Impact of lymphovascular invasion on survival of patients with oral cavity squamous cell carcinoma undergoing postoperative radiotherapy or postoperative chemoradiotherapy
Highlight box
Key findings
• For patients with oral cavity squamous cell carcinoma treated with postoperative radiotherapy (PORT) or postoperative chemoradiotherapy (POCRT), the 3-year overall survival (OS) and disease-free survival (DFS) were 73.8% and 62.5% respectively.
What is known and what is new?
• “Minor risk factors” including pT3 or pT4 primary, pN2 or pN3 nodal disease, perineural invasion, and lymphovascular invasion (LVI) are currently indications for PORT.
• We provide evidence that LVI significantly predicts poorer OS and DFS in patients receiving PORT or POCRT.
What is the implication and what should we change now?
• Patients with LVI should be considered as candidates for more intensive postoperative therapy or clinical trials as they have a worse prognosis.
Introduction
According to the “2021 Taiwan Cancer Registry Annual Report”, oral cavity squamous cell carcinoma (OCSCC) was the sixth most common type of head and neck cancer and the fourth leading cause of death for men in Taiwan (1). The primary treatment approach for nonmetastatic OCSCC involves curative surgical resection. The administration of postoperative radiotherapy (PORT) or postoperative chemoradiotherapy (POCRT) is guided by the presence of clinicopathological risk factor (2-4), such as pathological T and N stages, extranodal extension (ENE), margin status (close or positive), perineural invasion (PNI), and lymphovascular invasion (LVI). Of the clinicopathological risk factors, ENE and positive margin are regarded as “major” risk factors, and their presence calls for the administration of POCRT (4). The relative importance of other risk factors considered “minor” in influencing the prognosis of patients is still being debated, and thus, optimal postoperative treatment options remain elusive, prompting further research (5). Despite treatment, locoregional failure rates range from 18% to 31% (2,3). Treatment options for recurrent OCSCC are limited. In individuals with diseases amenable to salvage surgeries, a low 5-year survival rate of 39% was reported, but morbidity rates were reported to be high (6). If further surgeries are not feasible, the chances of survival decrease, with a 2-year survival rate ranging from 10% to 30% (7). We aim to analyze factors predicting disease-free survival (DFS) and overall survival (OS) of OCSCC patients undergoing curative surgery and postoperative therapies and compare our results with those of existing studies. We present this article in accordance with the STROBE reporting checklist (available at https://tro.amegroups.com/article/view/10.21037/tro-24-8/rc).
Methods
Study design
We retrospectively analyzed the data of non-metastatic OCSCC patients who underwent curative surgery and PORT/POCRT from January 2018 to December 2019 at Kaohsiung Medical University Hospital. Patients with synchronous malignancies and a history of head and neck cancer were excluded; moreover, patients who received radiation treatment to their head and neck regions before surgery were excluded. Curative surgery includes the excision of gross tumor. All the patients underwent unilateral or bilateral neck dissection; all surgical specimens were examined by board-certified pathologists in the pathology department of our hospital. Reports of PNI, LVI, tumor grade, and margin status were mandatory. Tumor grade was measured using a numerical scale, where grades 1, 2, and 3 corresponded to well differentiated, moderately differentiated, and poorly differentiated tumors, respectively. LVI is defined as presence of tumor cell infiltration of vascular or lymphatic vessels as shown by hematoxylin & eosin stain. The radiation delivery was based on either volumetric modulated arc therapy or helical tomotherapy, where 2 Gy per fraction was administered for 5 days a week. The total dose ranged from 50 to 70 Gy. Combined chemotherapy (if administered) comprised 30–40 mg/m2 of cisplatin every week or 75–80 mg/m2 of cisplatin every 3 weeks; it typically started within 2 weeks of radiotherapy initiation.
OS and DFS were the primary outcomes in this study. OS was defined as the period from the date of surgery to death from any cause. DFS was defined as the period from the date of surgery to any recurrence of cancer or death. The data of the patients who were still alive were censored until their last visit to the hospital. Variables such as tumor grade, ENE, pathological T and N stages, margin status (positive or negative), LVI, and PNI were analyzed. Moreover, the patients receiving concurrent chemoradiation were analyzed.
The study was conducted in accordance with Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of Kaohsiung Medical University (KMUHIRB-E(I)-20240086) and individual consent for this retrospective analysis was waived.
Statistical analysis
Kaplan-Meier survival analysis was used to estimate OS and DFS. Log-rank tests were employed to assess the statistical significance of differences in survival between various clinicopathological factors. Multivariate analysis was conducted using the Cox proportional hazard model. We used SPSS version 20 (IBM Statistics for Windows, Armonk, NY, USA: IBM Corp.) for data analysis. A P value of <0.05 was considered significant.
Results
In total, 128 patients were included in the final analysis. The median duration of follow-up was 34 months (range, 6–56 months). The mean age of the patients was 55.6 years (range, 32–82 years) with a male-to-female ratio of 12:1. All the patients underwent PORT, and of these patients, 83 patients (64.8%) underwent POCRT. The decision on whether to incorporate chemotherapy was made during the weekly interdisciplinary meetings. Demographic and clinicopathological characteristics of the patients are listed in Table 1.
Table 1
| Characteristics | Data |
|---|---|
| Age (years) | 55.6 |
| Sex | |
| Male | 119 (93.0) |
| Female | 9 (7.0) |
| LVI | |
| Yes | 26 (20.3) |
| No | 102 (79.7) |
| PNI | |
| Yes | 46 (35.9) |
| No | 82 (64.1) |
| Tumor grade | |
| 1 | 65 (50.8) |
| 2–3 | 63 (49.2) |
| Subsites | |
| Tongue | 32 (25.0) |
| Gingiva | 46 (35.9) |
| Buccal | 30 (23.4) |
| Others | 20 (15.6) |
| Concurrent chemoradiotherapy | |
| Yes | 83 (64.8) |
| No | 45 (35.2) |
| Margin | |
| Positive | 11 (8.6) |
| Negative | 115 (89.8) |
| Cannot be assessed | 2 (1.6) |
| pT | |
| T1–2 | 23 (18.0) |
| T3 | 32 (25.0) |
| T4 | 73 (57.0) |
| pN | |
| N0 | 67 (52.3) |
| N1 | 18 (14.1) |
| N2 | 24 (18.8) |
| N3 | 19 (14.8) |
| ENE | |
| Yes | 23 (18.0) |
| No | 105 (82.0) |
Data are presented as mean or n (%). LVI, lymphovascular invasion; PNI, perineural invasion; ENE, extranodal extension.
The mean OS rate was 45.1 months (range, 6–56 months), and the mean DFS rate was 38.2 months (range, 3–56 months). For the entire cohort, the 3-year OS and DFS rates were 73.8% and 62.5% respectively. The univariate analysis indicated that the 3-year OS (45.5% and P<0.001) and DFS (37.0% and P=0.001) rates among the LVI-positive patients were considerably lower than those of the LVI-negative patients (Figure 1). Moreover, tumor grades 2–3 and pN2–3 were associated with lower OS. In a multivariate analysis, LVI [P=0.006 and hazard ratio (HR): 2.91] was an independent predictor of OS and LVI (P=0.02 and HR: 2.13) was an independent predictor of DFS (Table 2).
Table 2
| Variables | Univariate analysis, P value | Multivariate analysis, P value | |||
|---|---|---|---|---|---|
| OS | DFS | OS | DFS | ||
| Subsites | 0.65 | ||||
| PNI (negative vs. positive) | 0.06 | 0.37 | 0.96 | ||
| LVI (negative vs. positive) | <0.001* | 0.001* | 0.006* | 0.02* | |
| Negative, HR (95% CI) | 1.00 (reference) | 1.00 (reference) | |||
| Positive, HR (95% CI) | 2.91 (1.35–6.25) | 2.13 (1.14–4.00) | |||
| Margin (negative vs. positive) | 0.31 | 0.50 | |||
| Grade (1 vs. 2–3) | 0.046* | 0.17 | 0.08 | 0.36 | |
| ENE (negative vs. positive) | 0.30 | 0.14 | |||
| pT (T1–2 vs. T3 vs. T4) | 0.53 | 0.53 | |||
| pN (N0–1 vs. N2–3) | 0.01* | 0.006* | 0.17 | 0.06 | |
*, P<0.05. OS, overall survival; DFS, disease-free survival; PNI, perineural invasion; LVI, lymphovascular invasion; HR, hazard ratio; CI, confidence interval; ENE, extranodal extension.
For the patients who underwent concurrent chemoradiation, a univariate analysis indicated that LVI, PNI, and tumor grade were significant predictors of OS and that LVI and tumor grade were significant predictors of DFS (Figure 2). In the multivariate analysis, LVI (P=0.06) and tumor grade (P=0.07) approached significance as independent predictors of OS and DFS, respectively (Table 3).
Table 3
| Variables | Univariate analysis, P value | Multivariate analysis, P value | |||
|---|---|---|---|---|---|
| OS | DFS | OS | DFS | ||
| Subsites | 0.39 | 0.27 | |||
| PNI (negative vs. positive) | 0.03* | 0.15 | 0.37 | 0.91 | |
| LVI (negative vs. positive) | 0.008* | 0.04* | 0.06 | 0.15 | |
| Margin (negative vs. positive) | 0.39 | 0.40 | |||
| Grade (1 vs. 2–3) | 0.02* | 0.02* | 0.10 | 0.07 | |
| ENE (negative vs. positive) | 0.82 | 0.25 | |||
| pT (T1–2 vs. T3 vs. T4) | 0.92 | 0.61 | |||
| pN (N0–1 vs. N2–3) | 0.26 | 0.06 | 0.26 | ||
*, P<0.05. OS, overall survival; DFS, disease-free survival; PNI, perineural invasion; LVI, lymphovascular invasion; ENE, extranodal extension.
Discussion
LVI or lymphovascular space invasion (LVSI) is a pathological condition characterized by the presence of tumor cells in the endothelium-lined spaces of either vascular or lymphatic vessels; these tumor cells are detected through the analysis of hematoxylin and eosin staining or immunohistochemistry (8). LVI is associated with the dissemination of tumors via the lymphatic system and serves as a prognostic factor for recurrence and poor survival in solid malignancies (9). LVI is one of the histopathological features that are present in surgical pathology specimens, as defined in by the eighth edition of the AJCC staging system. Our study results indicated that LVI is an independent predictor of poor survival in patients with OCSCC who have undergone adjuvant radiotherapy/concurrent chemotherapy. Moreover, this characteristic has been reported in two major studies. A population-based study by Comer et al. (10), which included 16,992 patients, reported LVI to be an independent risk factor for decreased OS, with an HR value of 1.30 among all the patients, 1.24 among patients receiving PORT, and 1.16 among patients receiving POCRT. Similarly, Huang et al. (11) reported LVI as a predictor of poor OS and DFS in a meta-analysis of 17 studies.
Several studies, and our study, have reported the association of LVI to PNI and other clinicopathological factors like advanced N stage. Regarding to N stage, LVI is associated to more advanced N stage (10), but even in the N2–3 group the presence of LVI still carries a worse prognosis. In Cassidy et al. (12), LVSI was associated with poorer locoregional control and OS in cN0 oral tongue cancer for patients with early-stage OCSCC. Thus, LVI seems to predict worse survival regardless of N stage. However, some have indicated that PNI, instead of LVI, is more closely associated with survival outcomes. Anand et al. (13) reported that PNI is an independent predictor of 2-year DFS, locoregional control, and OS for bucco-alveolar cancer and that while PNI is also associated to LVI, LVI itself is not a crucial predictor. Similarly, in Jardim et al. (14), a multivariate analysis indicated that PNI is an independent crucial predictor of OS and DFS for advanced OCSCC and LVI is only significant under univariate analysis. In contrast in Chen et al. (15), neither LVI nor PNI was found to be associated with DFS or OS for patients with early-stage OCSCC. A previous study (16) suggested that the effect of LVI and PNI on survival differed between subsites and stages, with PNI being an independent predictor of disease-specific survival in stages I and II and LVI (along with surgical margin) being an independent predictor of disease-specific survival in stages III and IV. Other studies (17,18) have argued that LVI with PNI or both PNI and ENE (double-positive and triple-positive, respectively) serve as predictors of poorer survival than LVI alone. However, our results did not seem to corroborate previous findings that LVI/PNI-double-positive patients have worse outcomes than LVI-positive patients, as argued by Ting et al. (17).
Hence, results on whether LVI affects patient survival have been inconsistent in the literature. This may be due to the following reasons. First, studies comparing adverse features of OCSCC have demonstrated considerable heterogeneity in patients’ clinical stage and anatomical subsites. Moreover, large clinical trials, which constitute the methodological gold standard in medical research, have typically included patients with squamous cell carcinoma (of the head and neck), with OCSCC patients emerging as a subset. Second, in Taiwan, patients with OCSCC tend to consume betel nuts and tobacco; only a few among these are human papillomavirus (HPV)-related. Moreover, men mostly are affected by OCSCC, with a male-to-female ratio exceeding 10 (compared with approximately 2–3 in Western countries). Thus, regional and etiological differences may be present. Finally, the prevalence of LVI varies considerably across related studies, ranging from 8.9% to 89.2% [(11), see Tab. II], reflecting the heterogeneity of these studies. However, interobserver variability among pathologists may also be present in their assessments of LVI; such variability may contribute to conflicting results on the effect of LVI on patient survival. A previous study (19) involving more than 1,000 patients with colon cancer noted considerable differences in the reporting practices of LVI among different hospitals with individual pathologists. A study on interobserver variability (20) that included 58 patients with floor-of-mouth squamous cell carcinoma concluded substantial interobserver agreement in their data on LVI status [Fleiss-Kappa (κ) =0.64]; however, the interobserver variability of LVI for patients with OCSCC in general was not thoroughly investigated. In our study, there were 20 pathologists involved with the pathology reports of patients. No apparent interobserver variability can be inferred from individual pathologist’s frequency of reporting positive LVI.
Another question that ought to be investigated is whether positive LVI, with regard to the prediction of recurrences and worse patient survival, influences the decision to choose between PORT and POCRT. Administering both PORT and POCRT to patients with OCSCC and minor risk factors is controversial. Several retrospective studies (21,22) have suggested the benefit of POCRT for patients with multiple minor risk factors. One study (23) recommended the categorization of patients into low-, intermediate-, and high-risk groups, suggesting PORT for the low-risk group, POCRT for the intermediate-risk group, and experimental therapies in clinical trials for the high-risk group. The results indicated that POCRT yielded better OS but not better DFS or locoregional failure-free survival. We noted that the heterogeneity of the aforementioned studies was high. Conversely, the meta-analysis of Lacas et al. (24) demonstrated that the benefit of chemotherapy is lower among older patients. In our study, all but one patients of ENE/positive margin underwent POCRT. More than 80% (22 out of 26) of the LVI-positive patients, owing to strong associations with other adverse features, underwent concurrent chemoradiation as well. Unexpectedly, the margin status and ENE levels of the patients did not serve as predictors of poorer survival in our study, which may be due to the administration of POCRT. However, the univariate analysis indicated that LVI still served as a strong indicator of poorer survival for the patients who underwent POCRT; LVI only approached significance in the multivariate analysis. Because our sample size was small, we did not attempt to analyze whether LVI-positive patients receiving POCRT have better outcomes than those receiving PORT. Because the choice of PORT or POCRT was not standardized for patients with minor risk factors, possible interactions among various minor risk factors with respect to different treatment modalities were not well understood; this topic requires further investigation in future studies.
Our study has the following limitations: First, this is a single-institution retrospective study. Second, the margin status was reported as “uninvolved”, and data on margin width were not available for eight patients. Pathologists deemed the margin status as “cannot be assessed” for two patients because their surgical specimens were fragmented. Thus, we did not consider a “close margin” category (typically considered to be <5 mm in the literature) in the analysis of margin status.
Conclusions
Our study revealed that among various risk factors, LVI is a crucial predictor of recurrences and poor survival for patients with OCSCC undergoing PORT or POCRT. Whether positive LVI should warrant an intensification of PO treatments or included in selection criteria for novel PO treatments is a question that require further research.
Acknowledgments
None.
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tro.amegroups.com/article/view/10.21037/tro-24-8/rc
Data Sharing Statement: Available at https://tro.amegroups.com/article/view/10.21037/tro-24-8/dss
Funding: None.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tro.amegroups.com/article/view/10.21037/tro-24-8/coif). C.J.H. serves as an unpaid editorial board member of Therapeutic Radiology and Oncology. The other authors have no 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. The study was conducted in accordance with Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of Kaohsiung Medical University (KMUHIRB-E(I)-20240086) and individual consent for this retrospective analysis was waived.
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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Cite this article as: Hsu HL, Chao TY, Chan LP, Chen CM, Yang SF, Kuo SH, Huang CJ. Impact of lymphovascular invasion on survival of patients with oral cavity squamous cell carcinoma undergoing postoperative radiotherapy or postoperative chemoradiotherapy. Ther Radiol Oncol 2025;9:3.
