Ratio of Metastatic Lymph Nodes: A Significant Prognostic Factor in Patients with Oral Squamous Cell Carcinoma

Introduction

Oral squamous cell carcinoma (OSCC) is the sixth most common malignancy worldwide.¹ With an estimated 2,63,900 new cases and 1,28,000 deaths per year, OSCC is a significant source of morbidity.² OSCC is the most common malig-nant tumor in the Asian subconti-nent, accounting for about one-third of all malignancies. In India, it accounts for approximately 30-40% of all cancers.³ The high incidence of oral cancer and oral potentially malignant disorders in India has been linked with the habit of betel nut and tobacco chewing, which is a major cause of mortality.⁴

Despite significant diagnostic and therapeutic advances, the prognosis of patients with OSCC has not improved in the past three decades¹, and survival rates remain below 50%.⁵ Therefore, it is crucial to improve treatment outcomes by finding reliable prognostic factors and identifying head and neck cancer patients who are at high risk of locoregional recurrence.⁶

The American Joint Committee on Cancer (AJCC) or the Union for International Cancer Control (UICC) staging system for OSCC is based on primary tumor classification (T), on quantification of nodal metastases (N) according to size, number, and distribution, and on the presence of distant metastases (M).⁷ However, pathologic lymph node status and current nodal classification may not necessarily predict prognosis.8 Apart from tumor node metastasis (TNM) staging, recent studies have shown the importance of other lymph-associated factors such as the exact number of positive nodes, total number of harvested nodes in the neck dissection, lymph node ratio, and the presence of extra nodal extension (ENE) as they can be the determinants of prognosis in OSCC.^9,10

Local spread of the tumor occurs mostly through the lymphatic vasculature to the lymph nodes of the neck.¹¹ For this reason, the primary assessment of lymph nodes is imperative for staging and treatment planning. The lymph node ratio (LNR) or ratio of metastatic lymph nodes (RML) and lymph node yield (LNY) have been successfully validated as a strong predictor of survival with potential prognostic implications in oral cancer.^11,12 LNY is defined as the number of lymph nodes retrieved after neck dissection, whereas RML or LNR is defined as the ratio of pathologically positive lymph nodes to the total number of retrieved lymph nodes after neck dissection. However, accurate estimation of RML depends on the LNY, which has been shown to vary depending on anatomical, surgical, and pathological factors.^12-14 It is likely that a higher RML means that more potential, occult, pathological tissue has been removed, and for this reason, this should be a favorable prognostic factor. On the other hand, a lower RML may signify that few lymph nodes are positive out of the total removed, and thus, higher the survival rate. Furthermore, multiple studies indicated that the LNR is superior to the conventional nodal staging system and should be considered in daily clinical routine.^2,10,12 The main objective of this study was to determine the prognostic value of RML in patients with OSCC and to ascertain the association of locoregional recurrence with sex, type of neck dissection, stages, grading, LNY, ENE, and perineural invasion.

Materials and methods

In this retrospective study, clinicopathological data were collected from tertiary care hospital records of patients who underwent management for biopsy- proven OSCC between January 2017 and December 2018. The inclusion criteria were patients with a confirmed diagnosis of OSCC with T1-T4a status of the primary tumor and N0-N2b status of the lymph nodes. All cases had a history of surgical excision of the primary lesion and neck dissection with a minimum follow-up period of two years. Primary tumor sites included buccal mucosa, tongue, alveolus, gingivo- buccal sulcus and retromolar trigone. Patients with loco-regionally advanced disease not suitable for surgical resection, history of any previous surgery or radiotherapeutic treatment of the head and neck, patients not available for follow-up, cases with T4b tumors and N2c and N3 status of neck nodes were excluded.

The procedures were followed in accordance with the ethical standards of the committee on human experi-mentation of the tertiary care centre and in accord with the Helsinki Declaration of 1975, revised in 1983.

The parameters collected included age, sex, type of dissection, pathological node staging(pN), UICC stage, grading, extra nodal extension (ENE), perineural invasion (PNI), lymph node yield and RML. Surgical resection of primary tumor i.e. wide local excision depending upon tumor extension along with ≥ 1cm clear margins, was done in all patients. Patients who were clinically classified as cN0 received selective neck dissection (level I-III/IV), and those with clinically positive cervical lymph node status (cN1) were treated with a modified radical neck dissection of levels I-V with or without preserving sternocleidomastoid muscles or internal jugular vein depending upon radiological imaging. Depending on the type of resection i.e., soft tissue or soft tissue with hard tissue reconstruction was done. The adjunct procedures like radiotherapy or/and chemotherapy were given on a case-to-case basis. The histopathological staging was done according to the American Joint Committee on Cancer (AJCC), TNM classification system 8th edition. The resected specimen was sent for intraoperative margin assess-ment to confirm ≥ 1 cm negative margin status. Depending upon the final histopathological staging and other factors (RML, PNI, ENE, and Grading), adjuvant treatment was decided. Patients were then kept on regular follow-up visits for periods of two years for clinical evaluation of recurrence or local and regional metastasis.

Statistical analysis was performed using univariate and multivariate analysis to analyse the associations between clinic-pathological features and recurrence. The dependent variable was the presence of recur-rence, and the independent variable was the clinicopathological parameters i.e., pathological staging, UICC stage, ENE, PNI, lymph node yield and RML. In multivariate analysis, the Cox proportional hazard model was used to estimate the impact of significant patient and tumor-related factors from univariate analysis on locoregional recurrence. p- value ≤ 0.001 was considered to be statistically significant. 5-year disease-free survival (DFS) was calculated using the Kaplan-Meier method, and the log-rank test assessed the difference in survival rate.

Results

Hospital databases of 231 patients were retrospectively reviewed. Six of these patients were excluded because of previous primary surgery and radiotherapy history. 225 patients aged 30 to 80 years with a mean age of 50 years (Male, n=190, Female, n=35) were collected. All patients underwent primary surgery and neck dissection. 165 patients (73.3%) were also treated with adjuvant radiotherapy(RT) (with or without chemotherapy). A negative resection margin (>1 cm) was achieved in all patients. The staging was domi-nated by patients with a stage IV tumor (41.7%), followed by stage III (25.3%), stage II (19.5%), and stage I (13.3%). Primary tumor (pT) in patients was confirmed histopathologically after surgery, where 29.3% of patients revealed T2 tumors. The conventional pathological staging of the lymphatic metastasis (pN) was done in 225 patients where the majority of patients showed N0 (63.1%) status and N3b in nearly 12.9% of patients. Specifically, the percentage of ENE was positive in 39 (17.3%) and negative in 186 (82.6%) patients.

In this cohort, patients with more nodal yield and positive lymph nodes were found to be associated with poor outcomes. The patients with positive lymph nodes were divided into high- or low-risk groups using the best nodal parameter cut-off values(0.06). Of the 83 patients with positive lymph nodes, 47 had RmL ≤0.06, and 36 had RML ≥0.06. The results of our univariate analysis revealed RML (p=0.02), a significant prognostic indicator for locoregional recurrence and 5-year DFS. We also found a significant correlation between locoregional recurrence and pN classification (p=<0.001), pathological staging (p=<0.001), grading (p=0.004), ENE(p=<0.001), PNI (p=<0.001), and RML (p=0.02). Therefore, patients with high RML underwent more adjuvant RT or concurrent chemoradiotherapy (CCRT) than those with low RML. (Table 1)

To further investigate whether RML predicts the prognosis of patients, a multivariate analysis was constructed where RML was shown as an independent risk factor for locoregional recurrence (p=0.04). Thus, RML ≤0.06 was associated with better locoregional control and DFS. Interestingly, histopathological grading was also found to be a significant predictor for DFS and locoregional control in multivariate analysis. However, other variables, including conventional N classification, were not determined as an independent risk factor for locoregional recurrence(Table 2).

DFS for N0 and N+ neck was 90.1% and 56.6%, respectively. Out of 36 patients with N+ presented with recurrence, 15 had RmL ≤0.06, and 21 had RML ≥ 0.06. The five-year DFS curves were plotted, and the risk of locoregional recurrence was higher for patients with RML ≥0.06. (Figures 1 and 2).

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Figure 1.

Disease-free survival rates calculated using Kaplan Meier method in patients with RML/LNR ≤0.06 (n=15)

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Figure 2.

Disease-free survival rates calculated using Kaplan Meier method in patients with RML/LNR ≥0.06 (n=21) results of our univariate(p=0.02) and multivariate analysis (p=0.04) also show that RML is superior to conventional N staging in predicting disease-free survival and locoregional recurrence.

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Discussion

Locoregional recurrence is an important factor for morbidity in 15-50% of patients with Head and Neck squamous cell carcinoma (HNSCC).¹⁵ The standard of care for patients with recurrent OSCC is more complex and includes combined treatment modalities such as salvage therapy, radiotherapy, chemotherapy, and CCRT.¹⁵ Various factors predispose to locoregional recurrence and affect the prognosis. The absence or presence of cervical lymph node metastases is the solitary prognostic factor in OSCC. Thus, the manage-ment of the neck is obligatory if metastases to the cervical lymph nodes are clinically visible. Our statisti-cal analysis found that cervical lymph node metastasis was significantly associated with locoregional recurrence (p = <0.001) for patients with OSCC.

Numerous studies show that conventional N staging, PNI, ENE, grading, and resection margin status were crucial predictors for poor prognosis.^12,16-19,23 Usually, a traditional N classification is associated with a higher risk of locoregional failure, worsening the prognostic outcome.^9,12 In this study, we found that 19% of patients with pN0 showed locoregional recurrence, whereas 30% of patients with pN+ experienced locoregional recurrence. However, the results of our univariate analysis show traditional N staging to be a significant prognostic indicator (p= <0.001), which is similar to the study by Safi et al¹⁰, Lee et al.,²⁰ and Patel et al.¹² who found a significant correlation between locoregional recurrence and classification. However, multivariate analysis did not prove N classification to be a significant predictor for prognosis. Various literature has demon-strated the shortcomings of conventional N staging in predicting locoregional recurrence.^2,10,12,21 Lymph node status is primarily based on sampling of lymph nodes and secondarily on examination by a pathologist. The RML has been described as a signifi-cant predictor of good disease-free outcomes in patients with OSCC. This ratio weighs three factors that can potentially influence nodal staging viz; tumor factors (number of positive lymph nodes), surgical factors (number of lymph nodes dissected during neck dissection and sampling factors (completeness of the pathological analysis, including those related to surgeon and pathologist).² In recent years, multiple studies have exhibited the influence of RML as a risk factor in locoregional recurrence in oral cancer. The Furthermore, the patients with positive necks were divided into two subgroups with a cut-off value of 0.06, in accordance with the study by Shah and Gill2, who used a cut-off value of 0.06 (RML threshold,6%). We found that patients with RML > 0.06 have a higher risk of locoregional recurrence (0.02). The Kaplan-Meier analysis revealed that patients with RML > 0.06 have poor disease-free survival, which revealed that patients with RML < 0.06 are associated with recurrence-free survival.

Potential errors in the resection or evaluation of lymph nodes are one of the major drawbacks due to its dependence on surgical technique and sampling by pathologists.¹³ However, to eliminate such errors, this study did not include patients with an RML score of zero; selective neck dissection with low nodal yield and high RML, as it cannot assess the extent of the disease, ultimately leading to poor prognosis. Shrime et al²² have demonstrated that high RML is correlated with inade-quate surgical resection and thus requires adjuvant treatments. In this study, LNY has clearly shown a significant correlation with locoregional recurrence as patients with smaller nodal yield have poor prognosis compared to patients with more nodal yield. For example, a patient with 2 positive lymph nodes among 20 lymph nodes examined has a better prognosis than a patient with 2 positive lymph nodes out of 6 excised lymph nodes, leading to higher RML. Similar to our article, Ebrahimi et al⁹ found that the prognostic significance of RML may be baffled by a limited number of resected lymph nodes or nodal yield. Thus, they suggested proper surgical technique, thorough pathological analysis, and tumor factors to reduce the incidence of loco-regional recurrence. Interpretation of the anatomical groups and proper labelling of the specimen by the surgeon can improve the accuracy of neck dissection and the precise analyses and processing by a pathologist rendering a good prognosis.

Univariate analysis shows other pathological markers, including, ENE and PNI to be significant in reference to locoregional control. However, the results of our multivariate analysis do not prove pathological markers (ENE and PNI) to be independent significant indicators for prognosis. It was also found that locoregional recurrence is closely associated with ENE status (p= <0.001) which is similar to other researchers who found that the presence of ENE with metastatic lymph nodes is associated with recurrent disease and requires adjuvant treatment protocols.^23,24 PNI has shown to be a valuable marker for predicting recurrence and disease- free survival (DFS) 25 similar to the results of our statistical analysis (p= <0.001).

The current edition of WHO classification head and neck tumors²⁶ differentiates grading systems as low, moderate, and high according to the Broders system of tumor grades. Moreover, they stated that histopathological grading is not independently associ-ated with locoregional recurrence, which is supported by many studies indicating the shortcomings of the prognostic significance of the grading system.^27,28 Although the present study revealed grading to be significant independently in association with the recurrence of primary tumor (p=0.09). Further studies on the importance of grading in the prognosis of patients with relapse are suggested as it requires more validations to be potentially effective.

The limitations of the present study are the potential inconsistency in neck dissection and processing of pathological specimens that affect the outcome. Therefore, we believe that potential errors can be retrieved by the quality of surgical technique by meticulous dissection of lymph nodes during neck dissection. The current study was also limited by its retrospective design and moderate sample size. Indeed, it lacked the statistical power to include other prognostic factors and their association with locoregional recurrence in multivariate analysis. However, the indication of adjuvant treatment in patients with high LNR should be taken into consider-ation for further research.

Conclusion

RML has proven to be an independent risk factor for the prognosis of patients with N+ disease, and high RML≥ 0.06.was associated with poor prognosis. In patients with N0 neck, the effectiveness of RML needs more literature evidence for further validation. To assess the prognostic behavior of RML as a reflection of tumor behavior, the potential errors affecting RML (dissection and examination of lymph nodes) should be minimized by standardized surgical and pathological protocols. However, the author further suggests that there is a need for well-planned multi-center prospective studies with long follow-up of OSCC cases and their biological behavior in relation to RML.