**5. The impact of tumor thickness in the risk of cervical lymph node metastasis and the role of sentinel lymph node biopsy**

The National Comprehensive Cancer Network Guidelines (2019) recommends that elective neck dissection be based on the risk of occult metastasis in the appropriated nodal basin [1]. Selective neck dissection of at least levels I–III is recommended for N0 oral cavity carcinoma.

Particularly, for oral cavity squamous cell carcinoma, sentinel lymph node biopsy or the primary tumor depth of invasion should guide decision making and these are currently the best predictors of occult metastatic disease [1, 22]. Earlier versions of NCCN state that for Stage I clinically N0 oral cavity cancer, elective neck dissection is recommended for tumor thickness >4 mm but recent evidence supports the effectiveness of elective neck dissection in patients with oral cavity cancers >3 mm depth of invasion [1, 22].

It is worthy of mention that the recently proposed 8th edition of the American Joint Committee on Cancer (AJCC) staging system for oral cavity squamous cell carcinoma is the addition of depth of invasion (DOI) as a modifier for the T category in the TNM staging [23]. It remains a controversy whether it is reasonable to substitute tumor thickness for DOI, since tumors with a larger DOI or thickness are associated with an increased risk of nodal metastasis and worse survival outcomes [24]. It has been concluded in a 2017 study by Dervin et al. that the T category and TNM stage prognostic performance of the eighth edition AJCC staging of oral cancer is similar regardless of whether DOI or thickness is used as the T-category modifier; hence, in centers or institutions without complete DOI data, it is reasonable to use tumor thickness [24].

Accuracy of sentinel lymph node biopsy for nodal staging of early oral cavity carcinoma has been tested extensively against the reference standard of immediately performed neck dissection or subsequent extended follow-up, with a pooled estimate of sensitivity of 0.93 and negative predictive values ranging from 0.88 to 1, with comparable survival outcomes [1, 22, 25–29]. A more recent systematic review revealed that sentinel lymph node biopsy is advantageous because it improves the accuracy of tumor staging, is a minimally-invasive procedure, avoids unnecessary nodal dissection, and results in limited morbidity and mortality with negative predictive value of 90–95% [6]. The disadvantages include posing difficulty for peri-tumoral injection for bulky invasive primary tumors that invade adjacent anatomic subsites, difficulty in floor of mouth tumors and those with proximity to the draining lymphatic basin, clinically positive nodes that are difficult to be identified by sentinel node mapping because of poor uptake of tracer, and the need for additional second stage surgery in case of positive neck node [6].

In addition, sentinel lymph node biopsy is a technically demanding procedure, with its success rates for sentinel node and occult lymphatic metastasis identification much dependent on technical expertise and experience [1]. Thus, sufficient caution must be exercised when offering it as an alternative to elective neck dissection [1].

### **6. Biomarkers as predictors of occult lymph node metastasis**

**Table 1** shows the various biomarkers which have been studied to detect occult lymph node metastasis.

Harada et al. showed that in normal squamous epithelium, cyclin B1 was localized in the nucleus and was expressed only in several cells of the basal and parabasal layers. In tumor tissues, however, cyclin B1 was expressed mainly in the cytoplasm. Cyclin B1 overexpression was positively correlated with occult cervical lymph node metastases and the number of mitotic cells [30].


**Table 1.**

*Predictors and non-predictors of occult lymph node metastases in oral cavity carcinoma.*

Zhang et al. showed that the secreted protein acidic and rich in cysteine (SPARC) has a positive rate in 49.1% of tongue cancer tissues and 0% in normal tissues. The expression of SPARC was positively correlated with occult lymph node metastasis and recurrence [31].

Huber et al. showed that the differentiation grade and down-regulation of E-cadherin expression significantly correlate with positive lymph node status in univariate and multivariate analyses. Thus, E-cadherin immunohistochemistry may be used as a predictor for lymph node metastasis in squamous cell carcinoma of the oral cavity and oropharynx [32].

Huber et al. showed that podoplanin expression correlated significantly with sentinel lymph node metastasis and remained a significant predictor for lymph node status even after controlling for tumor stage [33]. In relation to this, a more recent study revealed the association of podoplanin and SOX2 in the progression of oral squamous cell carcinoma [34]. OX2 is a transcription factor related to the maintenance of stem cells in a pluripotent state. Podoplanin is a type of transmembrane sialoglycoprotein, which plays an important role in tumor progression and metastasis [34]. There was a significant inverse correlation between the expression of SOX2 and podoplanin with the tumor grade, survival analysis showed that a high expression of SOX2 correlated positively with the disease-free survival, and a significant positive association between the pattern of SOX2 and podoplanin expression [34].

Mäkinen et al. showed that matrix metalloproteinase-7 (MMP-7) expression was associated with presence of occult metastases (OR 3.67; p = 0.013); increased invasion depth (OR 4.60; p = 0.005); high tumor grade (OR 3.30; p = 0.007). MMP-7 was predictive of poor outcome (p = 0.021) [35].

In a study by Kelner et al. in 2015, it was found that high immunohistochemical expression of activin A was significantly associated with presence of occult lymph node metastasis in oral tongue squamous cell carcinoma [36].

Non-predictors of occult lymph node metastases as shown in **Table 1** include vascular endothelial growth factor-C (VEGF-C) and High mobility group box 1 (HMGB1). No statistically significant difference was found between OSCC with and without occult lymph node metastasis in regard to VEGF-C immunoexpression by malignant cells [37]. Isolated VEGF-C expression by malignant cells is not of predictive value for occult lymph node metastasis in early stages of oral squamous cell carcinoma [37]. Likewise, Prediction of occurrence of late neck metastasis in early tongue squamous cell carcinoma by evaluating HMGB1 (high mobility group box 1) expression in the primary lesion showed that immunohistochemistry study of HMGB1 in early tongue squamous cell carcinoma did not appear to be very useful for predicting occult neck metastasis [38].

Most recently, immunohistochemistry quantification of partial epithelial-to-mesenchymal transition (p-EMT) in oral cavity squamous cell carcinoma primary tumors

**137**

**Author details**

**8. Conclusions**

Alfredo Quintin Y. Pontejos Jr. \* and Daryl Anne A. del Mundo Department of Otorhinolaryngology, University of the Philippines

lymph node metastasis may prove to have increasing utility.

Manila-Philippine General Hospital, Manila, Philippines

\*Address all correspondence to: docpontejosjr@yahoo.com

provided the original work is properly cited.

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*The Role of Neck Dissection in Oral Cavity Carcinoma DOI: http://dx.doi.org/10.5772/intechopen.90925*

**7. Post-operative follow-up**

scan may also be done for N0 neck [1].

has been reliably shown to be associated with nodal metastases, perineural invasion, and high grade [39]. EMT is thought to be a potential driver of invasiveness and metastasis in a variety of epithelial cancers [39]. It has been said that with prospective validation, p-EMT biomarkers may aid in decision making over whether to perform a

Based on the algorithm proposed by Paler et al., follow-up CT scan may be done for N1 disease and PET CT for N2/N3 disease 12 weeks after treatment [40]. CT

The NCCN guidelines follow-up recommendations for oral cavity carcinoma include a complete head and neck examination every 1–3 months for the first post-operative year, every 2–6 months for the second post-operative year, every 4–8 months for years 3–5, and every 12 months beyond 5 years post-operatively. Speech/hearing and swallowing evaluation, nutritional evaluation and rehabilitation, smoking cessation and alcohol counseling, and surveillance for depression are

Despite advances in imaging studies in detecting occult metastasis, the risk of occult metastases in necks categorized as N0 in patients with oral cavity squamous cell carcinoma (SCC) remains and the need for neck dissection should carefully be examined. Elective neck dissection, specifically, selective neck dissection, is recommended for Stage II oral cavity carcinoma given the high risk of occult metastasis. For Stage I clinically N0 oral cavity carcinoma, elective neck dissection has been historically recommended for tumor thickness >4 mm but recent evidence supports the effectiveness of elective neck dissection in patients with oral cavity carcinoma >3 mm depth of invasion. The role of sentinel lymph node biopsy in detection of occult cervical lymph node metastasis is promising but requires technical expertise and experience. Identification of biomarkers in predicting the presence of cervical

neck dissection in the N0 neck and/or for adjuvant therapy planning [39].

included in the post-operative supportive care recommendations [1].

has been reliably shown to be associated with nodal metastases, perineural invasion, and high grade [39]. EMT is thought to be a potential driver of invasiveness and metastasis in a variety of epithelial cancers [39]. It has been said that with prospective validation, p-EMT biomarkers may aid in decision making over whether to perform a neck dissection in the N0 neck and/or for adjuvant therapy planning [39].
