The most valuable finding in current study was that MRI-determined DOI was significantly associated with the presence of neck lymph node metastasis, it would add nearly 3-fold risk of neck lymph node metastasis if MRI-determined DOI was greater than 7.5mm, and MRI-determined DOI was an independent prognostic factor for the LRC and DSS. The finding might provide preoperative benefit in neck management in cT1N0 tongue SCC.
The feasibility of measurement of DOI by MRI has been widely analyzed [13, 14, 16, 17]. Murakami et al. compared the inter-rater reliability of different methods of DOI measurement by MRI, the authors found the method of the axial invasive portion had excellent inter-rater reliability. The data in current study was also obtained by the axial invasive portion. Lam et al. described that the tumor thickness measured on T1-sequence MRI was 0.8 mm greater than that measured in pathological sections, but 2 mm greater on T2 sequences than that measured in pathological sections on average. Similar finding was also noted by Preda et al.. T1-weighted images were more accurate for measuring the DOI than T2 sequences. DOI in T2 weighted images could be overestimated owing to the inflammation and surround tissue edema. Therefore, in current study, the MRI-determined DOI was obtained based on T1 sequences to increase our reliability. In the other hand, Park et al. reported compared to the data measured in postoperative pathological sections, the DOI on T1 MRI was 1.5 mm greater, but the mean difference between MRI-determined DOI and pathologic DOI was 2.7mm in current study, a little greater than previous finding [14, 19, 20], possible explanation was that only staged T1 tumors were included for analysis, relatively higher extent of tissue shrink existed in smaller tumors.
The presence of neck lymph node metastasis was an important prognostic factor for head and neck SCC [1, 3]. END was usually an important part in primary operation, but owing to the wide range of occult metastasis rate in cT1N0 tongue SCC , the neck management of cT1N0 tongue SCC has been debated over the years remaining its controversy. The ideal treatment for patients with cT1N0 tongue SCC must be balanced between and the possible surgical morbidity and optimal oncological outcomes. The common principle was that N0 necks should be treated electively when the occult metastatic rate was more than 20% [11, 21]. In current study, the overall occult metastasis rate was 17.2%, but all patients underwent END. There were at least three aspects for explaining this phenomenon: firstly, the high requirement of routine follow-up of wait-and-see policy was usually out of our patients’ ability, as described by our previous studies [22, 23], patients in our cancer hospital usually came from low income family and remote districts; secondly, there was abundant evidence indicating that there was often a low salvage rate on disease recurrence in patients who do not have prophylactic therapy of the clinically N0 neck [2-5], thirdly, also the most important one, there were no reliable predictors for occult neck lymph node metastasis from previous studies.
A number of researchers had aimed to explore the potential predictors for the occult neck lymph node metastasis. Tumor budding was defined as the presence of small clusters of cancer cells or isolated single cancer cell, it suggested a more aggressive biologic behavior and carried more possibility of migrating to the adjacent stroma. Xie et al. described the tumor budding intensity was significantly associated with occult lymph node metastasis. Systemic inflammatory response could promote tumor cell proliferation, microvascular regeneration, and tumor metastasis, further, the peripheral neutrophil-to-lymphocyte ratio (NLR) was an accurate and reliable inflammatory marker. High NLR is thought to be significantly associated with worse survival in solid cancers . Abbate et al. firstly presented there was higher risk for occult neck lymph node metastasis when pre-treatment NLR was greater than 2.93. Loganathan et al. recently reported END should be considered when the tumor thickness exceeds 5 mm based on the significant relationship between tumor thickness and occult neck lymph node metastasis. Other analyzed variables included perineural invasion, lymphovascular invasion, and pathologic DOI [28, 29]. However, data regarding the pathologic factors usually could not be obtained preoperatively, and pretreatment NLR were nonspecific parameters because they could be influenced by concomitant conditions, such as infections or inflammation. Therefore, more accurate indicators were needed.
As discussed as above, MRI-determined DOI could be reliably calculated preoperatively, and our result presented high predictive value of MRI-determined DOI≥7.5mm in identifying occult metastasis with sensitivity of 86.9%. In another study by Jung et al., the authors recommended a cut-off value of 10.5 mm in contrast-enhanced T1-weighted images and showed a significant correlation with nodal metastasis, but the authors failed to give the information about the sensitivity, and the variation from ours could be explained by the different calculation method of the cut-off value. The potential mechanism for our interesting finding was presented as follows: MRI-determined DOI could indirectly reflect the pathologic DOI, mean difference between MRI-determined DOI and pathologic DOI was 2.7mm in current study, therefore, a MRI-determined DOI cut-off value of 7.5mm would be indicating a pathologic DOI cut-off value of 5.0mm, extensive literature had reported the neck lymph node metastasis risk increased apparently if there was pathologic DOI >5.0mm [10, 11, 28, 29].
Prognostic factors for tongue SCC had been extensively analyzed, widely accepted risk factors included disease stage, tumor differentiation, perineural invasion, lymphovascular invasion, neck lymph node status, pathologic DOI, and so on [1, 12, 16, 23, 27, 31]. Similar finding was also noted in current study. But the significance of MRI-determined DOI in the survival of tongue SCC remained unknown, this was the first study to describe a significant association between MRI-determined DOI and the prognosis, MRI-determined DOI≥7.5mm mean higher risk of disease recurrence and cancer-caused death. The potential mechanism might be explained by that greater MRI-determined DOI indicated greater pathologic DOI, the negative affect of pathologic DOI on the prognosis had been widely suggested. Tam et al. recently reported the DOI was an independent predictor for both overall survival and DSS. Similar finding was also presented by Iida et al. and Jung et al..
Almost all the literature regarding MRI-determined DOI is just focused on evaluating the association between MRI-determined DOI and pathologic DOI, we hope the current research could provide assistance in neck management in patients with cT1N0 tongue SCC and looking for better ways to analyze and control its progression.
Limitation of this study must be acknowledged: firstly, there was inherent bias in a retrospective study. Second, the sample size was relatively small, possibly reducing the statistical power, therefore, larger sample-size studies were needed to clarify the question.
In summary, there is significant relationship between MRI-determined DOI and occult neck lymph node metastasis in cT1N0 tongue SCC, elective neck dissection is suggested if MRI-determined DOI is greater than 7.5mm, and MRI-determined DOI≥7.5mm indicates more risk for disease recurrence and cancer caused death.