The 2018 AJCC staging manual has introduced a novel pN3b classification for patients with OCSCC. While the presence of pN3b disease is generally believed to portend poor outcomes, we found that a scoring system based on SUV-nodal-max ≥ 15.9, LNR ≥ 0.17, and the presence of level IV/V metastases improves the prognostic stratification within this subgroup – with high-risk cases (scores 2 − 3) showing the most unfavorable 5-year outcomes. Notably, these patients had a markedly high rate (89%) of 5-year DM.
Several studies have assessed the prognostic significance of LNR in patients with OCSCC [3–10]. Investigations involving large samples (> 100 cases with pathologically positive nodes) identified optimal cutoff values varying from 0.06 to 0.2. These variations in the published literature can be explained by differences in the outcomes of interest (e.g., NC, locoregional control, DFS, DSS, and OS) and/or the choice of statistical testing. While the optimal cutoff value for LNR identified in our study (endpoint of interest: 5-year DFS; statistical test: Kaplan-Meier method) was as high as 0.17, this value is consistent with the published range. Notably, the main advantage of the Kaplan-Meier approach lies in the assessment of clinical events in a time-to-event perspective. This allowed the identification of reliable cutoff values for prognostic stratification in patients with pN3b disease. Importantly, on analyzing the association of LNR with clinical outcomes, we found that this factor was not only associated with survival endpoints, but it also predicted the 5-year DM rates. Accordingly, for patients with pN3 disease and LNR ≥ 0.17, we observed a 5-year DM rate of 66% − with all events occurring within the first two postoperative years.
The prognostic role of the cervical nodal metastases level in patients with OCSCC has been evaluated in a limited number of studies [1, 11, 12]. These investigations found that, compared with patients with level I − III metastases, cases with level IV/V metastases (i.e., lower neck metastasis) have less favorable outcomes in the subgroups of patients with pN1 − 3 disease (DSS) and pN2 disease/ENE (NC, DM, DFS, DSS, and OS). While distant metastases are rarely identified (1% of all cases) during the preoperative workup of patients with level IV/V metastases, the risk of distant spread at 5 years is as high as 60% . The 5-year DM rate observed in our study for cases with level IV/V metastases (69%) is in line with previous observations – albeit being slightly higher as a result of our focus on pN3b disease.
Several investigations involving patients with OCSCC have examined the clinical value of SUV-max calculated from FDG-PET images for preoperative staging , identifying second primary tumors , allocating patients to adjuvant therapy following tumor removal , and assessing response to treatment . Our study is the first to analyze the prognostic role of FDG-PET in patients with OCSCC and pN3 disease. Here, we found that a SUV-nodal-max ≥ 15.9 was independently associated with less favorable 5-year NC, DM, DFS, DSS, and OS rates. Notably, the 5-year DM rate of patients with SUV-nodal-max ≥ 15.9 was as high as 63%, and all events occurred within the first 18 postoperative months. Figure 5 shows an illustrative case of right tongue squamous cell carcinoma (stage: pT4aN3b; LNR: 0.038; no evidence of level IV/V metastasis). The patient’s preoperative FDG-PET stage and SUV-nodal-max were TxN2bM0 and 17.4, respectively. A follow-up FDG-PET scan performed 10 months after surgery revealed a T0N0M1 stage. The following distant metastatic sites were identified: left hilar and mediastinal lymph nodes, left pleura, left lung, and L3 spine.
The scoring system based on SUV-nodal-max ≥ 15.9, LNR ≥ 0.17, and the presence of level IV/V metastases allowed an effective prognostic stratification of patients with pN3b disease – with the subgroup of high-risk patients (score 2 − 3) showing dismal outcomes. While being relatively rare (16/257, i.e., 6% of all patients with pN3b disease in our study), patients in the high-risk group had a markedly high 5-year DM rate (89%). Therefore, they should be considered as candidates for novel treatment approaches in clinical trials or receive palliative systemic therapy – rather than traditional CCRT. However, it can be argued that reliable data concerning LRN values cannot be obtained in the preoperative phase. In this scenario, we propose that patients with cN3 disease and concomitant evidence of SUV-nodal-max ≥ 15.9 and level IV/V metastases on imaging studies (FDG-PET and MRI/CT) should undergo non-surgical treatment to minimize morbidity related to radical tumor excision.
Several caveats of our study need to be considered. First, its single-center design may have limited the external validity of the results; in addition, the retrospective nature of our investigation could be associated with information bias. Second, the study sample was ethnically homogeneous and all patients were living in a betel quid chewing endemic area; for that reason, more studies are necessary to confirm our findings in Western countries. Third, two different treatment guidelines were used throughout the study (NCCN guidelines before 2008 and CGMH guidelines thereafter). Future analyses stratified by treatment guidelines should work to address this limitation. Finally, on analyzing the variables associated with clinical outcomes, data on clinicopathological RFs were prospectively collected as of 1996; however, FDG-PET imaging was systematically introduced only five years thereafter (2001). Despite these limitations, these data represent a promising step in understanding the prognostic value of SUV-nodal-max, LNR, and the level of cervical nodal metastases in patients with OCSCC and pN3b disease.
On the one hand, our scoring system enables an objective assessment that is suitable for clinical prognostication. On the other hand, the use of our tool has the potential to tailor treatment at the individual level and can find application in clinical trial design.