Sentinel Lymph Node Biopsy in Patients With Melanoma

Although it has been known since the time of Hippocrates, melanoma was not described in Western literature until recognized by John Hunter in 1787. It was not until 1968 that specimens were examined microscopically when Dr Bodenham confirmed that the “black cancer” described by Hunter was in fact melanoma.[2] Melanoma is the most lethal type of skin cancer and continues to rise in incidence.

The American Cancer Society’s estimates for melanoma include 106,110 new diagnoses in 2021, with 7,180 deaths.[1] Melanoma is one of the fastest growing cancers and its incidence has continued to rise for the last few decades. It is also one of the most common malignancies in patients younger than 30 years, surpassing cervical cancer in young women.

Risk factors for development of melanoma include multiple clinically atypical moles or dysplastic nevi, family history, prior melanoma, inherited genetic mutations, and sun exposure.[3, 4] Although melanoma often arises in patients with fair skin and with significant sun exposure, it can affect any ethnicity and areas of the body with limited sun exposure.[5]

The concept of lymphatic spread of cancer has been known for quite some time. Accordingly, it was reasoned that removing lymph nodes before the spread of melanoma could prevent systemic disease. In 1898, Snow published his work on the concept of “anticipatory gland excision,” or what would be later known as elective lymph node dissection (ELND).[6] Although Snow’s reasoning was sound, multiple randomized controlled trials, short of subset analysis, showed no beneficial effect on survival or local control.[7, 8, 9] These trials were performed mainly on intermediate-depth melanomas (1-4 mm). In patients with thin melanomas (< 1 mm), the rate of nodal involvement seemed low enough that an ELND was not warranted.[10] For thicker melanomas (>4 mm), the risk of systemic metastasis appeared to outweigh the potential benefit of ELND.[11]

In 1955, Seaman and Powers used radiolabeled colloidal gold to describe the path of lymphatic channels followed by cancer cells.[12] Subsequent studies by Gould et al described the first node involved in lymphatic spread, which was then termed the "sentinel lymph node" (SLN).[13] Finally, in 1992, Morton et al showed that the SLN could accurately predict the potential for cancer in the associated nodal basin.[14]

Although the complex anatomy and lymphatic drainage of the head and neck (see Anatomic Considerations) can make treatment of melanoma in this area quite challenging, SLN biopsy (SLNB) can be performed with acceptable morbidity. SLNB carries profound prognostic implications and dictates subsequent therapeutic decisions. The impact of further therapy in patients with a positive SLN (eg, completion lymph node dissection [CLND] and/or systemic therapy) remains an active area of investigation.

For more information, see Malignant Melanoma, Head and Neck Mucosal Melanomas, and Malignant Melanoma Staging.

The National Comprehensive Cancer Network (NCCN) provides recommendations based on probability of sentinel lymph node (SLN) positivity. In patients with clinical stage I/II melanoma, SLN status is the most significant predictor of survival.

SNL biopsy (SLNB) is not recommended for patients with melanoma in situ (stage 0) or melanoma less than 0.8 mm in thickness in the absence of ulceration (T1a). Patients with melanomas less than or equal to 1 mm in thickness are at lower risk for nodal involvement (2-5%).[15] For clinical stage IB, T1b melanoma (Breslow depth < 0.8 mm with ulceration or other adverse features including age < 40 years, lymphovascular invasion, significant vertical growth phase, increased mitotic rate), the probability of SLN positivity is increased to 5-10%[5] . Thus, SNLB should be considered in these patients.

For patients with stage IB (T2a) or II (T2b and higher) melanoma, the probability of a positive SLN is generally greater than 10%. SLNB should be offered to these patients. For some patients (nonmitogenic, older patients) with stage IB (T2a) and stage II, the probability is actually < 10%. For these cases, SNLB may be considered but not necessarily offered.

SLNB should be offered to all patients with a clinically negative nodal basin and a primary melanoma greater than 1 mm in depth. As noted, evaluation of the nodal basins via elective lymph node dissection (ELND) was most commonly limited to melanoma with a depth of 1-4 mm. Biopsy of the sentinel node carries a lower risk of morbidity in comparison to a more extensive lymph node dissection. This has allowed for the expansion of the indications for evaluation of the nodal basins associated with melanoma, and SLNB should be routinely recommended for patients with 1-4 mm thick lesions (T2-T3).

SLNB may also be offered to patients with deep (>4 mm; T4) melanoma and clinically negative nodes, as it has proven to yield valuable prognostic information, with rates of positive SLNs ranging from 30-40%.[16, 17] The choice of adjuvant therapy or clinical trial enrollment for patients with very thick melanomas may be influenced by SLNB results.

Patients with melanoma exhibiting regression may also be considered for SLNB, although this is more controversial. Some studies have indicated that there may be no association between regression and positive SLN status.[18, 19, 20]

SLNB may still be performed following prior wide local excision, despite possible concern regarding accuracy.

For clinically or radiographically negative regional nodes and absence of distant metastases, SNLB may be considered for isolated in-transit metastasis or local recurrence of a primary melanoma.

Sentinel lymph node biopsy (SLNB) is not always warranted. It may be deemed unnecessary when patients present with systemic disease, as it does not alter treatment and does not offer any survival advantage. If a patient presents with a clinically evident node, the first step should be evaluation of that node with fine-needle aspiration (FNA) or core needle biopsy as opposed to SLNB.[5]

Whether SLNB should be performed after a wide local excision is somewhat controversial as there is concern regarding altered lymphatics. It appears, however, that if extensive reconstruction has not been performed, SLNB can be used in patients with a prior wide local excision.[21, 22]

For patients who have previously undergone SLNB, there is nothing in the melanoma literature to establish definitive recommendations. The breast cancer literature suggests that SLNB may be feasible,[23] but whether such limited data can be applied to melanoma patients is a matter of debate. Nevertheless, given the reliability of lymphatic mapping for the identification of nodal pathways, the authors believe that prior SLNB is not a contraindication to repeat biopsy.

Lastly, SNLB should not be recommended to patients who are poor surgical candidates. For patients who will not follow postbiopsy imaging and treatment recommendations, it is reasonable to avoid SNLB.

Guidelines from the American Society of Clinical Oncology and Society of Surgical Oncology are as follows[24] :

• Routine sentinel lymph node biopsy (SLNB) not recommended for T1a melanomas (nonulcerated lesions < 0.8 mm in Breslow thickness)
• SLNB considered for T1b melanomas (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
• SLNB recommended for T2 and T3 melanomas (Breslow thickness of >1 mm to 4 mm)
• SLNB may be recommended for T4 melanomas (>4 mm in Breslow thickness), after a discussion of potential benefits and risks
• In the case of a positive SLNB,  completion lymph node dissection (CLND) or careful observation are options for patients with low-risk micrometastatic disease, with due consideration of clinicopathologic factors; for higher-risk patients, careful observation may be considered only after a thorough discussion with patients about potential risks and benefits of foregoing CLND

Anatomically following the lymphatic channels below the neck is relatively straightforward. The lymphatics follow the path toward either the ipsilateral axilla or groin in the upper and lower extremities, respectively. Clinicians should be aware that although the majority of sentinel lymph nodes (SLNs) are found in the major nodal basins, some can also be found in the epitrochlear nodal basin in the upper extremities and the popliteal nodal basin in the lower extremities.

In the truncal region, lymphatic pathways can travel to multiple nodal basins. This highlights the value of SLN mapping, which eliminates some of the guesswork for determination of melanoma spread. It is important, however, to keep in mind that nodes may be found anywhere along the line from the melanoma site to the nodal basin and that any of these nodes has the potential to harbor metastasis.[25]

The lymphatic drainage of the head and neck is more extensive and variable than that of the trunk or extremities. The lymphatic drainage of the anterior neck is based on a system developed at Memorial Sloan-Kettering in the 1930s. Seven levels of lymph nodes exist (see the image below).

Lateral cervical lymph nodes I-VI. Level VII nodes are not shown.

Levels I-V describe the lateral neck lymph node basins, while levels VI and VII describe the central lymph node basins, as follows:

• Level I: Submandibular nodes, which lie between the mandible and the posterior and anterior bellies of the digastric muscle
• Level II: Upper jugular nodes, which lie between the skull and the hyoid bone along the internal jugular vein
• Level III: Middle jugular nodes, which lie between the hyoid bone and the omohyoid muscle along the internal jugular vein
• Level IV: Lower jugular nodes, which lie between the omohyoid muscle and the clavicle along the internal jugular vein
• Level V: Posterior triangle nodes, which lie between the trapezius and the sternocleidomastoid muscle above the clavicle
• Level VI: Centrally located nodes between the carotid sheath and above the suprasternal notch
• Level VII: Superior mediastinal nodes, which lie below the suprasternal notch

Traditionally, a line that bisected the ear caudad to cephalad marked the boundaries of the anterior and posterior drainage of the scalp (see the image below). Lesions anterior to this line would drain to the parotid, submandibular, and cervical lymph nodes (levels I-V). Lesions posterior to this line would drain to the posterior auricular, suboccipital, upper jugular, and posterior triangle lymph nodes. It was assumed that lymphatic drainage would not cross the midline.

Drainage patterns of the scalp.

The advent of lymphoscintigraphy, however, demonstrated that these assumptions are not always accurate. In 1994, Wells et al found that lymphoscintigraphy was discordant with clinical predictions of nodal drainage 84% of the time.[26] Even after revision of the clinical parameters, a study by O’Brien et al the following year still found a discordance rate of 33%.[27] Uren also reported discordance rates of 33% and demonstrated nodal basins draining across midline in 10% of cases.[28]

The staging of melanoma has undergone multiple changes. Common staging is according to the tumor, node, metastasis (TNM) system of the American Joint Committee on Cancer (AJCC) in collaboration with the Union for International Cancer Control (UICC).[29] Changes were made to the 8th edition, which are included in the Table below. Stage groupings are as above.

Table. AJCC TNM Classification of Melanoma (Open Table in a new window)

A positive sentinel lymph node (SLN) carries extremely valuable prognostic information. Survival rates for patients with a negative SLN have been shown to be superior to those with a positive SLN. In addition, the method of detection has been shown to be a predictor of survival as well. SLNs that are positive only on polymerase chain reaction (PCR) are associated with a better survival rate than those detected with hematoxylin and eosin (H&E) staining (see the image below).[30]

Survival rates of negative sentinel lymph node versus detection by polymerase chain reaction (PCR) and detection by PCR and H&E.

In patients with a positive SLN, previous recommendations were to perform completion lymph node dissection (CLND) and treat with adjuvant interferon—this was the first adjuvant therapy to show benefit in patients with positive nodes. There have since been major advances in immunotherapy for melanoma, and monoclonal antibodies like ipilimumab have shown equivalent efficacy. More recent studies show protein kinase (PK) inhibitors may be superior as adjuvant therapy and for stage IV disease. There has been identification of several drug targets for the treatment of stage IV disease, with newer drugs inhibiting BRAF, MEK, NRAS, and KIT. Significant clinical benefit has been seen for patients with BRAF mutations, although the most superior systemic therapy has not been established.

There is no question that SLN biopsy (SLNB) provides tremendous prognostic information but the actual degree of sentinel node disease that would benefit from treatment is not known. Some studies have shown that a small volume of disease within the SLN is rarely associated with disease in other lymph nodes. Some suggest that even a small amount of disease is associated with recurrence and decreased survival compared with patients with no SLN disease. The MSLT-II trial confirmed prior studies showing that with current treatment paradigms, while immediate CLND reduces regional recurrence slightly (ie, improves regional control), it does not increase melanoma-specific survival.[31] Thus, current NCCN Guidelines indicate both nodal basin surveillance and CLND as primary treatment options in the setting of a microscopically positive SLN, with adjuvant systemic therapy versus observation. The threshold of disease at which patients truly benefit from further surgical or immunologic treatment has not been determined.

A thorough discussion regarding the indications and potential complications of sentinel lymph node biopsy (SLNB) should be undertaken with each patient. The patient should be educated regarding the predicted probability of node positivity, based on tumor features and other factors. Patients should also agree to postbiopsy recommendations based on SLNB results, which may include further imaging, increased surveillance, completion lymphadenectomy, systemic treatment, and potential for clinical trial enrollment.

Currently, the identification rate of sentinel lymph nodes (SLNs) is up to 98%.[32] Initially, Morton and colleagues in the early 1990s used only blue dye and were able to identify SLNs in 194 (82%) of the 237 basins they examined.[14] The identification rates were improved by the use of radiolabeled isotopes. Gershenwald et al increased their identification rates of all sites from 87% to 99% when using 99mTc-labeled sulfur colloid.[33]

The identification rates for SLNs in the head and neck region are somewhat lower than those for other sites. Rates of successful SLN identification range from 90-96%,[34] as compared with higher rates in other body regions. This is largely because of the complex lymphatic pathways of the head and neck anatomy. In addition, the high-density lymphatic basins may cause significant background noise and interfere with use of the gamma probe.

The use of blue dye in combination with lymphoscintigraphy presents challenges specific to the face. Blue dye may persist for several weeks, which can be problematic for this highly visible and cosmetic region. Thus, careful consideration must be given to the use of blue dye, for example limiting its use to the area of resection and reducing the volume if the resection area is small. While blue dye can aid in identification of SLNs, it is generally not necessary for surgeons with substantial experience at head and neck SLN biopsy (SLNB).

For patients with a positive sentinel lymph node biopsy (SLNB), risk stratification is imperative. For low-risk patients, clinicopathologic factors are considered and completion lymph node dissection (CLND) or observation with close follow up and nodal basin monitoring can be offered.

The stage of disease dictates follow-up, as outlined by the National Comprehensive Cancer Network (NCCN) Guidelines (version 2.2021). All patients with melanoma should have a skin examination at least annually for life and should perform regular self-skin and lymph node examinations.

Patients with stage I-IIA disease should undergo physical examinations with attention to skin and nodes every 6-12 months for 5 years and then annually as clinically indicated. Routine laboratory and radiologic testing for surveillance is not recommended.

Patients with stage IIB-IIC disease should undergo physical examinations with attention to skin and nodes every 3-6 months for 2 years, and then every 3-12 months for 3 years. Imaging every 3-12 months for 2 years and then every 6-12 months for an additional 1-3 years should be considered.

Patients with stage IIB-IV should undergo examinations every 3-6 months for 2 years, then every 3-12 months for 3 years, then annually. Imaging every 3-12 months to screen for recurrence or metastasis (not recommended after 3-5 years) should be considered.

Patients with stage III disease and a positive sentinel node should be considered for ultrasound surveillance.

The use of screening chest radiography, CT, positron-emission tomography, and/or MRI in asymptomatic patients is left to the discretion of the treating physician. Previously, providers were not aggressive in obtaining imaging because treatment did not provide meaningful impact for these patients. However, with improving therapeutic options, early detection of recurrence may prove more meaningful, and, thus, routine screening imaging may have increasing value in high-risk patients.

After melanoma is diagnosed, if a sentinel lymph node biopsy (SLNB) is deemed appropriate, the patient undergoes wide local excision of the primary melanoma site with SLNB. Some centers routinely wait 24 hours after injection of the radiotracer before performing SLNB. The authors have found, however, performing injection the day of surgery is more practical with similar outcomes.

Lymphoscintigraphy is performed in the nuclear medicine department by injecting the radiotracer intradermally around the primary melanoma, followed by imaging with a gamma camera to confirm appropriate uptake of the radiotracer and provide general localization (see the image below). It may be beneficial to use a handheld gamma probe in the preoperative area to identify potential sites of SLNs. When there are multiple nodal basins, all are considered pertinent. Which basin lights up first does not matter, as all should undergo biopsy.

For optimal SLN mapping in head and neck melanoma, use of single-photon emission computed tomography (SPECT) imaging should be considered. It has been noted to improve anatomic localization of SLNs and to increase the number of SLNs identified, which can result in altered surgical planning, improved extraction of SLNs, and increased identification of regional nodal metastasis with improved survival.[35, 36]

Lymphoscintigraphy of a forehead melanoma with uptake in the parotid and submandibular nodes.

After the patient is transported to the operative suite, anesthesia is induced at the discretion of the anesthesiologist in consultation with the surgeon. If dye is to be used as an adjunct to the radiotracer, approximately 1 mL of blue dye is injected intradermally at the site of the lesion. Either isosulfan blue or methylene blue may be used, but methylene blue offers equivalent efficacy at lower cost. The lesion is then massaged for 4-5 minutes to enhance lymphatic drainage.

A handheld gamma probe is used to identify hot spots, which theoretically indicate the location of SLNs. A small incision is then made overlying the hot spot. Clinicians should be aware that  completion lymph node dissection (CLND) (completion lymphadenectomy) may be necessary after pathologic examination and should plan incisions to accommodate this possibility. Clinicians should also have a thorough discussion with the patient regarding the possibility of CLND and how this changes the extent of the surgical procedure.

For nodes in the parotid region, the authors have rarely found it necessary to perform a parotidectomy and facial nerve dissection to complete a SLNB, as the target nodes are generally superficial in the gland. Therefore, a preauricular incision is recommended for hot spots noted in the parotid region. With careful dissection parallel to the facial nerve branches, SLNs can usually be identified without a formal parotidectomy. The authors have found that repeat surgery for CLND can be performed with acceptable risk to the facial nerve, and the literature supports this finding.[37]

After the nodal basin is identified, blue lymphatics can help visually guide the surgeon to the grossly blue nodes (see the first image below). The handheld gamma probe is used to identify hot nodes in the field. Any nodes with significant radiotracer activity are removed and their radioactivity counts are measured ex vivo (see the second image below).

Intraoperative left axillary sentinel lymph node seen after uptake with blue dye.

Confirmation of the sentinel node based on a high radioactive count.

SLNs are then sent to pathology for appropriate staining. An SLN is defined as any of the following:

• Any grossly suspicious lymph node
• Any node that harbors blue dye
• Any node whose radioactivity count is greater than or equal to 10% of that of the hottest node removed

In general, dissection is continued until the nodal bed count is less than 10% of that of the hottest node removed.[38] The maximum number of lymph nodes that can be harvested has not been established. The nodes harboring malignancy are likely to be within the first four nodes harvested. Once four negative nodes have been obtained from a single drainage basin, detection of a subsequent positive node within that basin is extremely low. Thus, lymphadenectomy beyond four nodes is unlikely to reveal nodal metastasis and may confer increased morbidity. Once SLNB is complete, wide local excision of the primary melanoma is performed. Particularly when the SLNs are in close proximity to the primary melanoma (common for head and neck melanomas), the surgeon may wish to perform excision of the primary prior to SLNB to reduce gamma emissions from the injection site and facilitate localization of the SLNs.

It is important to stage patients radiographically prior to completion lymphadenectomy. When a SLN is positive, staging studies may obviate the need for CLND in the setting of metastatic disease.

Pathologic examination

Serial sectioning is important to detect micrometastasis in the pathologic specimen. National Comprehensive Cancer Network (NCCN) Guidelines recommend serial sectioning in addition to appropriate immunohistochemistry.[5] Staining for melanoma markers, including S100, HMB45, and Melan-A/Mart-1, increases sensitivity and can detect one positive cell within 100,000 cells. Consideration can also be given to performing polymerase chain reaction (PCR) on the sentinel lymph nodes (SLNs).

In SLN biopsy (SLNB) for melanoma, unlike that for breast cancer, the utility of routine intraoperative pathologic sectioning is somewhat debatable. Concerns have been raised about the possibility of frozen sectioning disrupting what few malignant cells may be present, preventing further analysis.[39]

In 2000, Koopal et al found that intraoperative frozen sectioning carried a sensitivity of 34% and a false-negative rate of 12%.[40] Tanis et al compared intraoperative frozen sectioning of SLNB for melanoma patients with breast cancer patients and demonstrated sensitivities of 47% and 74%, respectively.[41]

Others have found that frozen sectioning can provide accurate results and minimize trips to the operating room, thereby decreasing potential complications and cost of repeat surgery.[42, 43, 44] In 2008, Alkhatib et al reported a much higher sensitivity rate of 91%, supporting the use of routine intraoperative frozen section.[42]

With regard to head and neck melanoma, intraoperative frozen section should not be performed. Conversion from SLNB to a completion lymph node dissection (CLND) in the axilla or femoral triangle is relatively straightforward. Contrary to this, CLND in the neck may necessitate a lateral neck dissection, posterolateral neck dissection, or formal parotidectomy with facial nerve dissection, procedures that carry substantially more risk to the patient than isolated nodal biopsy. Because of this disparity, it is more practical to await final pathology, allowing a more comprehensive preoperative discussion with the patient. Additionally, in light of the findings of the Multicenter Selective Lymphadenectomy Trial II (MSLT-II),[31] CLND may not be warranted in every patient with SLN metastasis.

Also see Sentinel Lymph Node Biopsy in Melanoma Pathology.

Sentinel lymph node biopsy (SLNB) is associated with fewer complications than a more extensive lymphadenectomy. Radiotracer is generally well tolerated, with mild discomfort at the injection site. There are reports of allergic reactions to blue dye. The procedural false-negative rate is less than 5% for experienced practitioners. Rates of wound infection, nerve injury, deep venous thrombosis, and lymphedema are less than 1%. Hematoma and seroma formation occurs in less than 2% of patients. Risks for complications are greater in the groin compared with the axilla or neck. Specific to head and neck melanoma, facial nerve injury is a feared complication, although rates of injury are very low.

The potential for injury to the facial nerve has led some to recommend a superficial parotidectomy as opposed to mapping the parotid gland.[45] However, a study by Schmalbach et al on 80 patients with head and neck melanoma reported no dysfunction of the cranial nerves, including the facial nerve, and concluded that a superficial parotidectomy is unnecessary for evaluating SLNs in the parotid region.[46] The authors have had similar experiences.

Because the lymphatic system of the head and neck region is complex, some concern exists regarding the possibility of missing metastatic SLNs (ie, false-negative SLNB results) and the potential for recurrence in a nodal bed after a negative SLN dissection. The literature is not unanimous, suggesting a failure rate anywhere from 0-25%.[27, 37, 46, 47, 48, 49] False-negative rates should be below 5%, slightly higher in head and neck region.