32 Neck Management for Oral Malignancies
Summary
Oral cavity cancers are typically treated with surgery, and management of the regional neck lymph nodes is an important part of the initial treatment discussion. Oral cavity tumors can harbor early occult neck lymph node disease. Radiation therapy is an option for nonsurgical patients, but does not have good overall response or control rates. Patients with obvious neck disease require upfront surgical removal and potentially radiation with or without chemotherapy depending on high-risk pathologic factors. Management options of the clinically negative neck (N0) remains controversial. Elective treatment of the neck, including elective neck dissection (END) and irradiation (ENI) can play an important role and warrant careful multidisciplinary team discussion with the patient. Active investigation into the indications and timing of potential elective neck treatment will be important to guide treatment guidelines. Sentinel lymph node biopsy (SNB) may offer less invasive technique to investigate and treat the neck in oral cavity cancer patients.
32.1 Introduction
Oral cavity squamous cell carcinoma (OCSCC) represents a leading form of head and neck cancer worldwide. Initial presentation varies from early manifestations of leukoplakia or erythroplakia to advanced progressively enlarging tumors involving the oral cavity and often the regional cervical lymphatics in the neck. A multidisciplinary team approach for treatment is critical for the proper evaluation, diagnosis, and management of the primary tumor site as well as the regional lymphatics that may harbor clinically apparent or occult metastatic disease. Definitive management of OCSCC at initial disease presentation offers patients the best opportunity for locoregional control and overall survival.
The 2017 National Comprehensive Cancer Network (NCCN) guidelines for cancer of the oral cavity recommend that regardless of the presentation, patients should undergo careful clinical and radiographic evaluation of the primary site as well as at least the regional lymphatics that are at risk for harboring disease. For more advanced presentations and stages of disease, evaluation should at least include imaging of the chest if not more comprehensive systemic imaging. 1 The need for careful evaluation of the neck is due to the fact that disease involvement of the regional cervical lymph nodes is the most accurate negative predictor of overall oncologic outcome other than distant metastases. Despite advances in the therapy of OCSCC and the understanding of its causes, patient outcomes remain poor and presence of cervical lymph node metastases decreases the overall patient survival by roughly 50%. 2 – 4 Thus, management of the neck, including appropriate staging and treatment, is critical.
Surgical management of the neck can be broken down into treatment of clinically evident cervical lymph node disease (N +) and clinically negative neck (N0) that may be at risk of harboring occult neck disease. The decision to perform neck surgery has to be carefully evaluated and all the risks and benefits need to be taken into account. Therapeutic surgical dissection of the neck is warranted in cases of N + disease, unless patients are unable to tolerate surgery or have unresectable disease. 1 Much debate still remains about whether patients with N0 disease should undergo elective neck dissections (ENDs), observation, or even elective neck radiotherapy. 5 – 18 A recently published large prospective clinical trial and the updated 8th edition of American Joint Committee on Cancer (AJCC) cancer staging manual on OCSCC tumor classification and staging, are influencing management of the neck in these patients. 18 , 19 There is increasing support for the use of END for staging and therapeutic purposes at initial OCSCC diagnosis. 13 , 16 , 18 , 20 – 22 Comprehensive evaluation and treatment recommendations must also include discussion of potential merits of adjuvant radiation therapy as well as chemotherapy. 1
32.2 Epidemiology
Head and neck cancer is the sixth most common cancer in the world, with squamous cell carcinomas as the most prevalent form of oral malignancies (> 95%). The risk of developing cancer increases with tobacco use in a dose-dependent fashion, and alcohol consumption is synergistic when combined with tobacco use. While many advances in treatment and diagnosis have been made over time, oral cancer remains the ninth leading cause of cancer death among US males and overall survival rate has remained low. 23
Overall in the US and Europe, the rates of oral cancer incidence and mortality have declined over time, but these declines have not been consistent in all of the population subgroups. 24 In other parts of the world such as South Asia, oral cancer is a serious and growing problem. 25 Changes in risky behaviors like decreasing tobacco and alcohol use are thought to be the main reasons for the overall decline in oral cancer incidence while increase in the use of these products in other populations has increased its incidence. Geographic location, low socioeconomic status, and lack of awareness regarding the negative effects of preventable risk factors are important variables for development of oral cancer. 25 , 26
The most significant negative prognostic factor for recurrence and long-term survival is the presence of regional metastases in the cervical lymphatics. Cervical lymph node metastases diminish disease-free survival by about 50%. 5 , 9 , 27 , 28 Hence, the identification of neck disease is critical for appropriate multidisciplinary treatment and management discussion.
The risk of lymph node involvement increases with increasing depth of invasion and size of the tumor, making early diagnosis key for maximizing overall survival. 29 Even with negative physical examination and imaging studies, approximately 30% of all head and neck cancer patients with clinical N0 neck may harbor occult metastases. These metastases are too small to palpate or visualize on imaging. For oral cavity subsites, the rate of occult metastatic disease may be as high as 45% (▶ Table 32.1). 9 , 30 – 32 More than two-thirds of occult metastases measure less than 10 mm, with majority measuring less than 3 mm. 33 , 34 There are now pathologic and clinical parameters such as depth of tumor invasion that are used to determine if the risk of neck disease is high enough to electively treat the cervical lymphatics and identify potential lymphatic metastases that are clinically unappreciable. 18 , 35
32.3 Clinical Presentation
It is unusual for patients with oral cavity malignancies to present with an asymptomatic neck mass. Typically, patients first become symptomatic with suspicious mucosal changes, ulcers, or growths and the associated discomfort from the primary tumor itself. Cervical lymph node metastases are then likely identified during the initial examination or anatomic imaging evaluation. The neck masses are usually nontender, mobile, and most commonly found in the submental or submandibular region of the neck. 7 , 10 , 14 Specific attention needs to be given to the perifacial lymph nodes that are located adjacent to the mandible at the mandibular facial notch, as this is an area that may harbor neck disease. When there is presence of extracapsular extension in the lymph node, the neck mass may be less mobile or adherent to surrounding soft tissue or mandible and often becomes tender, indurated, and may have overlying skin changes or tethering. 36
Hard palate malignancies are overall less likely to have regional neck disease given that the lymphatic drainage of this area is less robust than other subsites of the oral cavity including the floor of mouth or tongue. 37 Larger and more advanced tumors, especially in the case of delayed evaluation, are more likely to have palpable neck masses, which represent a conglomeration of involved lymph nodes, during the initial evaluation. 36 , 38 For early lesions, the patient may have no apparent palpable cervical lymph nodes, and we must rely on imaging to identify potential suspicious lymphadenopathy. Even when imaging does not reveal any suspicious lymph nodes, oral cavity malignancies carry significant risk of occult microscopic neck disease that needs to be considered during management of this disease. 33 , 34
32.4 Diagnosis and Evaluation
Workup of oral cavity malignancies includes careful evaluation of the primary tumor site as well as the neck for possible regional disease spread into the cervical lymph nodes. Examination needs to include both careful visualization and palpation of the oral cavity and neck. Examination and palpation of the primary tumor help in providing a footprint for potential lymphatic drainage patterns and therefore understanding the at-risk nodal basins. Anatomic imaging studies are useful not only to evaluate the extent of tumor infiltration, but also to appropriately stage the neck for involved or suspicious lymphadenopathy. 1 This is especially helpful when there is no palpable cervical lymphadenopathy. A combination of physical examination and imaging has been shown to be more sensitive and specific when compared with physical examination alone for proper evaluation of the neck. 39 – 41 For more advanced tumors systemic evaluation for potential distant metastatic disease is also warranted as per the NCCN guidelines. 1
High-resolution imaging usually includes computed tomography (CT), magnetic resonance imaging (MRI), ultrasound (US), and more increasingly positron emission tomography (PET). PET/CT is usually more commonly used for advanced disease. 41 There are ongoing clinical studies (ACRIN 6685) designed to determine the negative predictive value of PET/CT imaging based upon pathologic analysis of the neck lymph nodes in patients with head and neck cancer. Criteria for determining involved lymph nodes on imaging can vary among institutions; the short axis diameter must usually be at least 11-12 mm including certain features such as central necrosis, avid node enhancement with rounded appearance or rim enhancement, and potential extracapsular spread (ECS) when present.
Imaging can provide both specific location and characteristics of any involved, suspicious, or indeterminate lymph nodes which can then be further interrogated with US-guided fine needle aspiration (FNA) cytopathology or other imaging modalities, as warranted. FNA sampling is recommended for any suspicious or indeterminate lymph nodes, as this information is critical for discussion of appropriate management of the malignant disease. 36 , 42 Ultrasound-guided FNA is a robust technique that allows for direct sampling of lymph nodes and establishing diagnosis of metastatic disease. This is especially important when deciding on the need for cervical lymphadenectomy.
32.4.1 Anatomic Considerations
The lymphatic drainage of the mucosal surfaces of the oral cavity is directed to the lymph nodes located within the fibroadipose tissue of the neck. The cervical lymph nodes are found between the investing superficial layer of the deep cervical fascia and the visceral and prevertebral layers deeper in the neck. The lymph nodes at risk for harboring metastatic disease from oral cavity cancers are called jugulodigastric lymph nodes, and they tend to be aggregated around important neural and vascular structures including the carotid artery, transverse cervical artery, internal jugular vein, and the vagus, spinal accessory, hypoglossal and lingual cranial nerves, as well as the phrenic nerve. 37
Recognizing the inherent complexity of the head and neck region, a uniform division and classification of the neck levels has been implemented which formally groups lymph nodes within designated anatomical boundaries into specific neck level compartments. 43 , 44 Development of this classification schema was important given the relatively predictable cervical lymphatic spread of oral cavity cancers (▶ Table 32.2). 30 , 32 With the increasing use of more limited selective neck dissection (SND), proper identification and labeling of the nodal compartments removed are critical. SNDs are now classified by the specific neck levels dissected to remove the fibrofatty contents that contain the cervical lymph nodes. 43 , 44
There are six anatomic neck levels (I-VI) in the neck but only the lateral neck compartments (I-V) are critical for evaluation of potential metastatic disease in oral cavity cancers (▶ Fig. 31.11). The anterior neck compartment level VI is unlikely to harbor any metastatic disease from these malignancies. Neck level I corresponds to the submandibular and submental nodes. Neck levels II, III, and IV are the upper, middle, and lower jugular nodes, and the posterior triangle nodes are referred to as neck level V. There are also sublevels within this classification including level IA (submental nodes), IB (submandibular nodes), IIA and IIB (separated by the spinal accessory nerve and together comprising the upper jugular nodes), VA (spinal accessory nodes), and VB (transverse cervical and supraclavicular nodes). 43 , 44
*There is variability among head and neck surgeons on whether level IV is regularly included.
Modified from Robbins et al. 44
32.5 Surgical Considerations and Approaches
Head and neck cancer, including oral cavity malignancies, commonly metastasize to cervical lymph nodes. When present or suspected, the cervical lymphatic metastases are typically treated with a neck dissection. Surgery usually involves removal of the fibrofatty contents of the neck while preserving the sternocleidomastoid muscle as well as critical neurovascular structures such as the carotid artery, internal jugular vein, and cranial nerves. Treatment of the neck is a key component of the management when there is obvious neck disease (N +), and it should be considered when there is significant risk of microscopic occult neck disease in the clinically N0 neck.
32.5.1 Cervical Lymph Node Metastases (N + Neck)
Surgical therapy is the mainstay of treatment of cervical lymph node metastasis in OCSCC, and therapeutic neck dissection is warranted. There are occasions when surgery may not be indicated, including patient refusal, inability to undergo surgery, or primary and/or neck disease that is unresectable. In these cases, careful multidisciplinary team approach must be adhered to for evaluation and discussion of all available treatment options, including clinical trials. When neck surgery is possible, the extent of surgery is dictated by the involved lymph nodes and the overall lymph node basins at risk for harboring occult metastatic disease. 36
For many decades there was a debate about whether an SND targeting the lymph nodes at risk was comparable to a more comprehensive or even radical neck dissection (RND). Over time studies have shown that treatment of the neck can become less radical and more conservative, sparing the nonlymphatic structures such as the spinal accessory nerve, sternocleidomastoid muscle, and internal jugular vein. The extent of this type of modified RND has also changed and the lymphatic levels removed has also decreased to involve only those lymphatic basins that potentially harbor disease or are at risk for occult metastases and disease spread. 7 , 45 Many studies have shown that there is no statistically significant difference in locoregional recurrence rates between an SND and the more extensive RND in head and neck cancer, including OCSCC. 9 , 31
The cervical lymph nodes at highest risk of developing metastases from OCSCC are in neck levels I, II, and III with metastatic rates to these sites of 58, 51, and 26%, respectively (▶ Table 32.2). 30 , 32 Follow-up studies by Byers et al noted a 15% rate of level IV skip metastasis, specifically for the oral tongue subsite and advocated that level IV should be included in SND. 31 More recently it has been demonstrated that isolated level IV lymph node metastases are less common than previously shown and that level IV can be dissected only if there are suspicious or involved nodes in that level and/or level II or III. 45 Based on surgeons’ experience and practice patterns, there is great variability among head and neck surgeons and clinical centers on whether level IV is regularly included as part of the SND for OCSCC (▶ Fig. 32.1).
It is also important to note the importance of sublevels of the neck, especially levels IA and IIB, in treatment of the neck for OCSCC. Level IA dissection should be complete and include the lymph nodes in the triangle bounded by the anterior bellies of the digastric muscle due to minimal morbidity associated with this dissection and improved nodal sampling of the submental lymph nodes. There is some debate regarding the need to dissect level IIB given that this area rarely harbors occult disease, with potential involvement ranging from 1.6 to 10% of patients. 46 – 48 There is concern that dissection of these nodes may lead to increased stretching and trauma of the spinal accessory nerve and potential shoulder dysfunction. 49 No functional studies have been published which evaluate the potential benefits of preservation of level IIB, and given the relative ease of this dissection, it is generally recommend that level IIB nodes should be included in SND (▶ Fig. 32.1).
Overall, SND markedly reduces the postoperative morbidity of neck cancer surgery by effectively eliminating the posterior triangle neck dissection and performing targeted anterior triangle dissection. 50 This procedure has relatively low morbidity and provides pathological staging of the neck, which provides long-term prognostic information.
32.5.2 Clinically Negative Neck (N0)
Great controversy has surrounded the management of the clinically negative (N0) neck. A clinically N0 neck is defined as having no clinical evidence of cervical lymph node metastases. Determination of this is quite challenging given the potential risk of occult nodal disease but it is an important part of multidisciplinary team evaluation and discussion. Examination includes careful palpation of the neck as well as anatomic imaging. To help stage the neck, high-resolution imaging is used usually including CT, MRI, US, and increasingly PET. 41 Imaging can provide both specific location and characteristics of any suspicious or indeterminate lymph nodes which can then be further interrogated with US-guided FNA cytopathology or other imaging modalities, as warranted. 36
Even with negative physical examination and imaging studies, approximately 30% of all head and neck cancer patients with clinical N0 neck may harbor occult metastases. 32 For oral cavity subsites, the rate of occult metastatic disease may be as high as 45% (▶ Table 32.1). 9 , 31 , 32 More than two-thirds of these occult metastases measured less than 10 mm, with majority of these measuring less than 3 mm. 33 , 34 The major issue is that these N0 patients may harbor lymphatic metastases that are just too small to be detected. The greatest challenge is therefore to correctly identify the subset of these patients without cervical nodal micrometastases who do not require elective neck treatment.
Given these limitations and challenges, the three management options for N0 patients are observations with therapeutic neck dissection once regional metastases become apparent, staging END, and elective neck irradiation (ENI). The debate surrounding these three options has lasted for many decades, but a recent prospective clinical trial has shed new light on the potential benefits of END, especially in treatment of tongue squamous cell carcinoma. 18
Observation versus Elective Neck Treatment
There is a great controversy regarding the optimal therapy for clinically negative necks. The main question is whether performing an END and clearing the occult neck disease have any survival and locoregional control benefits. Most studies with only few prospective randomized studies showed that patients undergoing END have lower regional recurrence rates, but the survival advantage was not as clear with some studies showing improved survival and others no difference when comparing surgery with observation (▶ Table 32.3). 5 , 6 , 8 , 10 , 11 , 16 , 20 , 21
Proponents of observation “wait and see” approach state that the morbidity of END, capability for close follow-up, and early detection and adequate prompt treatment of lymph node metastases are good arguments for observation. Given that the occult metastatic rate to the neck from oral cavity cancer is between 30 and 40%, a significant majority of patients would be exposed to the morbidity of a potentially unnecessary END. 9 , 30 – 32 Proponents of surgery note that removal of lymph nodes can be used as an important staging procedure and as further evaluation of the pathology and any high-risk features. If there is presence of any high-risk features such as perineural invasion (PNI), lymphovascular invasion (LVI), or ECS, the patient can be considered for adjuvant therapy. 28 , 51 , 52 Specifically, in patients who were initially observed but later developed lymph node metastases requiring therapeutic neck dissection, the majority of patients had pathologically adverse findings at the time of neck dissection, including ECS, and therefore required more extensive surgery and adjuvant therapy. Additionally, overall survival rate decreased significantly in therapeutic neck dissection patients, with a much lower ability to ultimately surgically salvage the neck. 7 , 8 , 22 , 53 Hence, these are the arguments that support elective neck treatment in patients with N0 necks.
Few studies are available to guide the management of the N0 neck, but one study by Weiss et al proposed that observation is preferred when the probability of occult metastasis is less than 20% and elective neck treatment (radiation therapy or surgery) is preferred if the probability of occult metastasis is greater than 20%. 54 Currently, the depth of invasion and thickness of tumor seem to be the only factors to have consistently shown promise as indicators of risk for occult nodal metastasis. The recommended cutoff for considering elective neck treatment varies greatly in the literature, ranging from 1.5 to 8 mm. In the case of N0 neck with primary tumor arising from a subsite with a less than 20% occult metastatic rate, observation may be appropriate. Low rate of occult nodal spread has been observed for early T1 to T2 lip carcinomas, oral tongue carcinomas that are less than 3-4 mm thick, and floor of mouth cancers that are 1.5 mm or thinner. 29 , 55 – 59
Recently, D’Cruz et al published a large prospective randomized trial that compared END to observation with therapeutic neck dissection (“watchful waiting”). Among 496 patients, a clear benefit was shown for the END group. Among patients with early stage OCSCC, END resulted in higher rates of overall (80 vs 67.5%) and disease-free survival (69.5 vs 45.9%) compared to the observation and therapeutic neck dissection. This study also suggested that patients with a minimal depth of invasion of the primary tumor of = 3 mm may not benefit from END. These data are robust for oral tongue cancers, given over 85% of enrolled patients had primary tumors located in this subsite. 18 Results of this trial suggest that END at the time of resection of the primary tumor confers an overall survival benefit in patients with early-stage, clinically N0 OCSCC. However, the significant caveat here is that more patients in the END arm received adjuvant radiation therapy since the pathological status of their neck was known. Thus, early management of the neck overall appears to be more beneficial than observation.
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