Management of the N0 Neck Treatment & Management

Treatment is planned after preoperative evaluation confirms the N0 status of the patient. If the likelihood of metastasis is low (< 15%), watchful waiting is appropriate. However, if the primary tumor contains aggressive characteristics such as perineural invasion, deep penetration (more than 3 mm in the oral cavity), or angiolymphatic invasion, prophylactic treatment is necessary. ^[1]

Radiation has been shown to control regional recurrences in 95% of cases in which the primary site remains free of disease. Radiation has the advantage of decreased operative time, lacks the morbidity of neck dissection (shoulder discomfort), and is usually necessary to treat the primary site. Disadvantages include neck stiffness, skin changes, loss of hair in the treatment field, xerostomia, and increased morbidity and mortality if surgery in the irradiated area becomes necessary. ^[11]

Surgery for the N0 neck has changed significantly and morbidity has greatly decreased. The first description of the radical neck dissection by George Crile in 1906 explains the importance of the fascial envelops that contains the lymph nodes that drain specific head and neck sites. These principles still apply today as the philosophy behind functional neck dissection.

Selective neck dissection is the mostly commonly used surgical therapy today in treating the N0 neck. The main advantages of selective neck dissection include pathologic identification of metastases (more accurate staging) and removal of occult disease. In selective neck dissection, nodal tissue is removed from the zones specifically related to the drainage patterns of a particular site. The internal jugular vein, sternocleidomastoid muscle (SCM), and spinal accessory nerve are preserved.

The oral cavity lymphatics drain into levels 1, 2, and 3, while the oropharynx, hypopharynx, and larynx drain into levels 2, 3, and 4.

Supraomohyoid neck dissection includes levels 1, 2, and 3 and is used to treat cancer of the oral cavity, some oropharyngeal cancers, and other cancers that drain to this nodal basin.

Lateral neck dissection includes levels 2, 3, and 4 and is used in patients with cancer of the hypopharynx or larynx or other cancers that drain to this nodal basin. Level 2 dissection requires dissection of the fibrofatty tissue around the jugular, digastric, and spinal accessory nerve.

Modified radical neck dissection involves dissection of nodal basins 1-5, with preservation of the internal jugular vein, SCM, and spinal accessory nerve. Because the incidence of nodal metastasis that involves level 5 in a clinically and radiologically negative neck or N0 neck is low (4%), the modified radical neck dissection is seldom used.

Retropharyngeal lymph node dissection is controversial for the N0 neck. The frequency of positive retropharyngeal node involvement in pyriform sinus with oropharyngeal invasion, postcricoid tumors, and tumors of the posterior wall are as follows:

• Stage 1 - 3%

• Stage 2 - 10.3%

• Stage 3 - 9.8%

• Stage 4 - 19.2%

In a study by Yoshimoto and Kawabata, patients with positive retropharyngeal nodes tend to have poor control rates; retropharyngeal node dissection did not improve survival. ^[12] A study on the prognostic influence of retropharyngeal adenopathy by Dirix noted more local recurrence (45%), and disease-free survival was significantly lower in the patients with retropharyngeal nodes. McLaughlin et al also noted that retropharyngeal adenopathy is a strong predictor of poor prognosis. ^[13] However, other studies by Shimizu et al and Gross et al revealed that no significant difference between survival rates and local recurrences can be found in patients with and without retropharyngeal lymph node metastasis. ^[14]

Another area of controversy is level 2B node dissection. A study by Elsheikh on level 2B nodes after supraomohyoid neck dissection for oral SCCA revealed that 31% were positive by histopathological analysis. ^[15] However, when molecular analysis was used, level 2B positivity increased to 45%. No instance of isolated metastasis to level 2B lymph nodes without involvement of other nodes was found.

Level 2B node dissection should be considered in histologically positive nodes in the N0 neck, histologically positive nodes in level 2 or 3, primary tumors in the pharynx, extracapsular spread in the lymph node, tongue cancers, tonsillar cancer, skin cancer that drains to level 2, and parotid cancers.

Level 2B involvement in laryngeal cancer in an N0 neck is rare. The prevalence of level 2B metastasis is 1% in the N0 neck. Moreover, a literature review by Ferreli et al indicated that in patients with oral SCCA who have a clinically negative neck (cN0), occult nodal metastases occur at a cumulative rate of just 0.8% at level 2B. ^[16] Therefore, level 2B dissection can be avoided in the clinically N0 neck, which in turn prevents postoperative shoulder dysfunction. However, studies have shown that the prevalence of level 2B metastasis in a clinically positive neck is 37%.

Cancer of the head and neck metastasizes in an orderly manner; however, skip metastasis or discontinuous metastasis can occur. The incidence of skip metastasis to level 2 and 3 in oral cancer is 10%. The incidence of metastasis to level 4 lymph nodes in tongue cancer is 15.8%.

Skip metastasis in cancer of the larynx, glossoepiglottic area, and parotid is uncommon.

Management of the neck in sinonasal malignancies deserves special attention. Since these tumors are uncommon compared with other malignancies of the head and neck, the evidence is still limited. In esthesioneuroblastomas, the high regional failure rate in the untreated neck has lead to authors reporting beneficial effects from elective neck dissection for patients with Kadish stage B and C. ^[17]

It is also recommended to perform elective neck dissection (levels I-III) in patients with T2, T3, or T4 maxillary, palatal alveolar, and gingival SCCA at the time of initial resection. ^[18]

Management of the N0 neck in patients with advanced T3-T4 SCC of the larynx is still controversial. ^[19] A 2009 study by Dias et al demonstrated that SND (2-4) might be adequate (97% locoregional control). ^[20]

The treatment options are as follows:

• Sentinel lymph node biopsy (SLN): Although supraomohyoid neck dissection is still the criterion standard treatment for the N0 neck, it is currently being evaluated for use in head and neck cancer patients. The accuracy of this technique depends on pathological diagnosis and the method of localization. This can be either through a blue dye, radio-labeled lymphoscintigraphy or a combination of techniques. Hu et al ^[21] reported on the excision of 3 lymph nodes with the highest radioactive counts for accurate identification of cervical lymph node metastases with clinically N0 necks in laryngeal and hypopharyngeal cancers. The main advantage of SLN biopsy is its decreased morbidity compared with selective neck dissection. ^[22]

• If extended supraomohyoid neck dissection (levels 1-4) is performed and if the level 4 is negative based on intraoperative assessment and or frozen section, then the patient can be followed up postoperatively. If level 4 is positive, the options are as follows:

  • Postoperative radiotherapy

  • Convert extended supraomohyoid neck dissection to comprehensive neck dissection (levels 1-5)

  • Comprehensive neck dissection and postoperative radiotherapy

• Supraomohyoid neck dissection and a sample of level 3 for frozen section: If the lymph node is negative, patient can be closely followed up postoperatively. If lymph node is positive, the options are as follows:

  • Level 4 included in the dissection and postoperative radiotherapy

  • Comprehensive neck dissection (levels 1-5)

  • Comprehensive neck dissection and postoperative radiotherapy

  • Note that extending the operation, with or without postoperative radiotherapy, makes a difference in regard to locoregional control, and survival remains to be seen.

• Extended supraomohyoid neck dissection (levels 1-4) is performed for oral and tongue cancer.

Radiation is indicated following selective neck dissection if 3 or more nodes contain metastases, if extracapsular spread is present, or if a nodal metastasis is found in 2 noncontiguous zones (ie, skip metastases). ^{[23, 24]} In patients who meet these criteria, radiation is recommended because it has been shown to significantly decrease the risk of recurrence.

Based on the American Head and Neck Society Practice guidelines, the suggested follow-up schedule is as follows:

• First year posttreatment - Every 1-3 months

• Second year posttreatment - every 2-4 months

• Third year posttreatment - every 3-6 months

• Fourth year posttreatment - every 4-6 months

• Fifth year posttreatment - every 12 months

Because the local recurrence occurs within 2 years, standard follow-up of patients with head and neck cancer should be based on the individual patient characteristics.

Life-long follow-up is recommended because of the 20% lifetime risk of developing a second primary tumor.

Studies regarding follow-up have implied that most are aware of significant changes and seek early intervention, making strict routines unnecessary. However, head and neck surgeons (otolaryngologist and general surgeons) currently monitor their patient routinely, regardless of whether the patient has any new reports.

Complications of prophylactic neck dissection include the following:

• Postoperative pain

• Wound infection

• Hematoma

• Spinal accessory weakness

Complications of radiation therapy include the following:

• Xerostomia

• Neck stiffness

• Inability to use radiation again in the area

• Esophageal strictures

The overall prognosis of patients with an N0 neck is quite good. Surgery and radiation offer control rates in excess of 95%. However, the prognosis changes if the N0 neck is not truly an N0 neck. Lymph nodes metastases identified with prophylactic neck dissection upstage the patient, and patient survival may decrease by 50%. The primary site and prognostic histologic characteristics affect the survival and should be taken into consideration.

Several investigational but promising new methods of early cancer detection are as follows:

• MRI spectroscopy: This allows for spectroscopic evaluation of a specific tissue area. By measuring levels of choline and creatinine, differentiating tumor from normal tissue is possible because the choline/creatinine ratio is much higher in SCCA.

• PET-MRI fusion: The anatomic resolution of MRI fused with the metabolic activity of tumor as determined by PET scan is presently being studied to determine its accuracy for head and neck tumors. Its role in the imaging for head and neck cancer remains to be defined.

• Dynamic MR lymphangiography and carbon dye for sentinel lymph node detection: A Gadomer and carbon dye mixture is injected to the primary site. The sentinel lymph node is identified with MR lymphangiography followed by sentinel lymph node biopsy. MR lymphangiography provides spatial and anatomical localization and the sequence of nodal filling, thus identifying the second echelon lymph nodes without exposure to radioactive tracer. The visual marker (carbon dye) can last for at least a week, and the carbon does not interfere with histologic evaluation of the node. This technique, however, is still experimental.

• Isosulfan blue/technetium scanning

  • Isosulfan blue and technetium are injected peritumoral or around the tumor. Injection of the blue dye and technetium in the tumor is not recommended since the lymphatic channels in the tumor are destroyed.

  • The sentinel node is detected using a Geiger counter to detect radioactivity, and the blue dye is visualized during lymph node dissection. The consensus of the second conference on sentinel lymph node biopsy in mucosal head and neck cancer recommends use of radiotracer, lymphoscintigraphy, and a hand-held gamma probe for lymphatic mapping as minimal requirements. The use of conventional hematoxylin and eosin staining and cytokeratin is mandatory, and step sectioning of the entire node at intervals of 150 μm is recommended.

  • This method is used routinely for melanomas outside the head and neck, and its application is gaining popularity among head and neck surgeons for detecting metastases from head and neck melanomas. A meta-analysis of 19 articles in the literature on the use sentinel lymph node biopsy in SCCA revealed that the results are reliable and reproducible. Other studies revealed that sentinel lymph biopsy in head and neck cancer is feasible, with a success rate of 90% and a false-negative rate of less than 5%; however, its clinical use in the oral cavity and the oropharynx is still investigational, and trials are in progress to determine its diagnostic efficacy.

• Sentinel lymph node biopsy using Lymphoseek

  • The perfect agent used in SLN mapping should have high sensitivity of localization, rapid efflux from the tumor site and should selectively target the sentinel nodes. A new agent, Lymphoseek, which is being tested ^{[25, 26]} delivers these properties and is stable enough to allow imaging to be performed one day prior to the surgery. It is a dextran-based product that is modified to be labelled with technetium-99 (Tc99). Its small size, with an average of 5 nm, together with its high water solubility allows for enhanced primary site efflux.

  • The product also has long-lasting selectivity for the sentinel nodes by targeting mannose receptors, which are expressed on the abundant dendritic and macrophage cells in the lymph nodes. A US Food and Drug Adminstration-monitored, prospective multi-institution phase 3 trial of Lymphoseek for SLN biopsy in patients with N0 neck with oral cavity squamous cell carcinoma is currently in progress. ^[4]

• Photosensitizing drugs used in photodynamic therapy: This has potential use for labeling occult metastases. These drugs remain in the tumor cells longer and fluoresce under black light. Studies are currently underway to assess the diagnostic applications of photodynamic therapy. In patients who undergo prophylactic neck dissection, the fatty lymphatic tissue is examined with a black light, and the areas that fluoresce are sent for pathologic examination to determine if they contain SCCA.

• Molecular markers for cancer diagnosis are being investigated. These markers and possible clinical applications for cancer diagnosis are as follows:

  • DNA markers

    • TP53 mutation - Detection in saliva; cancer detection in surgical margins

    • Loss of heterozygosity (chromosomes 3p, 9p, 17p, 18q) - Detection in saliva; cancer detection in surgical margins

    • p16 and MGMT methylation - Detection in serum or saliva; cancer detection in surgical margins

    • Clonality analysis by X-chromosome activation - Detection of lymph node metastasis

    • Amplification of chromosome region CCNL1 - Detection of cancer progression and prognosis

  • RNA markers

    • Cytokeratin expression - Detection of lymph node metastasis; detection of disseminated tumor cell

    • E48 antigen expression - Detection of lymph node metastasis; detection of disseminated tumor

    • Pemphigus vulgaris antigen - Detection of lymph node metastasis

    • Expression profiling - Detection of lymph node metastasis and prognosis

  • Protein-based markers

    • Telomerase - Detection in saliva and prognosis

    • Matrix metalloproteinase-9 - Detection in the serum

    • elF4E - Surgical margin analysis

    • Metastasis-associated protein 1 (MTA) - Found to be a useful marker to predict lymphatic metastasis in tonsillar cancer ^[27]

The clinician should bear in mind that the most effective treatment of cancer is to treat the cancer in its earliest stage (when its tumor burden is lowest and when the lymphatic spread is least).