- Email: [email protected]
The prognostic significance of the lymph node ratio in oral cancer differs for anatomical subsites
YIJOM-4313; No of Pages 6
Int. J. Oral Maxillofac. Surg. 2019; xxx: xxx–xxx https://doi.org/10.1016/j.ijom.2019.10.015, available online at https://www.sciencedirect.com
Clinical Paper Head and Neck Oncology
The prognostic significance of the lymph node ratio in oral cancer differs for anatomical subsites
J. Moratin1, Ka rl Metzger1, K. Kansy1, O. Ristow1, M. Engel1, J. Hoffmann1, C. Flechtenmacher2, K. Freier1,3, C. Freudlsperger1, D. Horn1,3 1
Department of Oral and Craniomaxillofacial Surgery, Heidelberg University Hospital, Heidelberg, Germany; 2Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany; 3Department of Oral and Craniomaxillofacial Surgery, Saarland University Hospital, Homburg, Germany
J. Moratin, Karl Metzger, K. Kansy, O. Ristow, M. Engel, J. Hoffmann, C. Flechtenmacher, K. Freier, C. Freudlsperger, D. Horn: The prognostic significance of the lymph node ratio in oral cancer differs for anatomical subsites. Int. J. Oral Maxillofac. Surg. 2019; xxx: xxx–xxx. ã 2019 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Abstract. The aim of this study was to validate the prognostic significance of the lymph node ratio (LNR) in patients suffering from oral squamous cell carcinoma in regard to different anatomical subsites. A cohort of 430 patients was investigated to determine the rates of primary metastasis and local and regional disease recurrence. Correlation analysis of the LNR with relevant clinical and pathological parameters was performed. Receiver operating characteristic (ROC) curve analysis was conducted to evaluate the prognostic impact for different subsites. Significantly differing rates of primary metastasis and loco-regional disease recurrence were found for cancer of different anatomical subsites of the head and neck. Furthermore, ROC curve analysis suggested that LNR has prognostic relevance in subsets of cancer (tongue, P < 0.001; alveolar process, P = 0.04; maxilla, P = 0.03; buccal mucosa, P = 0.02). The LNR of cancer located in the soft palate (P = 0.6) and floor of the mouth (P = 0.11) showed little or no association with the clinical outcome. There is the need for a more sensitive consideration of the LNR as a factor in the assessment of risk and the treatment decision, as the anatomical subsite plays a crucial role in its impact on the clinical outcome.
Head and neck squamous cell carcinomas (HNSCC) represent the sixth most common malignant disease worldwide. The majority of this entity originate in the oral mucosa (oral squamous cell carcinoma, OSCC)1. The survival of patients is mainly limited by disease recurrence and the development 0901-5027/000001+06
of loco-regional or distant metastases. There have been improvements in the management of HNSCC due to interdisciplinary treatment approaches and advanced adjuvant therapy regimens. Nevertheless, survival has improved only to a minor extent over the past decades2–5.
Key words: HNSCC; OSCC; oral cancer; lymph node ratio; metastasis; survival. Accepted for publication
Various risk factors to estimate the probability of loco-regional recurrence and subsequently of an adverse clinical outcome have been described. Among these parameters, advanced T stage, incomplete resection status, lympho-/vascular or perineural tumour invasion, the
ã 2019 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Moratin J, et al. The prognostic significance of the lymph node ratio in oral cancer differs for anatomical subsites, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.ijom.2019.10.015
YIJOM-4313; No of Pages 6
2
Moratin et al.
presence of cervical lymph node metastases, extracapsular spread, and the lymph node ratio (LNR) are the most relevant2,6– 8 . The LNR is calculated as the ratio of positive lymph nodes to dissected nodes and has been shown to be an independent prognostic factor in patients with OSCC and other malignancies by various authors9–11. Most scientific analyses have used an LNR cut-off value of between 0.06 and 0.08 to stratify patients according to the risk of an adverse clinical outcome. This stratification has been introduced for further treatment decision-making, especially in regard to adjuvant therapy7,12–18. Patel et al. have even proposed the inclusion of the LNR in the TNM staging system19. Most publications have mainly discussed the prognostic significance of the LNR in pooled cohorts of patients or have focused on only a subgroup of OSCC. The prognostic impact of different anatomical subsites has not yet been reported18,20,21. While there is increasing evidence of different survival and recurrence probability according to the localization of the primary tumour, evidence of the prognostic role of the LNR in this context is lacking. Therefore, the purpose of this study was to determine the rates of primary metastasis and local and regional disease recurrence in a large cohort of patients with squamous cell carcinoma of the oral cavity, with emphasis on the exact anatomical localization of the tumours. Furthermore, the prognostic value of the LNR was determined according to the different anatomical subsites. Materials and methods Data collection
Inclusion criteria were a histopathological diagnosis of primary squamous cell carcinoma of the oral cavity and primary surgical treatment in the Department of Oral and Craniomaxillofacial surgery, Heidelberg University Hospital between the years 2010 and 2017. The electronic patient records (SAP, Walldorf, Germany) were used for documentation, allowing optimal traceability of clinical progress and the clinical outcome. Patients with locally advanced tumours (T4), positive resection margins (R+), lymph node metastases (N+), or a combination of histopathological risk factors (lymphovascular invasion (L1V1) or perineural tumour infiltration (Pn1)) received adjuvant therapy. Written informed consent was obtained from all patients and the study was approved by the Ethics Committee of the
Medical Faculty of the University of Heidelberg (Ethics Vote: S-183/2015). The LNR was calculated as the ratio of positive lymph nodes to dissected nodes using the patients’ pathology records. Statistical analysis
The statistical analysis was conducted using Microsoft Excel 2013 (Microsoft, Redmond, WA, USA) and IBM SPSS Statistics version 22.0 (IBM Corp., Armonk, NY, USA). Clinical data were analysed by descriptive statistics; correlation analysis was performed using Pearson’s correlation coefficient. Receiver operating characteristic (ROC) curve analyses were used to estimate the prognostic impact of the LNR in the different subsites. The survival analysis was performed using the Kaplan–Meier method, and logrank testing was used to estimate differences in survival between the groups. A multivariate Cox regression analysis was applied to investigate the impact on overall and disease-specific survival. A P-value of 0.05 or less was considered to demonstrate statistical significance. Results Patient cohort
A total of 430 patients matched the inclusion criteria; 157 (36.5%) were female and 273 (63.5%) were male, and their mean age was 63.9 11.7 years (range 18–92 years). Table 1 gives an overview of the demographic, clinical, and pathological features of the cohort investigated. Correlation analysis
Correlation analysis was performed with a special interest in correlations of the LNR with other relevant clinical and pathological parameters (Table 2). Highly significant correlations of the LNR with the T and N stage (both P < 0.001), different pathological risk factors including vascular (P < 0.001), perineural (P = 0.002), and lymphatic tumour invasion (P < 0.001), and with extracapsular spread (P = 0.001) were found. There was a weak correlation of the LNR with the occurrence of late neck node metastases. No significant association was found with events of local disease recurrence or the development of distant metastases. Incidence of primary cervical metastasis
The subsites investigated displayed rates of primary cervical metastasis of 27.5% for floor
Table 1. Descriptive data regarding demographic and clinical features of the cohort investigated. Parameter
Number of cases (%)
Sex Female 157 (36.5) Male 273 (63.5) Age <65 years 214 (49.8) >65 years 216 (50.2) T stage T1 165 (38.4) T2 122 (28.4) T3 28 (6.5) T4 115 (26.7) Tumour localization Tongue 97 (22.6) Buccal mucosa 33 (7.7) Floor of the mouth 120 (27.9) Alveolar process 119 (27.7) Maxilla 29 (6.7) Soft palate 32 (7.4) N stage 0 280 (65.1) 1 50 (11.6) 2a 3 (0.7) 2b 52 (12.1) 2c 31 (7.2) 3a 1 (0.2) 3b 10 (2.3) Missing 3 (0.7) M stage 0 429 (99.8) 1 1 (0.2) UICC stage 1 138 (32.1) 2 73 (17.0) 3 47 (10.9) 4 172 (40) Differentiation grade 1 33 (7.7) 2 301 (70) 3 75 (17.4) Missing 21 (4.9) Resection status 0 399 (92.8) 1 23 (5.3) uncertain 8 (1.9) Risk factors Tobacco consumption Yes 240 (55.8) No 190 (44.2) Alcohol consumption Yes 171 (39.8) No 259 (60.2) Disease recurrence Local recurrence 49 (11.4) Regional metastasis 34 (7.9) Distant metastasis 17 (4.0) UICC, Union for International Cancer Control.
of the mouth, 27.8% for tongue, 37% for maxilla, 37.5% for soft palate, 42.4% for buccal mucosa, and 42.9% for alveolar process; the overall rate in this cohort was 34.4%. Table 3 and Fig. 1 depict the observed events with regard to the anatomical localization.
Please cite this article in press as: Moratin J, et al. The prognostic significance of the lymph node ratio in oral cancer differs for anatomical subsites, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.ijom.2019.10.015
YIJOM-4313; No of Pages 6
Lymph node ratio in oral cancer Table 2. Correlation analysis of the lymph node ratio with relevant clinical and pathological parameters for squamous cell carcinoma of the oral cavity; Pearson’s correlation coefficient. Parameter
Pearson’s correlation coefficient
P-value
T stage N stage Extracapsular spread Perineural invasion Vascular invasion Lymphatic invasion Tumour grading Regional recurrence
0.25 0.69 0.3 0.28 0.28 0.46 0.18 0.14
<0.001 <0.001 0.001 0.002 <0.001 <0.001 0.001 0.005
Table 3. Rates of primary cervical metastasis, local and regional disease recurrence in consideration of the primary tumour localization. Localization
Primary metastasis
Local disease recurrence
Regional disease recurrence
Tongue Buccal mucosa Floor of the mouth Alveolar process Maxilla Soft palate
27.8% 42.4% 27.5% 42.9% 37% 37.5%
8.2% 12.1% 10.0% 12.6% 17.2% 15.6%
11.3% 3.0% 9.2% 7.6% 6.9% 0%
Local disease recurrence
The overall rate of local disease recurrence was 11.4%, ranging from 8.2% (tongue), 10.0% (floor of the mouth), 12.1% (buccal mucosa), 12.6% (alveolar process), and 15.6% (soft palate) to 17.2% (maxilla). Table 3 displays the observed events of local recurrence with regard to the anatomical localization.
Regional recurrence
The overall rate of late neck node metastasis was 7.7%, with rates of 0% for the soft palate, 3.0% for the buccal mucosa,
6.9% for the maxilla, 7.6% for the alveolar process, 9.2% for the floor of the mouth, and 11.3% for the tongue, depending on the anatomical localization of the primary tumour (Table 3 and Fig. 1). All metastases occurring after primary surgical treatment were defined as late neck node metastases and the mean time to occurrence was 12.9 months. Prognostic significance of the lymph node ratio depending on the anatomical subsite
ROC curve analysis was performed for each anatomical subsite and demonstrated
3
significant differences between the groups regarding the prognostic impact of the LNR on overall survival (Fig. 2). The LNR had a significant impact on overall survival for patients with squamous cell carcinoma of the alveolar process (P = 0.04), the buccal mucosa (P = 0.02), the maxilla (P = 0.03), and the tongue (P < 0.001). In the ROC curve analysis, there was no significant association with overall survival in squamous cell carcinoma of the soft palate or squamous cell carcinoma the floor of the mouth. The only subsite with a significant association of the LNR with progressionfree survival was the tongue (P = 0.001).
Survival analysis
In the survival analysis, Kaplan–Meier curves were used to determine the association between the LNR and overall survival. Following the recommendations of recently published studies on LNR, a cutoff value of 0.08 was defined to differentiate between the low-risk and high-risk groups regarding the clinical outcome. A significant impact for squamous cell carcinoma of the oral cavity in general was found (log-rank test: P < 0.001, Fig. 3). In the multivariate Cox proportional hazards analysis, the LNR and tumour size were confirmed as independent prognostic factors for overall and progression-free survival of patients with squamous cell carcinoma of the oral cavity (P < 0.001, Table 4). Discussion
The primary goal of this investigation was to evaluate the prognostic significance of
Fig. 1. Cases of primary neck node metastasis and regional disease recurrence in consideration of the different tumour localizations in the oral cavity and the oropharynx.
Please cite this article in press as: Moratin J, et al. The prognostic significance of the lymph node ratio in oral cancer differs for anatomical subsites, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.ijom.2019.10.015
YIJOM-4313; No of Pages 6
4
Moratin et al.
Fig. 2. ROC curves depicting the prognostic impact of the lymph node ratio on overall survival for patients with head and neck squamous cell carcinoma in different anatomical subsites: (A) soft palate, AUC = 0.42, P = 0.6; (B) buccal mucosa, AUC = 0.88, P = 0.02; (C) floor of the mouth, AUC = 0.6, P = 0.11; (D) alveolar process, AUC = 0.63, P = 0.04; (E) maxilla, AUC = 0.78, P = 0.03; (F) tongue, AUC = 0.86, P < 0.001 (ROC, receiver operating characteristic; AUC, area under the ROC curve).
Fig. 3. Kaplan–Meier curves of (A) overall survival, and (B) progression-free survival, in consideration of the lymph node ratio for patients with squamous cell carcinoma of the oral cavity (A, log-rank test: P < 0.001).
Table 4. Multivariate Cox regression analysis of overall and progression-free survival in a cohort of patients suffering from squamous cell carcinoma of the oral cavity, in consideration of the lymph node ratio and relevant clinical and pathological variables. Overall survival Parameter T stage LNR Grading Age
Progression-free survival HR (95% CI) 1.4 (1.1–1.6) 2.9 (1.8–4.5) 1.3 (0.9–2.0) 1.0 (0.9–1.1)
P-value 0.002 <0.001 0.2 0.6
Parameter T stage LNR Grading Age
HR (95% CI) 1.4 (1.2–1.6) 34 (7.1–163.9) 0.7 (0.5–1.1) 1.0 (0.9–1.1)
P-value <0.001 <0.001 0.1 0.5
HR, hazard ratio; CI, confidence interval; LNR, lymph node ratio.
Please cite this article in press as: Moratin J, et al. The prognostic significance of the lymph node ratio in oral cancer differs for anatomical subsites, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.ijom.2019.10.015
YIJOM-4313; No of Pages 6
Lymph node ratio in oral cancer the LNR in different subsites affected by HNSCC. While in the past oral cancer was treated as a homogeneous entity, awareness has recently grown that different subsites within the head and neck area also imply different rates of treatment failure and clinical outcomes. This may partly be due to the underlying molecular mechanisms of tumourigenesis and to different patterns of invasion and metastasis. While the role of human papillomavirus infection in the development of carcinoma and in the survival of a large group of younger patients with squamous cell carcinoma of the oropharynx has been reported in recent years, this factor seems to be of minor importance in cancer of the oral cavity22,23. In the past, the LNR has been proposed as a supplement to the classical TNM staging system. Different authors have advocated its use in order to predict the patient risk of treatment failure and response rates to adjuvant therapy more sensitively17,19. While in most investigations pooled cohorts of patients with HNSCC have been used to evaluate the prognostic impact of the LNR, others have focused on specific subgroups of patients. It appears that a critical evaluation of the applicability of the LNR by comparison of different tumour localizations has not yet been performed. The present study data clearly show a strong correlation of the LNR with pathological lymphatic tumour invasion (r = 0.46, P < 0.001). This fact seems logical, as lymphatic tumour invasion will probably increase the risk of developing cervical metastases and consequently affect the LNR. This observation is in line with the findings reported in other pubincluding various lications malignancies24–27. The observed correlations with T stage and with further pathological risk factors such as tumour grading and perineural and vascular tumour invasion can be regarded as a sign of increased tumour aggressiveness and support the validity of the study data, as similar observations have been described by other authors18,28,29. The LNR is calculated as the ratio of positive nodes to dissected lymph nodes and therefore is strongly dependent on the extent of the neck dissection performed. This factor, however, is not considered in the calculation. There is no definition of a minimum number of nodes or a differentiation between unilateral or bilateral neck dissection to determine whether a ratio is representative. This fact further hampers the comparability and universality of the LNR, as early stage tumours in certain anatomical subsites, for example the ton-
gue, are often treated with unilateral neck dissection only30. While in most publications a single ROC curve analysis served to determine the cut-off point for the LNR, the present analysis showed that each ROC curve analysis led to individual cut-off values and demonstrated different measures of suitability as a prognostic marker for the subsite investigated (Fig. 2). In the floor of the mouth and in the soft palate, the LNR did not have a significant impact on overall survival, and in squamous cell carcinoma of the alveolar process the impact was weaker as compared to the tongue, the maxilla, and the buccal mucosa. While the tongue was the anatomical site that presented the lowest rate of primary neck node metastasis, the prognostic impact of the LNR showed the highest results for sensitivity and specificity of all investigated subsites. These results demonstrate that a universal cutoff probably does not exist and that the LNR cannot serve as a single factor to perform a risk assessment. The multivariate Cox regression analysis of overall and progression-free survival showed that the LNR and T stage were independent prognostic factors for squamous cell carcinoma of the oral cavity when the whole cohort was considered in the calculation. These results show that the LNR may be a useful tool for risk assessment regarding adverse clinical outcomes in terms of reduced overall survival in patients with OSCC. Nevertheless, patterns of metastasis and disease recurrence differ significantly between different subsites of the oral cavity. Subsequently, there remains a need for a more precise consideration of the LNR as a prognostic factor, as the tumour localization mainly affects its impact. This could be due to differing lymphatic anatomy or varying therapeutic radicalness regarding the extent of the tumour resection and the neck dissection, depending on the affected subsite. Finally, the LNR appears to be mainly influenced by the different rates of cervical metastasis depending on the primary tumour localization and the extent of the neck dissection performed. Therefore, we advocate bilateral neck dissection to facilitate the calculation of the LNR and accordingly to allow the optimal risk assessment for affected patients.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
5
Competing interests
All authors declare that they have no conflict of interest. Ethical approval
Approval was given by the institutional ethics committee (Heidelberg, S-183/2015). Patient consent
Written informed consent was given by all patients included in this study. Acknowledgements. The study was supported by the Medical Faculty of the University of Heidelberg.
References 1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127:2893–917. 2. D’Cruz AK, Vaish R, Kapre N, Dandekar M, Gupta S, Hawaldar R, Agarwal JP, Pantvaidya G, Chaukar D, Deshmukh A, Kane S, Arya S, Ghosh-Laskar S, Chaturvedi P, Pai P, Nair S, Nair D, Badwe R, Head and Neck Disease Management Group. Elective versus therapeutic neck dissection in node-negative oral cancer. N Engl J Med 2015;373:521–9. 3. Akhtar S, Ikram M, Ghaffar S. Neck involvement in early carcinoma of tongue. Is elective neck dissection warranted? J Pak Med Assoc 2007;57:305–7. 4. Pignon JP, le Maitre A, Maillard E, Bourhis J, MACH-NC Collaborative Group. Metaanalysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 2009;92:4–14. 5. Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, Kish JA, Kim HE, Cmelak AJ, Rotman M, Machtay M, Ensley JF, Chao KS, Schultz CJ, Lee N, Fu KK, Radiation Therapy Oncology Group 9501/Intergroup. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350:1937–44. 6. Baumeister P, Welz C, Jacobi C, Reiter M. Is perineural invasion of head and neck squamous cell carcinomas linked to tobacco consumption? Otolaryngol Head Neck Surg 2018;158:878–81. 7. Ding D, Stokes W, Eguchi M, Hararah M, Sumner W, Amini A, Goddard J, Somerset H, Bradley C, McDermott J, Raben D, Karam SD. Association between lymph node ratio and recurrence and survival outcomes in patients with oral cavity cancer. JAMA Otolaryngol Head Neck Surg 2019;145:53–61.
Please cite this article in press as: Moratin J, et al. The prognostic significance of the lymph node ratio in oral cancer differs for anatomical subsites, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.ijom.2019.10.015
YIJOM-4313; No of Pages 6
6
Moratin et al.
8. Greenberg JS, Fowler R, Gomez J, Mo V, Roberts D, El Naggar AK, Myers JN. Extent of extracapsular spread: a critical prognosticator in oral tongue cancer. Cancer 2003;97:1464–70. 9. Taylor MD, LaPar DJ, Thomas CJ, Persinger M, Stelow EB, Kozower BD, Lau CL, Jones DR. Lymph node ratio predicts recurrence and survival after R0 resection for non-small cell lung cancer. Ann Thorac Surg 2013;96:1163–70. 10. Wu SG, Chen Y, Sun JY, Li FY, Lin Q, Lin HX, He ZY. Using the lymph nodal ratio to predict the risk of locoregional recurrence in lymph node-positive breast cancer patients treated with mastectomy without radiation therapy. Radiat Oncol 2013;8:119. 11. Asiyanbola B, Gleisner A, Herman JM, Choti MA, Wolfgang CL, Swartz M, Edil BH, Schulick RD, Cameron JL, Pawlik TM. Determining pattern of recurrence following pancreaticoduodenectomy and adjuvant 5flurouracil-based chemoradiation therapy: effect of number of metastatic lymph nodes and lymph node ratio. J Gastrointest Surg 2009;13:752–9. 12. de Ridder M, Marres CC, Smeele LE, van den Brekel MW, Hauptmann M, Balm AJ, van Velthuysen ML. A critical evaluation of lymph node ratio in head and neck cancer. Virchows Arch 2016;469:635–41. 13. Eshraghi Samani R, Shirkhoda M, Hadji M, Beheshtifard F, Hamedani SMMG, Momen A, Mollashahi M, Zendehdel K. The prognostic value of lymph node ratio in survival of head-and-neck squamous cell carcinoma. J Res Med Sci 2018;23:35. 14. Hosni A, McMullen C, Huang SH, Xu W, Su J, Bayley A, Bratman SV, Cho J, Giuliani M, Kim J, Ringash J, Waldron J, Spreafico A, Weinreb I, de Almeida JR, Brown DH, Irish JC, O’Sullivan B, Goldstein DP, Hope A. Lymph node ratio relationship to regional failure and distant metastases in oral cavity cancer. Radiother Oncol 2017;124:225–31. 15. Sayed SI, Sharma S, Rane P, Vaishampayan S, Talole S, Chaturvedi P, Chaukar D, Deshmukh A, Agarwal JP, D’Cruz AK. Can metastatic lymph node ratio (LNR) predict survival in oral cavity cancer patients? J Surg Oncol 2013;108:256–63.
16. Feng Z, Xu QS, Wang C, Li JZ, Mao MH, Li H, Qin LZ, Han Z. Lymph node ratio is associated with adverse clinicopathological features and is a crucial nodal parameter for oral and oropharyngeal cancer. Sci Rep 2017;7:6708. 17. Urban D, Gluck I, Pfeffer MR, Symon Z, Lawrence YR. Lymph node ratio predicts the benefit of post-operative radiotherapy in oral cavity cancer. Radiother Oncol 2013;106:74–9. 18. Safi AF, Kauke M, Grandoch A, Nickenig HJ, Zoller J, Kreppel M. The importance of lymph node ratio for patients with mandibular infiltration of oral squamous cell carcinoma. J Craniomaxillofac Surg 2018;46:1007–12. 19. Patel SG, Amit M, Yen TC, Liao CT, Chaturvedi P, Agarwal JP, Kowalski LP, Ebrahimi A, Clark JR, Cernea CR, Brandao SJ, Kreppel M, Zo¨ller J, Fliss D, Fridman E, Bachar G, Shpitzer T, Bolzoni VA, Patel PR, Jonnalagadda S, Robbins KT, Shah JP, Gil Z, International Consortium for Outcome Research (ICOR) in Head and Neck Cancer. Lymph node density in oral cavity cancer: results of the International Consortium for Outcomes Research. Br J Cancer 2013;109:2087–95. 20. Rempel V, Safi AF, Drebber U, Nickenig HJ, Neugebauer J, Zoller JE, Kreppel M. The prognostic relevance of lymph node ratio in patients with oral squamous cell carcinoma treated with neoadjuvant therapy regimen and radical surgery. J Craniomaxillofac Surg 2018;46:1659–63. 21. Zirk M, Safi AF, Buller J, Nickenig HJ, Dreiseidler T, Zinser M, Drebber U, Zo¨ller JE, Kreppel M. Lymph node ratio as prognosticator in floor of mouth squamous cell carcinoma patients. J Craniomaxillofac Surg 2018;46:195–200. 22. Isayeva T, Li Y, Maswahu D, BrandweinGensler M. Human papillomavirus in nonoropharyngeal head and neck cancers: a systematic literature review. Head Neck Pathol 2012;6(Suppl 1). S104. 23. Kansy K, Thiele O, Freier K. The role of human papillomavirus in oral squamous cell carcinoma: myth and reality. Oral Maxillofac Surg 2014;18:165–72.
24. Moratin J, Fuchs A, Zeidler C, Mu¨ller-Richter UDA, Brands RC, Hartmann S, Ku¨bler AC, Linz C. Squamous cell carcinoma of the maxilla: analysis of clinicopathological predictors for disease recurrence and metastatic behavior. J Craniomaxillofac Surg 2018;46:611–6. 25. Zhang CD, Ning FL, Zeng XT, Dai DQ. Lymphovascular invasion as a predictor for lymph node metastasis and a prognostic factor in gastric cancer patients under 70 years of age: a retrospective analysis. Int J Surg 2018;53:214–20. 26. Werntz RP, Smith ZL, Packiam VT, Smith N, Steinberg GD. The impact of lymphovascular invasion on risk of upstaging and lymph node metastasis at the time of radical cystectomy. Eur Urol Focus 2018. 27. Min BH, Byeon SJ, Lee JH, Kim KM, An JY, Choi MG, Lee JH, Sohn TS, Bae JM, Kim S. Lymphovascular invasion and lymph node metastasis rates in papillary adenocarcinoma of the stomach: implications for endoscopic resection. Gastric Cancer 2018;21:680–8. 28. Safi AF, Grandoch A, Nickenig HJ, Zoller JE, Kreppel M. Importance of lymph node ratio for locoregional recurrence of squamous cell carcinoma of the buccal mucosa. Head Neck 2017;39:2488–93. 29. Safi AF, Grandoch A, Nickenig HJ, Zoller JE, Kreppel M. The importance of lymph node ratio for locoregional recurrence of squamous cell carcinoma of the tongue. J Craniomaxillofac Surg 2017;45:1058–61. 30. Moratin J, Metzger K, Engel M, Hoffmann J, Freudlsperger C, Freier K, Horn D. The occurrence of cervical metastases in squamous cell carcinoma of the tongue: is there a rationale for bilateral neck dissection in early-stage tumors? J Craniomaxillofac Surg 2019;47:1134–8.
Address: Julius Moratin Department of Oral and Craniomaxillofacial Surgery Heidelberg University Hospital Im Neuenheimer Feld 400 D-69120 Heidelberg Germany Tel.: +49 6221 39795. Fax: +49 6221 42222 E-mail: [email protected]
Please cite this article in press as: Moratin J, et al. The prognostic significance of the lymph node ratio in oral cancer differs for anatomical subsites, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.ijom.2019.10.015
Int. J. Oral Maxillofac. Surg. 2019; xxx: xxx–xxx https://doi.org/10.1016/j.ijom.2019.10.015, available online at https://www.sciencedirect.com
Clinical Paper Head and Neck Oncology
The prognostic significance of the lymph node ratio in oral cancer differs for anatomical subsites
J. Moratin1, Ka rl Metzger1, K. Kansy1, O. Ristow1, M. Engel1, J. Hoffmann1, C. Flechtenmacher2, K. Freier1,3, C. Freudlsperger1, D. Horn1,3 1
Department of Oral and Craniomaxillofacial Surgery, Heidelberg University Hospital, Heidelberg, Germany; 2Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany; 3Department of Oral and Craniomaxillofacial Surgery, Saarland University Hospital, Homburg, Germany
J. Moratin, Karl Metzger, K. Kansy, O. Ristow, M. Engel, J. Hoffmann, C. Flechtenmacher, K. Freier, C. Freudlsperger, D. Horn: The prognostic significance of the lymph node ratio in oral cancer differs for anatomical subsites. Int. J. Oral Maxillofac. Surg. 2019; xxx: xxx–xxx. ã 2019 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Abstract. The aim of this study was to validate the prognostic significance of the lymph node ratio (LNR) in patients suffering from oral squamous cell carcinoma in regard to different anatomical subsites. A cohort of 430 patients was investigated to determine the rates of primary metastasis and local and regional disease recurrence. Correlation analysis of the LNR with relevant clinical and pathological parameters was performed. Receiver operating characteristic (ROC) curve analysis was conducted to evaluate the prognostic impact for different subsites. Significantly differing rates of primary metastasis and loco-regional disease recurrence were found for cancer of different anatomical subsites of the head and neck. Furthermore, ROC curve analysis suggested that LNR has prognostic relevance in subsets of cancer (tongue, P < 0.001; alveolar process, P = 0.04; maxilla, P = 0.03; buccal mucosa, P = 0.02). The LNR of cancer located in the soft palate (P = 0.6) and floor of the mouth (P = 0.11) showed little or no association with the clinical outcome. There is the need for a more sensitive consideration of the LNR as a factor in the assessment of risk and the treatment decision, as the anatomical subsite plays a crucial role in its impact on the clinical outcome.
Head and neck squamous cell carcinomas (HNSCC) represent the sixth most common malignant disease worldwide. The majority of this entity originate in the oral mucosa (oral squamous cell carcinoma, OSCC)1. The survival of patients is mainly limited by disease recurrence and the development 0901-5027/000001+06
of loco-regional or distant metastases. There have been improvements in the management of HNSCC due to interdisciplinary treatment approaches and advanced adjuvant therapy regimens. Nevertheless, survival has improved only to a minor extent over the past decades2–5.
Key words: HNSCC; OSCC; oral cancer; lymph node ratio; metastasis; survival. Accepted for publication
Various risk factors to estimate the probability of loco-regional recurrence and subsequently of an adverse clinical outcome have been described. Among these parameters, advanced T stage, incomplete resection status, lympho-/vascular or perineural tumour invasion, the
ã 2019 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Moratin J, et al. The prognostic significance of the lymph node ratio in oral cancer differs for anatomical subsites, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.ijom.2019.10.015
YIJOM-4313; No of Pages 6
2
Moratin et al.
presence of cervical lymph node metastases, extracapsular spread, and the lymph node ratio (LNR) are the most relevant2,6– 8 . The LNR is calculated as the ratio of positive lymph nodes to dissected nodes and has been shown to be an independent prognostic factor in patients with OSCC and other malignancies by various authors9–11. Most scientific analyses have used an LNR cut-off value of between 0.06 and 0.08 to stratify patients according to the risk of an adverse clinical outcome. This stratification has been introduced for further treatment decision-making, especially in regard to adjuvant therapy7,12–18. Patel et al. have even proposed the inclusion of the LNR in the TNM staging system19. Most publications have mainly discussed the prognostic significance of the LNR in pooled cohorts of patients or have focused on only a subgroup of OSCC. The prognostic impact of different anatomical subsites has not yet been reported18,20,21. While there is increasing evidence of different survival and recurrence probability according to the localization of the primary tumour, evidence of the prognostic role of the LNR in this context is lacking. Therefore, the purpose of this study was to determine the rates of primary metastasis and local and regional disease recurrence in a large cohort of patients with squamous cell carcinoma of the oral cavity, with emphasis on the exact anatomical localization of the tumours. Furthermore, the prognostic value of the LNR was determined according to the different anatomical subsites. Materials and methods Data collection
Inclusion criteria were a histopathological diagnosis of primary squamous cell carcinoma of the oral cavity and primary surgical treatment in the Department of Oral and Craniomaxillofacial surgery, Heidelberg University Hospital between the years 2010 and 2017. The electronic patient records (SAP, Walldorf, Germany) were used for documentation, allowing optimal traceability of clinical progress and the clinical outcome. Patients with locally advanced tumours (T4), positive resection margins (R+), lymph node metastases (N+), or a combination of histopathological risk factors (lymphovascular invasion (L1V1) or perineural tumour infiltration (Pn1)) received adjuvant therapy. Written informed consent was obtained from all patients and the study was approved by the Ethics Committee of the
Medical Faculty of the University of Heidelberg (Ethics Vote: S-183/2015). The LNR was calculated as the ratio of positive lymph nodes to dissected nodes using the patients’ pathology records. Statistical analysis
The statistical analysis was conducted using Microsoft Excel 2013 (Microsoft, Redmond, WA, USA) and IBM SPSS Statistics version 22.0 (IBM Corp., Armonk, NY, USA). Clinical data were analysed by descriptive statistics; correlation analysis was performed using Pearson’s correlation coefficient. Receiver operating characteristic (ROC) curve analyses were used to estimate the prognostic impact of the LNR in the different subsites. The survival analysis was performed using the Kaplan–Meier method, and logrank testing was used to estimate differences in survival between the groups. A multivariate Cox regression analysis was applied to investigate the impact on overall and disease-specific survival. A P-value of 0.05 or less was considered to demonstrate statistical significance. Results Patient cohort
A total of 430 patients matched the inclusion criteria; 157 (36.5%) were female and 273 (63.5%) were male, and their mean age was 63.9 11.7 years (range 18–92 years). Table 1 gives an overview of the demographic, clinical, and pathological features of the cohort investigated. Correlation analysis
Correlation analysis was performed with a special interest in correlations of the LNR with other relevant clinical and pathological parameters (Table 2). Highly significant correlations of the LNR with the T and N stage (both P < 0.001), different pathological risk factors including vascular (P < 0.001), perineural (P = 0.002), and lymphatic tumour invasion (P < 0.001), and with extracapsular spread (P = 0.001) were found. There was a weak correlation of the LNR with the occurrence of late neck node metastases. No significant association was found with events of local disease recurrence or the development of distant metastases. Incidence of primary cervical metastasis
The subsites investigated displayed rates of primary cervical metastasis of 27.5% for floor
Table 1. Descriptive data regarding demographic and clinical features of the cohort investigated. Parameter
Number of cases (%)
Sex Female 157 (36.5) Male 273 (63.5) Age <65 years 214 (49.8) >65 years 216 (50.2) T stage T1 165 (38.4) T2 122 (28.4) T3 28 (6.5) T4 115 (26.7) Tumour localization Tongue 97 (22.6) Buccal mucosa 33 (7.7) Floor of the mouth 120 (27.9) Alveolar process 119 (27.7) Maxilla 29 (6.7) Soft palate 32 (7.4) N stage 0 280 (65.1) 1 50 (11.6) 2a 3 (0.7) 2b 52 (12.1) 2c 31 (7.2) 3a 1 (0.2) 3b 10 (2.3) Missing 3 (0.7) M stage 0 429 (99.8) 1 1 (0.2) UICC stage 1 138 (32.1) 2 73 (17.0) 3 47 (10.9) 4 172 (40) Differentiation grade 1 33 (7.7) 2 301 (70) 3 75 (17.4) Missing 21 (4.9) Resection status 0 399 (92.8) 1 23 (5.3) uncertain 8 (1.9) Risk factors Tobacco consumption Yes 240 (55.8) No 190 (44.2) Alcohol consumption Yes 171 (39.8) No 259 (60.2) Disease recurrence Local recurrence 49 (11.4) Regional metastasis 34 (7.9) Distant metastasis 17 (4.0) UICC, Union for International Cancer Control.
of the mouth, 27.8% for tongue, 37% for maxilla, 37.5% for soft palate, 42.4% for buccal mucosa, and 42.9% for alveolar process; the overall rate in this cohort was 34.4%. Table 3 and Fig. 1 depict the observed events with regard to the anatomical localization.
Please cite this article in press as: Moratin J, et al. The prognostic significance of the lymph node ratio in oral cancer differs for anatomical subsites, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.ijom.2019.10.015
YIJOM-4313; No of Pages 6
Lymph node ratio in oral cancer Table 2. Correlation analysis of the lymph node ratio with relevant clinical and pathological parameters for squamous cell carcinoma of the oral cavity; Pearson’s correlation coefficient. Parameter
Pearson’s correlation coefficient
P-value
T stage N stage Extracapsular spread Perineural invasion Vascular invasion Lymphatic invasion Tumour grading Regional recurrence
0.25 0.69 0.3 0.28 0.28 0.46 0.18 0.14
<0.001 <0.001 0.001 0.002 <0.001 <0.001 0.001 0.005
Table 3. Rates of primary cervical metastasis, local and regional disease recurrence in consideration of the primary tumour localization. Localization
Primary metastasis
Local disease recurrence
Regional disease recurrence
Tongue Buccal mucosa Floor of the mouth Alveolar process Maxilla Soft palate
27.8% 42.4% 27.5% 42.9% 37% 37.5%
8.2% 12.1% 10.0% 12.6% 17.2% 15.6%
11.3% 3.0% 9.2% 7.6% 6.9% 0%
Local disease recurrence
The overall rate of local disease recurrence was 11.4%, ranging from 8.2% (tongue), 10.0% (floor of the mouth), 12.1% (buccal mucosa), 12.6% (alveolar process), and 15.6% (soft palate) to 17.2% (maxilla). Table 3 displays the observed events of local recurrence with regard to the anatomical localization.
Regional recurrence
The overall rate of late neck node metastasis was 7.7%, with rates of 0% for the soft palate, 3.0% for the buccal mucosa,
6.9% for the maxilla, 7.6% for the alveolar process, 9.2% for the floor of the mouth, and 11.3% for the tongue, depending on the anatomical localization of the primary tumour (Table 3 and Fig. 1). All metastases occurring after primary surgical treatment were defined as late neck node metastases and the mean time to occurrence was 12.9 months. Prognostic significance of the lymph node ratio depending on the anatomical subsite
ROC curve analysis was performed for each anatomical subsite and demonstrated
3
significant differences between the groups regarding the prognostic impact of the LNR on overall survival (Fig. 2). The LNR had a significant impact on overall survival for patients with squamous cell carcinoma of the alveolar process (P = 0.04), the buccal mucosa (P = 0.02), the maxilla (P = 0.03), and the tongue (P < 0.001). In the ROC curve analysis, there was no significant association with overall survival in squamous cell carcinoma of the soft palate or squamous cell carcinoma the floor of the mouth. The only subsite with a significant association of the LNR with progressionfree survival was the tongue (P = 0.001).
Survival analysis
In the survival analysis, Kaplan–Meier curves were used to determine the association between the LNR and overall survival. Following the recommendations of recently published studies on LNR, a cutoff value of 0.08 was defined to differentiate between the low-risk and high-risk groups regarding the clinical outcome. A significant impact for squamous cell carcinoma of the oral cavity in general was found (log-rank test: P < 0.001, Fig. 3). In the multivariate Cox proportional hazards analysis, the LNR and tumour size were confirmed as independent prognostic factors for overall and progression-free survival of patients with squamous cell carcinoma of the oral cavity (P < 0.001, Table 4). Discussion
The primary goal of this investigation was to evaluate the prognostic significance of
Fig. 1. Cases of primary neck node metastasis and regional disease recurrence in consideration of the different tumour localizations in the oral cavity and the oropharynx.
Please cite this article in press as: Moratin J, et al. The prognostic significance of the lymph node ratio in oral cancer differs for anatomical subsites, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.ijom.2019.10.015
YIJOM-4313; No of Pages 6
4
Moratin et al.
Fig. 2. ROC curves depicting the prognostic impact of the lymph node ratio on overall survival for patients with head and neck squamous cell carcinoma in different anatomical subsites: (A) soft palate, AUC = 0.42, P = 0.6; (B) buccal mucosa, AUC = 0.88, P = 0.02; (C) floor of the mouth, AUC = 0.6, P = 0.11; (D) alveolar process, AUC = 0.63, P = 0.04; (E) maxilla, AUC = 0.78, P = 0.03; (F) tongue, AUC = 0.86, P < 0.001 (ROC, receiver operating characteristic; AUC, area under the ROC curve).
Fig. 3. Kaplan–Meier curves of (A) overall survival, and (B) progression-free survival, in consideration of the lymph node ratio for patients with squamous cell carcinoma of the oral cavity (A, log-rank test: P < 0.001).
Table 4. Multivariate Cox regression analysis of overall and progression-free survival in a cohort of patients suffering from squamous cell carcinoma of the oral cavity, in consideration of the lymph node ratio and relevant clinical and pathological variables. Overall survival Parameter T stage LNR Grading Age
Progression-free survival HR (95% CI) 1.4 (1.1–1.6) 2.9 (1.8–4.5) 1.3 (0.9–2.0) 1.0 (0.9–1.1)
P-value 0.002 <0.001 0.2 0.6
Parameter T stage LNR Grading Age
HR (95% CI) 1.4 (1.2–1.6) 34 (7.1–163.9) 0.7 (0.5–1.1) 1.0 (0.9–1.1)
P-value <0.001 <0.001 0.1 0.5
HR, hazard ratio; CI, confidence interval; LNR, lymph node ratio.
Please cite this article in press as: Moratin J, et al. The prognostic significance of the lymph node ratio in oral cancer differs for anatomical subsites, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.ijom.2019.10.015
YIJOM-4313; No of Pages 6
Lymph node ratio in oral cancer the LNR in different subsites affected by HNSCC. While in the past oral cancer was treated as a homogeneous entity, awareness has recently grown that different subsites within the head and neck area also imply different rates of treatment failure and clinical outcomes. This may partly be due to the underlying molecular mechanisms of tumourigenesis and to different patterns of invasion and metastasis. While the role of human papillomavirus infection in the development of carcinoma and in the survival of a large group of younger patients with squamous cell carcinoma of the oropharynx has been reported in recent years, this factor seems to be of minor importance in cancer of the oral cavity22,23. In the past, the LNR has been proposed as a supplement to the classical TNM staging system. Different authors have advocated its use in order to predict the patient risk of treatment failure and response rates to adjuvant therapy more sensitively17,19. While in most investigations pooled cohorts of patients with HNSCC have been used to evaluate the prognostic impact of the LNR, others have focused on specific subgroups of patients. It appears that a critical evaluation of the applicability of the LNR by comparison of different tumour localizations has not yet been performed. The present study data clearly show a strong correlation of the LNR with pathological lymphatic tumour invasion (r = 0.46, P < 0.001). This fact seems logical, as lymphatic tumour invasion will probably increase the risk of developing cervical metastases and consequently affect the LNR. This observation is in line with the findings reported in other pubincluding various lications malignancies24–27. The observed correlations with T stage and with further pathological risk factors such as tumour grading and perineural and vascular tumour invasion can be regarded as a sign of increased tumour aggressiveness and support the validity of the study data, as similar observations have been described by other authors18,28,29. The LNR is calculated as the ratio of positive nodes to dissected lymph nodes and therefore is strongly dependent on the extent of the neck dissection performed. This factor, however, is not considered in the calculation. There is no definition of a minimum number of nodes or a differentiation between unilateral or bilateral neck dissection to determine whether a ratio is representative. This fact further hampers the comparability and universality of the LNR, as early stage tumours in certain anatomical subsites, for example the ton-
gue, are often treated with unilateral neck dissection only30. While in most publications a single ROC curve analysis served to determine the cut-off point for the LNR, the present analysis showed that each ROC curve analysis led to individual cut-off values and demonstrated different measures of suitability as a prognostic marker for the subsite investigated (Fig. 2). In the floor of the mouth and in the soft palate, the LNR did not have a significant impact on overall survival, and in squamous cell carcinoma of the alveolar process the impact was weaker as compared to the tongue, the maxilla, and the buccal mucosa. While the tongue was the anatomical site that presented the lowest rate of primary neck node metastasis, the prognostic impact of the LNR showed the highest results for sensitivity and specificity of all investigated subsites. These results demonstrate that a universal cutoff probably does not exist and that the LNR cannot serve as a single factor to perform a risk assessment. The multivariate Cox regression analysis of overall and progression-free survival showed that the LNR and T stage were independent prognostic factors for squamous cell carcinoma of the oral cavity when the whole cohort was considered in the calculation. These results show that the LNR may be a useful tool for risk assessment regarding adverse clinical outcomes in terms of reduced overall survival in patients with OSCC. Nevertheless, patterns of metastasis and disease recurrence differ significantly between different subsites of the oral cavity. Subsequently, there remains a need for a more precise consideration of the LNR as a prognostic factor, as the tumour localization mainly affects its impact. This could be due to differing lymphatic anatomy or varying therapeutic radicalness regarding the extent of the tumour resection and the neck dissection, depending on the affected subsite. Finally, the LNR appears to be mainly influenced by the different rates of cervical metastasis depending on the primary tumour localization and the extent of the neck dissection performed. Therefore, we advocate bilateral neck dissection to facilitate the calculation of the LNR and accordingly to allow the optimal risk assessment for affected patients.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
5
Competing interests
All authors declare that they have no conflict of interest. Ethical approval
Approval was given by the institutional ethics committee (Heidelberg, S-183/2015). Patient consent
Written informed consent was given by all patients included in this study. Acknowledgements. The study was supported by the Medical Faculty of the University of Heidelberg.
References 1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127:2893–917. 2. D’Cruz AK, Vaish R, Kapre N, Dandekar M, Gupta S, Hawaldar R, Agarwal JP, Pantvaidya G, Chaukar D, Deshmukh A, Kane S, Arya S, Ghosh-Laskar S, Chaturvedi P, Pai P, Nair S, Nair D, Badwe R, Head and Neck Disease Management Group. Elective versus therapeutic neck dissection in node-negative oral cancer. N Engl J Med 2015;373:521–9. 3. Akhtar S, Ikram M, Ghaffar S. Neck involvement in early carcinoma of tongue. Is elective neck dissection warranted? J Pak Med Assoc 2007;57:305–7. 4. Pignon JP, le Maitre A, Maillard E, Bourhis J, MACH-NC Collaborative Group. Metaanalysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 2009;92:4–14. 5. Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, Kish JA, Kim HE, Cmelak AJ, Rotman M, Machtay M, Ensley JF, Chao KS, Schultz CJ, Lee N, Fu KK, Radiation Therapy Oncology Group 9501/Intergroup. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350:1937–44. 6. Baumeister P, Welz C, Jacobi C, Reiter M. Is perineural invasion of head and neck squamous cell carcinomas linked to tobacco consumption? Otolaryngol Head Neck Surg 2018;158:878–81. 7. Ding D, Stokes W, Eguchi M, Hararah M, Sumner W, Amini A, Goddard J, Somerset H, Bradley C, McDermott J, Raben D, Karam SD. Association between lymph node ratio and recurrence and survival outcomes in patients with oral cavity cancer. JAMA Otolaryngol Head Neck Surg 2019;145:53–61.
Please cite this article in press as: Moratin J, et al. The prognostic significance of the lymph node ratio in oral cancer differs for anatomical subsites, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.ijom.2019.10.015
YIJOM-4313; No of Pages 6
6
Moratin et al.
8. Greenberg JS, Fowler R, Gomez J, Mo V, Roberts D, El Naggar AK, Myers JN. Extent of extracapsular spread: a critical prognosticator in oral tongue cancer. Cancer 2003;97:1464–70. 9. Taylor MD, LaPar DJ, Thomas CJ, Persinger M, Stelow EB, Kozower BD, Lau CL, Jones DR. Lymph node ratio predicts recurrence and survival after R0 resection for non-small cell lung cancer. Ann Thorac Surg 2013;96:1163–70. 10. Wu SG, Chen Y, Sun JY, Li FY, Lin Q, Lin HX, He ZY. Using the lymph nodal ratio to predict the risk of locoregional recurrence in lymph node-positive breast cancer patients treated with mastectomy without radiation therapy. Radiat Oncol 2013;8:119. 11. Asiyanbola B, Gleisner A, Herman JM, Choti MA, Wolfgang CL, Swartz M, Edil BH, Schulick RD, Cameron JL, Pawlik TM. Determining pattern of recurrence following pancreaticoduodenectomy and adjuvant 5flurouracil-based chemoradiation therapy: effect of number of metastatic lymph nodes and lymph node ratio. J Gastrointest Surg 2009;13:752–9. 12. de Ridder M, Marres CC, Smeele LE, van den Brekel MW, Hauptmann M, Balm AJ, van Velthuysen ML. A critical evaluation of lymph node ratio in head and neck cancer. Virchows Arch 2016;469:635–41. 13. Eshraghi Samani R, Shirkhoda M, Hadji M, Beheshtifard F, Hamedani SMMG, Momen A, Mollashahi M, Zendehdel K. The prognostic value of lymph node ratio in survival of head-and-neck squamous cell carcinoma. J Res Med Sci 2018;23:35. 14. Hosni A, McMullen C, Huang SH, Xu W, Su J, Bayley A, Bratman SV, Cho J, Giuliani M, Kim J, Ringash J, Waldron J, Spreafico A, Weinreb I, de Almeida JR, Brown DH, Irish JC, O’Sullivan B, Goldstein DP, Hope A. Lymph node ratio relationship to regional failure and distant metastases in oral cavity cancer. Radiother Oncol 2017;124:225–31. 15. Sayed SI, Sharma S, Rane P, Vaishampayan S, Talole S, Chaturvedi P, Chaukar D, Deshmukh A, Agarwal JP, D’Cruz AK. Can metastatic lymph node ratio (LNR) predict survival in oral cavity cancer patients? J Surg Oncol 2013;108:256–63.
16. Feng Z, Xu QS, Wang C, Li JZ, Mao MH, Li H, Qin LZ, Han Z. Lymph node ratio is associated with adverse clinicopathological features and is a crucial nodal parameter for oral and oropharyngeal cancer. Sci Rep 2017;7:6708. 17. Urban D, Gluck I, Pfeffer MR, Symon Z, Lawrence YR. Lymph node ratio predicts the benefit of post-operative radiotherapy in oral cavity cancer. Radiother Oncol 2013;106:74–9. 18. Safi AF, Kauke M, Grandoch A, Nickenig HJ, Zoller J, Kreppel M. The importance of lymph node ratio for patients with mandibular infiltration of oral squamous cell carcinoma. J Craniomaxillofac Surg 2018;46:1007–12. 19. Patel SG, Amit M, Yen TC, Liao CT, Chaturvedi P, Agarwal JP, Kowalski LP, Ebrahimi A, Clark JR, Cernea CR, Brandao SJ, Kreppel M, Zo¨ller J, Fliss D, Fridman E, Bachar G, Shpitzer T, Bolzoni VA, Patel PR, Jonnalagadda S, Robbins KT, Shah JP, Gil Z, International Consortium for Outcome Research (ICOR) in Head and Neck Cancer. Lymph node density in oral cavity cancer: results of the International Consortium for Outcomes Research. Br J Cancer 2013;109:2087–95. 20. Rempel V, Safi AF, Drebber U, Nickenig HJ, Neugebauer J, Zoller JE, Kreppel M. The prognostic relevance of lymph node ratio in patients with oral squamous cell carcinoma treated with neoadjuvant therapy regimen and radical surgery. J Craniomaxillofac Surg 2018;46:1659–63. 21. Zirk M, Safi AF, Buller J, Nickenig HJ, Dreiseidler T, Zinser M, Drebber U, Zo¨ller JE, Kreppel M. Lymph node ratio as prognosticator in floor of mouth squamous cell carcinoma patients. J Craniomaxillofac Surg 2018;46:195–200. 22. Isayeva T, Li Y, Maswahu D, BrandweinGensler M. Human papillomavirus in nonoropharyngeal head and neck cancers: a systematic literature review. Head Neck Pathol 2012;6(Suppl 1). S104. 23. Kansy K, Thiele O, Freier K. The role of human papillomavirus in oral squamous cell carcinoma: myth and reality. Oral Maxillofac Surg 2014;18:165–72.
24. Moratin J, Fuchs A, Zeidler C, Mu¨ller-Richter UDA, Brands RC, Hartmann S, Ku¨bler AC, Linz C. Squamous cell carcinoma of the maxilla: analysis of clinicopathological predictors for disease recurrence and metastatic behavior. J Craniomaxillofac Surg 2018;46:611–6. 25. Zhang CD, Ning FL, Zeng XT, Dai DQ. Lymphovascular invasion as a predictor for lymph node metastasis and a prognostic factor in gastric cancer patients under 70 years of age: a retrospective analysis. Int J Surg 2018;53:214–20. 26. Werntz RP, Smith ZL, Packiam VT, Smith N, Steinberg GD. The impact of lymphovascular invasion on risk of upstaging and lymph node metastasis at the time of radical cystectomy. Eur Urol Focus 2018. 27. Min BH, Byeon SJ, Lee JH, Kim KM, An JY, Choi MG, Lee JH, Sohn TS, Bae JM, Kim S. Lymphovascular invasion and lymph node metastasis rates in papillary adenocarcinoma of the stomach: implications for endoscopic resection. Gastric Cancer 2018;21:680–8. 28. Safi AF, Grandoch A, Nickenig HJ, Zoller JE, Kreppel M. Importance of lymph node ratio for locoregional recurrence of squamous cell carcinoma of the buccal mucosa. Head Neck 2017;39:2488–93. 29. Safi AF, Grandoch A, Nickenig HJ, Zoller JE, Kreppel M. The importance of lymph node ratio for locoregional recurrence of squamous cell carcinoma of the tongue. J Craniomaxillofac Surg 2017;45:1058–61. 30. Moratin J, Metzger K, Engel M, Hoffmann J, Freudlsperger C, Freier K, Horn D. The occurrence of cervical metastases in squamous cell carcinoma of the tongue: is there a rationale for bilateral neck dissection in early-stage tumors? J Craniomaxillofac Surg 2019;47:1134–8.
Address: Julius Moratin Department of Oral and Craniomaxillofacial Surgery Heidelberg University Hospital Im Neuenheimer Feld 400 D-69120 Heidelberg Germany Tel.: +49 6221 39795. Fax: +49 6221 42222 E-mail: [email protected]
Please cite this article in press as: Moratin J, et al. The prognostic significance of the lymph node ratio in oral cancer differs for anatomical subsites, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.ijom.2019.10.015