Head and Neck Lymphadenopathy in Oral Cancer

Abstract

Ranging from localised to generalised, infectious to neoplastic, autoimmune, or miscellaneous aetiology; lymphadenopathies have a wide array of clinical presentations. Assessment of the true pathobiology of lymphadenopathies is a challenging process specially cases with lymphadenopathy due to malignancies in the head and neck region. A multitude of masking signs and symptoms make it even more complicated. However, a correct diagnostic workflow facilitates easy evaluation of such lymphadenopathies. Although, the correct clinical examination may help to achieve correct diagnosis in some lymphadenopathy cases, some suspicious and unexplained lymphadenopathies warrant further investigations. This chapter clearly focuses on the clinical, diagnostic, and histopathologic spectrum of head and neck lymphadenopathies arising in oral cancer and stressing upon the pathways of lymphatic spread of malignancy along with a multitude of lymph node characteristics which play a key role in diagnosis.

1. Introduction

Oral Squamous Cell Carcinoma (OSCC) is the sixth most commonly diagnosed cancer among all cancer types [1, 2]. While smoking, drinking, and HPV infection are known risk factors, genetics also plays a significant influence in tumour development, progression, and patient’s response to therapy [1, 3].

Lymphatic capillaries, afferent lymphatic vessels, lymph nodes, efferent lymphatic vessels, and diverse lymphoid organs are only a few of the anatomical parts that make up the lymphatic system. Lymph nodes (LNs) are tiny bean-shaped structures that line lymphatic channels. They act as a filter, check lymphatic fluid/blood composition, drain extra tissue fluid and plasma protein leaks, absorb pathogens, boost immune response, and get rid of infection [4]. As OSCC develops, it frequently metastasizes to nearby cervical LNs. During variable clinical assessment, it has been observed that 30 to 50 percent of OSCC patients had metastatic LN [5]. For proliferation, invasiveness, and metastasis in solid tumours, ECM degradation and reconstruction in the stroma and adjacent tissues are essential. Matrix metalloproteinases (MMPs) and their regulators, which come from tumour cells and stromal cells such fibroblasts, macrophages, dendritic cells, and neutrophils, cause the ECM to remodel. Lymphatic metastasis involves the expression of multiple MMPs and the variables that are connected with them for metastasis and prognosis [5].

Cervical lymph node metastasis has always been a harbinger of poor prognosis, with node-positive status immediately upstaging disease to stage 3 or higher and halving 5-year survival rates [6]. It is widely acknowledged that cervical lymph node involvement affects prognosis for HNSCC, and even one positive lymph node can result in a 50% decrease in overall survival [7]. Additionally, having affected lymph nodes has significant short-term therapy effects. For long-term survival and recurrence-free survival in patients with OSCC, the number of lymph nodes involved, the anatomical levels of positive lymph nodes, the size of the metastases, the presence of microscopic or macroscopic extracapsular spread, and soft tissue deposits are all significant prognostic factors [8].

This chapter therefore intends to focus upon the key determinants to head and neck lymphadenopathy in oral cancer to upscale the current evidence for its usage in determining the best therapeutic overlay for OSCC patients.

2. What are lymph nodes and the lymphatic system?

The kidney-shaped organs known as lymph nodes are positioned in groups all throughout the body, mainly in the groin, armpits, neck, and centre of the chest and belly. Lymphatic canals link lymph nodes to one another. Through lymphatic channels, lymphatic fluid travels from all bodily tissues to neighbouring lymph nodes, which act as a kind of filter. The immune cells in the lymphatic system known as lymphocytes can proliferate when the immune system is engaged, such as with infections or cancer. This results in lymphadenopathy, which is the enlargement of one or more lymph nodes [9].

3. What is lymphadenopathy?

Lymphadenopathy refers to nodes that are abnormal in either size, consistency or number. The global incidence of patients reporting unexplained lymphadenopathy ranges between 75% of localised to 25% of generalised types. It may be classified as: (1) localised when lymph nodes of only one area is involved (55% are exclusive to Head and neck region); and (2) generalised if lymph nodes are enlarged in two or more noncontiguous areas [10].

4. Sentinel node

The earliest lymph node(s) to drain a primary tumour are called sentinel lymph nodes [11]. It is still debatable whether sentinel lymph node biopsy (SLNB) or elective neck dissection (END) should be used to stage patients with early OSCC (T1 and T2 N0 disease) [12]. In the event that a lymphogenic tumour spreads, the sentinel lymph nodes (SLNs), which must be located and removed, are more likely to contain metastases. If metastatic tumour deposits are discovered in the SLN, further treatment (surgery and/or radiotherapy) of the nodal basin should be performed because the SLN’s histological condition reflects that of the rest of the nodal basin [13].

There is rising evidence in the literature that supports obtaining more sections or employing immunohistochemistry to detect micro metastases can improve the diagnosis of nodal metastases. The sensitivity of metastasis identification is increased by combining various methods [8].

5. Tumour biology as related to metastasis

A variety of genotypic, phenotypic and microenvironmental factors conspire to define the metastatic potential of a tumour. Previously, it was believed that cancer cells entered the lymphatic system through pre-existing lymphatic capillaries close to the tumour (Figure 1a). Solid tumours can stimulate lymphangiogenesis, according to recent research on animal models (Figure 1b). In this situation, lymph node metastasis has been linked to intra-tumoral and peritumoral lymphangiogenesis. By binding to VEGFR3, a tyrosine kinase receptor expressed on the surface of lymphatic endothelial cells, VEGF-C/D released by the tumour has been demonstrated to play a significant role in lymphangiogenesis. The existence and biological function of lymphatics within experimental and human tumours have remained debatable despite mounting evidence indicating an active role of VEGF-C- or VEGF-D-induced tumour lymphangiogenesis in cancer spread to local lymph nodes. According to the lack of lymphatic uptake of tracers that were injected near experimental tumours, high interstitial pressure within tumours has been postulated to inhibit intra-tumoral lymphatic vessel formation and function [14].

Figure 1.

Model of tumour metastasis: (a) traditional model, and (b) active model [14].

6. Mechanism of lymphatic metastasis

The majority of research supported the idea that lymphangiogenesis generated by tumours and greater levels of lymphangiogenic growth factors are linked to increased rates of LN metastasis and a poor prognosis. PDGF-BB, IGF1 and -2, FGF2, HGF, angiopoietin-2, sphingosine-1-phosphate, adrenomedullin, and IL-7 are among the additional mediators that have been associated to the development of lymphangiogenesis in cancers and other disorders in addition to growth factors from the VEGF family. Further investigation is still needed to determine the relative importance of these factors in contrast to VEGFs for various cancer types. The VEGF-C, VEGF-D, VEGF-A, and HGF produced by the main tumour are picked up by peritumoral lymphatic capillaries and delivered to the SLNs via collecting lymphatics, where they operate directly on preexisting lymphatic vessels in a manner similar to inflammation-induced lymphangiogenesis (Figure 2A and B).

Figure 2.

An important contribution of tumour and LN lymphangiogenesis to cancer metastasis. (A) Normal lymphatic tissue drainage through lymphatic capillaries, collecting lymphatics, and LNs, (B) lymphangiogenic factors produced by premetastatic tumours, and (C) once metastatic tumour cells have spread to their draining LNs, they serve as a major source of lymphangiogenic factors which promote secondary metastasis, including organ metastasis [11].

The remodelling and SMC rearrangement of distant (post-SLN) lymphatic vessels and LNs, as well as secondary metastasis, such as organ metastasis, have recently been observed. Metastatic tumour cells represent a significant source of lymphangiogenic factors, such as VEGF-C, once they have spread to their draining LNs [11].

Cancer cells with characteristics similar to stem cells might also find a home in lymphatic endothelium (Figure 2C). Lymphatic endothelium may offer a protective milieu for long-term tumour cell survival, according to clinical observations of so-called “in-transit metastases,” or metastatic tumours that form in lymphatic arteries between the source tumour and the draining LN. Moreover, when the original tumour has been removed, tumour cells may persist in dormancy within draining LNs for a long time [11, 15].

7. Head and neck cancer metastatic spread and lymphatic drainage patterns

The major lymphatic pathway, the posterior pathway, the anterior lymphatic pathway, and the superficial-lateral pathway are the four functional drainage pathways for the cervical lymphatics [16]. After tumour excision, lymph node metastasis greatly raises the risk of systemic cancer spread and recurrence and reduces the effectiveness of treatment, especially when extranodal extension is evident [17, 18]. As a result, the accurate staging and diagnosis of nodal metastases play a crucial role in determining the prognosis and treatment of head and neck cancer. In the N0 neck, for example, sampling of the sentinel node can identify patients who actually require a neck dissection while sparing others who do not show signs of disease [19].

8. The pathophysiology of lymphatic metastasis by head-and-neck cancers

In order to continue invading the surrounding tissue during metastasis, cancer cells must first penetrate the basement membrane of the epithelium from where they originated. Tumour cells may potentially infiltrate and move through lymphatic channels after invading surrounding lymphatics and metastasis to lymph nodes [20]. The lymph fluid carries the tumour cells to the closest lymph node when they reach the lymphatic system. The afferent lymphatic vessels guide these cells into the subcapsular sinus, which is the region immediately below the lymph node capsule where lymphocytes and antigen-presenting cells circulate [21]. The initial site of metastasis may take place here, in this sinus [22]. Tumour cells may create new colonies farther along the nodal chain as the metastatic colony expands. As nodal metastases expand and invade, the nodal endothelium may also be damaged, leading to extracapsular tumour invasion [22]. The latter symptoms are indicative of an advanced stage of metastatic dissemination and, for the majority of human malignancies, a dismal prognosis. While hematogenous disease spread is less frequent, head and neck squamous cell carcinoma (HNSCC), which accounts for 80–90% of tumours developing in the UADT of the head and neck [23], has a significant propensity for regional lymphatic metastasis. It’s not quite obvious why lymphatic metastasis tends to be biased. According to one explanation, HNSCC prefers to produce early lymphatic metastases because its lymphatic system is so rich in compared to the rest of the body in the head and neck [24]. Metastatic tumour cells may enter lymphatic vessels more easily than into other nearby venous, arterial, or capillary vessels due to the absence of tight connections between lymphatic endothelial cells. Additionally, the lymph’s gentle, low shearing flow makes the environment in which a travelling tumour cell or cell cluster lives less harsh, which greatly boosts the spread’s effectiveness while lessening the difficulty of establishing new tumour-genic colonies [24]. Along with lymph node invasion, head and neck tumours may exhibit blood vessel invasion; however, this occurrence often results from extracapsular lymph node metastases that have subsequently invaded the vascular system. Of course, these findings are related to a more advanced condition [19, 25].

9. Skip metastases

Skip metastases are a discontinuous spread of cancer in which foci of involvement are interspersed among unaffected, adjacent regions. It majorly happens because of the rich lymphatic network of the majority of intraoral anatomic sites. Incidence of skip metastasis in OSCC to level IV and V bypassing levels I to II, ranges from 0.2 to 4.8% [26].

10. Occult nodal disease

Occult nodal disease represent metastatic deposits which are small enough to evade detection by clinical and radiographic methods and are found on microscopic analysis.

Such small tumour deposits require keen observation of all lymph nodes along with confirmation using specific IHC markers. In this reference, micro metastases are tumour deposits between 0.2–2 mm within lymph nodes whereas, Isolated Tumour Cells (ITCs) refer to single/small clusters of tumour cells ˂0.2 mm inside the lymph nodes [27]. It has been reported that micro metastasis occurs in 3–7% of nodes and 9–22% of patients with clinically N₀ necks and can be detected by molecular markers such as cytokeratin [28, 29]. Some strong predictors of occult nodes within the primary tumour may be desmoplasia with or without perineural infiltration, pT4a clinical stage and thickness of the tumour (≥4 mm). Tumour burden within the lymph nodes have always stood the test of time as a valuable prognostic factor [27].

11. Lymph node characteristics

11.1 Lymph node ratio

Recent research has looked at the lymph node ratio (LNR), sometimes also denoted as lymph node density, as a novel feature for assessing prognosis in patients with pN1 illness. More is the ratio, poorer is the prognosis [7]. LNR has become a stand-alone prognostic factor for a number of tumour forms, including HNSCC, as inadequate LN retrieval may cause pathological understaging. This ratio makes an effort to account for any probable prejudice in the sampling technique. It takes into account three variables that may have an overall impact on the staging of LNs: (1) tumour aspects, which represent the disease’s actual regional spread (i.e., the number of lymph nodes that were actually positive); (2) surgical aspects (i.e., the number of nodes actually removed during neck dissection); and (3) detection aspects (i.e., the precision of the pathological analysis). Therefore, innovations like the greater use of immunohistochemistry, molecular methods, serial sectioning, and/or the discovery of tiny metastatic deposits in lymph nodes, as well as the tendency towards more limited/selective neck dissection, may also influence LNR [7, 30].

LNR is defined as the number of positive lymph nodes divided by the total number of lymph nodes excised, regardless of the extent of neck dissection [31]. LNR is a proxy for the sufficiency of neck dissection and corresponds majorly with total lymph node yield (LNY).

LNY (also referred to as lymph node harvest or lymph node count) is defined as the count of lymph nodes retrieved after neck dissection [32]. Numerous authors have discussed the importance of LNY and LNR as prognostic indicators, with higher LNY and lower LNR resulting in better survival [33]. Patients with lower LNRs who were node positive in several studies even had similar results to patients who were node negative. For instance, when compared to LNR and AJCC N staging, the number of positive nodes of more than five has greater prognostic influence [34].

11.2 Extranodal extension (ENE)

If the lymph node’s metastatic tumour penetrates the lymph node capsule and into the nearby connective tissue, whether or not there is a stromal reaction present, the ENE is deemed positive. The maximum millimetre distance, in either intact or reconstructed nodal capsules, between the most distant point of invasion into extranodal tissue and the extent of ENE can be calculated [33]. Since ENE was added to the most recent version of the American Joint Committee on Cancer (AJCC) handbook, it is advised to categorise the extent of ENE in most head and neck cancers (HNC) as minor (ENEmi 2 mm from the capsule) and significant (ENEma >2 mm) [35, 36].

11.3 Level of lymph node involvement

Another lymph node characteristic that has been linked to a poor prognosis in numerous studies is the incidence of lymph node metastases in the lower levels of the neck i.e., upto levels IV and V [33].

11.4 Size of the tumour deposit within the lymph node

The relationship between the size of the tumour deposit and ENE has been documented in numerous investigations. According to some research, a deposit size of 11.5 mm would accurately and specifically indicate ENE. Additionally, there is a strong correlation between a tumour deposit that is less than 14 mm in size and reduced disease-free and overall survival [33].

11.5 Metastatic lymph node clearance (MLNC)

Because the total number of removed LN varies depending on the method of neck dissection, it is important to take this into account when calculating the Lymph Node Ratio (LNR) and Lymph Node Yield (LNY) in the clinical environment [37].

12. Conclusion

Lymphadenopathy in head and neck cancer present with a plethora of characteristics with significant implications on patient outcomes. The pathways of lymph node metastasis are distinct and represent a variety of histopathological interpretations having a significant bearing on patient prognosis.