The Role of Sentinel Node Biopsy in Skin Cancer

The incidence of malignant melanoma is increasing rapidly, at a rate of 2-4% per year over the past decade, while the death rate is increasing less rapidly at a rate of 2-3% per year over the past decade. Malignant melanoma typically affects young patients (median age 48 y). The lifetime risk of developing melanoma for a person born in the United States is now estimated to be 1 in 27 for males and 1 in 42 for females.[1]

Historically, the treatment of malignant melanoma has been primarily surgical, and it remains largely so for early-stage disease while exciting advances in systemic therapies are shifting treatment paradigms for more advanced disease.

The natural history of cutaneous melanoma is most often an orderly progression from invasion at the primary site, to regional lymph nodes via dermal lymphatics, and then to distant sites. If a melanoma is identified and treated at an early stage, the likelihood of synchronous lymph node metastases is quite low, and patients are usually treated with wide local excision alone. While much effort has been directed toward using molecular, cellular, and biochemical markers to determine the prognosis and appropriate treatment of melanoma,[2, 3, 4, 5, 6] the presence or absence of lymph node metastases, absent distant metastatic disease, remains the most powerful predictor of outcome. Numerous studies support that sentinel lymph node status is the most important independent prognostic factor with respect to disease progression and melanoma-specific survival.[7, 8, 9, 10] Moreover, the microstaging afforded by sentinel node surgery further refines prognosis for stage III melanoma patients.[11]

One indicator of the degree to which sentinel lymph node biopsy with selective lymph node dissection has been accepted in the staging and treatment of melanoma is the evolution of the American Joint Commission on Cancer (AJCC) staging guidelines for melanoma, which, beginning in 2004, incorporate nodal microstaging and discriminate between microscopic and macroscopic nodal disease.[12] Additionally, the National Comprehensive Cancer Network (NCCN) guidelines for the treatment of melanoma include sentinel lymph node biopsy with selective lymph node dissection in their treatment algorithms, and this technique has been endorsed by the World Health Organization (WHO) as well as multiple other national and international cancer treatment organizations. Over the years as this technique has gained acceptance, it has been refined.

Rationale and objectives for sentinel lymph node biopsy

The sentinel lymph node concept is that a primary or sentinel lymph node (or nodes) exists through which tumor cells from a primary tumor in a particular location first must travel to spread to a particular regional lymph node basin. A tracer substance injected into the dermis at the primary tumor site provides a roadmap leading to the sentinel lymph node(s). In addition, the hypothesis that careful examination of the sentinel lymph node(s) indicates the status of the entire lymph node basin has been validated in several studies. Thus, sentinel lymph node biopsy with selective lymph node dissection has been embraced as an alternative to elective lymphadenectomy or observation for patients with clinically negative regional lymph nodes who are at risk for nodal metastases.

The objectives of combining sentinel lymph node biopsy with or without selective lymphadenectomy in clinical practice include both decreasing the extent of the operation for selected patients and increasing the identification rate of occult lymph node metastases, thereby increasing the accuracy of staging by providing the pathologist with the lymph node (or nodes) most likely to contain metastatic disease. Historical evidence of a survival benefit for elective lymph node dissection in selected melanoma patients, as well as immunohistochemical- and molecular-based detection of metastatic melanoma in lymph nodes deemed negative by standard histopathology, implies that some patients are understaged by conventional techniques.

The WHO truncal melanoma trial (No. 14) found a significant improvement in 5-year survival rates (48% vs 26%, P = .04) for patients with clinically occult metastatic lymph nodes who underwent elective lymph node dissection at the time of wide local excision versus patients who underwent therapeutic lymph node dissection after developing clinically detectable lymphadenopathy.[13]

In addition, a second randomized, prospective, multi-institutional study, the Intergroup Melanoma Trial, revealed a significant improvement in 10-year overall survival for patients who underwent elective lymph node dissection versus wide excision in several prospectively stratified subgroups.[14] Results indicated a 30% reduction in 10-year mortality rates for patients with nonulcerated melanomas (overall survival 84% vs 77%, P =.03), a 27% reduction in 10-year mortality rates for patients with melanomas from 1-2 mm thick (overall survival 86% vs 80%, P = .3), and a 27% reduction in 10-year mortality rates for patients with extremity melanomas (overall survival 84% vs 78%).

While these trials predate the rapidly shifting landscape of adjuvant systemic therapy options for melanoma patients, they provide a rationale for sentinel lymph node surgery to better stage appropriately selected clinically node-negative patients. The objective of sentinel lymph node biopsy is to identify patients who present with clinically occult regional disease. Sentinel lymph node biopsy also (1) minimizes morbidity by identifying those most likely to benefit from adjuvant therapies and/or lymphadenectomy after a minor outpatient procedure with a much diminished risk of lymphedema and other complications, (2) identifies patients who may benefit from postoperative adjuvant therapy and those who may avoid adjuvant therapy, (3) provides a means for homogeneous stratification of patients for and within randomized clinical trials, and (4) by ascertaining regional lymph node status, provides a means to assess quality and health outcome measures.

The technique of sentinel lymph node biopsy with selective lymph node dissection has been widely adopted by surgical oncologists, which has resulted in its use in the treatment of other cutaneous and noncutaneous malignancies with regional lymphatic metastatic potential.

Sentinel lymph node biopsy first was described more than 50 years ago and was used to stage carcinoma of the penis. As an alternative to elective node dissection in melanoma, sentinel lymph node biopsy was first proposed by Morton, who used blue dye injected around the primary melanoma to identify the sentinel node.[15] In 1992, in his initial report of 223 patients using vital blue dye alone, the sentinel lymph node was identified in 194 (82%) of 237 lymph node basins, 40 (21%) patients had metastatic disease in the sentinel lymph node, and 2 patients had falsely negative sentinel nodes (accuracy 99%, false-negative rate 4.8%).

Lymphoscintigraphy has been used since the 1950s to delineate lymphatic drainage pathways, first with radioactive colloid gold and, currently, with technetium Tc 99m sulfur colloid, albumin colloid, or human serum albumin. Antimony sulfide colloid, not available in the United States, is commonly used in Australia. In 1993, both Morton and Krag described radioguided sentinel lymph node biopsy with gamma-probe localization of sentinel lymph nodes.[16] This method permits transcutaneous identification of the hot sentinel lymph node and performance of sentinel lymph node biopsy through a small incision; it also helps limit the extent of the dissection needed to identify the sentinel lymph node.[17] The combined use of blue dye plus radiocolloid appears to be superior to either method alone.[18] However, more recently, expert melanoma surgeons may view blue dye as optional, citing concern for rare allergic reactions and a low rate of missed sentinel nodes with the use of radiotracer alone.[19]

Melanoma

Proper selection of patients for sentinel lymph node biopsy with selective lymphadenectomy is an important aspect of the procedure. National and international melanoma treatment guidelines recommend this procedure for patients with clinically node-negative intermediate-thickness (1-4 mm, AJCC T2 and T3) melanomas.[20] Debate continues among surgical oncologists regarding the appropriateness of sentinel lymph node surgery for patients with thinner or thicker tumors.

The rationale for sentinel lymph node biopsy with selective lymphadenectomy in patients with intermediate-thickness melanoma is that the incidence of occult regional disease is significant in these patients, while the likelihood of distant metastatic disease remains quite low. Several studies suggest a survival benefit for patients treated with regional lymphadenectomy for clinically occult disease rather than delayed therapeutic lymph node dissection when nodal metastases become clinically obvious. Further, accurate nodal staging is important for appropriately calculating the risks and benefits of adjuvant therapies.

No survival benefit has yet been proven for sentinel lymph node biopsy with selective lymphadenectomy for patients with clinically node-negative melanoma. However, for patients with clinically node-negative, pathologically node-positive disease, sentinel lymph node biopsy with completion lymph node dissection for sentinel node positive disease improves survival versus observation and delayed therapeutic lymphadenectomy.[9, 21]

Guidelines on sentinel lymph node biopsy for melanoma from the American Society of Clinical Oncology and Society of Surgical Oncology, discussed in greater detail below, are as follows[22] :

• Routine sentinel lymph node biopsy not recommended for patients with thin melanomas that are T1a (nonulcerated lesions < 0.8 mm in Breslow thickness)
• Sentinel lymph node biopsy considered for thin melanomas that are T1b (0.8-1 mm Breslow thickness or < 0.8 mm Breslow thickness with ulceration) after a thorough discussion with patient about potential benefits and risks associated with the procedure
• Sentinel lymph node biopsy recommended for patients with intermediate-thickness melanomas (T2 or T3; Breslow thickness of >1 mm to 4 mm)
• Sentinel lymph node biopsy may be recommended for patients with thick melanomas (T4; >4 mm in Breslow thickness), after a discussion of potential benefits and risks

Thin melanoma

Both the prior and most recent combined Society of Surgical Oncology and American Society of Clinical Oncology Guidelines reference a lack of high-level evidence supporting the routine use of sentinel lymph node biopsy for patients with thin (< 1 mm in thickness) melanomas.[20, 22] Prior to the AJCC seventh edition staging changes for T1 melanoma, NCCN guidelines recommended consideration of sentinel lymph node biopsy for patients with T1b melanomas, defined at the time as those with ulceration and/or level IV or V.[23] With the AJCC seventh edition changes in the definition of T1 melanoma to reflect mitogenicity rather than level of invasion, this recommendation for sentinel lymph node biopsy for T1b melanoma was dropped. The current recommendation is that sentinel lymph node biopsy should be “discussed and considered” for patients with T1b melanomas, currently defined as those 0.8 mm or thicker or thinner melanomas exhibiting ulceration.[24] While many melanoma surgical oncologists offer sentinel lymph node biopsy to “high-risk” patients with T1melanomas, consensus on the definition of high-risk T1 lesions is absent.

The reported rates of sentinel lymph node positivity in patients with thin melanomas ranges from 0-11%.[25, 26, 27] A 2015 analysis using Surveillance, Epidemiology, and End Results (SEER) data from over 32,000 T1 patients found that 3.5-6.6% of T1a and 7.1-8.5% of T1b melanoma patients undergoing sentinel node surgery were node positive.[28] Features that have been reported to be associated with a higher risk of disease recurrence or occult lymph node metastasis for patients with thin melanoma include increasing thickness (Breslow depth), Clark level IV or V, ulceration, angiolymphatic invasion, high mitotic rate, and younger patient age.[27, 29]

However, once a sentinel lymph node is found to contain metastatic disease in a patient with a thin melanoma, both disease-free and melanoma-specific survival at 10 years are adversely affected.[28, 30]

It is important to note that preoperative tumor thickness may be underestimated in patients diagnosed by shave biopsy, biopsy with a transected deep margin, when there is substantial residual pigmented lesion remaining after diagnostic biopsy, or in those whose biopsies are not reviewed by an experienced dermatopathologist.[31]

Thick melanoma

Guidelines suggest that T4 melanoma patients (with tumors thicker than 4 mm) may benefit from sentinel lymph node biopsy for staging and regional disease control.[20, 22, 24] In the past, a regional operation (elective lymph node dissection) was discouraged because of the high rate of concomitant occult or apparent systemic disease via hematogenous spread. After careful exclusion of patients with unresectable metastatic disease, sentinel lymph node biopsy should be recommended for these patients to identify individuals with a better prognosis (sentinel lymph node negative), to achieve long-term locoregional control of disease (selective lymphadenectomy), and to stratify patients for participation in clinical trials.

Pediatric melanoma patients

Melanoma is rare in children and adolescents younger than 20 years, comprising less than 1% of all newly diagnosed melanomas. Pediatric patients should be offered sentinel lymph node biopsy based on the same considerations outlined above, primarily based on tumor thickness. Reports suggest that occult lymph node disease is more prevalent in these young patients, while outcome may be better than in adults.[32, 33]

Elderly melanoma patients

The incidence of melanoma in patients aged 65 and older has tripled over the past 25 years and will increase further as the population ages. More than half of melanoma deaths now occur in elderly patients. The biologic behavior of melanoma in older patients may be different, largely postulated to be based on alterations in immune function.[34] However, absent contraindications (significant comorbidities affecting life expectancy, extreme frailty or unsuitability for anesthesia), these elderly melanoma patients should be offered sentinel lymph node biopsy based on the considerations outlined above, not chronologic age alone, as nodal status and treatment influences both disease-free and melanoma-specific survival.[35, 36]

Local recurrence

Sentinel lymph node biopsy also may be considered for patients with isolated local cutaneous recurrence or in transit disease in the absence of clinically evident regional nodal disease.[37] If imaging suggests regional nodal disease, fine-needle aspiration of the suspected metastatic is recommended, followed by therapeutic lymphadenectomy of the affected nodal basin. In addition, lymphoscintigraphy to identify other possible at-risk nodal basins may be considered.

Atypical or borderline Spitz tumors

Atypical Spitzoid lesions that are difficult to classify as clearly benign or malignant may represent undiagnosed malignant melanoma. Sentinel lymph node biopsy may be offered to patients with atypical or borderline lesions (whose features may include size >1 cm, ulceration, deep dermal mitoses, extension into subcutaneous fat, and cytologic atypia). The incidence of sentinel node metastasis is about 30%.[38]

Other skin cancers

Application of the principles of sentinel lymph node biopsy to other cutaneous malignancies with a propensity for regional lymphatic spread has garnered tremendous interest. The technique has been reported most frequently for neuroendocrine carcinoma of the skin (Merkel cell carcinoma or trabecular carcinoma), which frequently is a rapidly progressive and often fatal cutaneous cancer.

While only approximately 30% of Merkel cell carcinoma patients present with clinically apparent regional lymph node metastases, as many as 70% of the remainder of patients experience relapse in the regional lymph nodes within 2 years of diagnosis if the regional lymph nodes are not treated. Half the patients with regional failure develop systemic disease. In a meta-analysis, metastatic disease in a sentinel lymph node was a marker of poor prognosis and therapeutic lymph node dissection provided at least short-term regional nodal control.[39] The current NCCN guidelines now recommend sentinel lymph node biopsy with selective lymph node dissection for clinical stage I Merkel cell carcinoma patients.

Immunohistochemistry (with pancytokeratin AE1/AE3, cytokeratin 20, and chromogranin A antibodies) helps detect micrometastatic disease in these patients. Unlike patients with malignant melanoma, most patients with neuroendocrine carcinoma of the skin are offered adjuvant radiation therapy at the primary site. If lymph node metastases are found, the radiation field also may encompass the draining lymphatics and affected regional nodal basin(s). The combination of radiotherapy and selective lymphadenectomy improves survival compared with surgery or radiation alone. The technique of lymphatic mapping also helps identify the draining lymph node basin(s) more accurately, thereby helping avoid inadvertent treatment of the wrong nodal group.

Sentinel lymph node biopsy has also been used to treat high-risk squamous cell carcinomas of the skin. It may be considered for patients with tumors extending into subcutaneous fat or invading deeper structures, for patients with tumors greater than 4-6 mm in depth, for patients with extensive peritumoral lymphatic invasion, perineural invasion, for patients with Marjolin ulcer, and for some patients with locally recurrent carcinomas.[40]

Sentinel lymph node biopsy may be used to stage and treat eccrine and apocrine skin carcinomas, porocarcinoma, hidradenocarcinoma, and invasive mammary and extramammary Paget disease, which have a significant risk of lymphatic metastasis as well as selected patients with cutaneous lymphomas and sarcomas.

Noncutaneous malignancies

Since its initial description for melanoma patients, the concept and technique of sentinel lymph node biopsy with or without selective lymph node dissection has been applied to a number of noncutaneous malignancies with varying degrees of efficacy. Most widely accepted is sentinel lymph node biopsy for clinically node-negative breast cancer as an alternative to routine level I and II axillary lymph node dissection.

Sentinel lymph node biopsy has also been applied to the staging and treatment of noncutaneous squamous cell carcinomas of the head and neck, colon cancer, small bowel tumors (eg, carcinoid tumor), gastric cancer, pancreatic cancer, thyroid cancer, prostate cancer, vulvar carcinoma, penile cancer, pediatric soft tissue sarcoma, and clear cell sarcoma (melanoma of the soft parts).

The concept of sentinel lymph node biopsy is that a primary or sentinel lymph node (or nodes) exists through which tumor cells from a primary tumor in a particular location first must travel, via afferent lymphatics, to spread to a particular regional lymph node basin. The technique is well suited for application to cutaneous malignancies because of the well-developed dermal lymphatic plexus of the skin. In-transit lymph nodes also may be identified by this technique in conjunction with preoperative lymphoscintigraphy.

Several studies have demonstrated that the lymphatic drainage of melanomas of the head, neck, and trunk cannot be predicted reliably by the classic anatomic guidelines of Sappey. Lymphoscintigraphy documents direct drainage from these sites to sentinel nodes in aberrant locations, such as the triangular intermuscular space. Dual-basin drainage or interval nodes also may be identified. This underscores the importance of preoperative dynamic lymphoscintigraphy for accurate identification of sentinel nodes.

In certain clinical situations, sentinel lymph node biopsy with selective lymphadenectomy has no role. Patients with clinically palpable lymphadenopathy or suspected lymphadenopathy demonstrated on imaging studies (which may be confirmed by preoperative fine-needle aspiration [FNA]) should undergo a therapeutic lymph node dissection. However, in such patients, especially those with primary melanomas of the trunk or head and neck, lymphoscintigraphy should be considered to identify other nodal basins at risk, and sentinel lymph node biopsy of these secondary regionsmay be performed in conjunction with therapeutic lymphadenectomy of the clinically involved nodal basin.

Special situations

Sentinel lymph node biopsy is less accurate in patients who have undergone a prior wide local excision with a large rotational flap closure or a very wide excision with skin graft coverage. In these patients, the pattern of lymphatic drainage may be altered.[41] The situation is similar in patients who have undergone prior surgery involving the regional nodal basin, such as open lymph node biopsy or skin grafting, or prior surgery that disrupts the native lymphatic drainage patterns between the primary site and the at-risk nodal basin. Meticulous attention to lymphatic mapping is especially critical for the success of sentinel lymph node biopsy in these patients. Lymphatic mapping and sentinel lymph node biopsy concomitant with wide local excision is strongly preferred.

Pregnant women should be explained the potential risks of vital dyes and radiocolloid versus the benefits of undergoing lymphatic mapping and sentinel lymph node biopsy. After injection of 0.25-0.5 mCi of99m Tc sulfur colloid, the absorbed radiation dose to the fetus apparently is within safe limits (and < 10% of the teratogenic threshold of 50 mGy).[42] Methylene blue is contraindicated in pregnant patients because of its known teratogenic effects, including intestinal atresia. Isosulfan blue appears safe in the second and third trimesters of pregnancy, but some reports of potential neurologic and skeletal malformations in rat models caution against its use in the first trimester.[43] The US Food and Drug Administration (FDA) classifies Patent Blue V and isosulfan blue as pregnancy category C, thus blue dye generally is not used for sentinel node mapping in pregnant women. Patients with a history of cosmetic dye allergy should not receive isosulfan blue.

The use of sentinel lymph node biopsy and selective lymphadenectomy in patients with malignant melanoma with clinically negative regional lymph node basins has been widely adopted and supported by current national and international guidelines. With this approach, a complete regional lymph node dissection may then be performed only in patients with evidence of metastatic melanoma in the sentinel node(s), and patients may be best selected for adjuvant therapies and/or triaged to more intensive surveillance

Despite this, current compliance with these guidelines is only approximately 50% in the United States and is lower in Europe.[44, 45] Single-institution overall compliance data are better (74-84%) and appear to be improving over time, but data are lowest for those patients with thicker (T2 to T4) melanomas (47-74%) who stand to benefit the most.[23, 46] The technical details of sentinel lymph node biopsy for malignant melanoma are described below.

Multidisciplinary approach

Sentinel lymph node biopsy with selective lymphadenectomy is a team effort and requires close collaboration by dermatologists, surgical oncologists, nuclear medicine physicians, and pathologists. Adjuvant therapy may involve medical and radiation oncologists. A multidisciplinary programmatic approach provides optimal patient care.[47]

Injection technique

In the nuclear medicine department, 2-20 hours before the operation, the patient is injected intradermally around the site of the primary tumor or biopsy scar with radiocolloid, usually with a dose of 0.5-0.8 mCi. The area is massaged for 2-5 minutes.

Choice of isotope

While a variety of radiocolloids have been used successfully, unfiltered99m Tc sulfur colloid diffuses out of the sentinel lymph nodes (to second echelon lymph nodes) less rapidly than tracers with smaller particles. In the United States,99m Tc-labeled albumin colloid and human serum albumin also may be used. In March, 2013 the FDA also approved99m Tc-tilmanocept for sentinel lymph node mapping for melanoma and breast cancer. This radiocolloid appears to be as effective as vital blue dyes in identifying sentinel nodes, but there are no data comparing its efficacy with that of other radiocolloids. In Australia, colloidal antimony sulfide is used, and in Europe, human albumin nanocolloid is used.

Lymphoscintigraphy

Dynamic lymphoscintigraphy is essential for defining at-risk nodal basins, especially for truncal melanomas and melanomas of the head and neck. Lymphoscintigraphy may help define the number of sentinel lymph nodes by showing more than one afferent lymphatic channel leading from the primary tumor site to a regional nodal basin. It can also help define the location of the sentinel lymph node within the lymphatic basin and can identify in-transit or interval lymph nodes that may contain metastatic disease.

Lymphoscintigraphy demonstrates drainage to more than one nodal basin in 10-15% of patients and drainage to interval nodes in 3-5%. Metastatic disease is found at the same frequency in these interval sentinel lymph nodes as within sentinel lymph nodes from conventional lymph node basins, and the status of one basin does not predict the status of the other.[48] The sentinel node is not always found in the closest nodal basin. Accurate lymphoscintigraphy helps identify all nodes, regardless of their location, receiving direct lymphatic drainage from a primary tumor site. See the image below.

Lymphoscintigraphy is necessary to accurately identify the sentinel node(s) in patients with melanoma, and careful review of these images is needed to avoid missing at-risk nodes at operation. Drainage to nodal basins not predicted by standard anatomic considerations is observed with lymphoscintigraphy in as many as 60% of head and neck and 30% of truncal primary melanomas.[49]

Dynamic scintigraphy can be performed most conveniently immediately after injection of radiocolloid in the nuclear medicine department on the morning of the operation but may be performed 12-18 hours preoperatively to facilitate scheduling. Usually, the sentinel lymph node(s) is identified within 30 minutes of injection. The site of each hot sentinel lymph node is marked on the patient's skin for identification in the operating room. Two-view lymphoscintigrams are obtained for the surgeon. Delayed images may be taken. Delayed images are helpful in detecting sentinel lymph nodes close to the primary site, which may be obscured on the initial views, and to detect drainage to multiple nodal basins.[50]

Single-photon emission computed tomography/computed tomography (SPECT/CT) has been described as an adjunct to the lymphatic mapping technique described above to more precisely localize sentinel nodes, especially in head and neck melanoma, and decrease the false-negative rate of the procedure. Use of SPECT/CT is reported to increase the number of sentinel nodes removed at operation, the proportion of patients with a positive sentinel node, and disease-free survival.[51] However, consideration of increased cost and radiation exposure merit its judicious use.

After radioisotope is injected in the nuclear medicine suite and lymphoscintigraphy is performed, the patient is moved to the operating room. Vital blue dye (1-2 mL) is injected intradermally around the primary tumor or biopsy site after the patient is prepared and draped using sterile technique. This dual-tracer technique is more accurate than either tracer alone. Isosulfan blue dye (Lymphazurin 1%, Zenith Parenterals; Rosemont, Ill) is associated with the fewest complications when small volumes are used, but dilute methylene blue may also be used and indocyanine green fluorescence has also been described to detect sentinel nodes.

The injection site is massaged gently for 5 minutes. A handheld gamma probe (eg, C-Trak probe, Care Wise Medical Products; Morgan Hill, Calif) is used to identify hot spots in the identified regional lymph node basin or basins.

If in-transit or interval nodes are identified on preoperative lymphoscintigrams, these should also be sought. Interval nodes contain metastatic disease as often as the conventional nodal basins do and may represent the only site of metastatic disease.

See the images below.

The blue dye may also be seen coursing through the dermal lymphatics en route to the regional lymph node basin(s). See the image below.

A small incision is made over the hot spot. A blue-stained afferent lymphatic vessel is sought, and a combination of this visual cue and the gamma probe leads to the identification of a hot and/or blue sentinel lymph node or nodes. Care should be taken to minimize flap placement because this may interrupt the afferent lymphatics and make sentinel node identification more difficult. More than one sentinel lymph node (with a separate draining afferent lymphatic vessel) is identified in more than 50% of patients. See the image below.

After the sentinel lymph nodes are removed, the lymph node basin is scanned with the gamma probe for residual activity. Absent–to–low-level radioactivity confirms that the sentinel nodes have been removed. The ratio of activity of the sentinel lymph node to nonsentinel lymph nodes should be at least 3:1 in vivo. Generally, the ratio of activity of the ex vivo sentinel lymph node to nonsentinel lymph nodes should be greater than 10:1. At operation, a sentinel lymph node is any blue-stained node, any node with a blue-stained afferent lymphatic, any node with greater than 10% of the radioactivity ex vivo of the hottest node, or any visually or palpably suspicious node.

The "10% rule" was generated from the Sunbelt Melanoma Trial experience and suggests that any lymph node with greater than 10% of the ex vivo radioactivity of the hottest lymph node should be removed. Ex vivo counts eliminate the contribution of shine-through from the primary site or from sentinel nodes remaining in the lymph node basin. This method is reportedly associated with a detection failure rate of approximately 2%. Any clinically suspicious, enlarged, firm, or pigmented lymph nodes should also be removed because tumor cells blocking afferent lymphatics may prevent uptake of radioactive tracer and/or blue dye into a tumor-containing sentinel lymph node.

If, despite these techniques, no sentinel lymph node is identified, either dissection of the lymph node basin or termination of the procedure and close clinical follow-up of the patient may be chosen. This decision should be based on a preoperative discussion with the patient and the metastatic risk associated with the primary tumor. Sentinel node identification rates approach 99% when the procedure is performed by a trained multidisciplinary team.

Histopathology

Processing the sentinel lymph node involves taking step-sections at multiple levels and performing immunohistochemical staining with melanoma-specific markers.[10] Immunohistochemistry identifies an additional 10-20% of patients with positive sentinel lymph nodes, in whom micrometastases are not seen on routine sections stained with hematoxylin and eosin (H&E). At least some of the increased rate of detection of micrometastatic disease is attributable to step-sectioning at multiple levels.

See the image below.

Recommendations for optimal enhanced pathologic analysis vary, but all include step-sectioning and immunohistochemistry.[10, 52]

The sensitivity of intraoperative frozen-section examination of the sentinel lymph node is disappointingly low (< 50%), although false-positive results are almost never reported. Because of the low sensitivity, risk of tissue loss during frozen-section, value of immunohistochemistry, and the logistics of proceeding to completion lymph node dissection at the same operation, most melanoma centers eschew frozen section examination and rely on permanent sections, except to confirm grossly suggestive metastatic disease.[10, 47] Recommendations for pathology reporting include a description of the location of metastatic disease within the lymph node, the size of the largest discrete tumor focus, and comment on the presence or absence of extranodal extension of disease.

Reverse-transcriptase polymerase chain reaction (RT-PCR)

The value of molecular staging of sentinel lymph nodes removed from melanoma patients in an effort to improve the sensitivity of detecting occult metastatic disease is unproven. The sensitivity of RT-PCR for melanoma markers is estimated to be an order of magnitude greater than that of immunohistochemistry. The marker used most commonly is tyrosinase, the enzyme that governs tyrosine metabolism in pigment cells. RT-PCR can also be used to detect other melanoma surface antigens such as Gp-100, MART-1 or MELAN-A, melanoma-associated antigen 3, and melanoma inhibitory activity.

Studies suggest that the 2-year recurrence rate for patients with a histologically (including immunohistochemistry) negative and PCR-negative sentinel lymph node is 2-9%. The 2-year recurrence rate is 13-30% for patients with a histologically negative yet PCR-positive lymph node and 60-67% for patients with lymph nodes positive by both methods.[53, 54] These data suggest that lymph node metastases missed by pathologic assessment are clinically relevant. Other studies have not found molecular staging of sentinel lymph nodes to have prognostic significance.[55]

Completion regional lymphadenectomy

Complete regional lymphadenectomy or regional nodal surveillance with quarterly ultrasound for selected patients with low-volume disease is recommended for all patients with positive sentinel lymph nodes, even when the volume of disease is quite small.[22, 56] As yet, no method reliably predicts which patients will have residual metastatic disease in other nonsentinel lymph nodes in the regional basin. While, in most series, 70-80% of patients (range, 58-92%) have no further disease identified, the pathologic examination after regional lymph node dissection is, of necessity, less rigorous than that used for evaluation of the sentinel lymph node; therefore, these numbers probably underestimate the true incidence of additional nodal disease. Current national guidelines state quite clearly that as even isolated tumor cells are clinically significant, there is no sentinel node tumor burden too low to count as metastatic nodal disease, although efforts are underway using both molecular profiling and prospective clinical study to improve prognostic precision.

One population-based data analysis (National Cancer Institute's Surveillance, Epidemiology and End Results [SEER] database 1998 to 2001) showed that less than 70% of US melanoma patients with a positive sentinel lymph node receive a completion lymph node dissection.[44] Another, using National Cancer Data Base data from 2004-2005, found that only 50% of melanoma patients with a positive sentinel lymph node biopsy underwent completion lymph node dissection.[57] The Multicenter Sentinel Lymphadenectomy Trial (MSLT) II enrolled sentinel node-positive, intermediate-thickness (1.2-3.5 mm) melanoma patients. Patients with a metastatic disease identified in a sentinel lymph node (by H&E, immunohistochemistry, or RT-PCR) were randomized to completion lymph node dissection or observation (including follow-up nodal ultrasonography) with therapeutic lymph node dissection for relapse. Patients with extranodal extension of disease were excluded. Nodal disease burden was not considered in this trial. Publication of the MSLT-II trial data supports this clinical practice of nodal observation for selected clinically node-negative, sentinel lymph node–positive patients with two important caveats: (1) that the enrolled patients were highly selected with the majority (>80%) having low-volume disease in one sentinel node and (2) that the patients enrolled in clinical trials of adjuvant therapy with immune checkpoint inhibitors all had completion lymph node dissections and those with micrometastatic disease were required to have at least one metastasis measuring greater than 1 mm (a disease burden observed in only one third of MSLT-II patients).[56, 58, 59, 60] As noted in updated guidelines in 2018, benefits of completion lymph node dissection include improved disease-free survival and improved risk stratification for consideration of adjuvant therapies. Multidisciplinary discussion with the patient of the risks and benefits of the options for management of sentinel lymph node–positive disease, which range from observation with nodal ultrasound to both completion lymph node dissection and adjuvant immunotherapy, is the ideal approach.

Completion lymph node dissections

A complete axillary lymph node dissection should include all level I, II, and III nodes and should remove all lymph nodes and fatty and areolar tissue from within the anatomic boundaries of the axilla. Unless bulky nodal disease is present, these specimens should include a minimum of 15-20 lymph nodes. This is not the operation commonly performed for breast cancer patients and underscores the importance of including a trained surgical oncologist with experience in the treatment of melanoma as a member of the multidisciplinary team.

The appropriate extent of groin dissection remains controversial. Isolated pelvic, obturator, or iliac nodal disease may be seen without involvement of (superficial) inguinal nodes, but this is uncommon. After a positive inguinal sentinel lymph biopsy result, the approach may be to perform only a superficial groin dissection at all times, a radical groin dissection at all times, or the deep groin dissection selectively, depending on the number of involved superficial nodes, the status of the node of Cloquet, or the site of the primary tumor (extremity vs trunk) or be based on PET-CT imaging findings if performed.

The extent of cervical lymph node dissection is determined by the anatomic location of the primary tumor. This may include superficial parotidectomy or posterolateral neck nodes and may be modified based on intraoperative findings.

Whether or not disease volume is the best arbiter for decisions regarding completion lymph node dissection or systemic therapy remains a subject of great current interest. In some studies, isolated tumor cells in a sentinel lymph node have prognostic significance and are associated with additional melanoma-positive lymph nodes upon completion lymph node dissection in greater than 10% of patients, while other investigations have found no prognostic benefit for sentinel lymph node evaluation beyond routine H&E techniques.[55, 61] The European Organisation for Research and Treatment of Cancer (EORTC) Melanoma Group MINITUB registry trial is open for enrollment to evaluate the role of completion lymph node dissection versus observation with regional nodal ultrasound for melanoma patients with "sub-micrometastatic" disease (defined as < 0.1 mm or < 0.4 mm if subcapsular only) in the sentinel lymph node.

Postoperative care

In general, patients who undergo sentinel lymph node biopsy alone require no special postoperative care. They may be discharged the day of the procedure, depending on the nature of the treatment of the primary melanoma. Instructions and written materials on lymphedema prevention and precautions should be provided to patients. Extremity elevation and ACE bandage wraps may be used to decrease the risk of lymphedema in patients who undergo lower extremity surgery.

Appropriate follow-up monitoring of patients with intermediate-thickness and deep primary cutaneous melanoma after sentinel lymph node biopsy, and treatment in general, remains controversial. Advantages to a regular follow-up program include a detailed history and physical examination (with total skin and regional lymph node examinations), with particular focus on the site of the primary melanoma and regional lymph node basin(s). Follow-up monitoring may detect second primary melanomas (approximately 5% of patients at 5 y) and recurrent disease at an early stage, when it may be treated more easily. Follow-up care also may include psychosocial support, identification of familial melanoma, and ongoing patient education.

For excellent patient education resources, visit eMedicineHealth's Cancer Center. Also, see eMedicineHealth's patient education articles Skin Cancer and Skin Biopsy.

In the Sunbelt Melanoma Trial, the overall complication rate was less than 5% for sentinel lymph node biopsy alone and 23% for sentinel lymph node biopsy with completion lymph node dissection for metastatic disease. The mortality rate was 0% for both procedures. Interestingly, patient reported quality-of-life indicators were not different for patients treated with either sentinel lymph node surgery alone or sentinel lymph node biopsy followed by completion lymph node dissection.[62] Complications occur more frequently in patients with comorbidities, such as cardiac disease, obesity, diabetes mellitus, and cigarette smoking. The complication rate of sentinel lymph node biopsy alone has also been reported to increase with the number of sentinel nodes removed.

Immediate complications of the procedure include failure to identify a sentinel lymph node (generally, < 5%), anaphylaxis or other allergic reactions to the intradermal injection of blue dye (< 1%), and bleeding. The immediate false-negative rate is defined as the proportion of nodal basins with positive nonsentinel lymph node results after negative results are obtained from sentinel lymph node biopsy immediately followed by elective completion lymph node dissection. In published series that include initial cases early on in the learning curve, the immediate false-negative rate ranged from 4.7-8.3%, with an associated accuracy of 98-99%.[15, 63, 64] Further studies of this nature are unlikely, given the acceptance of sentinel lymph node biopsy with selective lymph node dissection.

Short-term postoperative complications of the procedure include hematoma, wound infection, seroma, and flap necrosis. In the Sunbelt Melanoma Trial, hematoma or seroma (2%) and wound infection (1%) were the most common complications of sentinel lymph node biopsy.

Long-term postoperative sequelae may include persistent blue discoloration of the skin at the injection site (for >30 d in < 10% of patients), lymphatic fistulae, lymphocele, lymphedema (generally < 2% and 0.66% in 1 large trial for sentinel node biopsy alone), and neurologic complications, including transient or persistent neurapraxia, cutaneous anesthesia, paresthesias, and neuropathy. Sentinel lymph node biopsy does not increase the risk of in-transit metastases.

The risk of lymphedema specifically and complications in general after completion lymph node dissection for a positive sentinel node is lower than that associated with therapeutic lymph node dissection for clinically positive nodes.[65]

Reports on the risk of locoregional recurrence with follow-up ranging from 13-60 months in 14 published series show that the risk of isolated nodal relapse in the mapped basin after a negative sentinel lymph node biopsy is 1-6%, while the locoregional relapse rate ranges from 5-10%. These data include varying numbers of patients with thin or otherwise low-risk melanomas expected to have minimal risk of relapse. One study found that the rate of locoregional disease alone as the first site of relapse was 33% in patients treated in a lymph node–noncompliant fashion versus 6% in patients who appropriately underwent sentinel lymph node biopsy followed by completion lymph node dissection for a positive sentinel lymph node.[46] Historic (presentinel lymph node biopsy era) rates of melanoma relapse in a previously dissected nodal basin (including cases with clinically apparent lymph node metastases) are in the range of 3-5%.[66]

Contemporary series of sentinel lymph node–negative melanoma patients with greater than or equal to 500 such patients followed for a median of 16-60 months report a failure rate (nodal recurrence in previously mapped basin in the absence of new in-transit or systemic disease or first recurrence in any regional nodal basin) of 1.5-6%. This corresponds to a false-negative rate (false-negative cases divided by true-positive plus false-negative cases) of 7-24%.[7, 9, 67, 68, 69, 70, 71] Data from the MSLT I trial suggest that the false-negative rate declines after 25 cases at an institution.[72]

Potential technical reasons for failure include errors in surgical technique; failure of nuclear medicine mapping; alterations in lymphatic drainage by inflammation, infection, or previous surgery; and errors in the pathologic examination of a correctly identified true sentinel node.[73] Reexamination of negative findings from sentinel lymph nodes from patients with regional nodal relapse using careful step-sectioning and immunohistochemistry has been demonstrated to detect micrometastatic disease in 40-80% of patients. Conversely, nodal relapse may result from newly developed nodal metastases arising from clinically occult or newly apparent local or in-transit disease. Most relapses in sentinel node–negative patients are distant metastasis without any evidence of local, in-transit, or regional disease.

The importance of microstaging using sentinel lymph node biopsy with selective lymph node dissection is emphasized by its inclusion in the pathological N staging of melanoma patients. The 5-year survival rates for stage III patients stratified by number and type (microscopic, ie, identified by sentinel lymph node biopsy or elective lymph node dissection, without extracapsular extension, and clinically and/or radiologically occult versus macroscopic) and primary tumor ulceration range from 69% (nonulcerated primary tumor, one microscopic positive lymph node) to 13% (ulcerated primary tumor, >3 macroscopic positive lymph nodes). This compares favorably with historic studies.[12] Stratification by patient, tumor and nodal disease burden results in heterogeneity of 5-year survival estimates for stage III patients ranging from 14-85%.[11] In a large series of patients who underwent regional lymph node dissection without using sentinel lymph node biopsy, 5-year survival estimates ranged from 46-60% for 1 positive lymph node, 33-54% for 2-3 positive lymph nodes, and 21-44% for 4 or more positive lymph nodes, depending on the extent and completeness of the regional lymph node dissection.[74]

A 2005 population-based study of 41,417 patients from the National Cancer Institute's SEER cancer registry validated the AJCC melanoma staging system, but it revealed more favorable survival rates. In this study, the 5-year survival rate for N2b (2-3 macroscopically positive nodes) with a nonulcerated primary tumor was 50%, which dropped to 27% for patients with more than 3 macroscopically positive nodes with an ulcerated primary tumor.

Interim results of the MSLT I trial show that while overall survival for intermediate-thickness patients randomized to wide local excision and sentinel lymph node biopsy with selective lymph node dissection versus observation is not yet statistically significant (93% vs 90% at 5 y), disease-free survival was significantly better for patients undergoing sentinel lymph node biopsy with selective lymph node dissection (78% vs 73% at 5 y, P = .009).[9] In addition, 5-year overall survival was significantly better for patients with positive sentinel lymph nodes who underwent immediate-completion lymph node dissection versus those who underwent therapeutic lymph node dissection for recurrence after wide excision alone (72% vs 52%, P = .004). Patients in the latter group had a greater number of involved lymph nodes (3.3 vs 1.4 for the sentinel lymph node–positive group) and 26% had N3 disease.

The final report of the results of the trial confirm these findings with 10 year overall survival after completion lymph node dissection for sentinel lymph node positive patients of 62.1% versus 41.5% for patients in the observation arm with nodal recurrence and subsequent therapeutic lymph node dissection. This was associated with a hazard ratio for death of 0.56 (0.37 to 0.84), p = 0.004, for node positive patients.[75] What is not known yet is whether sentinel lymph node surgery alone is equivalent to sentinel lymph node surgery with complete lymph node dissection, a hypothesis suggested for at least a subset of sentinel lymph node–positive patients based on the MSLT-II trial data.

In addition, sentinel lymph node status had prognostic significance, with 90% 5-year survival for sentinel node–negative patients versus 72% for sentinel node–positive patients (P< .001). Overall survival was identical for patients with a negative sentinel lymph node biopsy result and patients treated by wide excision and observation without recurrence. The proportion of sentinel lymph node–positive patients was 19.8%, and the proportion with nodal recurrence after wide excision alone was 20.3% at 7 years, further validating the sentinel lymph node concept. The data analysis includes the false-negative sentinel node patients. Sentinel lymph node biopsy did not increase the risk of developing in-transit disease.

The 8th AJCC staging system extensively revises stage III substaging for melanoma to better stratify patients based on both primary tumor characteristics, nodal disease burden, and presentation, as well as presence or absence of macroscopic or microscopic satellitosis.[76]

Directions for the future

High-frequency ultrasonography, with FNA of suggestive lymph nodes, is being investigated as a tool to identify or exclude nodal disease in melanoma patients. To date, the sensitivity and positive predictive value is low, but these may improve with technological advances. Ultrasonography is also being investigated as a tool to identify sentinel lymph nodes and to follow patients postoperatively for the development of new nodal disease.[77] Fluorodeoxyglucose positron-emission tomography scanning and positron-emission tomography scanning are being used increasingly in melanoma patients, but these studies are generally insensitive for detecting early nodal disease. False-positive results have been reported. Further technological refinements may decrease the size of the current detection limit of approximately 5 mm.

Proton magnetic resonance spectroscopy of FNA samples of sentinel lymph nodes has been reported.[78] Evaluation of sentinel lymph nodes removed surgically had a sensitivity of 88%, specificity of 90%, and accuracy of 89% in predicting sentinel lymph node status. These investigators propose a nonsurgical sentinel lymph node evaluation using ultrasound-guided FNA with this technique, without the need for histopathological evaluation.

Biologic and genetic alterations in primary melanomas and lymph node metastases continue to be studied. Preoperative molecular characterization of melanomas may lead to even less invasive or noninvasive staging and treatment in selected patients.

Conclusions

The use of sentinel lymph node biopsy with selective lymphadenectomy has increased the identification rate of micrometastatic disease and decreased the morbidity of treatment. Sentinel lymph node status has been shown repeatedly to be the most powerful indicator of prognosis for clinically node-negative patients. Sentinel lymph node biopsy identifies patients for whom early completion dissection or intensive nodal surveillance is beneficial and for whom adjuvant therapy might be considered; additionally, it stratifies patients into more homogeneous groups for inclusion in clinical trials.

Appropriately selected patients who undergo sentinel lymph node biopsy with selective lymph node dissection have improved disease free-survival and improved regional disease control compared with those who undergo wide local excision of the primary tumor and observation alone. This technique has  resulted in refinements of the staging system for malignant melanoma and greater understanding of the biologic behavior of melanoma.