Sentinel lymph node biopsy in early oral cancer: interpreting high significance in low-event cohorts

We would like to congratulate Struckmeier et al. on their recent publication in Oral Oncology, which provides valuable insights into the role and impact of sentinel lymph node biopsy (SLNB) in early-stage oral squamous cell carcinoma (OSCC) (1). We also wish to acknowledge the important observations made by Misra and Das and to further expand on their discussion (2).

In their retrospective cohort of 48 early-stage OSCC patients, Struckmeier et al. reported that sentinel lymph nodes (SLNs) in the contralateral neck occurred in approximately 17% of cases and were associated with a trend toward poorer locoregional control. These findings align with prior SLNB studies, including the SENT trial and the work by Stoeckli (3,4), which documented unexpected drainage rates of 14% and 13%, respectively—specifically drainage to the contralateral neck in well-lateralized tumors or to retropharyngeal lymph nodes (5). Notably, Struckmeier et al. reported the overall rate of contralateral drainage and observed that “of the five tumors that crossed the midline, only one tumor exhibited bilateral lymphatic drainage pathways”, although no additional details were provided (1).

The rate of positive SLNBs in the study by Struckmeier et al. was notably lower than that reported in the literature: 8.3% (with approximately 80% of cases being pT1) compared to 23% in the SENT trial. A recently published meta-analysis further indicated that “26% of T1N0 and 35% of T2N0 patients were sentinel-node positive” (6). According to their methodology, Struckmeier et al. performed serial sectioning (“bread-loafing”) of the SLNs with hematoxylin and eosin (H&E) staining. When HE microscopy is negative, most established SLNB protocols recommend additional immunohistochemical staining with the anti-pan cytokeratin antibody AE1/3 to detect micrometastases or isolated tumor cells (3,7)—a step not mentioned in the Struckmeier study. The reported positivity rate of 8.3% corresponds to four patients, two of whom were ultimately classified as pN1 and two as pN2b (1). Although not explicitly reported, it is assumed that a completion neck dissection was done in those cases.

All patients achieved R0 resection. Seven patients (14.5%) received postoperative radiotherapy, while one patient (2%) underwent adjuvant radiochemotherapy (8,9). The indication for the latter remains unclear, as all patients were R0 and none were staged as pN2a or pN3b, indicative of possible extranodal extension (8,9). The median follow-up for the cohort was not reported; overall, four patients developed recurrence, three of which occurred in the neck. There is no information on the fourth recurrence—this would be a helpful data point. Finally, the authors noted that patients who died within 30 days postoperatively were excluded. However, it is unclear why patients with early-stage oral cavity tumors would die within such a short period; clarifying this could help determine whether these deaths were related to surgical morbidity

Moving from this methodological discussion to the results of the study per se, the most striking finding was that the number of nodes removed during SLNB—rather than their metastatic status—was predictive of recurrence-free survival. Statistically significant differences in recurrence-free survival were observed both with respect to the number of sentinel nodes and the total number of nodes removed (P<0.001).

This finding is particularly intriguing, as it has, to the best of our knowledge, not been previously reported in this form. It is well established that, following a positive SLNB, the likelihood of identifying additional positive lymph nodes in the neck is approximately 31%, and that this probability increases with the size of the metastasis in the sentinel node (3). Since positive non-SLNs are frequently located near the sentinel node, one possible explanation for the reported finding could be that the removal of adjacent, non-sentinel nodes during SLNB had a beneficial impact on survival. However, this interpretation appears less likely, as patients with positive SLNs typically undergo completion neck dissection, which should remove all lymphatic tissue at risk.

Interestingly, Struckmeier et al. also identified the number of SLNs itself as a predictor of recurrence-free survival. Previous studies have shown that several factors influence the number of sentinel nodes detected, including tumor size and depth of invasion, tumor location (with lesions closer to the midline tending to yield a higher number of sentinel nodes), imaging modality [single photon emission computed tomography/computed tomography (SPECT/CT) vs. planar scintigraphy], and tracer type (^99mTc-nanocolloid vs. indocyanine green) (3,9-11). Notably, neither the SENT trial nor the GETTEC Senti-MERORL trial identified the number of sentinel nodes—rather than the number of positive sentinel nodes—as predictive of survival (3,7).

The findings reported by Struckmeier et al. are particularly noteworthy because they contradict the results of the two largest randomized controlled trials on the topic (3,7). Despite the small sample size and the limited number of events (only four recurrences in total), the authors report highly significant statistical results. Such disproportionate significance raises concerns about a possible analytical artifact rather than a true biological effect, especially given that these retrospective, single-center findings contrast sharply with evidence from multicenter prospective trials.

In conclusion, while the study by Struckmeier et al. provides valuable insight into the use of SLNB in early-stage OSCC, the unexpectedly high statistical significance observed despite the limited number of events should be interpreted with caution. These findings should be regarded as hypothesis-generating rather than conclusive and highlight the need for validation through larger, prospective, multicenter studies.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-aw-2206/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-aw-2206/coif). G.B.M. received consulting fees from KeyNote 869 Study, MSD. M.W.H. received grants and speaker honoraria from GE HealthCare, a fund by the Alfred and Annemarie von Sick legacy, a grant from the clinical research priority program (CRPP) Artificial Intelligence in Oncological Imaging Network of the University of Zurich, consulting fees from GE HealthCare, and a travel grant from Korean Society of Nuclear Medicine. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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