Factors affecting lymph node yield and density in neck dissection

Abstract

Background

Studies suggest that neck dissections with a minimum of 16–18 yielded nodes are associated with better overall survival compared to neck dissections with lower yields.

Aims

We aimed to identify factors affecting the lymph node yield and density in patients with oral cavity cancer undergoing elective neck dissection levels 1–3.

Materials and methods

Using prospectively registered data, we conducted a population-based cohort study on all patients surgically treated for oral cavity cancer including levels 1–3 neck dissection at our institution from 2018 to 2022. Uni and multivariate analyses were performed to identify factors associated with lymph node yields.

Results

In total, 221 patients were included. The mean lymph nodes yield and density were 19 (95%CI 18–20) and 0.12 (95%CI 0.09–0.16), respectively. In multivariate analysis, increasing body weight (p = .034) was positively and previous radiotherapy (p = .006) were negatively correlated with the number of yielded lymph nodes. Lymph node density was positively correlated with body weight (p = .011) and body mass index (p = .032) in univariate analysis.

Conclusions and significance

Increasing body weight was positively and previous radiotherapy was negatively correlated to lymph node yield. These factors should be taken into consideration when interpreting the lymph node yield as an indicator of neck dissection quality.

Chinese Abstract

背景

研究表明, 与出淋巴结数量较低的颈部清扫术相比, 出淋巴结数量至少为 16-18 个的颈部清扫术具有更好的总体生存率。

目的

我们旨在确定影响接受选择性 1-3 级颈部清扫术的口腔癌患者淋巴结数量和密度的因素。

材料和方法

我们使用前瞻注册数据, 对 2018 年至 2022 年期间在我院接受口腔癌手术治疗(包括 1-3 级颈部清扫术)的所有患者进行了一项基于人群的队列研究。进行了单变量和多变量分析以确定与出淋巴结数量相关的因素。

结果

共纳入 221 名患者。平均出淋巴结数量和密度分别为 19(95%CI 18-20)和 0.12(95%CI 0.09-0.16)。在多变量分析中, 体重增加(p = .034)与出淋巴结数量呈正相关, 而先前的放疗(p = .006)与出淋巴结数量呈负相关。在单变量分析中, 淋巴结密度与体重(p=.011)和体重指数(p=.032)呈正相关。

结论和意义

体重增加与出淋巴结数量呈正相关, 而先前的放疗与出淋巴结数量呈负相关。在将出淋巴结数量看作颈部清扫质量的指标时, 应考虑这些因素。

Keywords:

• Lymph node yield
• neck dissection
• metastasis
• cancer
• oral cavity
• malignancy

Introduction

Surgical resection is first choice for the treatment of oral cavity cancer [1]. In addition to resection of the tumour, ipsilateral elective neck dissection levels 1–3 is recommended, also in cases without clinical and radiological lymphadenopathy [2]. As an alternative to neck dissection, sentinel node biopsy may be performed in selected cases with T1-2N0 tumours [1]. Adjuvant, postoperative (chemo-)radiotherapy is standard care in cases with advanced tumours in Denmark [1].

Recent studies suggest that neck dissections with a minimum of 16–18 yielded nodes are associated with better overall survival compared to neck dissections with lower yields [3–9]. However, this threshold remains debatable. Irrespective of the threshold, the lymph node yield has become an important quality indicator for neck dissections. Together with lymph node density, the lymph node yield is used as prognostic factor for surgically treated patients [10]. In a number of other tumour sites, including HPV-related oropharyngeal cancers, the number of yielded lymph nodes with malignancy influences correct tumour staging [10,11].

For tumour sites outside the head and neck, the lymph node yield has shown to be prone to limitations. Factors, such as patient age and body weight, tumour size, stage and localisation, and previous radiotherapy have been found to influence the number of yielded lymph nodes [12–15]. However, no studies have been conducted aiming to analyse potential factors influencing the lymph node yield in neck dissections. Unawareness of such factors may lead to incorrect conclusions as to the minimum number of yielded notes associated with favourable outcome in general and the sufficiency/quality of the performed neck dissection for the individual patient.

Given the importance of knowledge on the minimum number of yielded lymph nodes to assess favourable quality of neck dissections, this study aimed to describe variables and factors that may affect the lymph node yield and lymph node density in patients with oral cavity cancer undergoing elective neck dissection levels 1–3.

Based on empiric clinical experience, we hypothesised that body weight was positively correlated and previous neck radiotherapy was negatively correlated with the number of yielded lymph nodes.

Materials and methods

Study population, setting, and data source

Using a prospectively recorded REDCap database including all patients surgically treated for oral cavity cancer at the Department of Otorhinolaryngology, Head and Neck Surgery, Aarhus University Hospital, in the five years period 2018–2022, we identified those undergoing neck dissection levels 1–3. Hence, patients treated with reduced or extended neck dissection (levels 4–5) were excluded. None of the patients had undergone previous lymph node removal in the area of neck dissection. Only lymph node yields from ipsilateral neck dissections were included (in cases with bilateral neck dissection, the contralateral lymph node yield was disregarded).

The REDCap database is in accordance with the ethical standards of our institution and with the Helsinki declaration and was approved by the Danish Data Protection Agency (#1-16-02-795-17). The Central Denmark Region Committees on Health Research Ethics has confirmed that no ethical approval is required.

The following data were identified: the total number of lymph nodes registered in the excised specimen, the number of nodes with metastasis, age, sex, body weight and height, previous radiotherapy to the neck, tobacco smoking, alcohol abuse (defined as >7/14 units per week for a minimum of one year for females/males, respectively), surgeon, pathologist, tumour site, and TNM stage.

Surgery

Throughout the study period, all surgeries were performed by the same four experienced oral cavity cancer surgeons. The surgical technique did not change during the study period. Neck dissection levels 1–3 were performed with the following boundaries; laterally: lateral border of the sternocleidomastoid muscle; medially: neck midline (level 1) and the lateral border of the sternohyoid muscle (level 3); superiorly: the body of the mandible, the mylohyoid muscle, and the digastric muscle (the submandibular gland was removed); inferiorly: the omohyoid muscle; posteriorly: the deep fascia of the neck; anteriorly: the platysma.

Histological technique

The evaluation of the surgical specimen followed local guidelines in accordance with national (Danish Head and Neck cancer Study Group) guidelines. All identified lymph nodes, with an intended minimum of 10 lymph nodes, were embedded in paraffin for subsequent microscopy. The number of lymph nodes in each cassette/paraffin block was carefully recorded. If the individual regions were properly marked by the surgeon, the number of lymph nodes was recorded for each individual anatomical level. Lymph nodes with a thickness of > 3 mm were dissected through the hilus, otherwise embedded undivided (in toto). If less than 10 lymph nodes were identified macro- or microscopically, the investigating pathologist could decide to investigate additional representative tissue to increase the likelihood of identifying small lymph nodes. The macroscopic procedure was performed by doctors of all training levels from residents (n = 15) to highly experienced consultants (n = 7). Subsequent microscopy was either performed or supervised by an experienced consultant before signing out.

Statistical analyses

Statistical analysis was performed using Stata version 15.1 IC (StataCorp LP, College Station, TX). All quantitative data are given as means (95%CI). Univariate analyses were performed separately for both lymph node yield and lymph node density. Logistic regression was used for categorical variables and linear regression was used for continuous variables. Subsequent multivariate analysis was performed for lymph node yield using statistically significant or nearly significant (p < 0.10) variables. Lymph node density was calculated by dividing the number of positive lymph nodes (for N+) with the total lymph node count. Students t-test were used for comparison of variables. A p value of .05 or less signified statistical significance.

Results

In total, 221 patients were included. Demographic and clinicopathological data are illustrated in Table 1.

Table 1. Clinical and pathological data from 221 patients surgically treated for oral cavity cancer including neck dissection levels 1–3.

Variables
Age (years), mean (95%CI)	68 (67 to 70)
Sex, No. (%)
Male	136 (62%)
Female	85 (38%)
Body weight (kg), mean (95%CI)	76 (73–78)
Radiotherapy, No. (%)
Yes	24 (11%)
No	197 (89%)
Smoking history, No. (%)
Never	30 (15%)
Previous	53 (26%)
Current	121 (59%)
No. pack-year, mean (95%CI)	30 (27–33)
Alcohol abuse, No. (%)
Yes	79 (47%)
No	89 (53%)
Surgeon, number of patients
#1	25
#2	46
#3	71
#4	79
T stage, No. (%)
T1	115 (52%)
T2	47 (21%)
T3	24 (11%)
T4	35 (16%)
N stage
N0	163 (74%)
N1	26 (12%)
N2a	0 (0%)
N2b	19 (9%)
N2c	2 (1%)
N3	10 (5%)
M0, no. (%)	221 (100%)
Lymph node yield, mean (95%CI)	19.2 (18.0 to 20.4)
Lymph node density (positive/counted), mean (95%CI)	0.12 (0.09 to 0.16)

Lymph node yield

Univariate analysis

The results of the univariate analysis for lymph node yields are illustrated in Table 2. A mean number of 19.2 (95%CI 18.0–20.4) lymph nodes were yielded in each patient. Patients with a history of radiotherapy to the neck had significantly lower lymph node yields (mean 15.0, 95%CI 11.7–18.2) compared to non-irradiated patients (mean 19.7, 95%CI 18.4–21.0) (p = .016, Students t-test). The number of yielded nodes was surgeon dependent, with surgeon 3 removing significantly more lymph nodes (mean 22.0) than surgeon 1 (mean 14.4) and surgeon 4 (mean 17.5), and surgeon 2 removing significantly more lymph nodes (mean 19.2) than surgeon 1. No statistically significant correlation between the number of yielded nodes and body weight was found (p = .063), though there was a trend towards a positive correlation to increased body weight (coefficient: 0.067 extra lymph nodes per kg body weight). Comparing the experience of the pathologists (residents vs. consultants), no statistically significant correlation was found to the number of yielded nodes (p = .069), though there was a trend towards higher yields among consultant (mean lymph node yield: 19.9) compared to residents (mean lymph node yield: 17.5).

Table 2. Uni and multivariate analysis for lymph node yield.

Variables	Univariate analysis Mean coefficient (95%CI)	p	Multivariate analysis Mean coefficient (95%CI)	p
Patient related
Age (per year)	0.01 (−0.10 to 0.12)	.854	–
Sex (male/female)	0.05 (−2.43 to 2.54)	.967	–
Body weight (per kg)	0.067 (−0.004 to 0.137)	.063	0.116 (0.009 to 0.223)	.034
Body Mass Index (per BMI increase)	0.18 (−0.04 to 0.41)	.102	–
Tobacco smoking history (yes/no)	0.26 (−2.88 to 3.40)	.872	–
No. pack-year (per pack-year)	0.01 (−0.5 to 0.07)	.726	–
Alcohol abuse history (yes/no)	2.39 (−0.42 to 5.19)	.095	1.42 (−2.42 to 5.28)	.463
Tumour related
T stage	−0.01 (−1.09 to 1.07)	.989	–
N stage	−0.09 (−0.90 to 0.73)	.838	–
No. positive nodes	−0.04 (−1.08 to 1.01)	.943	–
Procedure related
Surgeon 1	Reference	–	–
Surgeon 2	5.63 (1.15 to 10.11)	.014	3.32 (−3.53 to 10.17)	.339
Surgeon 3	8.39 (4.18 to 12.59)	<.001	8.34 (1.60 to 14.92)	.014
Surgeon 4	3.36 (−0.79 to 7.52)	.112	2.84 (−3.71 to 9.38)	.393
Miscellaneous
Radiotherapy (yes/no)	−4.74 (0.91 to 8.58)	.016	−7.73 (2.24 to 13.22)	.006
Pathologist (residents vs. consultants)	−2.40 (−4.99 to 0.19)	.069	−2.71 (−6.65 to 1.22)	.175

Multivariate analysis

In a subsequent multivariate analysis including significant (previous radiotherapy and surgeon) and near-significant variables (body weight, history of alcohol abuse, and pathologist), body weight (p = .034), previous radiotherapy (p = .006), and surgeon were significantly associated with lymph node yield (Table 2).

Lymph node density

The results of the univariate analysis for lymph node density are shown in Table 3. The mean lymph node density was 0.12 (95%CI 0.09–0.16). Lymph node density was positively correlated with body weight (p = .011, coefficient: 0.003) and body mass index (p = .034, coefficient: 0.008).

Table 3. Univariate Analysis for lymph node density.

Variables	Mean coefficient (95%CI)	p
Patient related
Age (per year)	0.0002 (−0.0028 to 0.0033)	.885
Sex (male/female)	0.04 (−0.03 to 0.11)	.254
Body weight (per kg)	0.003 (0.001 to 0.005)	.011
Body mass index (per BMI increase)	0.008 (0.0007 to 0.016)	.032
Tobacco smoking history (yes/no)	−0.01 (−0.06 to 0.04)	.679
No. pack-year (per pack year)	−0.0002 (−0.0013 to 0.0009)	.704
Alcohol abuse history (yes/no)	−0.03 (−0.07 to 0.01)	.165
Tumour related
T stage	0.01 (−0.02 to 0.05)	.351
N stage	0.023 (0.004 to 0.041)	.017
Miscellaneous
Radiotherapy (yes/no)	0.04 (−0.15 to 0.08)	.503

Discussion

We investigated potential factors and variables affecting the yield of lymph nodes and lymph node density for patients with oral cavity cancer undergoing neck dissection levels 1–3. In a multivariate analysis, three factors were found to have significant impact on lymph node yield: (1) increased body weight was positively correlated with the number of yielded lymph nodes, (2) previous radiotherapy to the neck was negatively correlated with the number of yielded lymph nodes, and (3) the operating surgeon. Increased body weight and body mass index was positively correlated with lymph node density.

The literature strongly suggests that higher lymph node yields for neck dissections are associated with improved long-term outcome [10] and even overall survival [3,8,16], with a threshold of 16–18 yielded nodes [3–9]. These studies are, however, very heterogeneous, as some studies investigated solely oral cavity cancer [3,4,6,9] or larynx cancers [5] while other studies included different head and neck cancers [7,8]. Furthermore, the dissected levels ranged from 1-3 ± 4 to 2-4 ± 5 [3,5,6] and some studies fail to provide this information [4,7–9]. Finally, some studies included all N stages while others included only pN0. In contrast to previous publications, we studied a homogenous population of patients with oral cavity cancers undergoing neck dissections levels 1–3 only. The mean number of extracted nodes was lower in this study (mean: 19) compared to the majority of previous studies investigating lymph node yields (mean range: 19–31). This difference is likely associated with the lower number of dissected levels in our study (levels 1–3) compared to previous studies (levels 1–3 ± 4 or 2–4 ± 5). Irrespective of the threshold for the number of yielded nodes associated with favourable outcome, the lymph node yield may serve as an objective quality control for institutions, individual surgeons, and (to some extent) for pathologists examining the specimen.

To the best of our knowledge, no previous studies have focused on factors affecting the number of yielded lymph nodes in neck dissections. In multivariate analysis, we found body weight, previous radiotherapy, and the operating surgeon to be statistically significant factors. In this study, an increasing body weight was positively associated with number of yielded lymph nodes. Only one previous study has investigated the correlation between body weight and lymph node yields in colorectal surgery [14]. Contrasting our results, Mekenkamp et al. reported lower lymph node yields in patients with overweight (defined as body mass index >25) compared to patients with normal and underweight [14]. More studies on this potential factor for lymph node yield is needed before solid conclusions can be drawn. While previous radiotherapy has been shown to lower the number of yielded nodes in multiple studies on colorectal and breast surgery [12–14,17], only a limited number of studies have focused on the operating surgeon as a factor for the lymph node yield [15,18]. These studies found no significant association. However, the operating techniques were found significantly correlated to the number of yielded lymph nodes, which may be a surrogate for the operating surgeon [13,14,17,18]. In this study, all surgeons performed the neck dissection by the same operating principals. In addition to body weight, radiotherapy, and operating surgeon, resident pathologists identified fewer lymph nodes compared to consultant pathologists (mean difference in identified lymph nodes: 2.4). These results were, however, not statistically significant (p = .069). In line with the present results, previous studies comparing the experience of the pathologist and pathologist assistant, found that the number of identified lymph node was increased with experience [15,18]. As such, if the lymph node yield is used as a prognostic factor, as suggested in some studies, body weight, previous radiation therapy, and to some extend the examining pathologist should be considered.

While the clinical significance of previous radiotherapy (mean difference in yielded lymph nodes: 8) and operation surgeon (maximum mean difference in yielded lymph nodes: 8) may be important, the impact of body weight on lymph node yield seems less, as an increase of 30 kg leads to a mean increase of 3–4 nodes (positive correlation of 0.116 lymph nodes per extra kg of body weight). Despite the lack of clinical significance, this may be of academic interest and importance for lymph node data comparisons and interpretations.

In multiple studies concerning head and neck cancers in general, high lymph node density has been shown to be associated with poorer prognosis [19,20]. The cutoff for high vs. low lymph node density remains unsettled, ranging from 0.01 to 0.20. In this study, the mean lymph node density was 0.12 (95%CI 0.09–0.16). The prognostic significance of the lymph node density is different from the lymph node yield. Instead of being a modifiable treatment factor, lymph node density is more representative for the extent of the disease. While knowledge on the association between lymph node density and prognosis is accumulating, the clinical significance of this value is unclarified. To our knowledge, no studies have investigated potential influencing factors for lymph node density. In this study, increasing body weight and body mass index was associated with a higher lymph node density.

This study is limited by the number of patients (n = 221), as this may be insufficient to detect weaker factors associated with lymph node yields. In contrast to previous studies, we included patients undergoing neck dissection levels 1–3 only. Hence, our results apply for this specific extent of surgery. As such, we find our homogenous group of patients a major strength, as more heterogeneous groups of patients undergoing different extents of neck dissections prevent solid conclusions on significant factors for lymph node yield as well as the cut off for high quality surgery.

In conclusion, we found that increased body weight was positively and previous radiotherapy was negatively correlated to the number of yielded lymph nodes in neck dissection levels 1–3. Increased body weight and body mass index was positively correlated to lymph node density. These factors are important to bear in mind when using lymph node yield as measure of surgical quality and lymph node density as prognostic marker.

Disclosure statement

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Pelle Hanberg and Tejs Ehlers Klug. The first draft of the manuscript was written by Pelle Hanberg and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

The authors have no relevant financial or non-financial interests to disclose. No funding was received for conducting this study.