eMedicine Specialties > Dermatology > Surgical
The Role of Sentinel Node Biopsy in Skin Cancer
Updated: Mar 10, 2009
Introduction
The incidence of malignant melanoma is increasing rapidly, at a rate of 4-8% per year. 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 51.1 Historically, the treatment of malignant melanoma has been primarily surgical, and it remains largely so despite advances in adjuvant therapy.
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 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
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 latest American Joint Commission on Cancer (AJCC) staging guidelines for melanoma, which, for the first time, incorporate nodal microstaging and discriminate between microscopic and macroscopic nodal disease.11 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) for the past decade. 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 high risk for nodal metastases.
The objectives of combining sentinel lymph node biopsy with selective lymphadenectomy in clinical practice include both decreasing the extent of the operation for selected patients (decreasing the number of nontherapeutic lymphadenectomies) and increasing the identification rate of occult lymph node metastases (increasing the accuracy of staging) by providing the pathologist with the lymph node (or nodes) most likely to contain metastatic disease. 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.12
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.13 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%).
The objective of sentinel lymph node biopsy is to identify the 20-25% of patients who present with clinically occult regional disease (AJCC stage IIIA and some IIIB). Sentinel lymph node biopsy also (1) minimizes the morbidity associated with elective lymphadenectomy for melanoma patients by identifying those most likely to benefit from 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.
History of the Procedure
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.14 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 et al and Alex and Krag described radioguided sentinel lymph node biopsy with gamma-probe localization of sentinel lymph nodes.15 This method permits transcutaneous identification of the hot sentinel lymph node and performance of biopsy through a small incision; it also helps limit the extent of the dissection needed to identify the sentinel lymph node.16 The combined use of blue dye plus radiocolloid appears to be superior to either method alone.17
Indications
Melanoma
Proper selection of patients for sentinel lymph node biopsy with selective lymphadenectomy is an important aspect of the procedure. Typically, the procedure is recommended for patients in whom the estimated risk of lymph node metastases is at least 10%. Appropriate candidates include patients with clinically node-negative melanomas thicker than or equal to 1 mm. While general agreement exists that sentinel lymph node biopsy is indicated for patients with intermediate-thickness melanomas (1-4 mm thick), debate continues among surgical oncologists regarding the expansion of these indications to patients with thinner or thicker tumors.
Most clinicians agree that sentinel lymph node biopsy is not indicated for patients with tumors thinner than 0.75 mm because the yield is 0% in most large series and less than 2% in a few others.18,19,20 Patients with high-risk lesions 0.75-0.99 mm in thickness should be considered for sentinel lymph node biopsy if their melanoma is Clark level IV or V, ulcerated, exhibits a vertical growth phase, or has angiolymphatic invasion or a high mitotic rate.19,21,22 The likelihood of identifying a sentinel lymph node containing metastatic disease in these patients remains quite low (approximately 5%), while the disease relapse rate may be as high as 20% at 5 years in high-risk subgroups, and population-based data analysis suggests that 15% of melanoma deaths occur in patients with thin primary tumors.23
Younger patient age and male sex also are associated with an increased incidence of sentinel lymph node metastases. One series of 409 patients with melanomas 0.75-1 mm found a 5% rate of positive sentinel nodes, of which half occurred in association with level II or III tumors without ulceration. They concluded that all patients with melanomas 0.75-1 mm should be offered the procedure.24 Another series of 223 patients with melanomas less than or equal to 1 mm thick who underwent sentinel lymph node biopsy found metastatic disease in 8 patients (3.6%). They did not find a single patient with a melanoma less than 0.75 mm in thickness and less than level IV with a positive sentinel lymph node.20 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.25
Importantly, note that a preoperative determination of exact tumor thickness may not be possible in patients diagnosed based on shave biopsy results (or when the melanoma extends to the deep margin of the biopsy) or in those whose tumors are not reviewed by an experienced and meticulous dermatopathologist. Up-staging of tumor thickness has been reported to occur in up to 50% of melanoma biopsy specimens reviewed by interested dermatopathologists. Nonetheless, sentinel lymph node biopsy remains controversial for patients with thin melanomas who, overall, have an excellent long-term prognosis.
Other patients who may benefit from sentinel lymph node biopsy include patients with tumors thicker than 4 mm. 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 may be considered in these patients to identify individuals with a better prognosis (negative sentinel lymph node biopsy results), to achieve long-term locoregional control of disease (selective lymphadenectomy), and to stratify patients for participation in clinical trials. Sentinel lymph node biopsy also may be considered for patients with isolated local cutaneous recurrence in the absence of clinically evident regional nodal disease.26
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 possible 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 as outlined above.
No survival benefit has yet been proven for sentinel lymph node biopsy with selective lymphadenectomy for patients with clinically node-negative melanoma. Three ongoing prospective randomized clinical trials are being conducted to address this and related issues.
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). In 3 small series of such patients, 29-44% of patients had sentinel lymph node metastases.27,28,29
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 patients with neuroendocrine carcinoma of the skin 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.30 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. Chemotherapy may be used as an adjunct to locoregional therapy.
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, for patients with Marjolin ulcer, and for some patients with locally recurrent carcinomas.
The authors, and others, have also applied this technique to the staging and treatment of eccrine and apocrine skin carcinomas, porocarcinoma, hidradenocarcinoma, and invasive extramammary Paget disease, which have a significant risk of lymphatic metastasis. Sentinel lymph node biopsy is also used to treat selected patients with cutaneous lymphomas and sarcomas. A report has been published that described sentinel lymph node biopsy for staging a patient with metastatic basal cell carcinoma (a rare phenomena) whose primary had evidence of malignant cells in a peritumoral dermal lymphatic vessel.
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 early-stage breast cancer as an alternative to routine level I and II axillary lymph node dissection.
Sentinel lymph node biopsy with selective lymphadenectomy has been used with varying degrees of success to stage noncutaneous squamous cell carcinomas of the head and neck. The importance of preoperative lymphoscintigraphy is generally acknowledged for the correct identification of the nodal basins at risk. As with melanoma of the head and neck, this alters the planned intervention in a significant number of patients. Preliminary results of a European multicenter trial suggest that this technique is valuable as the sole staging tool for early T1 and T2 oral cavity and oropharyngeal squamous cell carcinomas. This technique is now being investigated in an American College of Surgeons Oncology Group (ACOSOG) trial.
Sentinel lymph node biopsy has also been applied to the treatment of 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).
Relevant Anatomy
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 finding underscores the importance of preoperative lymphoscintigraphy for these patients.
Contraindications
Selection of patients
In certain clinical situations, sentinel lymph node biopsy with selective lymphadenectomy has no role. The presence of satellitosis or in-transit metastasis at the time of initial presentation is a relative contraindication to sentinel lymph node biopsy because the validity of the procedure in this setting is unknown. 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 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 in these areas may be performed in conjunction with therapeutic lymphadenectomy of the clinically involved nodal basin.
Sentinel lymph node biopsy should be considered with caution if the patient has undergone a prior wide local excision with a large rotation flap closure or a very wide excision with skin graft coverage. In these patients, the pattern of lymphatic drainage could theoretically be altered. 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. Elective lymph node dissection may be discussed with these patients; however, sentinel lymph node biopsy has been reported to be successful in a small series of patients with recurrent disease who had undergone previous lymph node surgery, suggesting that this merits further investigation.
Additional situations
Other situations merit special consideration. 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).31 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.32 Pediatric patients may undergo sentinel lymph node biopsy, when clinically indicated, without untoward effects. Patients with a history of cosmetic dye allergy should not receive isosulfan blue.
While lymphoscintigraphy is extremely helpful in identifying the at-risk nodal basins in patients with melanoma of the head and neck, sentinel lymph node biopsy has been less successful in this region, with a localization rate of less than 95%, even with the combination of dye and radiocolloid. The procedure is technically challenging in this location.
Drainage patterns are quite variable and unpredictable. A greater number of sentinel lymph nodes, often from multiple basins, are identified in the head and neck compared with other sites, which increases surgical morbidity. The rate of sentinel lymph node positivity is less than that for melanomas at other sites, and the failure rate and false-negative rate are higher (approximately 4-fold).33,34 Despite this, safety and accuracy are still acceptable.
If multiple sentinel nodes are identified either in the neck or parotid region, many surgeons perform a superficial parotidectomy or modified neck dissection, rather than multiple biopsies through multiple incisions, in an area in which the lymph nodes usually are quite small and more difficult to identify and in which avoidance of injury to surrounding structures (eg, facial nerves, cranial nerves, major blood vessels) is of paramount importance. Sentinel lymph node biopsy in this location also relies heavily on the use of the combined technique, especially for primary tumors that are overlying the parotid gland and cannot be shielded to avoid interference with the handheld gamma probe. In this setting, the use of blue dye and, sometimes, repeated injections of dye, is important. This is also a consideration for any primary melanoma immediately overlying a regional nodal basin.
In some patients, shielding the primary site is not feasible because the sentinel lymph node is subjacent or close to the injection site. Initial wide excision (5-10 min after intraoperative injection of blue dye) of the primary tumor may be helpful, or the blue dye technique with in-continuity dissection of the lymphatics may be applied. When sentinel lymph node biopsy is not successful in these situations, consideration should be given to elective in-continuity lymph node dissection, if this has been discussed with the patient preoperatively, because the likelihood of relapse in the underlying nodal basin is a concern in patients with high-risk primaries.
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References
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Further Reading
Keywords
sentinel node biopsy, sentinel lymphadenectomy, skin cancer biopsy, selective lymphadenectomy, melanoma surgery, skin cancer, melanoma, skin cancer surgery, malignant melanoma, lymph node metastasis, sentinel lymph node biopsy, melanoma staging, melanoma treatment, melanoma prognosis
