Sentinel Node Biopsy in Cancer of the Oral Cavity and Upper Aerodigestive Tract
Francisco J. Civantos
INTRODUCTION
The approach to the N0 neck in patients with early invasive squamous cell carcinoma of the upper aerodigestive tract remains controversial. A “watchful waiting” policy has traditionally been used in order to avoid the unnecessary morbidity in the majority of patients in whom neck metastases will never develop. Patients at risk have been identified by the characteristics of the primary lesion, such as thickness >4 mm, tumor size >2 cm, anatomic location, microinvasion, and perineural infiltration. However, none of these represent a fool proof means of defining the population at risk.
When an early, invasive primary cancer of the oral cavity is identified and no clinically or radiologically involved cervical lymph nodes (LNs) are present, we must still consider management of the LNs. The 20% to 30% risk of occult metastases must be weighed against the morbidity of dissecting necks that do not contain metastatic cancer. Sentinel node biopsy is appropriate for situations where the expected risk of metastases falls in the 5% to 15% range, which might be too high to feel comfortable with watchful waiting but too low to justify the potential morbidity of a selective neck dissection.
In order to validate this technique for cancer of the oral cavity, a trial funded by the National Cancer Institute was completed in North America under the auspices of the American College of Surgeons Oncology Group (ACOSOG). The results of the ACOSOG trial revealed, after central step sectioning and immunohistochemistry for cytokeratins, a negative predictive value (NPV) of 96% and false-negative rate of 9.8%. Interestingly, for T1 cancers in both groups of surgeons, in the setting of a 25% true-positive rate, the false-negative rate was 0% and NPV was 100%. Similarly, for the group of experienced surgeons, false-negative rate was 0% and NPV was 100%.
HISTORY
The typical patient who is a candidate for sentinel node biopsy presents with a visible and accessible cancer in the oral cavity. The patient will typically have seen or felt a lesion in the oral cavity, perhaps with the tongue, or at the time of brushing the teeth. The lesion is typically mildly uncomfortable. There may be a history of bleeding. The lesion may have been identified by the patient’s dentist or physician as biopsy-proven squamous cell carcinoma.
PHYSICAL EXAMINATION
On physical examination, there is a lesion, which is ideally <2 or 3 cm in size and has some degree of thickness, which the examiner estimates to be several millimeters thick but not massively invasive. The lesion may be red or white and will generally be rough or irregular. It may be ulcerated. The patient has no movement abnormalities of the tongue or trismus. There is no palpable pathologic adenopathy.
INDICATIONS
The sentinel node biopsy procedure is best applied to T1-T2 cancers. Thus, oral cavity, oropharynx, and selected supraglottic laryngeal cancers, staged cT1N0 or cT2N0, should be considered for sentinel lymph node (SLN) biopsy. Appropriate clinical and radiographic evaluation should be used to stage these preoperatively. This might correspond to about 2 to 6 mm depth of invasion, but this is a hypothetical concept at this point, and greater experience and larger published clinical trials on sentinel node biopsy as the initial approach to the neck are needed to confirm this concept. The majority of patients on the ACOSOG validation trial were in this group. Extremely thin lesions, which might be mistaken for in situ or dysplastic lesions and subsequently turn out to be minimally invasive on biopsy, are not appropriate as the risk of metastases to the cervical lymphatics is negligible, at 2% or less. Lesions that feel mildly thick or gritty, or have some firmness, without massive invasion, are ideal. Some authors report SLN biopsy for cT3N0 tumors, but the size (>4 cm) reduces the accuracy of lymphatic mapping due to alternative drainage patterns, and thus, these are not recommended for SLN biopsy in my experience.
CONTRAINDICATIONS
In my opinion, lesions that extend deep into tongue muscle or deep into the buccal or palate region are better served with selective neck dissection. If a cancer is <3 cm in maximum diameter but has significant fixation of the tongue or other manifestation of deep invasion, then this lesion is truly a T4 lesion and results with sentinel node biopsy are unlikely to prove accurate and useful. Sentinel node biopsy has a low false-negative rate, but the NPV will be less if the population selected has a very high rate of metastases. In other words, a 4% rate of false negatives is acceptable if applied to a population with a 15% risk of metastases, but if applied to a population where most of the patients have micrometastases, the miss rate will be unacceptably high. Thus, deeply invasive lesions or lesions >4 cm are better served by either selective neck dissection or, if desired, sentinel node mapping and biopsy followed by immediate neck dissection. The latter approach can assist in making decisions about the contralateral side of the neck and provide improved identification of micrometastases, while eliminating the risk of false negatives leading to undertreatment of the patient. Patients with suspicious LNs on physical examination or imaging are also not candidates for this procedure. T3-T4 lesions, with trismus, bone invasion, tongue fixation, or other signs of massive deep invasion, are too deep to feel comfortable that the injection has fully mapped the drainage of the lesion, and such findings represent a contraindication to sentinel lymph node biopsy (SLNB).
PREOPERATIVE PLANNING
Imaging Studies
If the primary tumor meets criteria described above, the next issue is whether the neck is grossly involved. While the sentinel node technique is an excellent technique for detecting micrometastases, it is less useful for detecting nonpalpable but grossly involved LNs. This appears to be particularly true with squamous cell carcinoma. It is postulated that when a large percentage of the LN is replaced by cancer, physiologic obstruction occurs and alternative patterns of lymphatic drainage develop. It is important to detect the presence of such gross disease on preoperative imaging and avoid applying this technique to that group of patients, in order to avoid false positives. Generally contrast-enhanced computerized tomography (CT) and magnetic resonance imaging (MRI) (if iodine allergic) are the imaging modalities used. These should be strictly interpreted, and patients should be excluded if there are nodes >1.5 cm in size for levels I and II; >1.2 cm in size for levels III, IV, V, and VI; with central necrosis, irregular enhancement, or a poorly defined or irregular capsular border; or with groups of three or more asymmetrically located LNs, with a minimal axial diameter of 8 mm or more, in the suspected tumor drainage basin (Fig. 1.1). The role of positron emission tomography (PET) remains to be delineated and is plagued by false positives, but this may ultimately also prove useful in ruling out such gross disease. It should be kept in mind that the sentinel node technology represents an excellent technique for detection of micrometastases in patients felt to have a reasonably low risk of metastases, but is not as accurate at detecting grossly involved nodes.
Imaging studies, including CT with iodine contrast, MRI with gadolinium contrast, and ultrasonography, should be used to better identify grossly involved, nonpalpable nodes. CT with contrast is standard in North America, though ultrasound, if done in a detailed fashion, is a reasonable alternative. MRI with gadolinium contrast is a good option in iodine allergic patients. Central necrosis of the lymph nodes, although highly predictive, is a late finding. The uptake of 2-deoxy-2-[18F]fluoro-d-glucose as measured by PET has been reported as significantly more sensitive and only slightly less specific than MRI. However, foci of cancer smaller than 1 cm are below the resolution of PET as with CT and MRI.
SURGICAL TECHNIQUE
Step 1: Injection of the Primary Tumor
The injection is performed prior to the surgical procedure, generally on the morning of surgery, in the radiology suite. Injection is also sometimes performed late the day before, although the effect of this on the success rate of sentinel node identification remains to be delineated. While awake injection and imaging in radiology are the most commonly used techniques, as we extend this procedure to endoscopically accessible oropharyngeal, supraglottic, and hypopharyngeal lesions, it is likely that cooperative efforts with the nuclear radiologist and the use of portable cameras will allow for intraoperative endoscopic injection, with or without radiologic imaging, and gamma probe-guided sentinel node biopsy without the need for uncomfortable injections in an awake patient. Theoretical advantages of injecting under general anesthesia include better exposure of the primary and avoidance of motion of the patient related to discomfort. This may eventually further increase the reliability of this method. Taking into account that the radiolocalization of the detected hot spots does not represent the drainage of the primary, but the drainage of the tracer deposits, which are supposed to mimic the lymphatic drainage of the primary, the impact of a thorough and representative tracer injection becomes evident. Due to density and direction of the head and neck lymphatics, the primary may drain into several alternative lymphatic pathways, all representing first draining “sentinel” LNs.
Nevertheless, due to regulatory issues related to the injection of radioactive substances and the lack of widely available portable nuclear imaging, awake injection remains the most commonly used technique at present. It is important to ensure that the patient is comfortable so that an adequate preoperative injection is obtained. I use topical anesthetic, mild oral sedation, and lingual, inferior alveolar, and/or sphenopalatine nerve blocks to ensure patient comfort during manipulation and injection of the primary tumor. Direct injection of the tumor with local anesthetic should not be performed as it may affect uptake of the radionuclide and reportedly may even cause it to precipitate in the tissues. The injection technique involves narrow injection with a fine 25-gauge needle circumferentially encompassing the leading edge of the lesion and an additional injection in the center of the lesion (Figs. 1.2 and 1.3). Five tuberculin syringes with 1-mL aliquots of technetium-99 sulfur colloid, with a total radioactivity of 400 millicuries, would represent a standard dose for the morning of surgery. A slightly higher dose would be used the night before. These dosages are extrapolated from the practice for melanoma and have worked well for cancer of the oral cavity, but formal comparative evaluation of dosages and volumes for use in the oral cavity have yet to be performed.
I have used this technique for visible oral lesions. For cutaneous lesions, it is well documented that a scar from a previous excisional biopsy can be injected to allow accurate sentinel node biopsy. Whether a previously excised oral lesion could undergo sentinel node excision by injection of an intraoral scar has yet to be determined. It is important to inject narrowly and not to inject the deep tissues. The radionuclide will extravasate more widely in the oral cavity around the site of injection than occurs in the skin and will usually go to the neck more quickly. There is no benefit to trying to inject a margin around the tumor, as this will lead to an unmanageable excess of radioactive nodes. I prefer to use unfiltered technetium-99 sulfur colloid. The presence of larger particles allows for retention of radioactivity in the proximal lymphatics. Retained particles at the site of primary injection are not a major issue as we recommend removal of the primary tumor first. However, it is also possible to obtain good results using filtered technetium sulfur colloid, and if there is a strong preference for addressing the lymphatics first, then this may be preferable as there is a better clearance of background radioactivity from the primary site. The more rapid migration of the filtered agent may also make it advantageous if injections of radionuclide are performed on the operating room table at the start of the procedure rather than prior to the surgical procedure.