Prognostic analysis of lymph node ratio of patients with disease recurrence previously submitted to cervical dissection surgery for head and neck cancer

ABSTRACT Introduction: the variable lymph node ratio has recently been studied as a possible influencer in the survival of patients diagnosed with head and neck cancer. Objective: to analyze the correlation between lymph node density and survival of recurred disease patients previously submitted to cervical dissection surgery due to head and neck squamous cell carcinoma. Method: we retrospectively analyzed 71 medical records of patients treated at the Head and Neck Surgery Service of the Pontifícia Universidade Católica de Campinas who had undergone cervical dissection surgery and presented tumor recurrence between 2006 and 2019. Patient and tumor data such as age, gender, skin color, smoking, alcohol consumption, location of the primary tumor, anatomopathological characteristics and lymph node status were correlated with the survival time. Results: we found a predominance of males and the mean age was 59.5 years. The most frequent primary site was the oral cavity followed by the larynx and oropharynx. The mortality rate was 53.52% and the mean lymph node ratio 0.28. We found influence on survival with statistical significance for the parameters: lymph node ratio, number of dissected and affected lymph nodes, T and N staging, type of treatment proposed (palliative or surgical), presence of compromited margins in the primary tumor and lymph node extravasation. Conclusion: the calculation of lymph node density in patients with recurred disease after cervical dissection surgery by head and neck squamous cell carcinoma should be taken into account during therapeutic planning and prognostic evaluation due to its direct influence on the survival.


Rev Col Bras Cir 49:e20223178
Ramos Prognostic analysis of lymph node ratio of patients with disease recurrence previously submitted to cervical dissection surgery for head and neck cancer system for the classification of malignant tumors (UICC) and the treatment depends on factors such as the tumor location, clinical staging as well as the patient's physical conditions.Treatment can include surgery, radiotherapy and/or chemotherapy, separately or in combination.
However, tumors with the same TNM staging may demonstrate different patterns of evolution, suggesting the need for assessing other factors capable of more accurately determining disease prognosis.
The main route of dissemination of head and neck SCC is lymphatic.Therefore, pathological neck condition is one of the determining factors for indicating adjuvant therapy 7 .
The concept of Lymph Node Density (LND), represented by a numerical ratio between the number of lymph nodes affected by the neoplasm, confirmed by an anatomopathological assessment, over the total number of lymph nodes surgically resected, has already been described and is used in oncology clinic in breast, esophagus, stomach, cardia and rectum tumors for example [8][9][10][11][12] ; however, since Shrime et al. 13 published their first article suggesting the application of this parameter in head and neck surgery, the possibility of LND being an independent prognostic factor in relation to head and neck patients surviving SCC has been discussed 14,15 .In addition, some studies compare the prognostic efficacy of LND with the actual TNM classification, showing different results [16][17][18][19] .
Thus, the objective of this study is to assess whether lymph node density had an impact on the survival of patients who had previously undergone cervical dissection surgery due to SCC of the oral cavity, larynx or pharynx.Patients with other histological types or who had already undergone chemotherapy or radiation therapy prior to the first surgery were excluded.

METHODS
In addition to the descriptive analysis of the

RESULTS
We  We can see in Figure 1, the Kaplan-Meier curve that illustrates the difference in survival between patients who had LND values greater than or equal to and less than 0.18.

DISCUSSION
Our study is characterized by the fact that the sample studied is composed exclusively of patients who had already undergone CE and yet experienced recurrence of the disease.Thus, we have a more homogeneous group for data analysis.
Although we are located in one of the most developed urban regions in the country, we often receive patients referred from different States.Therefore, we found results consistent with the Brazilian literature, especially regarding the demographic profile of patients 2 .
The unfavorable prognosis for patients with more Ramos Prognostic analysis of lymph node ratio of patients with disease recurrence previously submitted to cervical dissection surgery for head and neck cancer advanced stages such as III and IV has been described in the literature for some years 20,21 .the standardization of both the surgical technique and the anatomopathological evaluation.We showed with statistical significance that patients with affected tumor surgical margins had a shorter survival than those who had free margins.
Regarding LND, there is still no consensus in the literature as to what would be the ideal cutoff density value that influences the survival of individuals.
Prabhu et al. 25 evaluated patients with oral cavity and larynx SCC, and showed that lymph node density above 0.2 implied in decreased survival; in addition, it was calculated that with each 1% increase in the LND value, the risk of disease recurrence and death increased 1.02 times.Recently Talmi et al. 26 concluded that the lymph node density reported in the world literature that has an influence on survival ranged from 0.02 to 0.2 with an average of 0.09 26,27 .
The total value of the resected lymph nodes during dissection is extremely important in order to be able to have confidence from the perspective of surgical oncology.Some studies have used the total value of resected lymph nodes to study whether this parameter is an independent prognostic variable 28 .A criticism regarding the use of isolated lymph node density as an independent prognostic variable is precisely due to the fact that it is a simple numerical relationship.Therefore, we must also have access to the total number of lymph nodes resected during cervical dissection so that the lymph node density value can be valid.In our study, we had a considerably high number of lymph nodes resected by dissections (average of 50.4) most likely due to the greater number of radical than selective dissection, since we evaluated cases of greater severity.
Several authors have tried to evaluate the ideal number of lymph nodes resected in an EC in order to consider a reliable staging 29,30 .A recent systematic review found between 11 to 25 lymph nodes resected with an average of 18, so that the higher the number, the greater the survival of patients 28 .Divi et al. 7 ,after a large study involving an American database, also concluded that the minimum number of lymph nodes resected for adequate neck dissection is 18, and patients with a lower number of lymph nodes resected had a higher risk of death.In a recent publication, UICC considers the minimum number of 16 lymph nodes 31 .Regarding patients N2a and N2b, there was no statistical significant difference.We can therefore infer that the laterality factor may have had an influence in this case, since the main characteristic of the N2c is neck with counter or bilaterality metastases.
According to Ferlito et al. 22 , the presence of the contralateral lymph node, whether accompanied by ipsilateral cervical involvement or not, was shown to be an influencing factor in decreasing the survival of these individuals.
Still discussing the parameters related to the tumor, we identified with statistical significance that extracapsular extravasation had an influence on the survival of individuals.This finding was in agreement with what the literature has currently presented, a fact that contributed to the incorporation of this parameter in the new TNM staging system 8th edition of the UICC 23 .
Another widely used oncology parameter is the presence of margins that are affected or not after resection of the primary lesion 24 .Our study had a methodological advantage, i.e. it was carried out entirely with a sample of patients treated in the same service, with the same team of surgeons and pathologists, which, in a way, generates greater reliability due to Rev Col Bras Cir 49:e20223178 Ramos Prognostic analysis of lymph node ratio of patients with disease recurrence previously submitted to cervical dissection surgery for head and neck cancer Some studies argue that the LND may suggest a better survival forecast than the actual TNM classification, while others suggest that this variable, in some cases, can be used as a tool when indicating an adjuvant therapy such as chemo or radiotherapy 30,[32][33][34] .
In our study, we found a considerably high number of both resected and affected lymph nodes, and also lymph node density was higher than the average found in the literature 26 .This result is probably justified by the fact that the sample of patients evaluated in our study was composed exclusively of relapsed patients.
We believe that the simple application of TNM staging to define clinical and/or surgical procedures in patients with head and neck SCC may be insufficient.As we demonstrated in this study, there are several variables that should not be ignored for a complete assessment of each case.Intrinsic characteristics of individuals and anatomical specimens that are not included in the UICC TNM staging can and should be considered to minimize the indication of excessively morbid or even insufficient therapies from the standpoint of head and neck oncology.

CONCLUSION
We conclude that the lymph node density of recurrent patients previously submitted to cervical dissection surgery due to head and neck SCC had an influence on the individuals' survival, so that higher values of lymph node density are related to lower survival.In addition, both the total number of lymph nodes surgically resected and the absolute number of lymph nodes affected by the neoplasm had also an influence on the prognosis.The intrinsic characteristics of the surgical specimen, such as the size of the primary tumor, the N staging, the quality of the margins and the presence of extracapsular extravasation, also proved to be important variables for a more accurate post-surgical staging, since, in our study, all these parameters showed an influence on survival with statistical significance.

This is a longitudinal
retrospective study carried out by reviewing the medical records of patients at the Head and Neck Surgery outpatient clinic of an university hospital who underwent cervical dissection due to SCC of the oral cavity, larynx or pharynx between 2006 and 2019 and experienced recurrence of the disease.

Figure 1 .
Figure 1.Cox regression to assess factors associated with death (results that were statistically significant).

Table 1 -
Cox regression to assess factors associated with death (results that were statistically significant).
Note: Bold numbers represent results that were statistically significant.Abbreviations: CI: confidence interval; N: staging; RR: relative risk; T: staging.
RamosPrognostic analysis of lymph node ratio of patients with disease recurrence previously submitted to cervical dissection surgery for head and neck cancer Lin C-S, Yang C-Y, Lin C-K, Chen Y-W.Lymph node density as a prognostic predictor in patients with betel nut-related oral squamous cell carcinoma.Clin Oral Investig.2018;22(3):1513-21.doi: 10.1007/s00784-017-2247-3. 16.Reinisch S, Kruse A, Bredell M, Lübbers H-T, Gander T, Lanzer M. Is Lymph-node ratio a superior predictor than lymph node status for recurrencefree and overall survival in patients with head and neck squamous cell carcinoma?Ann Surg Oncol.Patel SG, Amit M, Yen TC, et al.Lymph node density in oral cavity cancer: results of the International Consortium for Outcomes Research.Br J Cancer.2013;109(8):2087-95. doi: 10.1038/bjc.2013.570.19.Roberts JT, Colevas AD, Hara W, Holsinger FC, Oakley-Girvan I, Divi V. Number of Positive Nodes Is Superior to the Lymph Node Ratio and American Joint