Sections

The Role of Sentinel Node Biopsy in Skin Cancer

Sections The Role of Sentinel Node Biopsy in Skin Cancer
Overview
Treatment
Media Gallery
References

Overview

Background

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.

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.^[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).

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 underscores the importance of preoperative dynamic lymphoscintigraphy for accurate identification of sentinel nodes.

Contraindications

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 of^99m 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.

Treatment & Management

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Media Gallery

Lymphoscintigram demonstrating 2 afferent lymphatics draining to 2 discrete axillary sentinel lymph nodes.
Blue dye seen traveling along afferent lymphatics of the leg after injection of isosulfan blue dye around a nodular melanoma of the dorsum of the foot.
Handheld gamma detector for radioguided sentinel lymph node biopsy.
Using the gamma probe to detect a hot spot in the inguinal area.
Blue-stained afferent lymphatic leading to blue-stained inguinal lymph node.
A small focus of subcapsular metastatic melanoma in a lymph node (hematoxylin and eosin, original magnification X200).
Scattered MELAN-A positive melanoma cells in a sentinel lymph node.

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Author

Tina J Hieken, MD, FACS Associate Professor of Surgery, Mayo Medical School

Tina J Hieken, MD, FACS is a member of the following medical societies: American Association for Cancer Research, American College of Surgeons, American Medical Association, American Society of Clinical Oncology, Association for Academic Surgery, Massachusetts Medical Society, Society for Melanoma Research, Society of Surgical Oncology

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: SkylineDx BV<br/>Received research grant from: Genentech; SkylineDx BV.

Specialty Editor Board

Michael J Wells, MD, FAAD Dermatologic/Mohs Surgeon, The Surgery Center at Plano Dermatology

Michael J Wells, MD, FAAD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Texas Medical Association

Disclosure: Nothing to disclose.

John G Albertini, MD Private Practice, The Skin Surgery Center; Clinical Associate Professor (Volunteer), Department of Plastic and Reconstructive Surgery, Wake Forest University School of Medicine; Past President, American College of Mohs Surgery

John G Albertini, MD is a member of the following medical societies: American Academy of Dermatology, American College of Mohs Surgery

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: QualDerm Partners; Novascan<br/>Have a 5% or greater equity interest in: QualDerm Partners - North Carolina.

Chief Editor

William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology

Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier; WebMD<br/>Served as a speaker for various universities, dermatology societies, and dermatology departments.

Additional Contributors

Susan M Swetter, MD Director, Pigmented Lesion and Melanoma Program, Professor, Department of Dermatology, Stanford University Medical Center and Cancer Institute, Veterans Affairs Palo Alto Health Care System

Susan M Swetter, MD is a member of the following medical societies: American Academy of Dermatology, Women's Dermatologic Society, American Society of Clinical Oncology, Society for Melanoma Research, Eastern Cooperative Oncology Group, American Medical Association, Pacific Dermatologic Association, Society for Investigative Dermatology

Disclosure: Nothing to disclose.