Sentinel Lymph Node Biopsy for Head and Neck Cutaneous Melanoma =20 November 2012

TITLE: Sentinel Lymph Node Biopsy for Head= and Neck Cutaneous Melanoma
SOURCE: Grand Rounds Presentation, Department of Otolaryngology
The University of Texas Medical Branch (UTMB Health) <= /span>
DATE: November 28, 2012
RESIDENT PHYSICIAN: S. Ross Patton, MD
FACULTY PHYSICIAN: Susan McCammon, M= D
DISCUSSANTS: Susan McCammon, MD; Bruce Leintz , MD
SERIES EDITOR: Francis B. Quinn, Jr., MD
ARCHIVIST: Melinda Stoner Quinn, MSICS

"This material was prepared by resident physicians in partial fulfillment of educational requirements established f= or the Postgraduate Training Program of the UTMB Department of Otolaryngology/= Head and Neck Surgery and was not intended for clinical use in its present form.= It was prepared for the purpose of stimulating group discussion in a conference setting. No warranties, either express or implied, are made with respect to= its accuracy, completeness, or timeliness. The material does not necessarily reflect the current or past opinions of members of the UTMB faculty and sho= uld not be used for purposes of diagnosis or treatment without consulting appropriate literature sources and informed professional opinion." =

Introduction

The treatment for cutaneous melanoma is primarily surgical with a role for adjuvant treatment (interferon or radiation therap= y) in select cases. Primary lesi= ons are treated with wide local excision (WLE) and clinically evident regional lymph nodes are treated with lymph node dissection followed by adjuvant the= rapy. Currently, there is no highly effe= ctive systemic treatment for melanoma. Distant metastases and recurrent disease a= re difficult to manage. As a res= ult, early detection and prompt surgical treatment of loco-regional disease befo= re distant metastases occur are critical in reducing mortality. Twenty percent of patients w= ith an intermediate thickness melanoma and no clinical evidence of nodal or distant spread will have occult regional metastasis (Morton 1991). Management of this group of patien= ts has been controversial over the past few decades. In a population of patients with no evidence of spread beyond the primary site, the question remains: How much surgery should be perform= ed? Elective lymph node dissection cau= ses 80% of patients with a primary melanoma to undergo unnecessary surgery whil= e a “watch and wait strategy” allows occult metastases to grow and spread to non-sentinel lymph nodes until they become clinically evident (Mo= rton 1991). Sentinel lymph node bi= opsy was developed in an effort to identify which of these patients would benefit from additional surgical treatment beyond wide local excision. Its use in melanoma, particularly = of the head and neck, has been a controversial topic of much ongoing research and debate.

Background

Cutaneous melanoma of the head and neck accounts = for 20% of all melanomas. The lif= etime incidence of cutaneous melanoma is now one in fifty-nine (up from 1/1500 in 1930), which has been increasing along with melanoma-related mortality over= the past few decades (Rigel 2010). Melanoma is an aggressive cancer w= ith unpredictable metastatic patterns making it more lethal than other solid tumors. Melanomas of the head and neck are= more likely to recur and have a higher mortality rate in the head and neck.

TNM classification reflects the natural history of disease. Tumor depth determin= es T classification. Thicker tumor= s have a higher rate of spread. The histology also affects staging. Ulcerated tumors have worse prognosis. Nodal classification also includes histology, meaning SLNB is necessary for staging. Stage I and II melanoma are confin= ed to the primary site.

Historical Treatment of the N0 Neck

Prior to the advent of sentinel lymph node biopsy, surgical treatment of the clinically N0 neck (and other regional nodal basi= ns) was controversial. Opinions a= bout management of regional lymph nodes varied widely and the subject was hotly debated. Some surgeons preferred immediate elective lymph node dissection (ELND) while others adopted a “watch a= nd wait” strategy. With the “watch and wait” approach, patients received only a wide local excision and were followed closely every few months. They only underwent a lymph node dissection if disease became clinically evident after excision of the prima= ry lesion. It was known that dep= th of invasion correlated with disease spread and increased mortality. Based on retrospective analysis so= me experts argued using the depth of invasion as a cut-off for performing regi= onal lymph node dissection. Propon= ents of an ELND argued that clinically negative regional lymph nodes may harbor occult metastases which could adversely affect survival. Rather than observation, they reas= oned that a prophylactic lymph node dissection would increase the changes of long-term loco-regional control. Routinely, patients with intermediate thickness (1-4mm) lesions underwent an elective lymph node dissection. Morbid= ity and complications associated with these procedures included injury to the facial/spinal accessory nerves, chyle leak, ski= n flap necrosis, bleeding, lymphedema, and cosmetic deformity. O’brien<= /span> et al. developed an algorithm= for predicting drainage patterns of the head and neck in melanoma, although many patients received a modified radical neck dissection (Obrien 1995).

Two landmark studies-- the WHO and Mayo Clinic st= udies—conducted in the late 1970’s/early 1980’s questioned the utility of elect= ive lymph node dissection in melanoma (Veronesi et = al 1982 and Sim et al 1978). The WHO trial studied 573 patients= with extremity melanoma. Patients = were randomized into either WLE and observation vs W= LE and immediate ELND (Veronesi 1982). The Mayo clinic trial include 173 patients with melanoma from all sites of the body. Patients were randomized into WLE = with ELND and WLE plus observation. Both of these randomized cont= rolled trials found no survival benefit from elective lymph node dissection. A retrospective case series limited specifically to patients with head and neck melanoma also found no survival advantage to ELND (Loree and Spiro 1989). Obrien also published a large retrospective case series of 631 head and neck melanoma patients and found = no statistically significant survival advantage for ELND. Kane also published a large cohort = study of 424 head and neck melanoma patients and found no difference in survival = for ELND vs watch and wait.

Mor= e recently, Balch et al also published data from a large multi-institutional trial (Intergroup Melanoma Surgical Trial) in 1996 which included 740 patients. Stage I and II patients were rando= mized to ELND vs observation. Although no difference between the= two groups were found overall, there was a statistically significant difference found in a subgroup of patients with 1-2mm tumor thickness (Balch 1996). This study was significant in that= it showed N0 melanoma patients as a group would not benefit from ELND. There was, however, a sub-group of patients that are at high risk of undetectable regional spread (but not dis= tant mets) who would benefit from lymphadenectomy (B= alch 2000).

Why is head and neck ELND not effective?

One proposed reason for the ineffectiveness of EL= ND particularly in the head and neck for melanoma is the complexity of head and neck lymphatic anatomy. Shah published a report of patients with head and neck melanoma who underwent radical neck dissection and found highly variable patterns of lymphatic spr= ead (Shah 1989). Morton published= a study in 1993 that found up to 10% of h&n lymphatic drainage patterns may drain to the contralateral side (1993). Correlation of lymphoscintigraphy in head and neck melanoma patients with clinical prediction of cervical lym= ph node spread found that over one in three patients would have a lymph node l= eft behind if clinical predictions were used alone to decided which areas of the neck to dissect (O’brien 1995). These studies argue that head and = neck lymphatic drainage is particularly complex and that previous selective lymph node dissections for occult metastases may have been directed to the wrong areas.

Sentinel lymph Node biopsy technique

During the controversy about the appropriateness = of ELND, Morton et al described sentinel lymph node biopsy (Morton 1990 and 19= 92). Sentinel lymph node biopsy offered= a much less invasive and less morbid method of staging the regional lymph node basin than ELND. The idea was= based on the model that cancer cells spread through regional lymph nodes in a sequential fashion. Starting = from the primary site they travel first to regional lymph nodes and then to dist= ant sites. The sentinel lymph nod= e is the first lymph node to receive direct lymphatic drainage from the primary = site in a lymph node basin. There = is a theoretical short window of time to remove regional mi= crometastases and remove the disease in its entirety in order to prevent distant metastas= is (Morton 1991). The incubator hypothesis states that the primary melanoma sends immunosuppressive factors= to the sentinel node which creates a favorable microenvir= onement for cancer growth. The tumor = can then spread elsewhere (Morton 2003). This theory is controversial (and contrasts with the marker theory) = and most likely does not apply to thick melanomas (Morton 2003).

The modern technique of sentinel lymph node biopsy involves a multi-disciplinary team which includes a nuclear medicine physic= ian, surgeon, and pathologist (Morton 2012).&nb= sp; Prior to the procedure (anywhere from 4 hours to 2 days) The skin surrounding the primary melanoma is injected with small volumes (0.05-0.1mL= ) of technectium 99-sulfer containing colloid. Lymphoscintig= raphy is performed using a gamma camera to help identify which nodal basins drain= the lesion and contain the sentinel lymph node(s). Alternatively, SPECT-CT can be use= d to locate candidates for SLNB. T= he patient is brought to the operating room and placed under general anesthesia. Blue dye is then injected into the dermis surrounding the lesion 10-20 minutes before the st= art of the procedure. A handheld = gamma probe is then used to detect the previously injected t= echnectium in the nodal basin which drains the lesion. An incision is made over the nodal basin. The blue dye and the g= amma probe are used to identify which nodes is the sentinel node. Frequently multiple nodes are iden= tified and removed. Generally all no= des that are greater than 10% of the radioactivity of the “hottest node” identified are removed to insure that the sentinel node is remo= ved (McMasters 2004). The lymph n= ode specimens are then sent to the pathologist for permanent section. H&E (hema= toxyln and eosin) stains are performed. Any sample that is negative on H&E stain can then undergo furthe= r melanoma-specific immuno-histochemistry stains such as S100, MelaninA, and HMB-45 (Wen 2011)

Landmark SLNB Studies

Since the invention of SLNB in 1992, a number of landmark studies have been performed. Some of all surgical sites, others of h&n alone.

The Multicenter Selective Lymphadenectomy Trial w= as an international NIH-funded prospective randomized, controlled surgical trial designed to evaluate the efficacy of SLNB.= The goal was to validate SLNB as a staging operation and to determin= e if there is a survival advantage to early CLND in the event of a positive SLNB. It randomized 2001 pati= ents with a cutaneous melanoma of >1mm thickness and no evidence of regional = or distant metastasis into two arms: wide local excision and observation vs w= ide local excision plus sentinel lymph node biopsy. If the sentinel lymph node biopsy = was positive, patients underwent immediate complete lymph node dissection. The trial enrolled 2001 patients w= ith intermediate-thickness cutaneous melanomas of all parts of the body from 1994-2002.

The Sunbelt trial is a multi-institutional, prosp= ective randomized trial that examined the role of interferon adjuvant therapy in melanoma. Patients were recru= ited between 1997 and 2002. Final results were reported by McMasters et al in 2008 in which no benefit to adjuvant therapy with interferon was shown. The study included 321 H&N, 11= 41 trunk, and 1148 patients. This trial was particularly significant because Chao et al reported on the differences in technique and effectiveness of SLN by body area.

Formed in 2003, the Sentinel Lymph Node Working G= roup (SLNWG) was a head and neck melanoma database of 614 patients. Each patient with H&N melanoma underwent WLE of the lesion plus SLNB.&nbs= p; The study, published in 2006 was the largest head and neck melanoma database with respect to SLNB.

Complications/Morbidity

SLNB is a relatively safe and low-morbidity proce= dure, especially when compared with ELND. Since 80% of SLNB’s wil= l be negative, most patients can avoid the morbidity of neck dissection (Morton 2012). The patients undergoin= g SLNB in the MSLT-I trial experienced complications 10% of the time. In the same study, patients underg= oing immediate lymphadenectomy experienced a 37% complication rate (Morton 2005). The Sunbelt Trial simi= larly found a much lower complication rate for patients undergoing SLNB vs lymphadenectomy (4.6% vs. 23%). Common complications in both of th= ese trials included hematoma/seroma, wound dehiscen= ce, and lymphedema (Boland and Gershwin 2008).=

Morton/MSLT-I trial compared early vs. delayed ne= ck dissections and found a statistically lower rate of lymphedema and shorter hospital stay with early neck dissection (Morton 2010).

Prognostic Value

SLNB yields important clinical information for st= aging, prognosis, and clinical decision making.&n= bsp; Histologic status of the sentinel lymph node has been shown to be the most important independent predictor of overall 5 year survival in patients with stage I and II melanoma; more important than Bres= low depth and histologic ulceration (Morton 2006). The 5 year survival of SLN-negative patients was 90% in the MSLT-I trial (Morton 2005).

Overall Accuracy/False Negative Rate for SLNB

The “success” of a SLNB procedure ove= rall for all parts of the body is usually high.= The SLN is identified 93-100% of the time (Leong 2011). In addition, the status of the sen= tinel lymph node accurately reflects status of the entire nodal basin. In Morton’s initial study in= 1992, patients received SLNB’s and then underwent CLND regardless of the st= atus of the SLN. Out of 3079 non-sentinel lymph nodes identified by their CLND, only 2 contained tumor (0.06%) when the SLN was negative (Morton 1992).

Controversy Over Head/Neck SLNB Accuracy

The accuracy of head and neck SLNB has been contr= oversial over the past 10 years. Chao conducted a sub-analysis of head and neck patients from the Sunbelt Trial.<= span style=3D'mso-spacerun:yes'> Conducted by McMasters et al, the Sunbelt Trial was a multi-institutional prospective randomized trial (McMas= ters 2004). Patients underwent WLE= of a primary cutaneous melanoma and SLNB. If the SLNB was positive, patients underwent CLND. Chao found a lower rate of identify= ing the SLN in the head and neck than in the trunk/extremities (97% vs 100%). The rate of identifying a positive SLN was also lower in the head and neck regi= on (15% head/neck vs 23% for trunk. The false negative rate was = also higher in the head/neck region (1.9% vs 0.5%).<= span style=3D'mso-spacerun:yes'> Although complications overall were= low, the only motor nerve injuries that occurred in the series were in the head/= neck region (Chao 2003). Other trials during the 2000’s published results that questioned the utility of head and neck SLNB. Published in 2005, the MSLT trial = found an 85% success rate of identifying the SLNB in the head and neck. This was lower than the overall su= ccess rate of 95% when all sites were considered (Morton 2005). Carlson et al found no difference = in nodal recurrence rates in the head/neck region between positive and negative SLNB’s (Carlson 2003).

Several explanations for the comparatively poorer results obtained in head/neck SLNB were proposed by Chao. First, washout occurs faster= in the head/neck region. Fewer head/neck lymph nodes were stained blue in the Sunbelt trial due to the increased vascularity of the region. Second, lymph nodes are smaller in the head/neck than other areas of= the body. Third, regional lymph n= ode basins are closed to the primary site.&nbs= p; This could allow greater shine-through effect in head/neck melanomas. Fourth, the head/n= eck region contains intricate and complicated anatomy which makes dissection mo= re difficult. A significant perc= entage of head/neck melanomas drain to the parotid. Finally, head and neck melanomas m= ay have an increased rate of in-transit metastases (Chao 2003).

In the last 2 years, several studies have been published to support the usefulness of head and neck SLNB. Leong conducted a meta-analysis of head/neck SLNB’s for melanoma. He found a 93-100% success rate of identifying the SLN in 16 differe= nt studies conducted from 1993-2006. The positivity of the SLN ranged from 10-21% with a mean of 16% (Leo= ng 2011). E= rman et al. published a 10 year operative experience of head and neck SLNB’= ;s conducted at the University of Michigan.&n= bsp; It was the largest single-institution study for head and neck SLNB.<= span style=3D'mso-spacerun:yes'> 353 patients underwent WLE and SLN= B with a 99.7% success rate of identifying the SLN. The study also yielded a 95.8% neg= ative predictive value for head/neck SLNB (Earman 2012). This figure mirrored t= he 98.1% negative predictive value published by Miller et al from Oregon in 20= 10 (Miller 2010). Furthermore, <= span class=3DSpellE>Earman found a 19.7% positivity rate in head/neck SLN’s which compares favorably to the 21.4% positivity rate found in = the trunk/extremity in the Sunbelt trial (Earman 20= 12). No facial nerve, cranial nerve, or bleeding complications were recorded. Earman concedes the unique challenges of head/neck SLNB and attributes the success of the Michigan experience to surgical familiarity of the head/neck.&nbs= p; All surgeons participating in the Earman= study were full-time head and neck cancer surgeons (Earman 2012).

SLNB and Survival

Based on the third interim analysis of the MSLT, = the study found no statistically significant difference in overall survival bet= ween the two groups (Morton 2005). It did, however, show that patients with intermediate thickness melanoma showe= d a statistically significant increase in disease-free survival with a 5 year disease free survival in the SLNB group of 78% vs 72% in the observation group (P=3D0.0074).&nbs= p; It did also showed that patients with intermediate thickness melanoma (1.2-3.5mm) who developed nodal disease in the SLNB group had a fewer numbe= r of positive nodes (1.9 vs 3.2) (Morton 2005).

Who should receive SLNB (Indications)?

NCCN recommendation states SLNB is indicated for patients with stage Ib or stage II (no evidence= of spread outside the primary lesion). This correlates to patients with primary melanomas less than 1 mm th= ick with ulcerated histology or high mitosis rate. Thinner melanomas have a lower propensity for spread and SLNB may be unnecessary.

Thick melanomas (>4mm) have been shown to be associated with early distant metastasis.&= nbsp; A SLNB and subsequent regional LND would not address distant metasta= ses and would not improve survival (Morton 2003)

Future areas of study

Currently, most patients who undergo SLNB with a positive node then undergo immediate complete neck dissection. Only 12 percent of patients with a positive SLN will have an additional positive non-sentinel node (Morton 2012). Since such few non-sen= tinel nodes will be positive, is SLNB a therapeutic as well as a diagnostic procedure? The second multice= nter selective lymphadenectomy trial (MSLT-II) strives to answer that question.<= span style=3D'mso-spacerun:yes'> MSLT-II is a = prospectieve randomized surgical trial comparing SLNB plus CLND vs<= /span> SLNB plus ultrasound observation of lymph nodes. The trial opened in 2005 and aims = to enroll nearly 2000 patients (Morton 2012).=

Conclusions/Summary

Elective Lymph node dissection in melanoma is controversial and rarely performed. As shown by Erman et al, sentinel lymph = node biopsy is an accurate and relatively safe procedure (low-morbidity) for sta= ging in experienced hands. The accuracy/false negative rate for SLNB for the head/neck region specifically is currently being debated in the literature. Finally, SLNB has= not been shown to increase overall survival in melanoma in a randomized control trial. It has, however, been = shown to increase disease-free survival. There continues to be ongoing research a= nd debate in this area.

Faculty discussion – Drs. McCammon, Bruce Leintz on Dr. Patton’s presentation= on Sentinel Nodes In Malignant Melanoma-

Dr. Leintz:

We must always think of skip metastases and that we don’t always know whether they are going to be distant or regional. The whole understanding of doing a sentinel lymph node biopsy requires that there be step-wise metastases from= the primary tumor and yet you are now thinking that doing a lymph node biopsy m= ight give you better information for doing an elective neck dissection. Why would anyone think that that w= ould be the case?

But the traditional literature says that it should be a radical or at most a modified radical neck dissection. So why wouldn‘t the sentinel lymph node have been more often t= han not? My last comment is= that I think it’s inappropriate to be talking about the complications that related to the various procedures that are available to treat melanoma when= you don’t know which is the better treatment. I also think that the complication rate related to who should be doing those procedures was unacceptably high for hematoma of over twenty percent in one of your larger series. I would hope that any= one here in this room who is doing elective neck dissection would have a much l= ower rate of hematoma. We sh= ould be getting five percent or less. &nbs= p;

Dr. McCammon:

I would add to the utility of the sentinel node localization in melanoma, like cutaneous (skin) cancers, which have a broader distribution than upper aerodigestive cancers anatomically and so you have th= ings on the ear which may go to the occipital region. You have the higher rate of contralateral metastases which only lymphosintigraphy<= /span> will indicate that you should do a contralateral dissection or a bilateral dissection and I th= ink that the whole question of the parotid is important because the sentinel ly= mph node…(inaudible) if you are going to use your radical or your modified radical paradigm to get the complete lymph node base from something up here then that kind of en-bloc dissection would include the parotid whereas if y= ou do lymphosintigraphy and your sentinel node is = below the parotid and it’s negative then you can spare any searching around= in the parotid bed. So those are= ways that I would find it more useful than just a completion lymphadenectomy.

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