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Sentinel lymph node biopsy for cutaneous head and neck malignancies Expert Rev. Anticancer Ther. Early online, 1–11 (2014)
Sunshine Dwojak and Kevin S Emerick* Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA and Department of Otology and Laryngology, Harvard Medical School, Boston, MA, USA *Author for correspondence: Tel.: +1 617 573 4084 Fax: +1 617 573 4131 [email protected]
Sentinel lymph node biopsy (SLNB) is a procedure that can provide critical information regarding pathologic lymph node status and accurate regional staging. This is very important for developing treatment plans and providing prognostic guidance for cutaneous malignancies. The head and neck (HN) region is unique from other body sites due to its complex lymphatic drainage pathways, multiple lymph node basins, proximity of important cranial nerves and potential for contralateral or bilateral drainage. These unique aspects of the HN previously created some uncertainty about the use of SLNB in the HN. This review will discuss the current reliable status of HN SLNB and provide a guide for its current application in cutaneous malignancy of the HN. KEYWORDS: cutaneous squamous cell carcinoma . head and neck cancer . lymph node metastasis . melanoma .
Merkel cell carcinoma
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sentinel lymph node biopsy
Most cutaneous malignancies metastasize via the lymphatic channels to the regional lymph nodes. Metastases are detected in lymph nodes by palpation on physical examination and by imaging. These methods are excellent for detecting macroscopic metastasis, where the volume of disease has grown to a level that is large enough to see radiographically or palpate. Thin cut computerized tomography (CT) and PET imaging can detect tumor metastasis beyond this threshold, on the order of 7–10 mm in size. However, we now recognize that identification of microscopic metastasis, beyond the detection level of physical examination and imaging, plays an important role in the management and outcome for patients with cutaneous malignancies. Gould et al. brought the concept of a sentinel node to the forefront in the 1960s [1]. For cutaneous lesions, they suggested that a specific area of skin would drain preferentially to specific lymph nodes. Therefore, a malignancy involving this skin would also drain to these lymph nodes first. Morton et al. applied lymphatic mapping and lymphoscintigraphy to this model [2]. They proposed and demonstrated that by injecting blue dye and later radiolabeled molecules into the skin, the material would migrate to these sentinel nodes.
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The nodes could be identified by the blue color and removed for histopathologic analysis. From this early work, the technique has been further refined and modified to take on an important role in the management of cutaneous malignancies [3]. This review will focus on the evolution of the technique for head and neck (HN) sentinel nodes and the current application for HN cutaneous malignancies. Evolution of sentinel lymph node biopsy technique in the HN
Generally, lymph node basins in the HN are categorized into levels I–V (FIGURE 1). However, this categorization excludes other at-risk lymph node basins, such as the external jugular chain, the parotid gland and the post-auricular and suboccipital lymph nodes. A new classification system for HN tumors has been developed, which includes these lymph nodes and divides them into 10 groups (FIGURE 2) [4]. This new classification allows for greater specificity in describing and treating metastatic tumors of the HN. HN lesions have a predictable drainage pattern; however, that pattern may include multiple lymph node basins. In comparison, areas such as the upper extremity will only drain to the axilla. Adding to this complexity, the early
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Figure 1. Head and neck lymph node basins. (A) The traditional I–V levels for aerodigestive tract malignancies and other head and neck primary tumors. (B) Additional at-risk lymph node basins to consider for head and neck cutaneous malignancies.
technique of Morton et al. used blue dye exclusively. It involved making an incision over the expected drainage area and visually observing the arrival and presence of the dye. Therefore, in the HN region it was difficult to know exactly which basin to look in to identify where the blue dye was arriving. This complex lymphatic drainage, as well as the limitations of the early technique, led people to believe that sentinel lymph node biopsy (SLNB) had limited utility in the HN region [2,3]. The addition of radiotracers to the technique was important for all sites, but especially for the HN. The lymphoscintigram is a raw, 2D image with limited detail. It provides direction and laterality to the location of interest (FIGURE 3). Since many HN lesions are near the midline, there is always the potential for
VIII (pA)
bilateral drainage. The lymphoscintigram can help identify a node on the right or left side of the neck. There are additional limitations of this technique in the HN. The injected isotope travels quickly, and can be taken up by multiple lymph nodes in a short period of time. It is also common for the tracer injected into the primary site to mask the sentinel lymph node because of the proximity of the tumor to the draining node [5]. It is for these reasons that hybrid single-photon emission computed tomography (SPECT)/CT, which combines the nuclear imaging with CT, has been used. In this technique, the lesion is injected with the radiotracer and then the patient is imaged using a combined CT and a gamma camera. This fuses the anatomic image of the CT with the functional image of the lymphoscintigram. Fusing these modalities provides much better preoperative and 3D localization [6]. Because of the number of lymphatic basins in the HN compared with other subsites, and the potential 3D overlap of these basins, SPECT/ CT is uniquely helpful in the HN region [7]. The addition of radiolabeled molecules also facilitated the introduction of the hand-held gamma probe. The hand-held gamma probe is a radiation detector that provides a count rate from gamma rays. This tool provides additional intraoperative guidance to the location and direction of the dissection. In the technique described by Morton et al., the gamma probe is moved systematically over the potential drainage basin to confirm the site of dissection. The gamma probe is then used to guide dissection by following the radioactivity. After a node is identified and dissected, the counts are checked [8]. Removing only the hottest node leaves behind approximately 15% of the true sentinel nodes. Therefore, removal of all nodes with greater than 10% of the hottest node’s radioactivity is recommended [8,9]. These additional techniques have been shown to help alter surgical approach and increase the yield of positive sentinel lymph nodes. Typically, one would consider the type of VIIa
Xa (Mt)
VIII (siP) Xb Xa (sA) II (Kütner)
VIII (diP) IX (M) IX (B) IX (F)
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Figure 2. Revised head and neck lymph node basins. Reprinted with permission from [4] Elsevier.
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SLNB for cutaneous HN malignancies
lymphadenectomy that would be needed if a positive sentinel node was identified. The incision for this type of procedure can then be drawn out. The location of anticipated dissection can then be identified with the hand-held probe and small incisions along the potential future incision can be made (FIGURE 4). This allows a minimally invasive approach without compromising future surgical incision planning [10]. There are two specific settings in the HN, where SPECT/ CT localization is particularly valuable, distinguishing parotid versus level II nodes and distinguishing external jugular chain versus internal jugular chain nodes. Consider a sentinel node in the tail of parotid; both lymphoscintigraphy and the g probe will direct the surgeon to an area over the tail of parotid. However, a high level II, and especially level IIb, lymph node localize in the same way with these two modalities. In this case, the SPECT/CT provides depth information to show if the node is in the tail of parotid and superficial to the sternocleidomastoid muscle (SCM), or if it is in level II deep to the SCM (FIGURE 5). Knowing this information allows the surgeon to make an appropriate incision and dissect directly to this region. Similarly, SPECT/CT is helpful in distinguishing internal versus external jugular chain lymph nodes. The CT image defines if the node is superficial or deep to the SCM (FIGURE 6). This changes incision planning. The incision to access the internal jugular chain lymph nodes is placed at the anterior border of the SCM and dissection is directed medial to the SCM. However, when dissecting along the external jugular chain, a small incision is made directly over the area of uptake with the g probe. Since the dissection is not very deep, a particularly small incision can be utilized. The evolution of this technique with lymphoscintigraphy, hand-held gamma probes and SPECT/CT has helped to make SLNB in the HN a very reliable technique equivalent to other sites in the body. Experience is also critical to the reliability of this technique. Early work by Morton et al. demonstrated that their own surgical technique became more reliable with experience, and that the technique was more reliable in the hands of a senior surgeon than an inexperienced junior surgeon [3]. This was also documented as part of the Multicenter Selective Lymphadenectomy Trial 1 (MSLT-1) [11]. It took surgeons 50 procedures to reach an accepted level of proficiency. Today, surgical oncologists who come from a background in general surgery as well as otolaryngology perform HN SLNB. There are a growing number of dedicated HN surgical oncologists from an otolaryngology background performing SLNB. Current applications
SLNB in the HN should be considered as safe, reliable and feasible as any other body site. Consideration for performing SLNB should be offered in the HN region as it would be in any other body site. When trying to identify who should undergo a SLNB, there are two basic principles to consider. Consideration should be given to any cutaneous malignancy that carries a 10% risk or greater of occult lymph node metastasis. Second, the information from SLNB should provide guidance on treatment informahealthcare.com
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Figure 3. Lymphoscintigram. A representative lymphoscintigram following injection of a right cheek primary melanoma. The drainage is in multiple nodes involving multiple possible areas that are difficult to distinguish.
management decisions and/or prognostic information that is important to the patient or clinician. Using these two principles, we will discuss the current application of HN SLNB for melanoma, Merkel cell carcinoma (MCC), cutaneous squamous cell carcinoma (cSCC) and unique periocular lesions. Melanoma
With 76,000 new cases each year and approximately 9500 deaths, melanoma is the fifth most common cancer in the USA [12]. The mainstay of treatment is surgical with wide local excision. Elective lymph node dissections were routinely performed for all melanomas, as nodal metastasis is the most significant predictor of survival [13]. However, a lymph node metastasis was only found 20% of the time [14]. This experience was one of the driving forces for the development of SLNB in cutaneous malignancy. Surgical treatment of melanoma has evolved and now integrates SLNB into routine management consideration. SLNB in melanoma has been shown to be effective at identifying metastatic disease, providing important staging and prognostic information, and to help guide therapeutic management for malignant melanoma [2,15]. Data from intermediate-thickness melanoma helped define the standard of care for treatment. Defined as a Breslow thickness of 1–4 mm, intermediate-thickness melanomas have a 20–25% risk of occult nodal metastasis [16]. The MSLT-1 compared wide local excision plus SNLB and lymphadenectomy with wide local excision plus nodal observation with lymphadenectomy only when macroscopic metastasis presented at a later time. Data from this trial corroborated other prospective trials showing that SLNB was feasible; a sentinel node was identified in 95% of patients [17]. It also demonstrated that a positive SLN was predictive of survival, with a hazard ratio (HR) of 3.19 for SLN-positive patients compared with SLN-negative patients [18]. doi: 10.1586/14737140.2015.990441
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Figure 4. Incision planning. (A) Typical incision used for combined parotidectomy and levels I–IV neck dissection. (B) Small preauricular incision can be used to access preauricular parotid lymph node. (C) Small incision along neck portion of the incision used to access a periparotid lymph node just inferior to the tail of parotid.
The 10-year follow-up data for MSLT-1 confirms that SLNB and subsequent treatment significantly affects survival for patients with intermediate-thickness melanoma. The study found no significant difference in 10-year melanoma-specific survival for all study participants. However, SLNB was associated with a significant increase in 10-year disease-free survival (71 vs 64%; p = 0.01). For those patients with a positive node, SLNB followed by lymphadenectomy improved the 10-year rate of distant disease-free survival (HR: 0.62; p = 0.02) compared with those who developed macroscopic lymph node metastasis [19]. Current joint guidelines from the American Society of Clinical Oncology and the Society of Surgical Oncology, as well as the revised 2013 National Comprehensive Cancer Network (NCCN) guidelines support these findings with their recommendations that SLNB be performed for all patients with cutaneous melanoma with a Breslow thickness of >1 mm [11,20].
A
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Figure 5. Parotid versus level II lymph node single-photon emission computed tomography/computerized tomography. These images highlight the ability of single-photon emission computed tomography/computerized tomography to distinguish a tail of parotid node from a level IIb node. These two nodes are indistinguishable by lymphoscintigraphy or gamma probe. (A) The bright area on this image is a level IIb lymph node. Note its location deep to the sternocleidomastoid muscle. (B) The bright area on this image is in the tail of parotid. This node is superficial to the sternocleidomastoid muscle and within the parotid tissue.
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A different role has been established for SLNB in thick melanoma, defined as Breslow thickness >4.0 mm. Multiple studies have established that the SLNB outcome is a significant predictor of overall survival in thick melanoma [21–25]. In addition, lymphadenectomy after SLNB-positivity has been shown to improve regional control compared with therapeutic dissection after clinical recurrence [26,27]. However, with rates of metastatic involvement between 30 and 50%, SLNB with lymphadenectomy has minimal benefit on overall survival [22]. Recent data from the MSLT-1 trial confirm that in patients with thick melanoma, >3.5 mm, there is no difference in 10-year disease-free or melanoma-specific survival when patients with a positive SNLB undergo immediate lymphadenectomy [19]. This new, long-term data support the current NCCN recommendation that SLNB be used for staging purposes and for local control in thick melanoma [11]. In the future, as new targeted treatments like ipilimumab and vemurafenib become widely available, the staging and prognostic information from SLNB in thick melanoma will likely become more important. The data are less clear and evolving for the role of SLNB in thin melanoma, defined as Breslow thickness 1 mm2 has also been shown to have an independent adverse effect on survival, but this factor does not consistently correlate with sentinel node positivity [28,31–33]. Breslow thickness has been shown to most consistently predict prognosis and SLN positivity [29,30,34,35]. For the subset of melanomas 0.75–1.0 mm, the rates of nodal metastasis are higher (5–11%) with a much higher probability of finding a positive SLN [29,36]. Han et al. in a large review of over 1000 patients with thin melanoma found that using Breslow thickness >0.75 mm alone would encompass the majority of patients with negative prognostic features and positive SLN [30]. Currently, the official NCCN and American Society of Clinical Oncology-Society of Surgical Oncology guidelines do not recommend SLNB for very thin lesions. The guidelines do suggest consideration of SLNB in thin melanoma 0.75–0.99 mm with ulceration or mitotic rate ‡1 mm2 [11,20]. These guidelines for melanoma management should be applied to the HN region as any other subsite (BOX 1). Three large single-institution reviews of SLNB for melanoma in the HN region show the technique is accurate, has low morbidity and has prognostic utility [36–38]. Despite bilateral drainage in 31% of patients, the sentinel node was identified in 96–98% of patients with a false omission rate comparable to other sites of the body of 1.4–4.5% 35. As would be anticipated in such a study group, 18–20% had a positive SLN, and this significantly correlated with overall and disease-free survival [36–38]. Merkel cell carcinoma
The successful use of SLNB in melanoma has led to its wider use in non-melanoma skin cancer. MCC is a much rarer skin tumor, with approximately 1500 new cases in the USA every year [39]. It arises from neuroendocrine cells in the basal layer of the skin and is causally associated with an oncogenic virus, Merkel cell polyomavirus [40–42]. MCC is predominantly a disease of older, white men with significant sun exposure [43,44]. Organ transplant patients and other immunocompromised patients are also at risk for MCC [45–47]. The HN is the most common region of presentation, accounting for 29–50% of the cases. The face, scalp, neck and lip are the most common sites [48,49]. The clinical course of MCC is quite aggressive with a combined 5-year overall survival of 30–60% [50–52]. Survival depends on stage, with the presence of regional lymph node involvement being the most significant predictor of survival. Five-year survival is 64% for local disease, 39% for regional nodal disease and 18% for distant metastatic disease [53–55]. Nodal recurrence rates for patients presenting without clinical lymphadenopathy are high, from 50 to 95% [56,57]. This nodal recurrence carries with it a 30–40% disease-specific mortality. This recurrence rate suggests a high rate of occult lymph node metastasis. Considering the importance of lymph node status on survival and the high propensity for occult metastasis, pathologic nodal staging and locoregional treatment is essential. This staging information provides prognostic information and can help guide and personalize treatment. Current NCCN guidelines recommend SLNB in the clinically N0 neck for MCC. PET CT is recommended as the imaging of choice in the evaluation of regional metastasis based on high sensitivity (90%) and specificity (98%), and the potential to upstage the disease [58,59]. Several studies have shown informahealthcare.com
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Figure 6. External jugular chain lymph node single-photon emission computed tomography/computerized tomography. This intense node is along the external jugular chain just inferior to the parotid gland. Note it is superficial to the sternocleidomastoid muscle but still over the sternocleidomastoid muscle and additional images would further show that it is just inferior to the parotid.
that SLNB for MCC is feasible with a SLN-positive rate of 19–38%, and an acceptable false-negative rate similar to melanoma [60–62]. Studies have also implied that SLNB may improve survival by allowing early adjuvant treatment. Gupta et al. found an improved relapse-free survival for those with a positive SLN (60 vs 0%; p < 0.01) [63]. However, the data on the prognostic implication of SLNB in MCC are mixed, and it is unclear if it carries the same prognostic guidance as it does for melanoma [64]. A report from Memorial Sloan Kettering found that SLN-positive patients received more adjuvant therapy, however, their 2-year recurrence and survival rates were not significantly different (12 vs 12%; p = 0.86 and 6.1 vs 5.7%; p = 0.89) [65]. A recent SEER review showed in a multivariate analysis that SLNB of the HN did not predict survival (HR: 2.37; p = 0.139) compared with other sites (HR: 2.71; p = 0.001) [66]. In contrast, a recent meta-analysis of SLNB in all subsites found that a positive SLNB predicted worse overall (HR: 4.42; p < 0.001) and disease-free survival (HR: 2.58; p < 0.001). Subgroup analysis was performed to examine the potential difference in the HN region. This did not show any difference in prognosis for the HN subsite compared with other sites. This review also supports the hypothesis that there is a disease-free survival benefit to SLNB compared with observation (HR: 1.64; p = 0.028) [67]. This is an important consideration as the morbidity of uncontrolled regional disease can significantly worsen a patient’s quality of life even in the palliative or end of life setting. doi: 10.1586/14737140.2015.990441
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Box 1. Indications for sentinel lymph node biopsy in head and neck melanoma. Indications for sentinel lymph node biopsy for melanoma .
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Very thin: Breslow thickness 1/mm2 Thin: Breslow thickness ‡0.75–0.99 mm Intermediate: Breslow thickness 1–4 mm Thick melanoma: Breslow thickness >4 mm (currently indicated for staging and regional control) Unknown complete depth when 2 mm thickness, Clark level ‡4, primary site of the ear or lip, perineural invasion and poorly/undifferentiated tumor grade. Presence of these factors predicts a much higher metastatic rate between 11 and 50% [74]. This is an important step in the attempt to better stratify these patients; however, more accurate prognostic data are needed to better refine this risk stratification. In one of the largest single institution reviews, Schmults et al. recently published a study that further define high-risk features for cSCC. It refines the staging system specifically creating a T2b group that captures the group with a higher risk of lymph node metastasis [75,76]. This study showed that tumor diameter ‡2.0 cm, poorly differentiated histology, perineural invasion and tumor invasion beyond fat were all associated with lymph node metastasis and decreased disease-specific survival. From these data, the group established a new staging system (TABLE 1). The key classification of interest for SLNB are the T2b and T3 groups. These groups have a 21 and 67% risk of lymph node metastasis, respectively. This system has been further compared with the existing American Joint Committee on Cancer and Union for International Cancer Control staging systems. The comparison showed that the Brigham and Women’s Hospital (BWH) system creates more distinct subgroups that better predict outcome [77]. Current NCCN treatment recommendations for cSCC tumors with features that increase the risk for occult metastasis include obtaining surgical resection with clear margins at the Expert Rev. Anticancer Ther.
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SLNB for cutaneous HN malignancies
primary site followed by quarterly physical examinations that include a regional lymph node assessment. Adjuvant radiation should be considered for lesions with multiple high-risk factors and perineural spread in particular. The presence of lymph node metastasis changes prognosis and management significantly. The presence of regional metastasis carries with it a significantly reduced 5-year survival of 26–50%. Treatment for metastatic cSCC is lymphadenectomy in addition to surgical resection of the primary lesion and adjuvant radiation to both areas. Current protocols in many institutions adopt practices similar to what is applied to SCC of the aerodigestive tract. The addition of concurrent chemotherapy with a cisplatin-based regimen is considered in the setting of a positive margin, number of nodes involved and the presence of extracapsular extension. However, the biology of these tumors is likely very different and the aerodigestive tract experience is likely not directly translatable. This is an important area for future investigation. Given the poor survival for metastatic cSCC compared with the very curable non-metastatic cSCC, there is a natural interest in the potential role of SLNB. This interest is further enhanced when considering recent data showing that patients with a single small metastasis 2 cm, poorly differentiated, perineural spread (>1 mm diameter), invasion beyond the subcutaneous fat. † Sentinel lymph node biopsy is recommended for T2b and T3 lesions.
the study of follow-up time [82,83]. These studies show promise, but they are small in nature with limited follow-up. We anticipate ongoing prospective studies will help provide more definitive data on the impact of SLNB on regional control and survival. Since occult cSCC is much more radiosensitive than melanoma, SLNB outcome could be used in a variety of ways similar to MCC. For example, one could potentially consider lymphadenectomy, radiation or lymphadenectomy and radiation for those with a positive SLNB. The optimal treatment will hopefully be answered in the next few years. Australia is embarking on a randomized controlled trial, SNIC-1, that randomizes patients to traditional surgery with observation or SLNB followed by lymphadenectomy or radiation therapy if the SLNB is positive. This RCT, as well as attempts to uniformly collect prospective data, will shed light on much of the current uncertainty regarding SLNB for cSCC. Periocular tumors
A last area that is uniquely applicable to the HN region is periocular tumors. The conjunctiva and periocular region has a unique set of tumors that also meet the criteria mentioned at the outset of this section for considering SLNB. This includes the histologic subtypes described above as well as less common tumors such as sebaceous cell carcinoma. The first key question in this setting is feasibility and reliability. A few studies have now shown the technique to feasibility [84,85]. It is important that this procedure be coordinated between an ophthalmologist, the nuclear medicine physician and the surgical oncologist performing the SLNB. The ophthalmologist plays an important role providing their expertise in performing injections in these sensitive areas that most nuclear medicine teams are not comfortable injecting. The second important question is whether this is a reliable technique. Does SLNB status actually represent the status of the lymph node basin and does the conjunctiva drain in a reliable manner similar to skin? Given the small experience to date, this question cannot be answered. In the largest series (30 cases) of conjunctival melanoma from MD Anderson, they identified a positive SLN in 5 patients [85]. This suggests that there is some reliability to the procedure. Additional long-term doi: 10.1586/14737140.2015.990441
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Box 2. Indications for sentinel lymph node biopsy in head and neck Merkel cell carcinoma. Considerations for sentinel lymph node biopsy for Merkel cell carcinoma .
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Sentinel lymph node biopsy should be considered for all Merkel cell carcinoma in the absence of clinically apparent nodal disease Utilize for lesions near midline to identify possible contralateral involvement Utilize sentinel lymph node biopsy result to determine radiation dosage
Adapted from [86].
follow-up assessing for regional recurrence in patients with negative SLNB is not available. Given the small volume of tumors occurring in this location, definitive data and guidance will likely not be achieved. Based on the limited experience to date, SLNB does appear to be feasible in this location and one should consider using SLNB for tumors with a significant risk of occult metastasis. Expert commentary
SLNB plays an important role in the management of HN cutaneous malignancy. This technique has evolved over the years and is now accepted to be as safe and reliable as other body subsites. The key to this evolution has been the introduction of technology and surgical experience. The hand-held gamma probe is a critical piece of technology. This alone can greatly help localize the location of hot lymph nodes. Given the multiple potential lymph node basins on both sides of the body, this tool can be critical for incision planning and then ultimately guiding dissection. SPECT/CT greatly augments this localization. This is perhaps uniquely important to the HN region. The 3D definition provided by this modality is very helpful. In particular, SPECT/CT can distinguish a level II node from a parotid node. This is critical for incision planning, approach to dissection and patient preparation regarding potential risk to the facial nerve or the spinal accessory nerve and hypoglossal nerve. Similarly, it can distinguish an external jugular chain node from an internal jugular chain node. This information preoperatively directs incision planning and facilitates an efficient dissection. Surgeon experience is also a key to the success and safety of the procedure. Today, this procedure is primarily performed by dedicated HN surgical oncologists who are intimately familiar with parotid and neck lymph node basin anatomy. These surgeons routinely perform parotidectomy and neck dissection providing critical translatable skills. SLNB should be applied to tumors with a high risk of occult metastasis. This includes thin melanoma with high-risk features, intermediate and thick melanoma, MCC and T2b cSCC. Lesions near the midline should also be included. Historically, some preferred not to map these patients due to the high likelihood of bilateral drainage. Similarly, lesions with a
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high likelihood of parotid drainage should be included. In experienced hands, parotid SLNB is safe and reliable. However, the potential risk of facial nerve injury does highlight the necessity of an experienced parotid HN surgeon in order to make this a safe procedure. The overall morbidity of SLNB is minimal when compared with clinical lymphadenectomy. Reported risks include wound separation (0.2–1.2%), lymphedema (0.6–0.7%), seroma/hematoma (2.3–5.5%) and surgical site infection (1.1–4.6%) [8]. The overall operative time is short and the procedure is done on an outpatient basis. Additionally, the incisions are typically small and well hidden in natural creases. Unlike axillary and groin dissection, there is no lymph edema following surgery. Five-year view The immediate future of SLNB in the HN centers on the question of whether or not SLNB is therapeutic. When a SLNB is positive, is additional lymphadenectomy needed? There is currently a prospective multicenter study, MSLT-2, which will help address this question for melanoma. The question may be even more relevant for MCC and cSCC since they are much more radiosensitive. If SLNB identifies occult lymph node metastasis, there is at least a 20% chance of other occult lymphadenopathy. For MCC and cSCC completion, lymphadenectomy followed by radiation is potentially equivalent to radiation alone for this type of microscopic disease. Avoiding lymphadenectomy will help decrease the morbidity of overall treatment for these patients. However, it will be important that we measure regional control as well as survival when we study this question. Uncontrolled regional disease can significantly worsen quality of life in some with distant metastasis. The next few years will hopefully provide more definitive guidance on the exact role of SLNB for cSCC. Further experience will provide data to refine the true primary tumor features that predict a higher rate of lymph node metastasis. Additionally, the role of immunosuppression as a risk factor for occult metastasis needs to be better understood. The information from SLNB in this patient population could be critical for transplant management as well. Ultimately, SLNB will not be needed. The genetic fingerprint of a tumor will likely best predict the potential risk for occult lymph node metastasis. Initially, this may provide a new set of inclusion criteria for the procedure. As cancer treatment evolves, this information alone may guide treatment without the need for pathologic confirmation. However, this evolution is likely beyond the next 5 years. Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.
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SLNB for cutaneous HN malignancies
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Key issues .
Sentinel lymph node biopsy (SLNB) in the head and neck (HN) is safe and reliable.
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Lymphoscintigraphy combined with single-photon emission computed tomography/computerized tomography and use of the hand-held g probe are important tools to increase the success of HN SLNB.
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Single-photon emission computed tomography/computerized tomography is particularly important for distinguishing parotid from level II nodes as well as EJ from IJ nodes.
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SLNB should be applied based on histologic features and not avoided due to location near midline or potential for parotid
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drainage basin. .
Clear guidelines exist for the application of SLNB in melanoma.
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SLNB has an evolving role in the management of cutaneous squamous cell carcinoma and should be considered for lesions that have features which increase the risk of occult lymph node metastasis.
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SLNB for Merkel cell carcinoma can provide important guidance for management but must be used in the context of a multidisciplinary group to be sure the information gained from the procedure will impact management.
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SLNB can be used for periocular tumors including those on the conjunctiva.
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Becker JC, Houben R, Ugurel S, et al. MC polyomavirus is frequently present in Merkel cell carcinoma of European patients. J Invest Dermatol 2009;129:248-50 Popp S, Waltering S, Herbst C, et al. UV-B-type mutations and chromosomal imbalances indicate common pathways for the development of Merkel and skin squamous cell carcinomas. Int J Cancer 2002;99:352-60 Albores-Saavedra J, Batich K, Chable-Montero F, et al. Merkel cell carcinoma demographics, morphology, and survival based on 3870 cases: a population based study. J Cutan Pathol 2010;37(1): 20-7 Koljonen V, Kukko H, Tukiainen E, et al. Incidence of Merkel cell carcinoma in renal
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Sentinel lymph node biopsy for cutaneous head and neck malignancies Expert Rev. Anticancer Ther. Early online, 1–11 (2014)
Sunshine Dwojak and Kevin S Emerick* Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA and Department of Otology and Laryngology, Harvard Medical School, Boston, MA, USA *Author for correspondence: Tel.: +1 617 573 4084 Fax: +1 617 573 4131 [email protected]
Sentinel lymph node biopsy (SLNB) is a procedure that can provide critical information regarding pathologic lymph node status and accurate regional staging. This is very important for developing treatment plans and providing prognostic guidance for cutaneous malignancies. The head and neck (HN) region is unique from other body sites due to its complex lymphatic drainage pathways, multiple lymph node basins, proximity of important cranial nerves and potential for contralateral or bilateral drainage. These unique aspects of the HN previously created some uncertainty about the use of SLNB in the HN. This review will discuss the current reliable status of HN SLNB and provide a guide for its current application in cutaneous malignancy of the HN. KEYWORDS: cutaneous squamous cell carcinoma . head and neck cancer . lymph node metastasis . melanoma .
Merkel cell carcinoma
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sentinel lymph node biopsy
Most cutaneous malignancies metastasize via the lymphatic channels to the regional lymph nodes. Metastases are detected in lymph nodes by palpation on physical examination and by imaging. These methods are excellent for detecting macroscopic metastasis, where the volume of disease has grown to a level that is large enough to see radiographically or palpate. Thin cut computerized tomography (CT) and PET imaging can detect tumor metastasis beyond this threshold, on the order of 7–10 mm in size. However, we now recognize that identification of microscopic metastasis, beyond the detection level of physical examination and imaging, plays an important role in the management and outcome for patients with cutaneous malignancies. Gould et al. brought the concept of a sentinel node to the forefront in the 1960s [1]. For cutaneous lesions, they suggested that a specific area of skin would drain preferentially to specific lymph nodes. Therefore, a malignancy involving this skin would also drain to these lymph nodes first. Morton et al. applied lymphatic mapping and lymphoscintigraphy to this model [2]. They proposed and demonstrated that by injecting blue dye and later radiolabeled molecules into the skin, the material would migrate to these sentinel nodes.
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The nodes could be identified by the blue color and removed for histopathologic analysis. From this early work, the technique has been further refined and modified to take on an important role in the management of cutaneous malignancies [3]. This review will focus on the evolution of the technique for head and neck (HN) sentinel nodes and the current application for HN cutaneous malignancies. Evolution of sentinel lymph node biopsy technique in the HN
Generally, lymph node basins in the HN are categorized into levels I–V (FIGURE 1). However, this categorization excludes other at-risk lymph node basins, such as the external jugular chain, the parotid gland and the post-auricular and suboccipital lymph nodes. A new classification system for HN tumors has been developed, which includes these lymph nodes and divides them into 10 groups (FIGURE 2) [4]. This new classification allows for greater specificity in describing and treating metastatic tumors of the HN. HN lesions have a predictable drainage pattern; however, that pattern may include multiple lymph node basins. In comparison, areas such as the upper extremity will only drain to the axilla. Adding to this complexity, the early
2014 Informa UK Ltd
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I III VI IV
1. Suboccipital 2. Post-auricular 3. Parotid 4. External jugular chain
Figure 1. Head and neck lymph node basins. (A) The traditional I–V levels for aerodigestive tract malignancies and other head and neck primary tumors. (B) Additional at-risk lymph node basins to consider for head and neck cutaneous malignancies.
technique of Morton et al. used blue dye exclusively. It involved making an incision over the expected drainage area and visually observing the arrival and presence of the dye. Therefore, in the HN region it was difficult to know exactly which basin to look in to identify where the blue dye was arriving. This complex lymphatic drainage, as well as the limitations of the early technique, led people to believe that sentinel lymph node biopsy (SLNB) had limited utility in the HN region [2,3]. The addition of radiotracers to the technique was important for all sites, but especially for the HN. The lymphoscintigram is a raw, 2D image with limited detail. It provides direction and laterality to the location of interest (FIGURE 3). Since many HN lesions are near the midline, there is always the potential for
VIII (pA)
bilateral drainage. The lymphoscintigram can help identify a node on the right or left side of the neck. There are additional limitations of this technique in the HN. The injected isotope travels quickly, and can be taken up by multiple lymph nodes in a short period of time. It is also common for the tracer injected into the primary site to mask the sentinel lymph node because of the proximity of the tumor to the draining node [5]. It is for these reasons that hybrid single-photon emission computed tomography (SPECT)/CT, which combines the nuclear imaging with CT, has been used. In this technique, the lesion is injected with the radiotracer and then the patient is imaged using a combined CT and a gamma camera. This fuses the anatomic image of the CT with the functional image of the lymphoscintigram. Fusing these modalities provides much better preoperative and 3D localization [6]. Because of the number of lymphatic basins in the HN compared with other subsites, and the potential 3D overlap of these basins, SPECT/ CT is uniquely helpful in the HN region [7]. The addition of radiolabeled molecules also facilitated the introduction of the hand-held gamma probe. The hand-held gamma probe is a radiation detector that provides a count rate from gamma rays. This tool provides additional intraoperative guidance to the location and direction of the dissection. In the technique described by Morton et al., the gamma probe is moved systematically over the potential drainage basin to confirm the site of dissection. The gamma probe is then used to guide dissection by following the radioactivity. After a node is identified and dissected, the counts are checked [8]. Removing only the hottest node leaves behind approximately 15% of the true sentinel nodes. Therefore, removal of all nodes with greater than 10% of the hottest node’s radioactivity is recommended [8,9]. These additional techniques have been shown to help alter surgical approach and increase the yield of positive sentinel lymph nodes. Typically, one would consider the type of VIIa
Xa (Mt)
VIII (siP) Xb Xa (sA) II (Kütner)
VIII (diP) IX (M) IX (B) IX (F)
Xa (Mt) Xb
VIII (sP)
Xa (sA)
Ib (sMB) Ia (sMT)
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VIb (iH)
III
la (sMT)
II SAN
SEJ V VIa (AJ)
VIb (pL) VIb (pT)
VIb (R) IVa IVb Vc TCA III (Poirier)
Figure 2. Revised head and neck lymph node basins. Reprinted with permission from [4] Elsevier.
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SLNB for cutaneous HN malignancies
lymphadenectomy that would be needed if a positive sentinel node was identified. The incision for this type of procedure can then be drawn out. The location of anticipated dissection can then be identified with the hand-held probe and small incisions along the potential future incision can be made (FIGURE 4). This allows a minimally invasive approach without compromising future surgical incision planning [10]. There are two specific settings in the HN, where SPECT/ CT localization is particularly valuable, distinguishing parotid versus level II nodes and distinguishing external jugular chain versus internal jugular chain nodes. Consider a sentinel node in the tail of parotid; both lymphoscintigraphy and the g probe will direct the surgeon to an area over the tail of parotid. However, a high level II, and especially level IIb, lymph node localize in the same way with these two modalities. In this case, the SPECT/CT provides depth information to show if the node is in the tail of parotid and superficial to the sternocleidomastoid muscle (SCM), or if it is in level II deep to the SCM (FIGURE 5). Knowing this information allows the surgeon to make an appropriate incision and dissect directly to this region. Similarly, SPECT/CT is helpful in distinguishing internal versus external jugular chain lymph nodes. The CT image defines if the node is superficial or deep to the SCM (FIGURE 6). This changes incision planning. The incision to access the internal jugular chain lymph nodes is placed at the anterior border of the SCM and dissection is directed medial to the SCM. However, when dissecting along the external jugular chain, a small incision is made directly over the area of uptake with the g probe. Since the dissection is not very deep, a particularly small incision can be utilized. The evolution of this technique with lymphoscintigraphy, hand-held gamma probes and SPECT/CT has helped to make SLNB in the HN a very reliable technique equivalent to other sites in the body. Experience is also critical to the reliability of this technique. Early work by Morton et al. demonstrated that their own surgical technique became more reliable with experience, and that the technique was more reliable in the hands of a senior surgeon than an inexperienced junior surgeon [3]. This was also documented as part of the Multicenter Selective Lymphadenectomy Trial 1 (MSLT-1) [11]. It took surgeons 50 procedures to reach an accepted level of proficiency. Today, surgical oncologists who come from a background in general surgery as well as otolaryngology perform HN SLNB. There are a growing number of dedicated HN surgical oncologists from an otolaryngology background performing SLNB. Current applications
SLNB in the HN should be considered as safe, reliable and feasible as any other body site. Consideration for performing SLNB should be offered in the HN region as it would be in any other body site. When trying to identify who should undergo a SLNB, there are two basic principles to consider. Consideration should be given to any cutaneous malignancy that carries a 10% risk or greater of occult lymph node metastasis. Second, the information from SLNB should provide guidance on treatment informahealthcare.com
Review
Figure 3. Lymphoscintigram. A representative lymphoscintigram following injection of a right cheek primary melanoma. The drainage is in multiple nodes involving multiple possible areas that are difficult to distinguish.
management decisions and/or prognostic information that is important to the patient or clinician. Using these two principles, we will discuss the current application of HN SLNB for melanoma, Merkel cell carcinoma (MCC), cutaneous squamous cell carcinoma (cSCC) and unique periocular lesions. Melanoma
With 76,000 new cases each year and approximately 9500 deaths, melanoma is the fifth most common cancer in the USA [12]. The mainstay of treatment is surgical with wide local excision. Elective lymph node dissections were routinely performed for all melanomas, as nodal metastasis is the most significant predictor of survival [13]. However, a lymph node metastasis was only found 20% of the time [14]. This experience was one of the driving forces for the development of SLNB in cutaneous malignancy. Surgical treatment of melanoma has evolved and now integrates SLNB into routine management consideration. SLNB in melanoma has been shown to be effective at identifying metastatic disease, providing important staging and prognostic information, and to help guide therapeutic management for malignant melanoma [2,15]. Data from intermediate-thickness melanoma helped define the standard of care for treatment. Defined as a Breslow thickness of 1–4 mm, intermediate-thickness melanomas have a 20–25% risk of occult nodal metastasis [16]. The MSLT-1 compared wide local excision plus SNLB and lymphadenectomy with wide local excision plus nodal observation with lymphadenectomy only when macroscopic metastasis presented at a later time. Data from this trial corroborated other prospective trials showing that SLNB was feasible; a sentinel node was identified in 95% of patients [17]. It also demonstrated that a positive SLN was predictive of survival, with a hazard ratio (HR) of 3.19 for SLN-positive patients compared with SLN-negative patients [18]. doi: 10.1586/14737140.2015.990441
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Dwojak & Emerick
Figure 4. Incision planning. (A) Typical incision used for combined parotidectomy and levels I–IV neck dissection. (B) Small preauricular incision can be used to access preauricular parotid lymph node. (C) Small incision along neck portion of the incision used to access a periparotid lymph node just inferior to the tail of parotid.
The 10-year follow-up data for MSLT-1 confirms that SLNB and subsequent treatment significantly affects survival for patients with intermediate-thickness melanoma. The study found no significant difference in 10-year melanoma-specific survival for all study participants. However, SLNB was associated with a significant increase in 10-year disease-free survival (71 vs 64%; p = 0.01). For those patients with a positive node, SLNB followed by lymphadenectomy improved the 10-year rate of distant disease-free survival (HR: 0.62; p = 0.02) compared with those who developed macroscopic lymph node metastasis [19]. Current joint guidelines from the American Society of Clinical Oncology and the Society of Surgical Oncology, as well as the revised 2013 National Comprehensive Cancer Network (NCCN) guidelines support these findings with their recommendations that SLNB be performed for all patients with cutaneous melanoma with a Breslow thickness of >1 mm [11,20].
A
B
Figure 5. Parotid versus level II lymph node single-photon emission computed tomography/computerized tomography. These images highlight the ability of single-photon emission computed tomography/computerized tomography to distinguish a tail of parotid node from a level IIb node. These two nodes are indistinguishable by lymphoscintigraphy or gamma probe. (A) The bright area on this image is a level IIb lymph node. Note its location deep to the sternocleidomastoid muscle. (B) The bright area on this image is in the tail of parotid. This node is superficial to the sternocleidomastoid muscle and within the parotid tissue.
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A different role has been established for SLNB in thick melanoma, defined as Breslow thickness >4.0 mm. Multiple studies have established that the SLNB outcome is a significant predictor of overall survival in thick melanoma [21–25]. In addition, lymphadenectomy after SLNB-positivity has been shown to improve regional control compared with therapeutic dissection after clinical recurrence [26,27]. However, with rates of metastatic involvement between 30 and 50%, SLNB with lymphadenectomy has minimal benefit on overall survival [22]. Recent data from the MSLT-1 trial confirm that in patients with thick melanoma, >3.5 mm, there is no difference in 10-year disease-free or melanoma-specific survival when patients with a positive SNLB undergo immediate lymphadenectomy [19]. This new, long-term data support the current NCCN recommendation that SLNB be used for staging purposes and for local control in thick melanoma [11]. In the future, as new targeted treatments like ipilimumab and vemurafenib become widely available, the staging and prognostic information from SLNB in thick melanoma will likely become more important. The data are less clear and evolving for the role of SLNB in thin melanoma, defined as Breslow thickness 1 mm2 has also been shown to have an independent adverse effect on survival, but this factor does not consistently correlate with sentinel node positivity [28,31–33]. Breslow thickness has been shown to most consistently predict prognosis and SLN positivity [29,30,34,35]. For the subset of melanomas 0.75–1.0 mm, the rates of nodal metastasis are higher (5–11%) with a much higher probability of finding a positive SLN [29,36]. Han et al. in a large review of over 1000 patients with thin melanoma found that using Breslow thickness >0.75 mm alone would encompass the majority of patients with negative prognostic features and positive SLN [30]. Currently, the official NCCN and American Society of Clinical Oncology-Society of Surgical Oncology guidelines do not recommend SLNB for very thin lesions. The guidelines do suggest consideration of SLNB in thin melanoma 0.75–0.99 mm with ulceration or mitotic rate ‡1 mm2 [11,20]. These guidelines for melanoma management should be applied to the HN region as any other subsite (BOX 1). Three large single-institution reviews of SLNB for melanoma in the HN region show the technique is accurate, has low morbidity and has prognostic utility [36–38]. Despite bilateral drainage in 31% of patients, the sentinel node was identified in 96–98% of patients with a false omission rate comparable to other sites of the body of 1.4–4.5% 35. As would be anticipated in such a study group, 18–20% had a positive SLN, and this significantly correlated with overall and disease-free survival [36–38]. Merkel cell carcinoma
The successful use of SLNB in melanoma has led to its wider use in non-melanoma skin cancer. MCC is a much rarer skin tumor, with approximately 1500 new cases in the USA every year [39]. It arises from neuroendocrine cells in the basal layer of the skin and is causally associated with an oncogenic virus, Merkel cell polyomavirus [40–42]. MCC is predominantly a disease of older, white men with significant sun exposure [43,44]. Organ transplant patients and other immunocompromised patients are also at risk for MCC [45–47]. The HN is the most common region of presentation, accounting for 29–50% of the cases. The face, scalp, neck and lip are the most common sites [48,49]. The clinical course of MCC is quite aggressive with a combined 5-year overall survival of 30–60% [50–52]. Survival depends on stage, with the presence of regional lymph node involvement being the most significant predictor of survival. Five-year survival is 64% for local disease, 39% for regional nodal disease and 18% for distant metastatic disease [53–55]. Nodal recurrence rates for patients presenting without clinical lymphadenopathy are high, from 50 to 95% [56,57]. This nodal recurrence carries with it a 30–40% disease-specific mortality. This recurrence rate suggests a high rate of occult lymph node metastasis. Considering the importance of lymph node status on survival and the high propensity for occult metastasis, pathologic nodal staging and locoregional treatment is essential. This staging information provides prognostic information and can help guide and personalize treatment. Current NCCN guidelines recommend SLNB in the clinically N0 neck for MCC. PET CT is recommended as the imaging of choice in the evaluation of regional metastasis based on high sensitivity (90%) and specificity (98%), and the potential to upstage the disease [58,59]. Several studies have shown informahealthcare.com
Review
Figure 6. External jugular chain lymph node single-photon emission computed tomography/computerized tomography. This intense node is along the external jugular chain just inferior to the parotid gland. Note it is superficial to the sternocleidomastoid muscle but still over the sternocleidomastoid muscle and additional images would further show that it is just inferior to the parotid.
that SLNB for MCC is feasible with a SLN-positive rate of 19–38%, and an acceptable false-negative rate similar to melanoma [60–62]. Studies have also implied that SLNB may improve survival by allowing early adjuvant treatment. Gupta et al. found an improved relapse-free survival for those with a positive SLN (60 vs 0%; p < 0.01) [63]. However, the data on the prognostic implication of SLNB in MCC are mixed, and it is unclear if it carries the same prognostic guidance as it does for melanoma [64]. A report from Memorial Sloan Kettering found that SLN-positive patients received more adjuvant therapy, however, their 2-year recurrence and survival rates were not significantly different (12 vs 12%; p = 0.86 and 6.1 vs 5.7%; p = 0.89) [65]. A recent SEER review showed in a multivariate analysis that SLNB of the HN did not predict survival (HR: 2.37; p = 0.139) compared with other sites (HR: 2.71; p = 0.001) [66]. In contrast, a recent meta-analysis of SLNB in all subsites found that a positive SLNB predicted worse overall (HR: 4.42; p < 0.001) and disease-free survival (HR: 2.58; p < 0.001). Subgroup analysis was performed to examine the potential difference in the HN region. This did not show any difference in prognosis for the HN subsite compared with other sites. This review also supports the hypothesis that there is a disease-free survival benefit to SLNB compared with observation (HR: 1.64; p = 0.028) [67]. This is an important consideration as the morbidity of uncontrolled regional disease can significantly worsen a patient’s quality of life even in the palliative or end of life setting. doi: 10.1586/14737140.2015.990441
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Box 1. Indications for sentinel lymph node biopsy in head and neck melanoma. Indications for sentinel lymph node biopsy for melanoma .
. .
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.
.
Very thin: Breslow thickness 1/mm2 Thin: Breslow thickness ‡0.75–0.99 mm Intermediate: Breslow thickness 1–4 mm Thick melanoma: Breslow thickness >4 mm (currently indicated for staging and regional control) Unknown complete depth when 2 mm thickness, Clark level ‡4, primary site of the ear or lip, perineural invasion and poorly/undifferentiated tumor grade. Presence of these factors predicts a much higher metastatic rate between 11 and 50% [74]. This is an important step in the attempt to better stratify these patients; however, more accurate prognostic data are needed to better refine this risk stratification. In one of the largest single institution reviews, Schmults et al. recently published a study that further define high-risk features for cSCC. It refines the staging system specifically creating a T2b group that captures the group with a higher risk of lymph node metastasis [75,76]. This study showed that tumor diameter ‡2.0 cm, poorly differentiated histology, perineural invasion and tumor invasion beyond fat were all associated with lymph node metastasis and decreased disease-specific survival. From these data, the group established a new staging system (TABLE 1). The key classification of interest for SLNB are the T2b and T3 groups. These groups have a 21 and 67% risk of lymph node metastasis, respectively. This system has been further compared with the existing American Joint Committee on Cancer and Union for International Cancer Control staging systems. The comparison showed that the Brigham and Women’s Hospital (BWH) system creates more distinct subgroups that better predict outcome [77]. Current NCCN treatment recommendations for cSCC tumors with features that increase the risk for occult metastasis include obtaining surgical resection with clear margins at the Expert Rev. Anticancer Ther.
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SLNB for cutaneous HN malignancies
primary site followed by quarterly physical examinations that include a regional lymph node assessment. Adjuvant radiation should be considered for lesions with multiple high-risk factors and perineural spread in particular. The presence of lymph node metastasis changes prognosis and management significantly. The presence of regional metastasis carries with it a significantly reduced 5-year survival of 26–50%. Treatment for metastatic cSCC is lymphadenectomy in addition to surgical resection of the primary lesion and adjuvant radiation to both areas. Current protocols in many institutions adopt practices similar to what is applied to SCC of the aerodigestive tract. The addition of concurrent chemotherapy with a cisplatin-based regimen is considered in the setting of a positive margin, number of nodes involved and the presence of extracapsular extension. However, the biology of these tumors is likely very different and the aerodigestive tract experience is likely not directly translatable. This is an important area for future investigation. Given the poor survival for metastatic cSCC compared with the very curable non-metastatic cSCC, there is a natural interest in the potential role of SLNB. This interest is further enhanced when considering recent data showing that patients with a single small metastasis 2 cm, poorly differentiated, perineural spread (>1 mm diameter), invasion beyond the subcutaneous fat. † Sentinel lymph node biopsy is recommended for T2b and T3 lesions.
the study of follow-up time [82,83]. These studies show promise, but they are small in nature with limited follow-up. We anticipate ongoing prospective studies will help provide more definitive data on the impact of SLNB on regional control and survival. Since occult cSCC is much more radiosensitive than melanoma, SLNB outcome could be used in a variety of ways similar to MCC. For example, one could potentially consider lymphadenectomy, radiation or lymphadenectomy and radiation for those with a positive SLNB. The optimal treatment will hopefully be answered in the next few years. Australia is embarking on a randomized controlled trial, SNIC-1, that randomizes patients to traditional surgery with observation or SLNB followed by lymphadenectomy or radiation therapy if the SLNB is positive. This RCT, as well as attempts to uniformly collect prospective data, will shed light on much of the current uncertainty regarding SLNB for cSCC. Periocular tumors
A last area that is uniquely applicable to the HN region is periocular tumors. The conjunctiva and periocular region has a unique set of tumors that also meet the criteria mentioned at the outset of this section for considering SLNB. This includes the histologic subtypes described above as well as less common tumors such as sebaceous cell carcinoma. The first key question in this setting is feasibility and reliability. A few studies have now shown the technique to feasibility [84,85]. It is important that this procedure be coordinated between an ophthalmologist, the nuclear medicine physician and the surgical oncologist performing the SLNB. The ophthalmologist plays an important role providing their expertise in performing injections in these sensitive areas that most nuclear medicine teams are not comfortable injecting. The second important question is whether this is a reliable technique. Does SLNB status actually represent the status of the lymph node basin and does the conjunctiva drain in a reliable manner similar to skin? Given the small experience to date, this question cannot be answered. In the largest series (30 cases) of conjunctival melanoma from MD Anderson, they identified a positive SLN in 5 patients [85]. This suggests that there is some reliability to the procedure. Additional long-term doi: 10.1586/14737140.2015.990441
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Box 2. Indications for sentinel lymph node biopsy in head and neck Merkel cell carcinoma. Considerations for sentinel lymph node biopsy for Merkel cell carcinoma .
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.
Sentinel lymph node biopsy should be considered for all Merkel cell carcinoma in the absence of clinically apparent nodal disease Utilize for lesions near midline to identify possible contralateral involvement Utilize sentinel lymph node biopsy result to determine radiation dosage
Adapted from [86].
follow-up assessing for regional recurrence in patients with negative SLNB is not available. Given the small volume of tumors occurring in this location, definitive data and guidance will likely not be achieved. Based on the limited experience to date, SLNB does appear to be feasible in this location and one should consider using SLNB for tumors with a significant risk of occult metastasis. Expert commentary
SLNB plays an important role in the management of HN cutaneous malignancy. This technique has evolved over the years and is now accepted to be as safe and reliable as other body subsites. The key to this evolution has been the introduction of technology and surgical experience. The hand-held gamma probe is a critical piece of technology. This alone can greatly help localize the location of hot lymph nodes. Given the multiple potential lymph node basins on both sides of the body, this tool can be critical for incision planning and then ultimately guiding dissection. SPECT/CT greatly augments this localization. This is perhaps uniquely important to the HN region. The 3D definition provided by this modality is very helpful. In particular, SPECT/CT can distinguish a level II node from a parotid node. This is critical for incision planning, approach to dissection and patient preparation regarding potential risk to the facial nerve or the spinal accessory nerve and hypoglossal nerve. Similarly, it can distinguish an external jugular chain node from an internal jugular chain node. This information preoperatively directs incision planning and facilitates an efficient dissection. Surgeon experience is also a key to the success and safety of the procedure. Today, this procedure is primarily performed by dedicated HN surgical oncologists who are intimately familiar with parotid and neck lymph node basin anatomy. These surgeons routinely perform parotidectomy and neck dissection providing critical translatable skills. SLNB should be applied to tumors with a high risk of occult metastasis. This includes thin melanoma with high-risk features, intermediate and thick melanoma, MCC and T2b cSCC. Lesions near the midline should also be included. Historically, some preferred not to map these patients due to the high likelihood of bilateral drainage. Similarly, lesions with a
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high likelihood of parotid drainage should be included. In experienced hands, parotid SLNB is safe and reliable. However, the potential risk of facial nerve injury does highlight the necessity of an experienced parotid HN surgeon in order to make this a safe procedure. The overall morbidity of SLNB is minimal when compared with clinical lymphadenectomy. Reported risks include wound separation (0.2–1.2%), lymphedema (0.6–0.7%), seroma/hematoma (2.3–5.5%) and surgical site infection (1.1–4.6%) [8]. The overall operative time is short and the procedure is done on an outpatient basis. Additionally, the incisions are typically small and well hidden in natural creases. Unlike axillary and groin dissection, there is no lymph edema following surgery. Five-year view The immediate future of SLNB in the HN centers on the question of whether or not SLNB is therapeutic. When a SLNB is positive, is additional lymphadenectomy needed? There is currently a prospective multicenter study, MSLT-2, which will help address this question for melanoma. The question may be even more relevant for MCC and cSCC since they are much more radiosensitive. If SLNB identifies occult lymph node metastasis, there is at least a 20% chance of other occult lymphadenopathy. For MCC and cSCC completion, lymphadenectomy followed by radiation is potentially equivalent to radiation alone for this type of microscopic disease. Avoiding lymphadenectomy will help decrease the morbidity of overall treatment for these patients. However, it will be important that we measure regional control as well as survival when we study this question. Uncontrolled regional disease can significantly worsen quality of life in some with distant metastasis. The next few years will hopefully provide more definitive guidance on the exact role of SLNB for cSCC. Further experience will provide data to refine the true primary tumor features that predict a higher rate of lymph node metastasis. Additionally, the role of immunosuppression as a risk factor for occult metastasis needs to be better understood. The information from SLNB in this patient population could be critical for transplant management as well. Ultimately, SLNB will not be needed. The genetic fingerprint of a tumor will likely best predict the potential risk for occult lymph node metastasis. Initially, this may provide a new set of inclusion criteria for the procedure. As cancer treatment evolves, this information alone may guide treatment without the need for pathologic confirmation. However, this evolution is likely beyond the next 5 years. Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.
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Review
Key issues .
Sentinel lymph node biopsy (SLNB) in the head and neck (HN) is safe and reliable.
.
Lymphoscintigraphy combined with single-photon emission computed tomography/computerized tomography and use of the hand-held g probe are important tools to increase the success of HN SLNB.
.
Single-photon emission computed tomography/computerized tomography is particularly important for distinguishing parotid from level II nodes as well as EJ from IJ nodes.
.
SLNB should be applied based on histologic features and not avoided due to location near midline or potential for parotid
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drainage basin. .
Clear guidelines exist for the application of SLNB in melanoma.
.
SLNB has an evolving role in the management of cutaneous squamous cell carcinoma and should be considered for lesions that have features which increase the risk of occult lymph node metastasis.
.
SLNB for Merkel cell carcinoma can provide important guidance for management but must be used in the context of a multidisciplinary group to be sure the information gained from the procedure will impact management.
.
SLNB can be used for periocular tumors including those on the conjunctiva.
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doi: 10.1586/14737140.2015.990441
