6) 25 (17.6) 17 (12.0) <0.001   3-4D 100 (70.4) 27 (19.0) 73 (51.4)  Lymphatic invasion   Negative 115 (86.5) 43 (32.3) 72 (54.1) 0.112   Positive 18 (13.5) 3 (2.3) 15 (11.3)  Vascular invasion   Negative 94 (70.7) 39 (29.3) 55 (41.4) 0.010   Positive 39 (29.3) 7 (5.3) 32 (24.1) Characteristics Total FDG–a FDG+ a P n (%) n (%) n (%) Clinical factors  Sex   Men 125 (61.0) 36 (17.6) 89 (43.4) 0.284   Women 80 (39.0) 29 (14.1) 51 (24.9)  Ageb   ≤62 105 (51.2) 36 (17.6) 69 (33.7) 0.455   >62 100 (48.8) 29 (14.1) 71 (34.6)  Clinical T category   T1 95 (46.3) 37 (18.0) 58 (28.3) 0.050   T2 110 (53.7) 28 (13.7) 82 (40.0)  Clinical N category   N0 156 (76.1) 53 (25.9) 103 (50.2) 0.291   ≥N1c 49 (23.9) 12 (5.9) 37 (18.0)  Smoking   No 97 (47.3) 34 (16.6) 63 (30.7) 0.369   Yes or unknown 108 (52.7) 31 (15.1) 77 (37.6)  Alcohol drinking   No 77 (37.6) 23 (11.2) 54 (26.3) 0.757   Yes or unknown 128 (62.4) 42 (20.5) 86 (42.0) Pathological factors  Pathological T category   T1 84 (58.7) 42 (29.4) 42 (29.4) <0.001   ≥T2 59 (41.3) 10 (7.0) 49 (34.3)  Tumor thicknessb   ≤3 mm 74 (52.9) 41 (29.3) 33 (23.6) <0.001   >3 mm 66 (47.1) 9 (6.4) 57 (40.7)  YK classification   1–2 42 (29.6) 25 (17.6) 17 (12.0) <0.001   3-4D 100 (70.4) 27 (19.0) 73 (51.4)  Lymphatic invasion   Negative 115 (86.5) 43 (32.3) 72 (54.1) 0.112   Positive 18 (13.5) 3 (2.3) 15 (11.3)  Vascular invasion   Negative 94 (70.7) 39 (29.3) 55 (41.4) 0.010   Positive 39 (29.3) 7 (5.3) 32 (24.1) FDG-PET/CT, 2-deoxy-2-[18F] fluoro-d-glucose-positron emission tomography/computed tomography; YK, Yamamoto-Kohama. aWhether FDG uptake is negative or positive in visual interpretation. bMedian value was used as the cutoff. cNodal metastases were suggested only by FDG-PET/CT. Results Table 1 During the follow-up period (range 2.8–69.6 months, mean 32.9 months), patients developed local and regional recurrences (n = 10), cervical nodal metastases (n = 32) and multiple bone metastases (n = 1). Ten patients died of the following reasons: OSCC (7 patients), lung cancer (1 patient), and unknown causes (2 patients). Prognosis prediction By visual interpretation, 140 and 65 primary tumors were judged as positive and negative for FDG uptake, respectively. Patients with primary lesions with visually positive FDG uptake had significantly shorter RFS compared to the other (63.0 months vs. 52.9 months, P = 0.005). The mean SUVmax, MTV and TLG of 140 primary lesions with visually positive FDG uptake were 10.2 (range, 3.6–32.7), 5.9 ml (range, 0.35–33.0) and 30.6 g (range, 1.2–257.8). As shown in Fig. 2B–D, RFS tended to be shorter in patients with higher PET/CT parameter values. However, differences in RFS between the two groups divided by parameter cutoff value were not significant for all the parameters (SUVmax, 54.8 months vs. 51.5 months, P = 0.215; MTV, 56.7 months vs. 48.0 months, P = 0.125; TLG, 57.1 months vs. 46.8 months, P = 0.063). Time-dependent ROC curves are shown in Supplemental Fig. 1. The time-dependent ROC analysis suggested that 1 year after treatment was the optimal cutoff time for tumors with visually positive FDG uptake. Although the area under the curve for SUVmax was larger than those for MTV and TLG at any time-point, SUVmax was considered to be an unsatisfactory predictor of recurrence. As shown in Fig. 2E,F, there were no significant differences in RFS between groups divided on the basis of clinical T and N stages (cT, 54.5 months vs. 57.3 months, P = 0.573; cN, 55.9 months vs. 55.9 months, P = 0.599). Figure 2. View largeDownload slide Kaplan–Meier curves of RFS with regard to FDG visibility (A), SUVmax (B), MTV (C), TLG (D), cT category (E) and cN category (F). SUVmax, MTV and TLG were analysed only in primary tumours with visually positive FDG uptake. FDG, 2-deoxy-2-[18F] fluoro-D-glucose; MTV, metabolic tumour volume; RFS, recurrence free survival; SUVmax, maximum standardized uptake value; TLG, total lesion glycolysis. Figure 2. View largeDownload slide Kaplan–Meier curves of RFS with regard to FDG visibility (A), SUVmax (B), MTV (C), TLG (D), cT category (E) and cN category (F). SUVmax, MTV and TLG were analysed only in primary tumours with visually positive FDG uptake. FDG, 2-deoxy-2-[18F] fluoro-D-glucose; MTV, metabolic tumour volume; RFS, recurrence free survival; SUVmax, maximum standardized uptake value; TLG, total lesion glycolysis. Relationship between FDG uptake and clinical or pathological findings Pathological findings of surgical specimen were available by medical chart review in 165 patients. After excluding 22 patients due to any treatment between FDG-PET/CT and surgery, 143 patients were enrolled in the statistical analysis. Pathological T stage was judged as pT1 in 84 patients (58.7%), pT2 in 46 patients (32.2%), pT3 in two patients (1.4%), pT4a in 10 patients (7.0%), and pT4b in one patient (0.7%). Tumor thickness was 4.4 ± 3.8 mm (range, 0.2–20 mm). Yamamoto-Kohama (YK) classification was judged as YK-1 in six patients (4.2%), YK-2 in 36 patients (25.2%), YK-3 in 65 patients (45.5%), YK-4C in 33 patients (23.1%) and YK-4D in two patients (1.4%). Table 2 shows the relationship between positivity of FDG uptake and patients’ clinical or pathological factors. Some pathological factors (pT, tumor thickness, YK classification and vascular invasion) showed significant correlation with FDG uptake (P < 0.05). Diagnostic performance of FDG-PET/CT for detection of metastatic lesions and synchronous cancers Neck dissection or cervical nodal biopsy had been performed in 68 patients, and 16 patients were pathologically judged to have cervical nodal metastasis. In addition, 15 patients were judged positive for metastasis by clinical follow-up. Totally, 31 patients were judged to have cervical nodal metastasis at the time of FDG-PET/CT. Table 3 shows the diagnostic performance of FDG-PET/CT for N staging. The sensitivity, specificity and accuracy of FDG-PET/CT for cervical nodal metastases were 32.3% (95% CI, 19.3–47.8), 77.6% (95% CI, 75.3–80.4) and 70.7% (95% CI, 66.8–75.4). Table 3. Diagnostic values of FDG-PET/CT in the detection of cervical nodal metastasis Cervical nodal metastasis, n (%) Present Absent Total FDG-PET/CT+ 10 (4.9) 39 (19.0) 49 (23.9) FDG-PET/CT– 21 (10.2) 135 (65.9) 156 (76.1) Total 31 (15.1) 174 (84.9) 205 Cervical nodal metastasis, n (%) Present Absent Total FDG-PET/CT+ 10 (4.9) 39 (19.0) 49 (23.9) FDG-PET/CT– 21 (10.2) 135 (65.9) 156 (76.1) Total 31 (15.1) 174 (84.9) 205 FDG-PET/CT, 2-deoxy-2-[18F] fluoro-d-glucose -positron emission tomography/computed tomography. Table 3. Diagnostic values of FDG-PET/CT in the detection of cervical nodal metastasis Cervical nodal metastasis, n (%) Present Absent Total FDG-PET/CT+ 10 (4.9) 39 (19.0) 49 (23.9) FDG-PET/CT– 21 (10.2) 135 (65.9) 156 (76.1) Total 31 (15.1) 174 (84.9) 205 Cervical nodal metastasis, n (%) Present Absent Total FDG-PET/CT+ 10 (4.9) 39 (19.0) 49 (23.9) FDG-PET/CT– 21 (10.2) 135 (65.9) 156 (76.1) Total 31 (15.1) 174 (84.9) 205 FDG-PET/CT, 2-deoxy-2-[18F] fluoro-d-glucose -positron emission tomography/computed tomography. There were no patients in whom distant metastases were detected in FDG-PET/CT. Unexpected synchronous cancers were detected in 14 patients (Table 4). FDG-PET/CT could detect eight synchronous cancers (3.9%), however, overlooked two esophageal cancers, one gastric cancer, one colorectal cancer, one hepatocellular carcinoma and one uterine cervical cancer. Table 4. Synchronous cancers recognized in our patients Total (%) FDG-PET/CT detected (%) Colorectal cancer 4 (2.0) 3 (1.5) Esophageal cancer 3 (1.5) 1 (0.5) Uterine cervical cancer 2 (1.0) 1 (0.5) Pancreatic cancer 1 (0.5) 1 (0.5) Renal cancer 1 (0.5) 1 (0.5) Prostate cancer 1 (0.5) 1 (0.5) Gastric cancer 1 (0.5) 0 Hepatocellular carcinoma 1 (0.5) 0 Total 14 (6.8) 8 (3.9) Total (%) FDG-PET/CT detected (%) Colorectal cancer 4 (2.0) 3 (1.5) Esophageal cancer 3 (1.5) 1 (0.5) Uterine cervical cancer 2 (1.0) 1 (0.5) Pancreatic cancer 1 (0.5) 1 (0.5) Renal cancer 1 (0.5) 1 (0.5) Prostate cancer 1 (0.5) 1 (0.5) Gastric cancer 1 (0.5) 0 Hepatocellular carcinoma 1 (0.5) 0 Total 14 (6.8) 8 (3.9) FDG-PET/CT, 2-deoxy-2-[18F] fluoro-d-glucose-positron emission tomography/computed tomography. Table 4. Synchronous cancers recognized in our patients Total (%) FDG-PET/CT detected (%) Colorectal cancer 4 (2.0) 3 (1.5) Esophageal cancer 3 (1.5) 1 (0.5) Uterine cervical cancer 2 (1.0) 1 (0.5) Pancreatic cancer 1 (0.5) 1 (0.5) Renal cancer 1 (0.5) 1 (0.5) Prostate cancer 1 (0.5) 1 (0.5) Gastric cancer 1 (0.5) 0 Hepatocellular carcinoma 1 (0.5) 0 Total 14 (6.8) 8 (3.9) Total (%) FDG-PET/CT detected (%) Colorectal cancer 4 (2.0) 3 (1.5) Esophageal cancer 3 (1.5) 1 (0.5) Uterine cervical cancer 2 (1.0) 1 (0.5) Pancreatic cancer 1 (0.5) 1 (0.5) Renal cancer 1 (0.5) 1 (0.5) Prostate cancer 1 (0.5) 1 (0.5) Gastric cancer 1 (0.5) 0 Hepatocellular carcinoma 1 (0.5) 0 Total 14 (6.8) 8 (3.9) FDG-PET/CT, 2-deoxy-2-[18F] fluoro-d-glucose-positron emission tomography/computed tomography. Discussion This single center study evaluated the clinical performance of FDG-PET/CT using a cohort including only the early OSCC patients (cT1-2N0M0). Some studies have shown that FDG-PET/CT parameters have potential for predicting prognosis of OSCC patients (9,10,14,15). Tumor thickness and perineural invasion were conjectured to be prognosticators of early OSCC in other studies (16,17). Our study revealed that FDG-PET/CT could also be used to predict RFS even though limited to patients with early OSCC. Patients with visually positive FDG uptake in the primary tumor showed significantly shorter RFS. However, when dividing patients with visually positive FDG uptake to two groups on the basis of SUVmax, MTV and TLG, no significant difference in RFS could be discerned between the groups with higher or lower parameter. Semi-quantitative PET/CT parameters might not have additional value for further prognostication of patients with visually positive FDG uptake in primary tumors. On the other hand, PET/CT parameter values tended to be higher in patients with shorter RFS. In addition, because our study included only the patients with early OSCC, underestimation of FDG uptake due to a partial volume effect may have occurred in some cases. Further studies with a larger population might show different results in terms of the relationship between PET/CT parameter values and patients’ survival. On the other hand, our study revealed that not only the size but also several pathological factors of primary tumor contributed to visually positive FDG uptake. Compared to conventional imaging studies, FDG-PET/CT may reflect more detailed tumor characteristics. It is possible that these points led significant difference of RFS between patients with visually positive and negative FDG uptake in primary tumors. Two meta-analyses showed that FDG-PET/CT has sensitivity of 66% (4) and 50% (18) for detecting cervical nodal metastases in cN0 patients. Our study showed a lower sensitivity than them (32.3%). However, we excluded patients who were judged as having cervical nodal metastases by not only physical examination but also other imaging modalities such as CT, MRI and US. With sufficient screening for cervical lymph node metastases, the performance of FDG-PET/CT is considered to be limited for early OSCC. FDG-PET/CT overlooked some synchronous cancers in our study. Particularly, endoscopic screening for detection of esophageal cancer and gastric cancer cannot be disregarded in OSCC patients (7,8,19). Thus, we conclude that benefit of FDG-PET/CT for staging of early OSCC patients is limited. Our study had some limitations. First, because this was a retrospective study, there may have been a selection bias caused by FDG-PET/CT indication and treatment selection. Second, because the primary tumors were small in our cohort, the number of patients with tumor recurrence was even smaller. Third, some cervical nodal metastases were diagnosed by clinical follow-up; therefore, whether nodal metastases actually existed at the time of FDG-PET/CT is unclear in these cases. In conclusion, although its utility for staging is limited, FDG-PET/CT is potentially prognostic indicator in patients with early OSCC (cT1-2N0M0). Supplementary data Supplementary data are available at Japanese Journal of Clinical Oncology online. Funding This work was supported in part by grants from Scientific Research Expenses for Health and Welfare Programs, the Grant-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare, No. 15K09885, the Scientific Research Expenses for Health and Welfare Programs, [grant number 29-A-3] (Takashi Terauchi and Ukihide Tateishi: squad leaders), Practical Research for Innovative Cancer Control and Project Promoting Clinical Trials for Development of New Drugs by Japan Agency for Medical Research and Development (AMED). Conflict of interest statement None declared. References 1 Siegel RL , Miller KD , Jemal A . Cancer Statistics, 2017 . CA Cancer J Clin 2017 ; 67 : 7 – 30 . Google Scholar CrossRef Search ADS PubMed 2 Pasha MA , Marcus C , Fakhry C , Kang H , Kiess AP , Subramaniam RM . FDG PET/CT for management and assessing outcomes of squamous cell cancer of the oral cavity . Am J Roentgenol 2015 ; 205 : W150 – 61 . Google Scholar CrossRef Search ADS 3 National Comprehensive Cancer Network . NCCN Clinical Practice Guidelines in Oncology Head and Neck Cancers Version 1 2017 . Fort Washington : National Comprehensive Cancer Network , 2017 ; 187 . 4 Liao LJ , Lo WC , Hsu WL , Wang CT , Lai MS . Detection of cervical lymph node metastasis in head and neck cancer patients with clinically N0 neck-a meta-analysis comparing different imaging modalities . BMC Cancer 2012 ; 12 : 236 . Google Scholar CrossRef Search ADS PubMed 5 Liao CT , Wang HM , Huang SF , et al. . PET and PET/CT of the neck lymph nodes improves risk prediction in patients with squamous cell carcinoma of the oral cavity . J Nucl Med 2011 ; 52 : 180 – 7 . Google Scholar CrossRef Search ADS PubMed 6 Krabbe CA , Dijkstra PU , Pruim J , et al. . FDG PET in oral and oropharyngeal cancer. Value for confirmation of N0 neck and detection of occult metastases . Oral Oncol 2008 ; 44 : 31 – 6 . Google Scholar CrossRef Search ADS PubMed 7 Hanamoto A , Takenaka Y , Shimosegawa E , et al. . Limitation of 2-deoxy-2-[F-18]fluoro-D-glucose positron emission tomography (FDG-PET) to detect early synchronous primary cancers in patients with untreated head and neck squamous cell cancer . Ann Nucl Med 2013 ; 27 : 880 – 5 . Google Scholar CrossRef Search ADS PubMed 8 Yabuki K , Kubota A , Horiuchi C , Taguchi T , Nishimura G , Inamori M . Limitations of PET and PET/CT in detecting upper gastrointestinal synchronous cancer in patients with head and neck carcinoma . Eur Arch Otorhinolaryngol 2013 ; 270 : 727 – 33 . Google Scholar CrossRef Search ADS PubMed 9 Ryu IS , Kim JS , Roh JL , et al. . Prognostic significance of preoperative metabolic tumour volume and total lesion glycolysis measured by (18)F-FDG PET/CT in squamous cell carcinoma of the oral cavity . Eur J Nucl Med Mol Imaging 2014 ; 41 : 452 – 61 . Google Scholar CrossRef Search ADS PubMed 10 Abd El-Hafez YG , Moustafa HM , Khalil HF , Liao CT , Yen TC . Total lesion glycolysis: a possible new prognostic parameter in oral cavity squamous cell carcinoma . Oral Oncol 2013 ; 49 : 261 – 8 . Google Scholar CrossRef Search ADS PubMed 11 Shinohara S , Kikuchi M , Suehiro A , Kishimoto I , Harada H . Is 18F-fluorodeoxyglucose positron emission tomography/computed tomography helpful in the decision-making process for neck dissection in patients with T1-T2 lingual cancer? Acta Otolaryngol 2015 ; 135 : 181 – 6 . Google Scholar CrossRef Search ADS PubMed 12 Ciernik IF , Dizendorf E , Baumert BG , et al. . Radiation treatment planning with an integrated positron emission and computer tomography (PET/CT): a feasibility study . Int J Radiat Oncol, Biol, Phys 2003 ; 57 : 853 – 63 . Google Scholar CrossRef Search ADS 13 Larson SM , Erdi Y , Akhurst T , et al. . Tumor treatment response based on visual and quantitative changes in global tumor glycolysis using PET-FDG imaging: the visual response score and the change in total lesion glycolysis . Clin Pos Imag 1999 ; 2 : 159 – 71 . Google Scholar CrossRef Search ADS 14 Kao CH , Lin SC , Hsieh TC , et al. . Use of pretreatment metabolic tumour volumes to predict the outcome of pharyngeal cancer treated by definitive radiotherapy . Eur J Nucl Med Mol Imaging 2012 ; 39 : 1297 – 305 . Google Scholar CrossRef Search ADS PubMed 15 Yabuki K , Shiono O , Komatsu M , et al. . Predictive and prognostic value of metabolic tumor volume (MTV) in patients with laryngeal carcinoma treated by radiotherapy (RT)/concurrent chemoradiotherapy (CCRT) . PLoS One 2015 ; 18 : e0117924 . Google Scholar CrossRef Search ADS 16 Imai T , Satoh I , Matsumoto K , et al. . Retrospective observational study of occult cervical lymph-node metastasis in T1N0 tongue cancer . Jpn J Clin Oncol 2017 ; 47 : 130 – 6 . Google Scholar CrossRef Search ADS PubMed 17 Tai SK , Li WY , Yang MH , Chu PY , Wang YF . Perineural invasion in T1 oral squamous cell carcinoma indicates the need for aggressive elective neck dissection . Am J Surg Pathol 2013 ; 37 : 1164 – 72 . Google Scholar CrossRef Search ADS PubMed 18 Kyzas PA , Evangelou E , Denaxa-Kyza D , Ioannidis JP . 18F-fluorodeoxyglucose positron emission tomography to evaluate cervical node metastases in patients with head and neck squamous cell carcinoma: a meta-analysis . J Natl Cancer Inst 2008 ; 100 : 712 – 20 . Google Scholar CrossRef Search ADS PubMed 19 Nakaminato S , Toriihara A , Makino T , Kawano T , Kishimoto S , Shibuya H . Prevalence of esophageal cancer during the pretreatment of hypopharyngeal cancer patients: routinely performed esophagogastroduodenoscopy and FDG-PET/CT findings . Acta Oncol 2012 ; 51 : 645 – 52 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Japanese Journal of Clinical Oncology Oxford University Press

Clinical usefulness of 2-deoxy-2-[18F] fluoro-d-glucose-positron emission tomography/computed tomography for assessing early oral squamous cell carcinoma (cT1-2N0M0)

Japanese Journal of Clinical Oncology , Volume Advance Article (7) – Apr 28, 2018

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
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0368-2811
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1465-3621
DOI
10.1093/jjco/hyy065
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29718274
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Abstract

Abstract Background Positron emission tomography with 2-deoxy-2-[18F] fluoro-d-glucose integrated with computed tomography (FDG-PET/CT) is a useful method to evaluate patients with oral squamous cell carcinoma (OSCC). However, the prognostic significance of FDG-PET/CT for assessing early OSCC remains unclear. Methods Pretreatment FDG-PET/CT of 205 consecutive patients (125 men, 80 women, mean age 59.7 year old) with early OSCC (cT1-2N0M0) between June 2010 and December 2014 were retrospectively analyzed. FDG avidity in primary lesions was assessed by visual interpretation. Thereafter, maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were measured in primary lesions. The relationship between each parameter and recurrence free survival (RFS) was assessed using the log-rank test. The performance of FDG-PET/CT for diagnosing metastatic lesions and synchronous cancer was also assessed. Results During the follow-up period (mean 32.9 months), 43 patients developed recurrences (21.0%). Patients with visually positive FDG uptake in primary lesions showed significantly shorter RFS than the others (63.0 months vs. 52.9 months, P = 0.005). In those patients, greater SUVmax, MTV, and TLG did not significantly predict shorter RFS. The sensitivity and specificity of FDG-PET/CT for cervical nodal metastases detection were 32.3% and 77.6%, respectively. FDG-PET/CT detected eight synchronous cancers (3.9%) and overlooked six synchronous cancers (2.9%). Conclusions Although its utility for detecting cervical nodal metastases and synchronous cancers is limited, FDG-PET/CT is a potentially prognostic indicator in early OSCC. oral squamous cell carcinoma, FDG-PET/CT, staging, synchronous cancer, prognosis Introduction A previously published report estimates that 32 670 cases of oral cancer will be newly diagnosed and 6650 patients will die from the disease in the United States in 2017 (1). 2-deoxy-2-[18F] fluoro-d-glucose-positron emission tomography/computed tomography (FDG-PET/CT) is a useful method to evaluate patients with oral squamous cell carcinoma (OSCC). A review article has revealed the utility of FDG-PET/CT for staging, screening of recurrent lesions, monitoring therapy and predicting prognosis (2). The National Comprehensive Cancer Network (NCCN) guideline for cancer of the oral cavity refers to the consideration of performing FDG-PET/CT for patients with Stage III–IV disease because it may change their therapeutic strategy (3). On the other hand, there is no statement referring to FDG-PET/CT for Stage I–II disease in this guideline. Some studies have shown the limited potential of FDG-PET/CT for detecting nodal metastases in patients of clinical N0 (cN0) (4–6) and detecting synchronous primary cancers, particularly esophageal cancer and gastric cancer (7,8). However, many OSCC patients enrolled in previous studies investigating the utility of FDG-PET/CT for prognosis prediction had advanced disease (9,10). To the best of our knowledge, one investigator has evaluated the clinical usefulness of FDG-PET/CT in patients with early lingual cancer (11). Thus, it is unclear whether FDG-PET/CT has potential of predicting prognosis of early OSCC. The purpose of this study was to assess the clinical usefulness of FDG-PET/CT for determining prognosis and for staging of early OSCC (cT1-2N0M0) in a large cohort. Patients and methods Our ethics committee approved this retrospective study (approval number: M2016-215). Written informed consent was waived. Subjects From June 2010 to December 2014, a total of 252 consecutive patients with early OSCC (cT1-2N0M0) underwent FDG-PET/CT prior to treatment in our hospital. Diagnosis of OSCC was confirmed histopathologically in all patients. Staging was performed by clinical examination, CT of the head and neck and chest, magnetic resonance imaging (MRI), and cervical ultrasonography (US). Although actual therapeutic strategy was decided on the basis of findings from conventional and FDG-PET/CT examinations, the patient population in this study was assessed without FDG-PET/CT findings, because one aim of this study was to confirm that additional FDG-PET/CT could enhance detection of unexpected metastatic lesions in early OSCC patients. We excluded 47 patients using the following criteria: (a) previous history of other malignant tumors in the past 5 years, (b) previous history of other head and neck cancers at any time, (c) previous history of neck dissection or radiotherapy for head and neck region, (d) hyperglycemia (>150 mg/dl), (e) age (<20 years), (f) complete resection by biopsy before FDG-PET/CT and (g) having multiple OSCC lesions at the time of FDG-PET/CT. Finally, 205 patients (125 men, 80 women, mean age 59.7 ± 14.9 years) were enrolled in this study (Fig. 1). Table 1 shows clinical characteristics of the enrolled patients. Figure 1. View largeDownload slide Flow chart of the patient selection process. Figure 1. View largeDownload slide Flow chart of the patient selection process. Table 1. Clinical characteristics of the patients Characteristic n (%) Sex  Men 125 (61.0)  Women 80 (39.0) Primary site  Oral tongue 135 (65.9)  Upper alveolus and gingiva 23 (11.2)  Lower alveolus and gingiva 32 (15.6)  Buccal mucosa 9 (4.4)  Floor of mouth 5 (2.4)  Hard palate 1 (0.5) Clinical T category  T1 88 (42.9)  T2 117 (57.1) Treatment  Surgery 188 (91.7)   Partial glossectomy 120 (58.5)   Partial glossectomy + cervical node biopsy 7 (3.4)   Partial glossectomy + neck dissection 61 (29.8)    Surgery alone 154 (75.1)    Surgery + radiotherapy 5 (2.4)    Surgery + chemoradiotherapy 7 (3.4)    Surgery + chemotherapy 22 (10.7)  Brachytherapy 16 (7.8)  Photon beam therapy + intra-arterial chemotherapy 1 (0.5) Smoking  No 97 (47.3)  Yes 102 (48.8)  Unknown 6 (2.9) Alcohol drinking  No 77 (37.6)  Yes 108 (52.7)  Unknown 20 (9.8) Characteristic n (%) Sex  Men 125 (61.0)  Women 80 (39.0) Primary site  Oral tongue 135 (65.9)  Upper alveolus and gingiva 23 (11.2)  Lower alveolus and gingiva 32 (15.6)  Buccal mucosa 9 (4.4)  Floor of mouth 5 (2.4)  Hard palate 1 (0.5) Clinical T category  T1 88 (42.9)  T2 117 (57.1) Treatment  Surgery 188 (91.7)   Partial glossectomy 120 (58.5)   Partial glossectomy + cervical node biopsy 7 (3.4)   Partial glossectomy + neck dissection 61 (29.8)    Surgery alone 154 (75.1)    Surgery + radiotherapy 5 (2.4)    Surgery + chemoradiotherapy 7 (3.4)    Surgery + chemotherapy 22 (10.7)  Brachytherapy 16 (7.8)  Photon beam therapy + intra-arterial chemotherapy 1 (0.5) Smoking  No 97 (47.3)  Yes 102 (48.8)  Unknown 6 (2.9) Alcohol drinking  No 77 (37.6)  Yes 108 (52.7)  Unknown 20 (9.8) Table 1. Clinical characteristics of the patients Characteristic n (%) Sex  Men 125 (61.0)  Women 80 (39.0) Primary site  Oral tongue 135 (65.9)  Upper alveolus and gingiva 23 (11.2)  Lower alveolus and gingiva 32 (15.6)  Buccal mucosa 9 (4.4)  Floor of mouth 5 (2.4)  Hard palate 1 (0.5) Clinical T category  T1 88 (42.9)  T2 117 (57.1) Treatment  Surgery 188 (91.7)   Partial glossectomy 120 (58.5)   Partial glossectomy + cervical node biopsy 7 (3.4)   Partial glossectomy + neck dissection 61 (29.8)    Surgery alone 154 (75.1)    Surgery + radiotherapy 5 (2.4)    Surgery + chemoradiotherapy 7 (3.4)    Surgery + chemotherapy 22 (10.7)  Brachytherapy 16 (7.8)  Photon beam therapy + intra-arterial chemotherapy 1 (0.5) Smoking  No 97 (47.3)  Yes 102 (48.8)  Unknown 6 (2.9) Alcohol drinking  No 77 (37.6)  Yes 108 (52.7)  Unknown 20 (9.8) Characteristic n (%) Sex  Men 125 (61.0)  Women 80 (39.0) Primary site  Oral tongue 135 (65.9)  Upper alveolus and gingiva 23 (11.2)  Lower alveolus and gingiva 32 (15.6)  Buccal mucosa 9 (4.4)  Floor of mouth 5 (2.4)  Hard palate 1 (0.5) Clinical T category  T1 88 (42.9)  T2 117 (57.1) Treatment  Surgery 188 (91.7)   Partial glossectomy 120 (58.5)   Partial glossectomy + cervical node biopsy 7 (3.4)   Partial glossectomy + neck dissection 61 (29.8)    Surgery alone 154 (75.1)    Surgery + radiotherapy 5 (2.4)    Surgery + chemoradiotherapy 7 (3.4)    Surgery + chemotherapy 22 (10.7)  Brachytherapy 16 (7.8)  Photon beam therapy + intra-arterial chemotherapy 1 (0.5) Smoking  No 97 (47.3)  Yes 102 (48.8)  Unknown 6 (2.9) Alcohol drinking  No 77 (37.6)  Yes 108 (52.7)  Unknown 20 (9.8) FDG-PET/CT protocol Prior to scanning, the patients were instructed to fast for at least 4 h before receiving an injection of FDG (3.7 MBq/kg). At 60 min (early phase) and 120 min (delayed phase) after the injection, PET/CT images of the head and neck (from the skull base to subclavicular area) were obtained, without breath holding, using a PET/CT system (Aquiduo, Toshiba Medical Systems, Japan). CT images for attenuation correction were acquired using a 16-row MDCT scanner with the following parameters: 120 kV, 150 mA, an FOV of 500 mm, a pitch of 15.0, and a 2.0-mm slice thickness. PET emission data were acquired in 3D mode using a full-ring PET scanner utilizing lutetium oxyorthosilicate crystals. The parameters of PET were as follows: 4 min per bed position (for 8 min total), matrix size of 256 × 256, and a gaussian filter size of 5 mm. Patients also underwent whole-body scanning at 75 min after FDG injection. Contrast medium was not used in all patients. Image evaluation Two nuclear medicine physicians, experienced in FDG-PET/CT assessment of head and neck cancers for 11 and 10 years, respectively, evaluated the FDG-PET/CT images of all enrolled patients. First, they visually determined whether the primary lesion had elevated FDG uptake. Generally, evaluators judged asymmetrical nodular FDG uptake in the oral cavity as positive FDG uptake. On the other hand, unclearly bound, low-to-moderate uptake matching that of a tooth was regarded as physiological or caries-related FDG uptake and judged to be negative. The evaluators were allowed to refer to non-attenuation corrected PET images to exclude dental metallic artifacts. If the lesions were judged positive for FDG uptake, their sites were identified on the fused PET/CT images. When the judgments of two evaluators were discordant, the third independent nuclear medicine physician, who had experience of FDG-PET/CT evaluation for 7 years, was asked to evaluate the FDG-PET/CT images under the same conditions and reach a consensus opinion. Thereafter, if FDG uptake was not concordant with the primary tumor site, the tumor was considered as negative for FDG uptake. For primary tumors with positive FDG uptake, maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were measured on the head and neck PET/CT images in the delayed phase (12,13). To calculate MTV and TLG, we used the previously published cutoff SUV of 2.5 (14,15). The evaluators also judged whether cervical nodal metastasis, distant metastasis and synchronous cancer in other organs were detected by FDG-PET/CT. For evaluating cervical lymph nodes, head and neck PET/CT images were obtained during the delayed phase and judged positive for nodal metastases using the following criteria: (a) visually asymmetrical FDG uptake exceeding background, and (b) lymphadenopathy with short axis greater than 10 mm on CT. Whole-body PET/CT images were used for screening of distant metastasis and synchronous cancer. Prognostic prediction Recurrence free survival (RFS) was defined as the number of months from the start of treatment to recurrence confirmation and used as the clinical endpoint. The cutoff value of each PET/CT parameter in tumors with visually positive FDG uptake was determined by time-dependent receiver operating characteristics (ROC) curve analysis using the free software R (version 3.4.0). Diagnostic performance of FDG-PET/CT for detection of metastatic lesions and synchronous cancers As the secondary purpose, we evaluated the diagnostic performance of FDG-PET/CT in early OSCC patients. The sensitivity, specificity and accuracy of detecting cervical nodal metastasis were calculated. The definite diagnosis was confirmed by pathological examination or clinical follow-up. If the cervical nodes did not increase in size or number after at least 6 months of clinical follow-up, they were considered negative for metastasis at the time of the FDG-PET/CT study. On the other hand, if cervical nodes increased in size or number within 6 months after the treatment, they were judged as positive when pathological examination confirmed metastasis, or decrease in size was observed following anticancer treatment. We calculated the frequency of distant metastasis or synchronous cancers from clinical or follow-up data. Statistical analyses We used SPSS version 22 (IBM, Armonk, New York) for the following statistical analyses. We used the Kaplan–Meier method to estimate RFS, followed by univariate analysis using the log-rank test to compare the difference in RFS between two groups in each category. A population for log-rank test based on semi-quantitative PET/CT parameters included only the patients with visually positive FDG uptake in primary tumors. Fisher’s exact test was performed to evaluate the relationship between FDG uptake and some clinical or available pathological factors as shown in Table 2. A P < 0.05 was considered as significant. Table 2. Relationship between FDG uptake and patients’ characteristics Characteristics Total FDG–a FDG+ a P n (%) n (%) n (%) Clinical factors  Sex   Men 125 (61.0) 36 (17.6) 89 (43.4) 0.284   Women 80 (39.0) 29 (14.1) 51 (24.9)  Ageb   ≤62 105 (51.2) 36 (17.6) 69 (33.7) 0.455   >62 100 (48.8) 29 (14.1) 71 (34.6)  Clinical T category   T1 95 (46.3) 37 (18.0) 58 (28.3) 0.050   T2 110 (53.7) 28 (13.7) 82 (40.0)  Clinical N category   N0 156 (76.1) 53 (25.9) 103 (50.2) 0.291   ≥N1c 49 (23.9) 12 (5.9) 37 (18.0)  Smoking   No 97 (47.3) 34 (16.6) 63 (30.7) 0.369   Yes or unknown 108 (52.7) 31 (15.1) 77 (37.6)  Alcohol drinking   No 77 (37.6) 23 (11.2) 54 (26.3) 0.757   Yes or unknown 128 (62.4) 42 (20.5) 86 (42.0) Pathological factors  Pathological T category   T1 84 (58.7) 42 (29.4) 42 (29.4) <0.001   ≥T2 59 (41.3) 10 (7.0) 49 (34.3)  Tumor thicknessb   ≤3 mm 74 (52.9) 41 (29.3) 33 (23.6) <0.001   >3 mm 66 (47.1) 9 (6.4) 57 (40.7)  YK classification   1–2 42 (29.6) 25 (17.6) 17 (12.0) <0.001   3-4D 100 (70.4) 27 (19.0) 73 (51.4)  Lymphatic invasion   Negative 115 (86.5) 43 (32.3) 72 (54.1) 0.112   Positive 18 (13.5) 3 (2.3) 15 (11.3)  Vascular invasion   Negative 94 (70.7) 39 (29.3) 55 (41.4) 0.010   Positive 39 (29.3) 7 (5.3) 32 (24.1) Characteristics Total FDG–a FDG+ a P n (%) n (%) n (%) Clinical factors  Sex   Men 125 (61.0) 36 (17.6) 89 (43.4) 0.284   Women 80 (39.0) 29 (14.1) 51 (24.9)  Ageb   ≤62 105 (51.2) 36 (17.6) 69 (33.7) 0.455   >62 100 (48.8) 29 (14.1) 71 (34.6)  Clinical T category   T1 95 (46.3) 37 (18.0) 58 (28.3) 0.050   T2 110 (53.7) 28 (13.7) 82 (40.0)  Clinical N category   N0 156 (76.1) 53 (25.9) 103 (50.2) 0.291   ≥N1c 49 (23.9) 12 (5.9) 37 (18.0)  Smoking   No 97 (47.3) 34 (16.6) 63 (30.7) 0.369   Yes or unknown 108 (52.7) 31 (15.1) 77 (37.6)  Alcohol drinking   No 77 (37.6) 23 (11.2) 54 (26.3) 0.757   Yes or unknown 128 (62.4) 42 (20.5) 86 (42.0) Pathological factors  Pathological T category   T1 84 (58.7) 42 (29.4) 42 (29.4) <0.001   ≥T2 59 (41.3) 10 (7.0) 49 (34.3)  Tumor thicknessb   ≤3 mm 74 (52.9) 41 (29.3) 33 (23.6) <0.001   >3 mm 66 (47.1) 9 (6.4) 57 (40.7)  YK classification   1–2 42 (29.6) 25 (17.6) 17 (12.0) <0.001   3-4D 100 (70.4) 27 (19.0) 73 (51.4)  Lymphatic invasion   Negative 115 (86.5) 43 (32.3) 72 (54.1) 0.112   Positive 18 (13.5) 3 (2.3) 15 (11.3)  Vascular invasion   Negative 94 (70.7) 39 (29.3) 55 (41.4) 0.010   Positive 39 (29.3) 7 (5.3) 32 (24.1) FDG-PET/CT, 2-deoxy-2-[18F] fluoro-d-glucose-positron emission tomography/computed tomography; YK, Yamamoto-Kohama. aWhether FDG uptake is negative or positive in visual interpretation. bMedian value was used as the cutoff. cNodal metastases were suggested only by FDG-PET/CT. Table 2. Relationship between FDG uptake and patients’ characteristics Characteristics Total FDG–a FDG+ a P n (%) n (%) n (%) Clinical factors  Sex   Men 125 (61.0) 36 (17.6) 89 (43.4) 0.284   Women 80 (39.0) 29 (14.1) 51 (24.9)  Ageb   ≤62 105 (51.2) 36 (17.6) 69 (33.7) 0.455   >62 100 (48.8) 29 (14.1) 71 (34.6)  Clinical T category   T1 95 (46.3) 37 (18.0) 58 (28.3) 0.050   T2 110 (53.7) 28 (13.7) 82 (40.0)  Clinical N category   N0 156 (76.1) 53 (25.9) 103 (50.2) 0.291   ≥N1c 49 (23.9) 12 (5.9) 37 (18.0)  Smoking   No 97 (47.3) 34 (16.6) 63 (30.7) 0.369   Yes or unknown 108 (52.7) 31 (15.1) 77 (37.6)  Alcohol drinking   No 77 (37.6) 23 (11.2) 54 (26.3) 0.757   Yes or unknown 128 (62.4) 42 (20.5) 86 (42.0) Pathological factors  Pathological T category   T1 84 (58.7) 42 (29.4) 42 (29.4) <0.001   ≥T2 59 (41.3) 10 (7.0) 49 (34.3)  Tumor thicknessb   ≤3 mm 74 (52.9) 41 (29.3) 33 (23.6) <0.001   >3 mm 66 (47.1) 9 (6.4) 57 (40.7)  YK classification   1–2 42 (29.6) 25 (17.6) 17 (12.0) <0.001   3-4D 100 (70.4) 27 (19.0) 73 (51.4)  Lymphatic invasion   Negative 115 (86.5) 43 (32.3) 72 (54.1) 0.112   Positive 18 (13.5) 3 (2.3) 15 (11.3)  Vascular invasion   Negative 94 (70.7) 39 (29.3) 55 (41.4) 0.010   Positive 39 (29.3) 7 (5.3) 32 (24.1) Characteristics Total FDG–a FDG+ a P n (%) n (%) n (%) Clinical factors  Sex   Men 125 (61.0) 36 (17.6) 89 (43.4) 0.284   Women 80 (39.0) 29 (14.1) 51 (24.9)  Ageb   ≤62 105 (51.2) 36 (17.6) 69 (33.7) 0.455   >62 100 (48.8) 29 (14.1) 71 (34.6)  Clinical T category   T1 95 (46.3) 37 (18.0) 58 (28.3) 0.050   T2 110 (53.7) 28 (13.7) 82 (40.0)  Clinical N category   N0 156 (76.1) 53 (25.9) 103 (50.2) 0.291   ≥N1c 49 (23.9) 12 (5.9) 37 (18.0)  Smoking   No 97 (47.3) 34 (16.6) 63 (30.7) 0.369   Yes or unknown 108 (52.7) 31 (15.1) 77 (37.6)  Alcohol drinking   No 77 (37.6) 23 (11.2) 54 (26.3) 0.757   Yes or unknown 128 (62.4) 42 (20.5) 86 (42.0) Pathological factors  Pathological T category   T1 84 (58.7) 42 (29.4) 42 (29.4) <0.001   ≥T2 59 (41.3) 10 (7.0) 49 (34.3)  Tumor thicknessb   ≤3 mm 74 (52.9) 41 (29.3) 33 (23.6) <0.001   >3 mm 66 (47.1) 9 (6.4) 57 (40.7)  YK classification   1–2 42 (29.6) 25 (17.6) 17 (12.0) <0.001   3-4D 100 (70.4) 27 (19.0) 73 (51.4)  Lymphatic invasion   Negative 115 (86.5) 43 (32.3) 72 (54.1) 0.112   Positive 18 (13.5) 3 (2.3) 15 (11.3)  Vascular invasion   Negative 94 (70.7) 39 (29.3) 55 (41.4) 0.010   Positive 39 (29.3) 7 (5.3) 32 (24.1) FDG-PET/CT, 2-deoxy-2-[18F] fluoro-d-glucose-positron emission tomography/computed tomography; YK, Yamamoto-Kohama. aWhether FDG uptake is negative or positive in visual interpretation. bMedian value was used as the cutoff. cNodal metastases were suggested only by FDG-PET/CT. Results Table 1 During the follow-up period (range 2.8–69.6 months, mean 32.9 months), patients developed local and regional recurrences (n = 10), cervical nodal metastases (n = 32) and multiple bone metastases (n = 1). Ten patients died of the following reasons: OSCC (7 patients), lung cancer (1 patient), and unknown causes (2 patients). Prognosis prediction By visual interpretation, 140 and 65 primary tumors were judged as positive and negative for FDG uptake, respectively. Patients with primary lesions with visually positive FDG uptake had significantly shorter RFS compared to the other (63.0 months vs. 52.9 months, P = 0.005). The mean SUVmax, MTV and TLG of 140 primary lesions with visually positive FDG uptake were 10.2 (range, 3.6–32.7), 5.9 ml (range, 0.35–33.0) and 30.6 g (range, 1.2–257.8). As shown in Fig. 2B–D, RFS tended to be shorter in patients with higher PET/CT parameter values. However, differences in RFS between the two groups divided by parameter cutoff value were not significant for all the parameters (SUVmax, 54.8 months vs. 51.5 months, P = 0.215; MTV, 56.7 months vs. 48.0 months, P = 0.125; TLG, 57.1 months vs. 46.8 months, P = 0.063). Time-dependent ROC curves are shown in Supplemental Fig. 1. The time-dependent ROC analysis suggested that 1 year after treatment was the optimal cutoff time for tumors with visually positive FDG uptake. Although the area under the curve for SUVmax was larger than those for MTV and TLG at any time-point, SUVmax was considered to be an unsatisfactory predictor of recurrence. As shown in Fig. 2E,F, there were no significant differences in RFS between groups divided on the basis of clinical T and N stages (cT, 54.5 months vs. 57.3 months, P = 0.573; cN, 55.9 months vs. 55.9 months, P = 0.599). Figure 2. View largeDownload slide Kaplan–Meier curves of RFS with regard to FDG visibility (A), SUVmax (B), MTV (C), TLG (D), cT category (E) and cN category (F). SUVmax, MTV and TLG were analysed only in primary tumours with visually positive FDG uptake. FDG, 2-deoxy-2-[18F] fluoro-D-glucose; MTV, metabolic tumour volume; RFS, recurrence free survival; SUVmax, maximum standardized uptake value; TLG, total lesion glycolysis. Figure 2. View largeDownload slide Kaplan–Meier curves of RFS with regard to FDG visibility (A), SUVmax (B), MTV (C), TLG (D), cT category (E) and cN category (F). SUVmax, MTV and TLG were analysed only in primary tumours with visually positive FDG uptake. FDG, 2-deoxy-2-[18F] fluoro-D-glucose; MTV, metabolic tumour volume; RFS, recurrence free survival; SUVmax, maximum standardized uptake value; TLG, total lesion glycolysis. Relationship between FDG uptake and clinical or pathological findings Pathological findings of surgical specimen were available by medical chart review in 165 patients. After excluding 22 patients due to any treatment between FDG-PET/CT and surgery, 143 patients were enrolled in the statistical analysis. Pathological T stage was judged as pT1 in 84 patients (58.7%), pT2 in 46 patients (32.2%), pT3 in two patients (1.4%), pT4a in 10 patients (7.0%), and pT4b in one patient (0.7%). Tumor thickness was 4.4 ± 3.8 mm (range, 0.2–20 mm). Yamamoto-Kohama (YK) classification was judged as YK-1 in six patients (4.2%), YK-2 in 36 patients (25.2%), YK-3 in 65 patients (45.5%), YK-4C in 33 patients (23.1%) and YK-4D in two patients (1.4%). Table 2 shows the relationship between positivity of FDG uptake and patients’ clinical or pathological factors. Some pathological factors (pT, tumor thickness, YK classification and vascular invasion) showed significant correlation with FDG uptake (P < 0.05). Diagnostic performance of FDG-PET/CT for detection of metastatic lesions and synchronous cancers Neck dissection or cervical nodal biopsy had been performed in 68 patients, and 16 patients were pathologically judged to have cervical nodal metastasis. In addition, 15 patients were judged positive for metastasis by clinical follow-up. Totally, 31 patients were judged to have cervical nodal metastasis at the time of FDG-PET/CT. Table 3 shows the diagnostic performance of FDG-PET/CT for N staging. The sensitivity, specificity and accuracy of FDG-PET/CT for cervical nodal metastases were 32.3% (95% CI, 19.3–47.8), 77.6% (95% CI, 75.3–80.4) and 70.7% (95% CI, 66.8–75.4). Table 3. Diagnostic values of FDG-PET/CT in the detection of cervical nodal metastasis Cervical nodal metastasis, n (%) Present Absent Total FDG-PET/CT+ 10 (4.9) 39 (19.0) 49 (23.9) FDG-PET/CT– 21 (10.2) 135 (65.9) 156 (76.1) Total 31 (15.1) 174 (84.9) 205 Cervical nodal metastasis, n (%) Present Absent Total FDG-PET/CT+ 10 (4.9) 39 (19.0) 49 (23.9) FDG-PET/CT– 21 (10.2) 135 (65.9) 156 (76.1) Total 31 (15.1) 174 (84.9) 205 FDG-PET/CT, 2-deoxy-2-[18F] fluoro-d-glucose -positron emission tomography/computed tomography. Table 3. Diagnostic values of FDG-PET/CT in the detection of cervical nodal metastasis Cervical nodal metastasis, n (%) Present Absent Total FDG-PET/CT+ 10 (4.9) 39 (19.0) 49 (23.9) FDG-PET/CT– 21 (10.2) 135 (65.9) 156 (76.1) Total 31 (15.1) 174 (84.9) 205 Cervical nodal metastasis, n (%) Present Absent Total FDG-PET/CT+ 10 (4.9) 39 (19.0) 49 (23.9) FDG-PET/CT– 21 (10.2) 135 (65.9) 156 (76.1) Total 31 (15.1) 174 (84.9) 205 FDG-PET/CT, 2-deoxy-2-[18F] fluoro-d-glucose -positron emission tomography/computed tomography. There were no patients in whom distant metastases were detected in FDG-PET/CT. Unexpected synchronous cancers were detected in 14 patients (Table 4). FDG-PET/CT could detect eight synchronous cancers (3.9%), however, overlooked two esophageal cancers, one gastric cancer, one colorectal cancer, one hepatocellular carcinoma and one uterine cervical cancer. Table 4. Synchronous cancers recognized in our patients Total (%) FDG-PET/CT detected (%) Colorectal cancer 4 (2.0) 3 (1.5) Esophageal cancer 3 (1.5) 1 (0.5) Uterine cervical cancer 2 (1.0) 1 (0.5) Pancreatic cancer 1 (0.5) 1 (0.5) Renal cancer 1 (0.5) 1 (0.5) Prostate cancer 1 (0.5) 1 (0.5) Gastric cancer 1 (0.5) 0 Hepatocellular carcinoma 1 (0.5) 0 Total 14 (6.8) 8 (3.9) Total (%) FDG-PET/CT detected (%) Colorectal cancer 4 (2.0) 3 (1.5) Esophageal cancer 3 (1.5) 1 (0.5) Uterine cervical cancer 2 (1.0) 1 (0.5) Pancreatic cancer 1 (0.5) 1 (0.5) Renal cancer 1 (0.5) 1 (0.5) Prostate cancer 1 (0.5) 1 (0.5) Gastric cancer 1 (0.5) 0 Hepatocellular carcinoma 1 (0.5) 0 Total 14 (6.8) 8 (3.9) FDG-PET/CT, 2-deoxy-2-[18F] fluoro-d-glucose-positron emission tomography/computed tomography. Table 4. Synchronous cancers recognized in our patients Total (%) FDG-PET/CT detected (%) Colorectal cancer 4 (2.0) 3 (1.5) Esophageal cancer 3 (1.5) 1 (0.5) Uterine cervical cancer 2 (1.0) 1 (0.5) Pancreatic cancer 1 (0.5) 1 (0.5) Renal cancer 1 (0.5) 1 (0.5) Prostate cancer 1 (0.5) 1 (0.5) Gastric cancer 1 (0.5) 0 Hepatocellular carcinoma 1 (0.5) 0 Total 14 (6.8) 8 (3.9) Total (%) FDG-PET/CT detected (%) Colorectal cancer 4 (2.0) 3 (1.5) Esophageal cancer 3 (1.5) 1 (0.5) Uterine cervical cancer 2 (1.0) 1 (0.5) Pancreatic cancer 1 (0.5) 1 (0.5) Renal cancer 1 (0.5) 1 (0.5) Prostate cancer 1 (0.5) 1 (0.5) Gastric cancer 1 (0.5) 0 Hepatocellular carcinoma 1 (0.5) 0 Total 14 (6.8) 8 (3.9) FDG-PET/CT, 2-deoxy-2-[18F] fluoro-d-glucose-positron emission tomography/computed tomography. Discussion This single center study evaluated the clinical performance of FDG-PET/CT using a cohort including only the early OSCC patients (cT1-2N0M0). Some studies have shown that FDG-PET/CT parameters have potential for predicting prognosis of OSCC patients (9,10,14,15). Tumor thickness and perineural invasion were conjectured to be prognosticators of early OSCC in other studies (16,17). Our study revealed that FDG-PET/CT could also be used to predict RFS even though limited to patients with early OSCC. Patients with visually positive FDG uptake in the primary tumor showed significantly shorter RFS. However, when dividing patients with visually positive FDG uptake to two groups on the basis of SUVmax, MTV and TLG, no significant difference in RFS could be discerned between the groups with higher or lower parameter. Semi-quantitative PET/CT parameters might not have additional value for further prognostication of patients with visually positive FDG uptake in primary tumors. On the other hand, PET/CT parameter values tended to be higher in patients with shorter RFS. In addition, because our study included only the patients with early OSCC, underestimation of FDG uptake due to a partial volume effect may have occurred in some cases. Further studies with a larger population might show different results in terms of the relationship between PET/CT parameter values and patients’ survival. On the other hand, our study revealed that not only the size but also several pathological factors of primary tumor contributed to visually positive FDG uptake. Compared to conventional imaging studies, FDG-PET/CT may reflect more detailed tumor characteristics. It is possible that these points led significant difference of RFS between patients with visually positive and negative FDG uptake in primary tumors. Two meta-analyses showed that FDG-PET/CT has sensitivity of 66% (4) and 50% (18) for detecting cervical nodal metastases in cN0 patients. Our study showed a lower sensitivity than them (32.3%). However, we excluded patients who were judged as having cervical nodal metastases by not only physical examination but also other imaging modalities such as CT, MRI and US. With sufficient screening for cervical lymph node metastases, the performance of FDG-PET/CT is considered to be limited for early OSCC. FDG-PET/CT overlooked some synchronous cancers in our study. Particularly, endoscopic screening for detection of esophageal cancer and gastric cancer cannot be disregarded in OSCC patients (7,8,19). Thus, we conclude that benefit of FDG-PET/CT for staging of early OSCC patients is limited. Our study had some limitations. First, because this was a retrospective study, there may have been a selection bias caused by FDG-PET/CT indication and treatment selection. Second, because the primary tumors were small in our cohort, the number of patients with tumor recurrence was even smaller. Third, some cervical nodal metastases were diagnosed by clinical follow-up; therefore, whether nodal metastases actually existed at the time of FDG-PET/CT is unclear in these cases. In conclusion, although its utility for staging is limited, FDG-PET/CT is potentially prognostic indicator in patients with early OSCC (cT1-2N0M0). Supplementary data Supplementary data are available at Japanese Journal of Clinical Oncology online. Funding This work was supported in part by grants from Scientific Research Expenses for Health and Welfare Programs, the Grant-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare, No. 15K09885, the Scientific Research Expenses for Health and Welfare Programs, [grant number 29-A-3] (Takashi Terauchi and Ukihide Tateishi: squad leaders), Practical Research for Innovative Cancer Control and Project Promoting Clinical Trials for Development of New Drugs by Japan Agency for Medical Research and Development (AMED). 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Japanese Journal of Clinical OncologyOxford University Press

Published: Apr 28, 2018

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