Lymph Node Yield and Ratio during Surgery for Advanced Laryngeal Carcinoma

Abstract

Lymph node metastasis represents one of the most important prognostic factors in patients with head and neck squamous cell carcinomas (HNSCC). Lymph node yield (LNY) is the term used to indicate the total number of dissected lymph nodes following neck dissection, while lymph node ratio (LNR) is the proportion of metastatic lymph nodes to the total number of removed lymph nodes following neck dissection. This ratio serves to determine both the extent of cancer lymphatic spread and the effectiveness of its clearance. Calculating LNY and LNR following neck dissection holds particular significance when dealing with advanced laryngeal cancer. These values are supposed to have a direct impact on both prognosis and oncological outcomes, warranting their inclusion in the staging of such patients. Wide variations were observed in both LNY and LNR, which were mainly dependent not only on the tumor burden but also on surgical and pathological skills. Therefore, standardization is required in the pathological processing as well as surgical techniques of neck dissections to minimize these variations. Further studies are needed to validate these observations and to guide their inclusion in pathological TNM classification.

1. Introduction

1.1 The anatomy and morphology of cervical lymph nodes

The neck is characterized by the presence of a rich plexus of lymph nodes and channels. In the 1930s, the Memorial Sloan-Kettering Cancer Center designed a classification system of cervical lymph nodes groups into various anatomic levels. This system, initially used for labeling neck dissection specimens, since then gained a worldwide acceptance. A large study in the same center adopting this classification system is considered a landmark study describing the pattern of lymphatic metastasis of different head and neck primaries and the lymph node groups at high risk of metastasis for each primary [1].

In 1991, the American Head and Neck Society subsequently adopted that system [2], and then the classification system was revised in 2002 [3]. This scheme is now widely implemented as a “common language” between clinicians involved in the care of head and neck cancer patients to describe and report lymphatic metastasis status [4]. In this classification, the neck is divided into six levels (Figure 1 and Table 1).

Figure 1.

Lymph node levels and sublevels of the neck (adapted from Givi and Andersen [4]).

Border
Level	Superior	Inferior	Anterior (medial)	Posterior (lateral)
IA	Symphysis of mandible	Body of hyoid	Anterior belly of contralateral digastric muscle	Anterior belly of ipsilateral digastric muscle
IB	Body of mandible	Posterior belly of digastric muscle	Anterior belly of digastric muscle	Stylohyoid muscle
IIA	Skull base	Horizontal plane defined by the inferior body of the hyoid bone	Stylohyoid muscle	Vertical plane defined by the spinal accessory nerve
IIB	Skull base	Horizontal plane defined by the inferior body of the hyoid bone	Vertical plane defined by the spinal accessory nerve	Posterior border of the sternocleidomastoid muscle
III	Horizontal plane defined by the inferior body of the hyoid	Horizontal plane defined by the inferior border of the cricoid cartilage	Lateral border of the sternohyoid muscle	Posterior border of the sternocleidomastoid muscle
IV	Horizontal plane defined by the inferior border of the cricoid cartilage	Clavicle	Lateral border of the sternohyoid muscle	Posterior border of the sternocleidomastoid muscle
VA	Apex of the convergence of the sternocleidomastoid and trapezius muscle	Horizontal plane defined by the inferior border of the cricoid cartilage	Posterior border of the sternocleidomastoid muscle or sensory branches of cervical plexus	Anterior border of the trapezius muscle
VB	Horizontal plane defined by the inferior border of the cricoid cartilage	Clavicle	Posterior border of the Sternocleidomastoid muscle or sensory branches of cervical plexus	Anterior border of the trapezius muscle
VI	Hyoid bone	Suprasternal notch	Common carotid artery	Common carotid artery
VII	Suprasternal notch	Innominate artery	Common carotid artery	Common carotid artery

Table 1.

Anatomic boundaries of the lymph node levels of the neck [4].

Patterns of lymphatic flow and region-specific lymphatic drainage:

There are approximately 150 lymph nodes on either side of the neck. The normal range in size is from 3 mm to 3 cm, but most nodes are less than a centimeter. Within level II, the largest node is often called the jugulodigastric node and is situated within the triangle formed by the internal jugular vein, facial vein, and posterior belly of the digastric muscle. It is important because it receives lymph from a wide area, which includes the submandibular region, the oropharynx, palatine tonsils, and oral cavity. The jugulo-omohyoid nodes are situated at the junction between the middle and lower cervical group (low level III/high level IV) where the omohyoid muscle crosses the internal jugular vein and receives lymph from a wide area, which includes the anterior floor of mouth, oropharynx, and larynx.

In the neck lymphatic flow follows an orderly and predictable path. Through studying metastasis pattern of squamous-cell carcinoma of the larynx and hypopharynx prior to surgical therapy. In 1964, Fisch [5] studied the patterns of cervical lymphatic flow by injecting oil-based contrast media into the post-auricular lymphatics followed by lymphography, the flow of contrast was from post-auricular lymphatics to nodes just below and behind the angle of the mandible (highest Level IIB or VA nodes) called the junctional nodes then contrast flowed to nodes along the spinal accessory nerve posteriorly and along the jugular nodes anteriorly. Contrast in the posterior triangle then flowed to transverse cervical nodes (level VB) and then medially to low jugular nodes (level IV). The contrast from spinal accessory nodes flowed to jugular nodes anteriorly but never moved in the opposite direction. There was also no contralateral or retrograde lymphatic flow. This important observation is the basis of the notion that metastases to level V nodes are extremely rare and this means that junctional nodes are not involved in the majority of cancer (Figure 2) [5].

Figure 2.

Patterns of lymphatic flow based on Fisch experiments (adapted from Givi and Andersen [4]).

It is important to realize that contralateral neck spread may occur early in those tumors situated in or near the midline.

A landmark study by Lindberg [6] reviewed 2044 patients with HNSCC of oral cavity, oropharynx, nasopharynx, supraglottis, and hypopharynx and published the topographical distribution of clinically evident cervical metastases was set out. Byers et al. [7], from MD Anderson Cancer Center, identified these distinct patterns of spread to the neck based on the primary site relying on patterns of nodal metastasis among 428 patients with HNSCC.

The laryngeal lymphatic drainage is separated into upper and lower systems based on its embryological origins, with a division that occurs at the level of the true vocal cord. The supraglottis drains through vessels that accompany the superior laryngeal pedicle via the thyroid membrane to reach levels II/III, with a greater tendency for bilateral nodal drainage. The lower system drains directly into levels III/IV through vessels that pass through or behind the cricothyroid membrane and also into the prelaryngeal, pretracheal, or paratracheal nodes (level VI), before reaching the deep cervical nodes. Because the vocal cords are relatively avascular, they have a sparse lymphatic drainage, hence lymph node metastases from small carcinomas at this site are uncommon [6, 7].

1.2 Cervical lymph node metastasis in advanced laryngeal carcinoma

Laryngeal cancer constitutes about one-third of all head and neck cancers [8]. Its incidence continues to increase in South-East Asia, Africa, and the Western Pacific, while the incidence is declining in Western countries. Heavy and prolonged smoking and alcohol ingestion are the main risk factors for laryngeal cancer. Other risk factors include laryngopharyngeal reflux disease, occupational exposure to solvents, sulfuric acid, asbestos, and human papillomavirus (HPV) infection [9].

Cervical lymph node metastases are one of the most adverse prognostic factors in squamous cell carcinoma (SCC) of the larynx and are always associated with poor oncological outcomes. Despite advances in diagnostic imaging, currently, there are no imaging modalities capable of accurately detecting occult disease in the clinically negative neck (cN0). Neck dissection remains the gold standard for nodal staging in cN0 patients with high-risk HNSCC if the risk of neck metastasis is more than 15–20%. The accuracy of surgical staging in the cN0 neck depends on the extent of neck dissection as well as on the scrutiny of histopathologic examination for detecting occult metastatic disease. Therefore, the probability of identifying metastasis in lymph nodes relies on the skills of both surgeons and pathologists [10].

In the eighth edition of the pathological pTNM classification, the pN classification of neck dissection in laryngeal carcinomas is based on the size and laterality, presence of single or multiple metastatic lymph nodes, and presence of extracapsular spread (ECS) in metastatic lymph nodes [11].

However, several studies have highlighted some serious limitations in pN classification. First, it does not take into consideration the number of metastatic lymph nodes in the neck. In a study on 8351 hypopharyngeal and laryngeal cancer patients, the overall survival is inversely proportionate to the number of metastatic lymph nodes in neck dissection specimens, while the node size or contralateral lymph node involvement did not have a statistically significant impact on survival. Therefore, the authors recommended the incorporation of quantitative metastatic nodal burden in nodal classification for laryngeal and hypopharyngeal cancers to improve its prognostic value and better identify the need for adjuvant treatment [11]. Second, this pN classification does not assess the number of removed lymph nodes in the neck dissection specimen. Many studies have proved that a higher number of dissected lymph nodes in the neck dissection specimen was associated with improved survival in HNSCC patients [12, 13].

The accumulating evidence in support of the prognostic value of both the number of dissected lymph nodes and the number of metastatic lymph nodes in the neck dissection specimen has inspired many head and neck surgeons to further investigate their prognostic capacity, standardize their terminology, and discover their uses and limitations.

2. Aim of this chapter

This is a review chapter to illustrate the prognostic importance of lymph node yield and ratio during surgery for advanced laryngeal carcinoma as well as their uses and limitations.

3. Lymph node yield (LNY)

3.1 Definition

LNY refers to the total number of removed lymph nodes following neck dissections [14]. LNY was first described by Agrama et al. in modified radical neck dissection (MRND) for HNSCC, showing variations in LNY values [15].

3.2 Prognostic value

There has been a growing interest in LNY among head and neck surgeons in the last decades. Ebrahimi et al. [16] were the first to try to study the prognostic value of LNY in 225 patients undergoing elective neck dissection for oral SCC. This single institutional study concluded that nodal yield <18 was significantly associated with decreased overall survival, disease-specific survival, and disease-free survival. In a larger study cohort of 1567 cN0 oral SCC patients from nine international cancer centers, Ebrahimi et al. [17] confirmed the same finding, proving that LNY is a strong independent prognosticator for decreased survival and increased risk of locoregional recurrence. In a study of 4341 patients with pN0 oral SCC undergoing elective neck dissection, Lemieux et al. [18] found that greater LNY of more than 22 nodes was significantly associated with increased overall survival. Two studies in HNSCC patients, including node-positive patients of all primary sites, have shown that LNY ≥ 18 was associated with improved overall survival and reduced risk of locoregional failure [19, 20].

In laryngeal SCC patients, some studies found that LNY was not significantly correlated with the overall survival and disease-free survival. These studies had a retrospective study design with a small sample size [21, 22, 23]. In one of them, the neck dissection was done by different surgeons, and lymph node examination was performed by different histopathologists, making more bias [22]. Additional prospective studies with larger sample sizes are required to accurately define the minimum LNY and verify its prognostic capacity in patients with laryngeal SCC.

LNY is an objective tool for surgical adequacy of neck dissection as well as pathological processing of neck dissection specimens, particularly when standardization of the surgical techniques and pathological processing will be necessary to allow reproducibility and statistical comparison of similar patient groups [24]. Moreover, a review has shown the volume of neck dissection specimen is an indicator of surgical expertise that could be used to assess trainees’ progress and for quality maintenance in large head and neck centers [25].

3.3 Variations in LNY

The surgeon should dissect a significant number of lymph nodes from the neck levels as possible, to approach the average count of dissected lymph nodes as close to the average lymph node count as possible [25]. In a cadaveric study, there were an average of 20 lymph nodes in supraomohyoid neck dissection compared to an average of 30 in lateral neck dissection [26]. Similar LNY was retrieved in a retrospective review of 414 patients undergoing therapeutic neck dissection, obtaining mean LNY of 21.7 in supraomohyoid neck dissection compared to 27.1 in lateral neck dissection [27]. Preoperative CT-planned neck level volume estimates correlate with neck dissection specimen volume but did not correlate with LNY [28].

According to the 8th edition of the TNM classification, pN pathological classification requires a selective neck dissection specimen to include 10 or more lymph nodes, while a radical or modified radical neck dissection specimen should encompass 15 or more lymph nodes [11]. However, the minimum LNY in patients with laryngeal SCC was quite variable (35.9–12) with an average of 24 for selective level II–IV neck dissections [22, 24].

Norling et al. [29] have compared LNY values in cadaveric and clinical selective neck dissections (SND). Based on literature review, the minimum average LNY was 19.4 in clinical supraomohyoid SND (levels I–III) and 26.4 in clinical lateral SND (levels II–IV), while the lowest mean LNY was 8.8 in cadaveric supraomohyoid SND (levels I–III) and 10.4 LNs in cadaveric lateral SND (levels II–IV) [29]. Four clinical studies reported the mean nodal yield for levels I, II, III, IV, and V. Means for level I were 5.7, 5.27, and 4.0, for level II: 12.6, 11.2, 11.2, and 9.43, for level III: 8.49, 7.6, 7.6 and 7.2, for level IV: 8.7, 7.43, 7.3 and 6.9, and for level V: 9.7 and 9.02 [29, 30]. In a study of LNY in SND (levels II–IV) in 45 advanced laryngeal cancer patients, the mean LNY for level II was 9.1, for level III: 11.5, and for level IV: 6.2 with level III containing most lymph nodes. The mean LNY of SND (levels II–IV) was 47.7 [31].

Over the last decades, there have been wide variations in reported LNY values in many studies because some studies were conducted on patients with different tumor locations together with the lack of uniformity in the proper extent of neck dissection between different centers and surgeons, making it difficult to set the standards for LNY values in different neck dissection types. Moreover, the current literature has moved towards superselective neck dissection, adding more difficulty. For this reason, separating neck dissection specimens into the individual neck levels before being sent for the histopathological examination should be recommended in the future guidelines to establish standard LNY values in different neck levels and, therefore, to assess the adequacy of neck dissection [30, 32].

3.4 Factors influencing LNY

Many factors could affect the nodal yield in neck dissections for different head and neck cancers. (1) Patient and tumor factors: a univariate analysis of patient and tumor factors in oral SCC revealed that women, older people, BMI <25, small (T1, T2) tumors, absent positive lymph nodes, and absent perineural invasion were significantly associated with reduced LNY. However, the multivariate analysis of significant factors found that older age and BMI <25 are the most significant patient factors, while T classification and the presence of positive lymph nodes are the most significant tumor factors [33, 34]. In mucosal HNSCC, p16-positive tumors have yielded around 2.4 more lymph nodes than their p16-negative tumors. HPV status significantly affected LNY, particularly in oral SCC [30]. (2) Pathological factors: A newly developed pathology protocol with examination of residual fibrofatty tissue in neck dissection specimen has significantly increased LNY [34]. (3) Treatment factors include surgical factors or preoperative or postoperative radiation. Both standard surgical technique and surgical experience had a significant impact on nodal yield in neck dissections. The horizontal neck dissection using standard fascia unwrapping technique was associated with a significantly superior nodal yield in levels I, II, III, and IV, and in overall nodal yield than the vertical neck dissection in the control group [24]. Level-by-level neck dissection resulted in a statistically significant higher LNY than en bloc or monoblock neck dissection in both selective neck dissection and individual neck levels [32]. Surgical experience influences not only LNY in neck dissections but also oncological outcomes with more recurrences occurring with less-experienced surgeons [25]. Both preoperative radiotherapy and chemoradiotherapy over the head and neck region reduce the nodal yield significantly in neck dissections, compared with patients who did not receive radiotherapy or who received postoperative radiotherapy [21, 27, 34, 35, 36, 37].

4. Lymph node ratio (LNR)

4.1 Definition

Lymph node ratio (LNR) or lymph node density (LND) is defined as the ratio of the metastatic lymph nodes to the total number of dissected lymph nodes following neck dissection. This ratio determines the extent of cancer lymphatic spread and extent of its clearance. Both LNR and LND are being used interchangeably in the current literature [14]. For laryngeal and hypopharyngeal SCC, LNR ranges from 0.03 to 0.14 [38].

The standard histopathological examination of lymph nodes in neck dissection specimens starts with making a single, longitudinal section through the center of each lymph node followed by Hematoxylin and Eosin (H&E) staining and examination of the section under light microscopy for metastatic deposits. This standard technique is widely used [39]. Serial section H & E staining at 3–4 mm of the lymph node and cytokeratin immunohistochemical analysis demonstrated a higher detection rate of micrometastatic disease in pN0 specimens [40].

4.2 Prognostic value

In their extensive multi-institutional study involving 4254 patients with oral SCC, Patel et al. [30, 41] reported that higher LND was significantly associated with lower overall survival, disease-specific survival, disease-free survival, and higher rates of locoregional and distant metastases. Comparing a newly developed TNM staging based on LND with the standard TNM staging revealed that the new TNM staging was superior to the standard TNM staging in all survival parameters [41].

In laryngeal and hypopharyngeal SCC patients, a meta-analysis found that higher LNR values were significantly associated with shorter overall survival, disease-specific survival, and disease-free survival [38]. Several studies have reported similar results and proved a significant association between increased LNR and higher risk for locoregional and distant recurrences in patients with advanced laryngeal or hypopharyngeal SCC, which should be considered for adjuvant treatment. Therefore, LNR could be used for risk stratification of laryngeal SCC patients as well as adjuvant treatment planning and follow-up [42, 43, 44, 45, 46, 47].

Wang et al. [47] investigated the potential role of LNR in the staging of laryngeal SCC. They gathered data from the SEER database, encompassing 1963 patients, and supplemented it with an additional 27 patients from their own institution for validation. By determining optimal LNR cutoff values, the patients were categorized into three risk groups based on LNR values: ≤0.09, 0.09–0.20, and >0.20, which were significantly different in disease-specific survival and overall survival. Therefore, the authors recommended that incorporating LNR in N classification could enhance the staging process.

However, two studies found that LNR was not significantly correlated with the overall survival and disease-free survival in laryngeal SCC patients. These studies had a retrospective study design with a small sample size [21, 22]. In one of them, the neck dissection was done by different surgeons, and lymph node examination was performed by different histopathologists, making more bias [22].

4.3 Factors affecting LNR in neck dissections

Three main factors can potentially affect LNR and nodal staging as follows: (1) tumor factors (the extent of neck involvement): the number of metastatic lymph nodes in neck specimens directly influences LNR; (2) surgical factors (the extent of neck dissection): the total number of dissected lymph nodes in neck dissection specimens varies significantly in different neck dissection types, with modified radical neck dissection producing the largest number of LNs (around 34), followed by SND level II–V (around 23), SND level I–III (about 18), and SND II–IV (about 17). With the current trend towards superselective neck dissection, LNR is expected to vary significantly in more limited neck dissections [13]. Therefore, further studies are required to define the cutoff points for LNR in different types of neck dissection; (3) pathological factors (the accuracy of the histopathological examination): variations in harvesting higher number of lymph nodes from neck specimens by different pathologists as well as increased detection of lymph node micrometastases by serial sectioning, immunohistochemistry, and/or the use of molecular techniques were proved to be associated with changes in the value of LNR [13, 36, 48]. Therefore, LNR is a reflection not only of disease burden but also of surgical and pathological quality standards. This clearly highlights the need for standardized protocols in the processing of the neck dissection specimens as well as surgical practice [49].

4.4 Limitations

Some limitations might affect the value of the LNR. First, LNR does not include the prognostic information associated with the presence of metastatic lymph nodes with ECS. In a retrospective study on 1190 patients with HNSCC, the number of metastatic lymph nodes with ECS was significantly related to the disease-specific survival [50]. Second, for pN0 patients, the value of LNR regardless of the number of dissected lymph nodes is always 0%, leading to loss of information on the nodal yield in this group of patients. Many studies have proved that an increased lymph node yield in pN0 patients resulted in significant survival improvement [18, 51].

4.5 Weighted lymph node ratio (WLNR)

The weighted lymph node ratio (WLNR) is a newly developed equation designed to integrate predictive data related to the number of metastatic lymph nodes with ECS and LNY for pN0 patients to LNR. The calculation of WLNR is outlined in the following equation: WLNR = [((number of positive lymph nodes without ECS × 1.054) + (number of positive lymph nodes with ECS × 1.199) + 0.5)/(total number of dissected lymph nodes +0.5)] × 100 [52].

Using the WLNR value, HNSCC patients are categorized into four groups, which exhibit notable differences in 5-year disease-specific survival rates as we compare one category to the next. The groups are as follows: Category I (WLNR ≤ 3.4%); Category II (WLNR ranging from 3.5% to 7.4%); Category III (WLNR ranging from 7.5% to 15.4%); and Category IV (WLNR ≥ 15.5%) [52].

Compared with the TNM pN classification (pN0, pN1, pN2, pN3), the WLNR classification was more reliable in predicting disease-specific survival along with both regional and distant recurrence-free survival. This classification improves the prognostic accuracy of the eighth edition of the pTNM classification and serves as a valuable resource for assessing the postoperative staging of the neck dissections in HPV-negative HNSCC patients [52]. In a study of 197 HNSCC patients with regional recurrence treated with salvage neck dissection, WLNR had proved to provide a significant prognostic capacity for disease-specific survival [53].

5. Conclusions

The estimation of LNY and LNR following neck dissection holds significant importance, particularly in advanced laryngeal cancer because they have a direct impact on both the prognosis and the oncological outcomes of such patients. Therefore, incorporation of LNR in the nodal staging of advanced laryngeal cancer is needed, once its prognostic capacity is well studied. Wide variations in both LNY and LNR were mainly affected by tumor, surgical, and pathological factors. Therefore, standardized protocols are needed in the pathological processing and surgical techniques of neck dissections to minimize these variations. Some limitations were observed with the use of LNR, leading to the introduction of weighted LNR. More well-designed research with larger samples is required to verify the reliability of LNY and LNR and clearly define their uses and limitations in the future.

Acknowledgments

No dedicated funding was provided for this study by any external source, whether governmental, commercial, or non-profit.

Conflict of interest

The authors declare no conflict of interest.

Notes/thanks/other declarations

This study did not receive any dedicated funding from external organizations, whether they are commercial enterprises or non-profit sectors. The authors have stated that there are no conflicts of interest.

Acronyms and abbreviations

HNSCC	head and neck squamous cell carcinoma
LNY	lymph node yield
LNR	lymph node ratio
HPV	human papilloma virus
SCC	squamous cell carcinoma
cN0	clinically negative neck
MRND	modified radical neck dissection
ECS	extracapsular spread
pN0	pathologically negative neck
SND	selective neck dissection
RND	radical neck dissection
UICC	International Cancer Control
AJCC	American Joint Committee on Cancer
WLNR	weighted lymph node ratio