21 Sentinel Node Dissection Abstract The technology and indications for sentinel node dissection have continued to expand over the last several years. It is used routinely for intermediate thickness melanoma and Merkel cell carcinoma, and has been used for cutaneous squamous cell carcinoma of the head and neck. Sentinel node biopsy has been shown to be a reliable staging technique for intermediate thickness oral cavity cancer, with sensitivity and negative predictive value rates mirroring those for melanoma. Its use in pharyngeal and laryngeal cancer continues to be investigated. The use of 99mTc tilmanocept, a CD206 receptor target, allows for more specificity for the first echelon sentinel lymph nodes and may result in improved accuracy and a lower false-negative rate. The widespread availability and accuracy of combined SPECT/CT imaging provides a scrollable three-dimensional analysis of the drainage basins, resulting in better targeted dissections and patient counseling. Despite these technological advances, the use of the gamma probe for sentinel node dissection is not always intuitive and requires specific training and expertise, especially in cutaneous lesions that show frequent metastases to the parotid gland. Serial step sectioning and immunohistochemistry analysis are critical to the detection of micrometastases. Intraoperative frozen section analysis has also shown great promise for identifying sentinel nodes in oral cavity squamous cell carcinoma, allowing for completion lymphadenectomy in the same setting. Sentinel node biopsy and dissection remains an intriguing prognostic and potentially therapeutic option for malignancies with an intermediate risk of regional metastases, with increased diagnostic information compared to watchful waiting with serial imaging but sparing the morbidity of a full elective neck dissection in patients who end up with microscopically negative lymphatic basins. Keywords: melanoma, oral cavity squamous cell carcinoma, lymphoscintigraphy, gamma probe, tilmanocept, SPECT, immunohistochemistry Management of the clinically node-negative neck in patients with early-stage head and neck cancer remains controversial. A significant body of literature, culminating in a recent randomized trial, has proven there is significant risk of decreased survival and increased morbidity with a watchful waiting/observational approach for lesions with a relatively high (> 15%) rate of regional metastasis.1 However, this must be balanced with the morbidity of systematic cervical lymphadenectomy, which may include temporary or permanent lower lip weakness, shoulder dysfunction, lymphedema, chyle leak, and a long list of rarer neurological and vascular complications. This dilemma is magnified for lesions that approximate the midline, where bilateral neck dissections are under consideration. Sentinel node dissection and biopsy (SNB) involves the integration of radiologic and surgical techniques. While lymphoscintigraphy can be used alone for anatomic mapping of the drainage pathways of a lesion, evaluation of the true histopathological status of the lymph node is the only strategy for detection of micrometastases. Cross-sectional imaging studies such as computed tomography (CT), magnetic resonance imaging (MRI), and fused positron emission tomography (PET)/CT continue to improve in their sensitivity for regional lymphatic spread; however, they generally will not reliably identify metastatic disease less than 1 cm in size, and will almost never detect micrometastases less than 5 mm in size. Morton et al reintroduced the concept of sentinel node biopsy to surgical practice in publications describing the technical details and their early prospective clinical experience in patients with clinically N0 cutaneous malignant melanoma.2,3 After injection of vital blue dye at the primary site, 259 sentinel nodes were identified in 194 of 237 lymphatic nodal basins, and the incidence of false-negative sentinel nodes (i.e., the identified sentinel node is found to be disease free when metastatic disease is present in the regional lymphatic vessels) was less than 1%. The model of initial sentinel node biopsy with detailed pathologic analysis followed by completion dissection if positive has been subsequently validated for multiple head and neck subsites. Based on the work of Krag and Alex et al,4,5 modern sentinel node biopsy has been performed using peritumoral intradermal injections of radiotracers such as unfiltered technetium 99 m (99mTc) sulfur colloid and intraoperative gamma detection probes. This combined modality allows placement of the biopsy incision directly over the radiolabeled sentinel node (s), with dissection aimed directly at the most radioactive node without disturbance of surrounding tissues. Sentinel node biopsy in melanoma using the gamma probe resulted in retrieval of sentinel nodes in over 80% of cases, with a very low incidence of false negatives.6,7 Sentinel node retrieval has continued to improve to approximate 99% in more recent studies. In addition, nearly all authors have reported occasional unusual drainage patterns that would have been missed in standard cervical lymphadenectomy, particularly unexpected bilateral drainage for lateralized lesions, “skip” drainage to a more distant node in a group than might be anticipated, and drainage to multiple lymph node groups in the neck. As has occurred in clinically node-negative melanoma, sentinel node biopsy ultimately offers the possibility of identifying those patients with clinically N0 carcinomas of the other head and neck subsites, including aerodigestive tract sites, who harbor occult metastases in the cervical lymphatics. At this point, it has primarily been applied in the more accessible oral cavity site. It is important that an established negative predictive value (NPV) and false-negative rate (FNR) be available for each tumor type before incorporating it into routine clinical practice. In particular, the NPV is an important value that might be used in the informed consent process for an appropriate patient who might truly not harbor disease in his neck. The NPV for a particular tumor type should estimate the risk that a patient would recur in the neck after a negative sentinel node biopsy. Since selective neck dissection is an excellent technique for staging the cervical lymphatics, with moderate but generally acceptable morbidity, it is important that quality data be generated before accepting the less invasive sentinel node biopsy approach. On the other hand, particularly for oral cancer, patients presenting with relatively superficial lesions, perhaps estimated to be 1 to 3 mm in thickness, for which the cervical lymphatics would often be observed, sentinel node biopsy may theoretically represent a more aggressive approach for those who desire a more intense evaluation of the lymph nodes relative to what is currently standard. Reports from multiple large-volume centers have shown the benefit of sentinel node biopsy for patients with invasive, intermediate-risk clinically node-negative melanoma. This led to the creation of a phase III prospective trial termed the “Multicenter Selective Lymphadenectomy Trial (MSLT-1),” which randomized 2,001 patients with cutaneous melanoma of all subsites to either (1) wide excision and observation, with lymphadenectomy for nodal recurrence, or (2) wide excision and sentinel node biopsy, with immediate lymphadenectomy for positive nodal disease. Among patients whose lymphatic basins turned out to harbor micrometastases, in those with intermediate thickness (Breslow depth: 1.2–3.5 mm) melanomas, sentinel node biopsy significantly improved mean 10-year disease-free survival (71.3 vs. 64.7%), as well as rates of 10-year distant disease-free survival (hazard ratio: 0.62) and melanoma-specific survival (hazard ratio: 0.56). In addition, again only for those who actually harbored lymphatic metastases, sentinel node biopsy improved mean 10-year disease-free survival in patients with thick (> 3.5 mm) cutaneous melanoma (50.7 vs. 40.5%).8 National Comprehensive Cancer Network (NCCN) guidelines currently recommend sentinel node biopsy for N0 patients with cutaneous melanoma thickness of 0.76 to 1 mm and either ulceration or mitotic rate of ≥ 1 per mm2, and for all N0 patients with melanoma of thickness of greater than 1 mm.9 More recently, the second Multicenter Selective Lymphadenectomy Trial (MSLT-2) was performed in an effort to evaluate the utility of completion lymphadenectomy in patients with intermediate thickness cutaneous melanoma and positive SNB. A total of 1,934 patients with positive SNB were randomized to either (1) immediate completion lymphadenectomy or (2) observation with ultrasound. Patients with immediate lymphadenectomy had an increased rate of regional control (mean: 92 vs. 77%) and a slightly higher disease-free survival (mean: 68 vs. 63%), but had a nearly equivalent rate of melanoma-specific survival (86% in both groups). The authors suggest that any survival benefit from early surgery may occur in patients with disease limited to the sentinel nodes. The prognostic value of completion lymphadenectomy has to be weighed against the risk of complications, as MSLT-II showed a significant increase in the incidence of lymphedema (24.1 vs. 6.3%) in the lymph node dissection group.10 No anatomic subsite data were provided in this study. However, given the importance of avoiding the local effects of regional recurrence in the head and neck, and to a lesser degree the lymphedema that occurs relative to extremity melanoma, most authors still advocate completion lymphadenectomy for positive sentinel nodes in the head and neck region. Merkel cell carcinoma is a rare, aggressive neuroendocrine cutaneous malignancy that frequently arises in the head and neck. While increasing tumor size appears to be the main risk factor for lymphatic spread, even small (< 2 cm) lesions have high rates of regional metastases. Although there is conflicting evidence regarding a survival benefit to sentinel node biopsy in Merkel cell carcinoma, NCCN guidelines currently recommend SNB for all clinical N0 tumors due to improved prognostic information on regional control.11 Adjuvant radiation therapy appears to be associated with improved survival, and can be considered as an alternative to completion lymphadenectomy in sentinel node–positive patients.12 For larger, deeper lesions, elective lymphadenectomy should be considered, as the rate of sentinel node positivity is exceedingly high.13 The role of sentinel node biopsy in the treatment of cutaneous squamous cell carcinoma remains unclear. The NCCN recommends the consideration of SNB in certain high-risk lesions, “although the benefit of and indication for this technique has yet to be proven.”14 Systematic reviews have shown positive and negative predictive values of over 90%, with similar FNRs to that of melanoma.15,16 However, larger prospective trials are needed to validate the technique in this patient population. Most importantly, appropriate selection criteria delineating which squamous cell carcinomas are appropriate for the sentinel node procedure need to be identified. Aerodigestive tract malignancies show an increased propensity for regional metastases, especially lesions with high-risk features such as size greater than 2 cm, thickness greater than 3 to 4 mm, angiolymphatic invasion, and perineural invasion. Several analyses have shown a survival benefit to the prophylactic treatment of the N0 neck in early-stage head and neck squamous cell carcinoma (HNSCC), including a recent prospective trial that showed improved survival in patients with stage I/II lateralized oral cavity cancers who received unilateral elective neck dissection versus those who were observed and underwent therapeutic neck dissection if/when they developed N + disease.1 The risk of occult metastases must be weighed against the morbidity of neck dissections for patients, many of who will not have pathologic neck disease. Sentinel node biopsy offers a diagnostic technique to identify subclinical cervical metastases and is ideal for situations where the expected risk of metastases falls in the 5 to 15% range, which might be too high to feel comfortable with observation but too low to justify a full selective neck dissection. It also may be particularly useful for patients with stage 1 lesions of borderline size and thickness that approximate the midline, for whom the morbidity of bilateral neck dissection for clinically and radiologically negative cervical lymphatic basins is difficult to justify. Multiple centers in the United States and Europe initiated single-institution trials of sentinel node biopsy for upper aerodigestive tract malignancies in the 1990s and 2000s, mostly for oral cavity cancer, as this is the most accessible subsite, though some included oropharyngeal lesions as well. Studies consistently reported NPVs of 95 to 100%, similar to the rates seen in cutaneous melanoma. They also described unexpected patterns of lymphatic drainage, including unexpected contralateral drainage, and upstaging made possible by the identification of micrometastases via fine sectioning and immunohistochemistry (IHC) in 10 to 20% of cases.17 The importance of appropriate step sectioning and IHC of sentinel nodes to the accuracy of the technique has been emphasized in nearly every study. Christensen et al in 2010 performed an exhaustive step sectioning and IHC at 150 µm of the numerous nonsentinel nodes in their completion neck dissections from their validation trial after initial SNB and subsequent lymphadenectomy showed extremely low rates of additional occult metastases. In no case, with the additional fine sectioning of nonsentinel nodes, did they find a micrometastasis in a nonsentinel node in a patient with negative sentinel nodes.18 Only in one case with a positive sentinel node and positive nonsentinel node by routine technique was an additional micrometastasis found. This study validates the current algorithm of fine sectioning of sentinel nodes with IHC and routine analysis of nonsentinel nodes. In addition, in another review, Jefferson et al performed reexamination of 35 negative sentinel nodes from 10 patients and sectioned the nodes at 150 µm rather than the original 2-mm sections. In this study, they did not find any additional microcarcinomas, suggesting that the additional yield of finer than 2-mm sectioning is small.19 Clearly an additional micrometastasis may occasionally be found, and this infrequent occurrence could make a major difference for a patient. Currently, 150 µm sectioning is standard practice in Europe, but in North America the labor intensity of this practice is felt unjustifiable by most pathology departments, and 2-mm thick sections are more common. The first large European multicenter trial evaluating the accuracy of SNB for HNSCC was published in 2010. A total of 227 SNB procedures were carried out on 134 patients; 79 patients underwent SNB alone, while 55 underwent sentinel node-assisted neck dissection. The authors reported a 93% successful sentinel node identification rate, with a 95% NPV for sentinel node biopsy. Patients receiving SNB did not have significantly different long-term survival compared to patients receiving elective neck dissection, prompting the authors to conclude that SNB is a viable alternative to lymphadenectomy in N0 patients with early-stage HNSCC. There was concern that the technique was problematic for floor of the mouth tumors, as four of the five false negatives came from these patients.20 In order to formally validate sentinel node biopsy for oral cavity cancer, an NCI-funded trial was completed in North America under the auspices of the American College of Surgeons Oncology Group (ACOSOG). One-hundred forty patients with T1 or T2 clinically N0 oral cancer underwent lymphoscintigraphy with 99mTc sulfur colloid, nuclear imaging, and narrow-exposure SNB followed by immediate completion neck dissection. SNB with step sectioning and IHC had an NPV of 96% for all tumors, and an NPV of 100% for T1 tumors. The FNR was 9.8%. Investigators were categorized as experts who came in with significant numbers of cases versus intermediate users who took the animal course and were trained on the protocol. None of the false negatives occurred in the expert group of investigators on this study.21 Based on the strong validation data, it has been felt that it was appropriate to transition to sentinel node biopsy as primary neck management, in a research setting, for appropriately selected cases. A meta-analysis of 21 pooled validation studies and 847 patients showed an overall sensitivity of 93% for SNB.22 Techniques have been reported for accurate SNB for squamous cell carcinoma in the floor of mouth, alleviating a prior concern. These techniques do involve more extensive level I dissection to separate the lymphatic basins from the primary tumor. In 2015, the results of the EORTC-approved Sentinel European Node Trial (SENT) with SNB as primary neck management in oral cancer, with neck dissection for positive sentinel nodes only, was published. This was the first prospective trial to use SNB as the sole staging procedure in oral cancer, without concurrent END. Four-hundred fifteen patients with T1–2N0 HNSCC underwent SNB followed by neck dissection within 3 weeks if positive. A sentinel node was detected in 99.5% of cases; 109 of the 415 patients (26%) had occult metastases. SNB showed a sensitivity of 86% and an NPV of 95%. The disease-free survival for the cohort was 92%, prompting the authors to confirm SNB as a safe oncologic procedure. Unexpected contralateral lymphatic drainage occurred in 12% of cases, with seven positive contralateral sentinel nodes that would have been missed with an en-bloc unilateral neck dissection. The FNR was higher than expected at 14%, which is likely related to technical issues in a multi-institutional trial consisting of a large group of surgeons with a variety of techniques and experience levels. The authors in their discussion imply that this number would come down with continued refinements in technique.23 Multiple single institution studies looking at SNB with completion neck dissection only for positive sentinel nodes have also been completed concurrent with this trial and are detailed in An appropriate patient for sentinel node dissection is one with a small, injectable lesion that carries a significant risk of lymphatic micrometastases but a relatively low risk of distant metastases. In the head and neck region, SNB is standard for intermediate-thickness melanoma. It can be used for stage 1 melanoma, but the yield of micro metastases is low and it usually is not justified in this group without other risk factors. On the other hand, for deeply invasive melanoma with greater than 4 mm depth of invasion, the traditional concept is that high risk of distant disease makes prophylactic treatment of lymphatic micrometastases irrelevant. The MSLT-1 trial calls the latter concept into question, as significant benefits in terms of regional control, reduced morbidity, and increased disease-free survival may occur even in this group. For cutaneous lesions of other histologies, the criteria are less well defined in the literature, and surgeons tend to extrapolate from the experience in melanoma. In cancer of the oral cavity, criteria for sentinel node biopsy remain controversial. The standard approach in 2017 is selective neck dissection for all significantly invasive lateralized lesions (stage 1 and above) and watchful waiting for extremely thin stage 1 lesions. Thickness estimates are based on physical examination and generous biopsy of the thickest appearing portion of the lesion. Management of midline stage 1 lesions of intermediate thickness may represent an area of continued controversy. The “most aggressive” advocates of sentinel node biopsy argue for SNB for all N0 patients, stages I and II. We believe a reasonable way to apply this technology is to use it in those situations where watchful waiting has been applied frequently, but where a reasonable argument could also be made for selective neck dissection. This would certainly include stage I and early stage II tumors with an intermediate depth of invasion, corresponding to estimates of 2 to 4 mm depth of invasion, and stage 1 midline lesions with even thicker depths. It could be offered as an alternative to neck dissection for lateralized lesions with estimated depths up to 8 mm, for patients who are concerned about the morbidity of neck dissection, with caveats related to small false omission rates (the NPV subtracted from 100), and the need to perform two stages of surgery when sentinel nodes are detected to be positive on final pathology. The bulk of patients in the ACOSOG validation trial were in this last group. With greater experience and larger published clinical trials on SNB, the proper group for selection will be better delineated. Since early cancer of the oral cavity has a smaller risk of distant metastases than melanoma, the manner in which these patients need to be approached is somewhat different from the way we approach melanoma patients. We do not want to lose the opportunity for cure with timely lymphadenectomy, but need to balance this against the morbidity of formal neck dissection in numerous patients who do not harbor lymphatic metastases. Multiple series have confirmed that the technique is not appropriate for T3 and T4 primary tumors due to the significant volume of tissue that would need to be injected, the excessively large number of radioactive nodes generated, the greater risk that grossly positive nodes exist, the potential for false negatives due to incomplete injection, and the technical futility of removing a large number of nodes in piecemeal fashion. Furthermore, since the risk of having a positive node increases with increasing stage, there comes a point where the percentage of patients who will convert to neck dissection is too large to justify the SNB procedure. To the contrary, the technique is best applied to T1 lesions and smaller T2 lesions. If a lesion is less than 3 cm in maximal 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. If the primary tumor meets criteria, the next issue is to determine whether the cervical lymph nodes are clinically involved. While SNB is an excellent technique for detecting micrometastases, it is less useful for detecting nonpalpable but grossly involved lymph nodes. This appears to be particularly true with squamous cell carcinoma. It is postulated that when a large percentage of the lymph node is replaced by cancer, physiologic obstruction can occur and alternative patterns of lymphatic drainage develop. It is important to detect the presence of such gross disease on preoperative imaging and physical exam and, as a last opportunity, at the time of intraoperative palpation. We should avoid applying SNB to this group of patients in order to avoid false positives. Generally, contrast-enhanced CT or MRI are the cross-sectional imaging modalities most commonly used. These should be strictly interpreted, and patients should be excluded if there are nodes greater than 1.2 to 1.5 cm in size with central necrosis, irregular enhancement, or a poorly defined or irregular capsular border, or with groups of three or more asymmetrically located lymph nodes with a minimal axial diameter of 8 mm or more in the suspected tumor drainage area. Fused PET/CT is also useful in ruling out regional metastases greater than 1 cm, but remains plagued by false positives and should be evaluated with some skepticism, particularly if the PET scan is performed shortly after an oral biopsy or if superinfection of the tumor is suspected. Inflammatory nodes can have elevated SUV values and patients may be inappropriately denied the opportunity for a SNB approach. The injection is performed prior to the surgical procedure, generally on the morning of surgery. Injection can also sometimes be performed late on the day before, although the effect of this on the success rate of sentinel node identification is still unclear. While awake injection and imaging in radiology is the most commonly used technique, 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 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 increase the reliability of this method. Taking into account that the radio localization of the detected hot spots does not represent the drainage of the primary but rather the drainage of the tracer deposits, which act as a surrogate for the lymphatic drainage of the primary, the impact of a thorough and representative tracer injection is evident. Due to the density and direction of the head and neck lymphatics, the primary may drain into several alternative lymphatic pathways, all representing first echelon “sentinel” lymph nodes ( Nevertheless, due to regulatory issues related to the injection of radioactive substances and the scarcity of widely available portable nuclear imaging, awake injection remains the most commonly used technique. It is important to ensure that the patient is comfortable so that an adequate preoperative injection is obtained. We use topical anesthetic, mild oral sedation, and/or lingual, inferior alveolar, 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 on a tuberculin syringe, circumferentially encompassing the leading edge of the lesion and, for thicker lesions, an additional injection in the center of the lesion. Typically, we have used five tuberculin syringes with 1 mL aliquots of technetium 99 sulfur colloid, similar to doses used for melanoma, with a total radioactivity of 400 millicuries representing a standard dose for the morning of surgery. A higher dose would be used the night before. More recently, we have begun using 99mTc tilmanocept, a CD206 receptor targeting pharmaceutical, instead of technetium sulfur colloid. The receptor targeting nature of tilmanocept eliminates the shine-through effect that may be seen with radiolabeled colloids that are retained for long periods of time at the injection site. Also, tilmanocept appears to have greater retention in first echelon nodes with less movement downstream due to its receptor binding properties, and appears to have greater flexibility in the timing of imaging and surgery (same day vs. next day). One phase III multi-institutional trial has shown lower FNRs and greater accuracy with 99mTc tilmanocept when compared to 99mTc sulfur colloid.28 Peritumoral injection with 50 μg of 99mTc-tilmanocept within 15 hours (same day) or between 15 and 30 hours of surgery (next day) is accomplished in a similar manner as described earlier.
21.1 Introduction
21.2 Sentinel Node Biopsy for Cutaneous Malignancies
21.2.1 Melanoma
21.2.2 Merkel Cell Carcinoma
21.2.3 Cutaneous Squamous Cell Carcinoma
21.3 Sentinel Node Biopsy in Oral Cavity and Aerodigestive Tract Malignancies
Table 21.1.24,25,26,27 All studies report acceptable NPV, and several larger trials report significantly lower FNRs, in the range of 6 to 9%, indicating that technical factors may explain some of the variations in data. It should be mentioned that in smaller series with few positive sentinel nodes, one false negative could skew the FNR tremendously.
21.4 Surgical Technique: Practical Guidelines
21.4.1 Patient Selection
21.4.2 Injection of the Primary Tumor
Fig. 21.1).
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