The question of whether elective neck dissection should be performed or a conservative observation approach should be taken for cervical lymph nodes in early-stage oral squamous cell carcinoma has been a matter of debate.13,14 It was reported that approx. 25% of patients with TSCC present with occult metastasis at their first medical examination15,16 and that not only local recurrence, but also cervical lymph node metastases affect overall survival.17-20 Our present findings also suggest that late lymph node metastases affect overall survival. There are many reports that elective neck dissection is recommended if the risk of nodal metastasis is >15%,21-24 but there is another opinion proposing a conservative observation approach in which strict follow-up is performed in order to avoid unnecessary neck dissection. In any case, we believe that the predictive factors for the late cervical lymph nodes metastasis in early TSCC are important and necessary when considering elective neck dissection or as the conditions for strict follow-up by the conservative observation approach.
Many studies have searched for predictors of late cervical lymph node metastasis by using immunohistochemical techniques for primary tumors. The immunohistochemical expression patterns of pan-cytokeratin and podoplanin were reported to be an effective predictor of late cervical lymph node metastasis of TSCC.25 A 2004 study attempted to predict late cervical lymph node metastasis by detecting vessels.26 Such research requires complicated methods (e.g., immunostaining or specific staining), whereas only the common tissue stain hematoxylin-eosin was the only method needed in the present study. We also used the MOI as an index; the MOI was first reported by Yamamoto et al.12 and is classified into five types. Type 4D, which has the highest invasive tendency, is highly metastatic. Shimizu et al. reported an association between the MOI and cervical lymph node metastasis.27 In our present analyses as well, there was a significant difference between the MOI and the occurrence of late cervical lymph node metastasis (p=0.03).
Many data have been published concerning the relationship between the DOI and cervical nodal metastasis with many studies emphasizing its role as a valid predictor.21,24, 28–30 O-charoenrat et al. used 5mm as a cut-off in early oral tongue cancer and demonstrated that the 5-year survival was 95% with the tumor thickness of 5mm and 30% when the tumor thickness was >5 mm.31 In the current UICC TNM classification (8th ed.), the DOI is incorporated into the T staging, and the DOI has been shown to be an important factor in redefining the staging system, resulting in up-grading based on the DOI cut-off of 5mm and 10 mm.11 Our present findings demonstrate that compared to the UICC 7th edition, the clinical staging of the UICC 8th edition shows late cervical lymph nodes metastasis in most cases of stage II, but the difference was not significant.
When we conducted the present investigation with the DOI cut-off set at 4 mm, a significant number of cases of late cervical lymph node metastasis were found among the cases with a DOI ≥4 mm. Moreover, our multivariate analysis of the association of the DOI and late cervical lymph node metastasis revealed that the cases with a DOI ≥4 mm were at a fourfold greater risk of developing late cervical lymph node metastasis compared to cases with a DOI <4 mm. Balasubramanian et al. reported that the cervical lymph node metastasis rate was 11.2% in patients with a DOI <4 mm and 38.5% in those with a DOI ≥4 mm,32 and our data support their findings. Moreover, a cut-off point of 4 mm has traditionally been used to guide the decision for elective neck dissection, based on a study by Kligerman et al..17 These results suggest that even a tumor that has a DOI shallower than the cut-off value of 5 mm in the UICC 8th edition may cause late cervical lymph node metastasis.
Other DOIs have been reported to be predictive factors of late cervical lymph node metastasis,33 and further validation of the past and present data is required. Herein we observed that when we combined the DOI and the MOI, in cases with a tumor other than MOI type 4D or with a DOI <4 mm, the occurrence of late cervical lymph node metastasis was very rare (p=0.004). Moreover, this combination provided 88.9% sensitivity, 75.0% specificity, the positive predictive value 66.7% and the negative predictive value 92.3%. Evaluating the combination of DOI and MOI may therefore be useful as a factor for identifying patients who do not develop late lymph node metastasis.
Many of the present patients with PNI had late lymph node metastasis (p = 0.012). Lymph node metastasis was observed in another study including patients with PNI, and the patients’ prognoses were poor;34 we obtained a similar result. We observed that by combining the present of PNI and the MOI, there were very few cases of late lymph node metastasis among the patients with MOI type 4D or PNI (p=0.002), and the combination provided 55.6% sensitivity, 93.8% specificity, the positive predictive value 83.3%, and the negative predictive value 79.0%. Therefore, evaluating the combination of PNI and the MOI may be useful as a predictive factor of late cervical lymph node metastasis.
Our study had several limitations. First, this study was based on a small sample size because the incidence of oral cancer is 1.6% of all malignant neoplasms,35 which is not so common, and this study targeted early TSCC without cervical lymph node metastasis at the time of their initial treatment. Second, because our study was a retrospective cohort, there could be missing data. Eventually, despite these limitations, this study provides an interesting relationship between the pattern and spread of invasion in early TSCC and late cervical lymph node metastases.