Sentinel Lymph Node Biopsy in Melanoma of the Head and Neck

TITLE: Sentinel Lymph Node Biopsy in Melanoma = of the Head and Neck
SOURCE: Grand Rounds Presentation, UTMB, Dept. of Otolaryngology
DATE: June 6, 2007
RESIDENT PHYSICIAN: Camysha Wright, MD
FACULTY PHYSICIAN: Shawn Newlands, MD, PhD, MBA
SERIES EDITORS: Francis B. Quinn, Jr., MD and Matthew W. Ryan, MD

"This material was prepared by resident physicians in partial fulfillment of educational requirements established for 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, completen= ess, or timeliness. The material does not necessarily reflect the current or past opinions of members of the UTMB faculty and should not be used for purposes= of diagnosis or treatment without consulting appropriate literature sources and informed professional opinion."

Introductio= n

The inc= idence of melanoma is rising more rapidly than any other malignancy. The National Comprehensive Cancer Network report that in the ear 2007, an estimated 59,9= 40 new cases of melanoma will be diagnosed and about 8119 patients will die of= the disease in the Unite= d States. They report that although melanoma= is the fifth and sixth most common malignancy in men and women, respectively, melanoma ranks second to leukemia in terms of loss of years of potential li= fe, per death. The median age at diagnosis is 45-55 years.

Diagnosis

The his= tory should include details such as bleeding, itching, ulceration, pain. A history of dysplastic nevi or a = family history of melanoma should also be sought. Risk factors for melanoma include strong family history, pigmented lesions, multiple clinically atypical mole= s or dysplastic nevi and inherited genetic mutations. Individuals with an inability to t= an and a fair skin that sunburns easily have a greater risk of developing melanoma. Sun exposure may al= so play a contributing role, however any ethnic group and those without substantial sun exposure can develop melanoma. Unlike other cutaneous malignancie= s, melanoma has been associated with brief intense exposures of actinic exposu= re versus chronic exposure.

The physical exam should cover the standard ABCD’s, as well as assess for other nevi. Common sites of presentation inclu= de sun exposed areas such as the arms and legs, as well as the back for men and the scalp for thin or balding patients. If a family history of melanoma is present, the physical should incl= ude all sun shielded areas as well, since melanomas can arise with minimal sun exposure.

A – Asymmetry

B – Border irregularities

C – Color variega= tion

D – Diameter (inc= rease or > 6mm)

&= nbsp;

Any sus= picious lesion requires a histologic examination.&= nbsp; It is recommended that small lesions undergo excisional biopsy with 1-2 mm margins. Exceptio= ns can be made for critical areas where minimal tissue removal is preferable. Excisional biopsy is not recommend= ed for larger lesions due to deformity before diagnosis, and possible alteration of lymph draining patterns that may be needed later for sentinel lymph node mapping. It is also not recom= mended for lesions on the face. When excision is not performed, a full-thickness incisional or a punch biopsy is recommended to assess the depth of the lesion. Needle and shave biopsies should n= ot be done.

For the= depth of resection of thin lesions, a deep margin of subcutaneous tissue has been described. For intermediate thickness lesions, depending on the location, d= eep margins include all the subcutaneous tissue down to the underlying fascia. = In the scalp, the galea may be left intact to allow for skin grafting. For melanomas greater than 4-mm in thickness, depending on the location and greatest thickness, resection of the underlying facial muscles as well as t= he galea and pericranium may be necessary to achieve a safe deep margin. After proper resection has been achieved, the surgeon must determine the status of the surgical margins.

The pat= hology report should include Breslow thickness, ulceration status, Clark level, as well as deep and peripheral biopsy margin status. Ulceration has been found to be an independent predictor of outcome for primary melanoma and has been incorpor= ated into the AJCC staging system.

Staging

Both th= e Clark and Breslow systems are commonly used in the staging of the primary lesion. The Clark stage is based on the tissue level of invasion, and absolute depth may diff= er depending upon the region of the body involved. The Breslow system is based upon t= he absolute depth, and has been shown in several studies to be the more reliab= le factor in predicting outcome. The definition of the levels in each system is given below.

Clark

Level I Involves = only the epidermis

Level II &nbs= p; Involves the basal layer and extends into the papillary dermis

Level III &nb= sp; Involves the papillary dermis to the boundary of the reticular dermis

Level IV &nbs= p; Involves the reticular dermis

Level V = ; Involves the subcutaneous tissues

Breslow

Stage I < 0.75 mm

Stage II &nbs= p; 0.75 – 1.5 mm

Stage III &nb= sp; 1.5 – 4.0 mm

Stage IV &nbs= p; > 4.0 mm

As with= nearly all malignancies, the outcome of melanoma initially depends on the stage at presentation. The National Comprehensive Cancer Network report that, in general, the prognosis is excellent for patients with localized disease and primary tumors 1.0 mm or = less in thickness, with long-term survival achieved in more than 90% of patients= . For patients with melanomas greate= r than 1.0 mm in thickness, survival rates range from 50-90%.

The lik= elihood of regional nodal involvement increases with increasing tumor thickness. When regional nodes are involved, survival rates are roughly halved. However, within stage III, 5 year survival rates range from 10-60%, depending on factors such as nodal tumor burden. Long-term survival in patients with distant metastases is roughly 10%.

= AJCC Staging Summary

Stage 0 – in situ

Stage IA – (low-risk primary), 1.0= mm thick or less without ulceration, Clark = level II-III

Stage IB – (intermediate-risk prim= ary), 1.0 mm thick or less with ulceration, or Clark level IV-V

Stage II – (high-risk primary), gr= eater than 1.0 mm in thickness, with any characteristic and clinically negative n= odes

Stage III – sentinel node positive, or clinically positive nodes

Stage III – in-transit nodes (In t= ransit metastasis is > 2 cm from primary but not beyond the regional lymph node= s).

Stage IV – distant metastatic disease<= /span>

Treatment

Stage 0

Surgical excision with 0.5 cm margins. No further work= up is needed. No neck dissection or lymph node biopsy is recommended due the low incidence of metastasis.

Stage I

Surgery= is the only recommended treatment. F= or these thin lesions, margins of 1 - 2 cm are acceptable. Minimal workup, including chest x-= ray, can be optionally performed to rule out metastasis for IB lesions, as this = test is insensitive. Sentinel lymp= h node biopsy should be encouraged especially in patients with IB disease.<= /p>

Stage II

Workup = for stage II lesions includes optional CXR as with stage IB lesions. Some authors recommend lymph node m= apping and a CT metastatic workup in cases such as ulcerative lesions or recurrent disease. The treatment of sta= ge II lesions is probably the most complicated.&= nbsp; This difficulty stems from the significant percentage of occult metastasis present with these lesions.&nbs= p; While higher stage lesions require more complex and invasive therapi= es due to their obvious clinical findings, treatment of stage II lesions invol= ves controversial therapies with inherent morbidity to treat a low yet statistically significant percentage of metastasis. The primary therapy for stage II l= esions is surgical, with a wide local excision and 2 cm margins. Sentinel lymph node biopsy should = be encouraged to look for occult metastasis.

Electiv= e neck dissection has been used frequently in stage II lesions. One of the inherent difficulties w= ith this method is defining the route of lymph drainage. Tumors of the occipital area and t= he posterior scalp (separated by a vertical line through the EAC), are conside= red to drain posteriorly into the postauricular and suboccipital nodes. These lesions should undergo a posterolateral neck dissection. Lesions on the forehead and scalp anterior to the line are believed = to drain into the periparotid and upper jugular nodes. A dissection for these lesions sho= uld a parotidectomy and a lateral neck dissection. Lesions which arise on the anterio= r face generally spread to the submental, submandibular, and deep cervical nodes.<= span style=3D'mso-spacerun:yes'> A supraomohyoid neck dissection is generally recommended.

Sentine= l lymph node biopsy is a relatively new technique, developed in the early 1990s. Recent studies have shown that usi= ng a combination of dye and a radioisotope can yield first order lymph nodes in = > 95%. These studies have also = shown that the status of the sentinel lymph node highly correlates with the metastatic status and overall outcome of the patient. However, many of the current studi= es cited involve regions other than the head and neck. It has also been shown that a lear= ning curve exists for adequate performance of this procedure. This will be discussed in more det= ail later.

Myers e= t al (2004) stated that&nbs= p; although elective neck dissection for the clinically negative neck is still an option for patients with intermediate thickness (1–4= mm) lesions, they favor radiotherapy or sentinel lymph node biopsy. In their opinion, the only formal indication for neck dissection in CMM of the head = and neck is the presence of clinically or radiographically positive lymphadenopathy.

Stage III

Stage I= II lesions have clinically positive nodes, have positive sentinel nodes, or ha= rbor in-transit nodal disease. The= workup of these lesions includes optional CXR and LDH for occult disease, and = a CT of the neck. For clinic= ally positive neck, suspicion of regional metastatic disease, preferably with either fine needle aspiration biopsy or open biops= y of the clinically enlarged lymph node. A CT to evaluate for distant metastasis should be considered. The surgical exci= sion should attempt 2 cm margins. = If a node is present distant to a lesion, all in-tran= sit node basins should be addressed. This means for lesions of the temple, cheek, or anterior scalp regio= n, a parotidectomy should be performed. As mentioned before, an appropriat= e neck dissection, i.e. posterolateral, lateral, or supraomohyoid, should be performed. Radiotherapy has been shown to dec= rease local recurrence rates. Chemo= therapy may be considered.

Stage IV

Workup = for these lesions includes CXR, LD= H, CT of the abdomen, MRI of t= he brain, and some recommend a CBC and liver panel. Primary excision with 2 cm margins should be attempted. Radiothe= rapy for local control should be considered.&nb= sp; Chemotherapy for palliation should be considered.

For all= types of cancer it is known that occult metastasis may exist in the absence of clinically identifiable disease. In cases such as melanoma, where the presence or absence of these metastases w= ill drastically affect the course of treatment and the prognosis, diagnostic SL= NB is often employed. Before sen= tinel node biopsy was used, the alternatives were neck dissection, which has inhe= rent morbidity, or clinical follow-up. SLNB has the benefit of allowing for pathologic analysis of the first order lymph nodes while incurring minimal surgical morbidity.

Sentine= l lymph node biopsy (SLNB) is based on the principle that the sentinel lymph node is the first node to receive drainage from the primary tumor and is therefore = at highest risk for metastasis. This procedure is a staging procedure wherein patients are selected who would potentially benefit from further treatment. Although SLNB for melanoma arising in the head and neck region has been sho= wn to be feasible, long-term follow-up showing that a negative SLNB accurately predicts the absence of microscopic metastasis in the neck is lacking. Therefore, our present use of SLNB is within a prospective protocol designe= d to address this question. Our protocol includes the following: (1) preoperative lymphocintigraphy; (2) intraoperative lymphatic mapping with a radiotracer;= (3) separation of the SLN from its basin ex vivo; and (4) histologic analysis by hematoxilin-eosin and immunohistochemistry of serial sections of the lymph nodes.

The tec= hnique of SNLB involves injecting both a radioisotope and a visible dye into the a= rea of the tumor and examining the drainage basin for dye and isotope uptake. The radioisotope is commonly Tc99,= which may be injected several hours prior to surgery. Localization of this isotope is ca= rried out intraoperatively by use of a handheld gamma counter. The dye is typically isosulfan blu= e, which can be injected in the operating room before the start of the procedure. Once the patient is asleep, a dissection of the first order lymph node basin is carried out, wh= ich can be guided by the gamma counter. If the radioisotope fails to localize adequately, the isosulfan dye = can be tracked to the first set of stained nodes. A node is considered to be a ̶= 0;sentinel node” if it localizes a high amount of isotope, takes up the dye, or both. Morton developed this technique in the early 1990s. Early in the development of the SLNB technique, when only the vital dye technique= was employed, the rates of identification of a sentinel node were only 60-80%, = even with experienced surgeons. To= day, with the combination of both methods, identification of sentinel nodes is commonly reported as 96%, as reported by Gershenwald.

Surgeons who do a sentinel-node biopsy procedure should = use the information provided by preoperative lymphoscintig= raphy to find and remove every node that has been identified as a definite sentin= el node by the nuclear-medicine physician, and should find and check every node that has been reported as a possible sentinel node. This task is made easier and more reliable if both blue dye and radioactive colloid are used as trac= ers; several studies have now shown that the greatest accuracy is achieved when = both agents are used for sentinel-node identification. When doing this surgery, = as with the nuclear-medicine physician, the surgeon should recognize that any sentinel node can contain micrometastatic disease—not just the most intensely blue node on inspection or the hottest node on testing with a gamma probe^. (McMasters et al, 2002). They recommended that all blue nod= es and all nodes that measure > 10% of the ex vivo radioactive count of = the hottest SLN be harvested and designated as SLNs= (McMasters et al, 2001). If every sentinel node is not removed, micrometastatic disease in the regional nodes could remain undetected, which might be detrimental to the patient, w= ho will be given incorrect information on outlook and whose chance of improved survival could be jeopardized.

Thompso= n et al (2005) describe that the colloid injections should be made as close as poss= ible to the original melanoma site (ie, before excis= ion), and should be truly intradermal and not subcuta= neous if the lymphatic pathways followed by melanoma cells traveling to regional lymph nodes from cutaneous primary sites (ie, in the epidermis and dermis) are to be identified accurately. One pitfall which can occur if sentinel lymph node excision is performed prior to complete excison of the tumo= r with margin is that the signal from the primary site may be too strong causing o= ne to miss reactivity in a close lymph nodes.

In the = SLN mapping technique described by Gershenwald (199= 9), most patients underwent preoperative lymphoscintigraph= y in which^99mTc-human serum albumin or ^99mTc-sulfur colloid was intradermally administered to estab= lish lymphatic drainagepatterns and identify those basins at risk fo= r metastatic melanoma.Lymphatic mapping and= SLN biopsy were performed after the intradermal administration of 1 to 3 mL of isosulfan<= /span> blue dye around the intacttumor or biopsy site immediately befo= re the procedure. Patients later alsoreceived an intradermal injection of 0.5 to 1.0 mCi of unfiltered^=
99mTc-sulfur colloid 1 to 4 hours before surgery;lymphatic mapping was then performed with the aid of a hand-heldgamma counter. The half-life of ^{99mTc
is 6 h.}

In patients who underwent map= ping of more than one basin, thebasin with predominant drainage by p= reoperative lymphoscintigraphywas explored firs= t. An SLN was defined as one that localizedblue dye and/or concentrat= ed radiolabeled colloid within a regionalnod= al basin. Each SLN was excised and submitted for pathologicanalysi= s. All patients underwent wide local excision of theprimary melano= ma with margins appropriate for tumor thickness.

When micrometastatic disease is identified in a sentinel n= ode, a completion lymph-node dissection of the regional nodes should be done. Howe= ver, the probability of finding metastatic disease in additional non-sentinel lymph nodes is low (ie, <25% in most series). (McMasters, 2002)

The uti= lity of SLNB has been under investigation since its development, specifically regar= ding the following areas: 1) How often are SLN’s identified, 2) How often = are the nodes positive for metastasis, 3) How often are positive nodes not identified by SLNB, and 4) What prognostic or treatment data can be deducted from a positive node?

In the prediction of overall survival, Gershenwald found that 3-year disease-speci= fic survival for a negative biopsy was 96.8%, while a positive biopsy was 69.9%. While it was also foun= d that sentinel nodes were more likely to be positive with increasing Breslow meas= urements (T1, T2 4.8%; T3 19.2%; T4 34.4%), covariate analysis of tumor thickness, <= st1:place w:st=3D"on">Clark level, and status of SLNB found that the stat= us of the sentinel node was the most significant prognostic factor for survival.<= span style=3D'mso-spacerun:yes'> Gershenwald also noted that 11% of= his patients developed a recurrence following a negative sentinel node biopsy.<= span style=3D'mso-spacerun:yes'> It was noted that regional recurre= nce was the primary site. In 80% = of the patients that had regional recurrence following negative SLNB, it was found that nodal disease was missed by conventional histologic techniques; and th= at the application of serial sectioning and immunostaining with S-100 or HMB-45 increases the yield. The bene= fits of SLN were found not to be limited onlyto those patients with a positive sentinel node. Those witha negative SLN comprise a favorable patient group with significantlyless risk for recurrence.

In a 20= 05 study by Morton et al on SNB for early stage melanoma, the accuracy of lymphatic mapping and sentinel node biopsy (LM/SNB) was determined by comparing the r= ates of SN identification and the incidence of SN metastases in the lymphatic mapping/sentinel node biopsy (LM/SNB) group versus the subsequent developme= nt of nodal metastases in the regional nodal basin of those patients with tumor-negative SNs. Early morbidity of LM/SNB was evaluated by comparing complication rates between the 2 treatment groups. Trial accrual was comple= ted on March 31, 2002, after enrollment of 2001 patients.

Morton = et al (2005) found that the initial SN identification rate was 95.3% overall: 99.= 3% for the groin, 95.3% for the axilla, and 84.5% for the neck basins. The rat= e of false-negative LM/SNB during the trial phase, (as measured by nodal recurre= nce in a tumor-negative dissected SN basin), decreased with increasing case vol= ume at each center: 10.3% for the first 25 cases versus 5.2% after 25 cases. Th= ere were no operative mortalities. The low (10.1%) complication rate after LM/S= NB increased to 37.2% with the addition of CLND; CLND also increased the sever= ity of complications. Early complications from MSLT-I were<= /span> uncommon and were not increased by the addition of LM/SNB to treatment of t= he primary site. Complications o= f CLND range from those confined to the wound such as seroma, hematoma, or infecti= on to more chronic abnormalities of dysesthesia or lymphedema

They co= ncluded that LM/SNB is a safe, low-morbidity procedure for staging the regional nod= al basin in early melanoma. Even after a 30-case learning phase and 25 additio= nal LM/SNB cases, the accuracy of LM/SNB continues to increase with a center's experience. LM/SNB should become standard care for staging the regional lym= ph nodes of patients with primary cutaneous melanoma.

In a fo= llow-up study in 2006 evaluating SNB vs nodal observation in melanoma, Morton et al found that the staging of intermediate-thickness (1.2 to 3.5mm) primary melanomas according to the results of sentinel-nodebiop= sy provides important prognostic information and identifiespatients with nodal metastases whose survival can be prolongedby immedia= te lymphadenectomy. Their findin= gs indicated that sentinel-node biopsy has stagingand prognostic v= alue in patients with intermediate-thicknessmelanoma and, when coupl= ed with immediate complete lymphadenectomy,improves survival among patients with a tumor-positive sentinelnode. They concluded tha= t in patients with primary melanomas that are 1.2 to 3.5mm in thickn= ess, sentinel-node biopsy should be preferred toobservation.<= /p>

Conclusion<= /span>

Many st= udies have evaluated sentinel node biopsy since it was first described in the ear= ly 1990s by Morton. Lymphatic mapping/sentinel node biopsy has been found to be a safe, low-morbidity procedure for staging the regional nodal basin in early melanoma and is becoming the standard of care when evaluating early and intermediate stage melanomas. It is recommended = that patients have lymphatic mapping done in conjunction with injection of dye for SLNB.<= span style=3D'mso-spacerun:yes'> Elective neck dissection has not b= een found to change outcome if SLNB is negative, but increases morbidity. Discussion of SLNB should be encou= raged in patients with stage I and II melanoma.

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Appendix. AJCC TNM Staging for Melanoma