The incidence of malignant melanoma is increasing at an alarming rate, doubling in women and growing by more 300% in men during the past 25 years. The importance of diagnosing nodal metastatic disease, with the ability to detect smaller and smaller volumes of tumor in the sentinel lymph nodes (SLNs) biopsied using immunohistochemical staining, has impacted the accurate staging and stratification of melanoma patients. The role that elective lymph node dissection now plays in staging the melanoma patient and determining subsequent treatment has been greatly diminished in favor of less morbid and less invasive techniques that have a higher degree of accuracy in detecting occult nodal disease. This article explores what has driven the advent of selective or SLN biopsy, the rationale behind obtaining a preoperative lymphoscintigram, the technical details of the SLN biopsy procedure, and the refinement in the pathologic detection of ever smaller volumes of tumor in nymph node tissue removed. The role that these new modalities have played in changing the dynamic field of melanoma care is emphasized.
The incidence of malignant melanoma is increasing at an alarming rate, doubling in women and growing by more 300% in men during the past 25 years. In the United States, the projected number of newly diagnosed cases of melanoma for 2008 is 62,000, with 8000 people expected to die from the disease. Although the incidence of melanoma has increased over the last 25 years, mortality from the disease has not. This improvement is in part due to the great strides in greater public awareness, dermatologic screening examinations, and earlier diagnosis. The surgical treatment of melanoma has also undergone tremendous change with the establishment of recommended wide local excision margins determined by tumor thickness and based on prospective studies, and the introduction of selective lymph node biopsy to allow the more accurate staging of clinically node-negative patients. The importance of diagnosing nodal metastatic disease, with the ability to detect smaller and smaller volumes of tumor in the sentinel lymph nodes (SLNs) biopsied using immunohistochemical staining, has impacted the accurate staging and stratification of melanoma patients, allowing various treatment protocols to be rigorously compared and evaluated. Lastly, the development of effective chemotherapy in the form of FDA-approved interferon-α2b for high-risk primary melanomas and those with nodal disease has begun to show promise for extending survival in those with this highly lethal disease.
The importance of nodal status featured prominently in the most recent American Joint Committee on Cancer (AJCC) staging system for melanoma, which was revised in 2002 and completely implemented in 2003 ( Table 1 ). The role that elective lymph node dissection now plays in staging the melanoma patient and determining subsequent treatment has been greatly diminished in favor of less morbid and less invasive techniques that have a higher degree of accuracy in detecting occult nodal disease. This article explores what has driven the advent of selective or SLN biopsy, the rationale behind obtaining a preoperative lymphoscintigram, the technical details of the SLN procedure, and the refinement in the pathologic detection of ever smaller volumes of tumor in nymph node tissue removed. Finally, the role that these new modalities have played in changing the dynamic field of melanoma care is emphasized.
| Stage | Description |
|---|---|
| IA |
|
| IB |
|
| IIA |
|
| IIB |
|
| IIC |
|
| IIIA |
|
| IIIB |
|
| IIIC |
|
| IV | Tumor of any thickness with any nodes and any distant metastases |
Variables that influence prognosis in cutaneous melanoma
There are many variables that have been found to predict clinical outcomes and therefore may influence the treatment of patients with melanoma. Among the most prognostic variables in AJCC stage I and II (absence of nodal disease) that determine the risk for nodal involvement and 5-year survival are tumor thickness, the presence of tumor ulceration, anatomic location (extremity versus trunk versus head and neck), surgical treatment of the primary tumor, and male gender. If melanoma has been found to be metastatic to regional lymph nodes, the significance of the microscopic characteristics of the primary tumor as well as any clinical variables become significantly less important. Once lymph node involvement is established, the 5-year survival rate drops precipitously by approximately 40% compared with those patients who demonstrate no nodal involvement. Knowing the nodal status therefore has significant importance in discussing prognosis in melanoma patients and in orchestrating further treatments such as completion/therapeutic nodal basin dissection (TLND), meeting with a medical oncologist to discuss the possibility of starting chemotherapy, and also in qualifying for and subsequently enrolling in clinical trials.
The sentinel lymph node concept
The relationship between the primary cancer location and the metastatic spread of that cancer to a specific regional lymph node was first described by Virchow in 1863. In 1955 Seaman and Powers, using radiolabeled colloidal gold, described the metastatic spread of cancer cells to regional lymph nodes by way of lymphatic channels. The first use of the term “sentinel node” was in 1960 by Gould and colleagues to describe the presence of a first lymph node or “sentinel node” in a nodal basin to which cancers would initially travel. Radiologic lymphatic mapping in the evaluation of cutaneous cancer metastases was first introduced clinically by Cabanas in the treatment of penile carcinoma in 1977. Morton and colleagues were the first to popularize the concept that lymphatic drainage was neither capricious nor random, and that melanoma nodal metastases occur in an orderly, stepwise fashion. These investigators also asserted that a sentinel node biopsy was representative of the nodal basin to which it belonged, and that a negative sentinel node correlated very closely to lack of metastatic involvement of the remaining lymph nodes in that basin. Further confirmatory studies published by Thompson and colleagues and Reintgen and colleagues showed very similar results, indicating that the SLN biopsy provides equally reliable diagnostic data as that obtained by an elective lymph node basin dissection. If the SLN is found to be negative for metastatic disease then the negative predictive value for the remaining nodal basin is on the order of 95%. The current use of the term sentinel node biopsy incorporates the preoperative localization of the nodal basin(s) at risk, the intraoperative harvesting of the sentinel node(s) usually using radioisotope as well blue dye localization, and the comprehensive pathologic evaluation of the nodal tissue once removed.
The concept of an SLN provides an elegant means to explain the pattern of metastatic disease in not only cutaneous cancers such as melanoma, squamous cell, basal cell, and Merkel cell carcinoma but also other organ-specific tumors such as breast, colon, and other visceral malignancies. Melanoma typically metastasizes initially to regional lymph node basins and from there to distant sites such as the liver, bone, brain, and so forth. This fact was the primary driving force behind performing elective lymph node dissections (ELND) in the preselective lymph node biopsy era. The theory behind SLN mapping is that for any given area of skin, there is an afferent lymphatic channel that leads to a specific first-draining lymph node, the sentinel node. The sentinel node, therefore, is the first node to which melanoma would spread. Melanoma nodal metastases are believed to progress in an orderly and nonrandom fashion. The SLN therefore accurately reflects the status of the lymph nodes contained in that nodal basin. The likelihood that the SLN is negative while another nonsentinel node in the same nodal basin is positive (a “skip” metastasis or false negative) is rare, occurring in less than 1% of SLNs removed. Sentinel lymph node biopsies are particularly useful for melanomas in areas with ambiguous lymphatic drainage (eg, head and neck, the midline trunk) and where multiple SLNs are the rule rather than the exception. Failure to identify and subsequently remove all the SLNs represents an inadequate nodal staging procedure that may potentially place the patient at higher risk for nodal as well as visceral recurrences.
The sentinel lymph node concept
The relationship between the primary cancer location and the metastatic spread of that cancer to a specific regional lymph node was first described by Virchow in 1863. In 1955 Seaman and Powers, using radiolabeled colloidal gold, described the metastatic spread of cancer cells to regional lymph nodes by way of lymphatic channels. The first use of the term “sentinel node” was in 1960 by Gould and colleagues to describe the presence of a first lymph node or “sentinel node” in a nodal basin to which cancers would initially travel. Radiologic lymphatic mapping in the evaluation of cutaneous cancer metastases was first introduced clinically by Cabanas in the treatment of penile carcinoma in 1977. Morton and colleagues were the first to popularize the concept that lymphatic drainage was neither capricious nor random, and that melanoma nodal metastases occur in an orderly, stepwise fashion. These investigators also asserted that a sentinel node biopsy was representative of the nodal basin to which it belonged, and that a negative sentinel node correlated very closely to lack of metastatic involvement of the remaining lymph nodes in that basin. Further confirmatory studies published by Thompson and colleagues and Reintgen and colleagues showed very similar results, indicating that the SLN biopsy provides equally reliable diagnostic data as that obtained by an elective lymph node basin dissection. If the SLN is found to be negative for metastatic disease then the negative predictive value for the remaining nodal basin is on the order of 95%. The current use of the term sentinel node biopsy incorporates the preoperative localization of the nodal basin(s) at risk, the intraoperative harvesting of the sentinel node(s) usually using radioisotope as well blue dye localization, and the comprehensive pathologic evaluation of the nodal tissue once removed.
The concept of an SLN provides an elegant means to explain the pattern of metastatic disease in not only cutaneous cancers such as melanoma, squamous cell, basal cell, and Merkel cell carcinoma but also other organ-specific tumors such as breast, colon, and other visceral malignancies. Melanoma typically metastasizes initially to regional lymph node basins and from there to distant sites such as the liver, bone, brain, and so forth. This fact was the primary driving force behind performing elective lymph node dissections (ELND) in the preselective lymph node biopsy era. The theory behind SLN mapping is that for any given area of skin, there is an afferent lymphatic channel that leads to a specific first-draining lymph node, the sentinel node. The sentinel node, therefore, is the first node to which melanoma would spread. Melanoma nodal metastases are believed to progress in an orderly and nonrandom fashion. The SLN therefore accurately reflects the status of the lymph nodes contained in that nodal basin. The likelihood that the SLN is negative while another nonsentinel node in the same nodal basin is positive (a “skip” metastasis or false negative) is rare, occurring in less than 1% of SLNs removed. Sentinel lymph node biopsies are particularly useful for melanomas in areas with ambiguous lymphatic drainage (eg, head and neck, the midline trunk) and where multiple SLNs are the rule rather than the exception. Failure to identify and subsequently remove all the SLNs represents an inadequate nodal staging procedure that may potentially place the patient at higher risk for nodal as well as visceral recurrences.
The diminishing role of elective lymph node biopsy in favor of selective lymph node biopsy
Controversy continues to surround the issue of how to address the possibility of occult regional nodal metastases in clinically node-negative melanoma patients (AJCC stages I and II). In the preselective node biopsy era, patients with thin melanomas (<1.00 mm) without clinical nodal involvement were believed to have a very good chance for cure with local excision alone without a prophylactic or ELND (removal of a clinically negative nodal basin). In contrast, patients with thick melanomas (>4.00 mm) and no clinical nodal disease were not believed to benefit from ELND, as they exhibit a very high incidence of both regional and distant metastatic disease. These individuals would be followed and if nodal disease developed, a therapeutic node dissection would be offered. Therefore, elective lymph node dissection had been advocated for the lymphatic basins draining the site of a primary melanoma of intermediate thickness (1.00–4.00 mm) in an attempt to remove occult nodal metastases before nodal spread became palpable. To date, of the 4 randomized prospective studies designed to evaluate the benefit of ELND in patients with 1.00- to 4.00-mm thick primary melanoma, none has demonstrated a clear survival advantage with this technique in this population of patients. A major concern in performing an ELND is that only about 20% of patients will be found to have nodal metastases, and therefore 80% of patients undergoing an ELND will be subjected to the potentially significant morbidity of an operation that they did not require. Furthermore, in patients with melanoma primaries located in areas with ambiguous nodal drainage patterns such as over the head and neck and midline trunk, more than one nodal basin may need to be dissected. If these nodal basins are not discovered by preoperative lymphoscintigraphy, the ELND may be performed on nodal basins at low risk of harboring disease, decreasing the effectiveness of the operation even further. There are some data to suggest that elective lymph node dissection may improve survival in some patients mainly those with intermediate-thickness melanomas who have an ELND guided by preoperative lymphatic mapping. A subgroup analysis of one such trial, the Intergroup Melanoma Surgical Trial, demonstrated improved survival rates in individuals with melanoma primaries between 1 and 2 mm thick located on the extremities in persons younger than 60 years. If an SLN biopsy cannot be performed for whatever reason, these clinical guidelines should be considered in determining future surgical care (see later discussion).
Waiting until palpable disease develops in a nodal basin before performing a nodal basin dissection (a TLND) has been shown to correlate with a worse outcome (50%–60% for TLND vs 15%–35% for ELND). Only patients who have a high likelihood of having nodal involvement ideally would be offered a full nodal basin dissection. This area is where sentinel node technology may have its greatest impact. With this relatively new technology, the indications for ELND are becoming increasingly limited, saving many melanoma patients the potential morbidity and costs associated with this type of a staging procedure. The prognostic value of a staging SLN biopsy is clearly demonstrated by the 5-year survival statistics from the AJCC melanoma database analyzing tumors greater than 1.0 mm. With clinical node-negative staging the 5-year survival was 65%, for negative staging based on ELND it was 75%, while based on negative SLN data the survival rate was 90%.
Regardless of the method used, local nodal basin evaluation is intended to provide regional lymph node staging based on pathologic tissue sampling, regional disease control, and provision of potential cure by removing nodal disease. These goals would ideally be met with the lowest morbidity possible, while still achieving a high diagnostic and prognostic yield.
Lymphatic mapping
Blood vessels are porous to water and low molecular weight proteins, allowing the translocation of edema fluid into the interstitial space, thereby creating lymph. Lymphatic fluid is removed by lymphatic channels, which serve to return the third space fluid back to the venous and eventually to the arterial circulation. The lymphatic channels also channel the fluid to regional lymph nodes, where any foreign debris and bacteria are phagocytosed and removed by white blood cells. Most carcinomas use the lymphatic channels during their metastatic spread and become “trapped” in regional lymph nodes, where they may be subjected to the sterilizing action of immunocompetent cells. Taking into consideration the molecular weight of lymphatic fluid, liquids of similar composition can be injected intradermally around a cutaneous cancer site and can be traced to the regional nodal basin(s), identifying lymph nodes at risk for harboring metastatic cells. This process is called lymphatic mapping, and may be performed using either dyes or radioactive colloids. Both methods are used to perform an SLN biopsy when treating melanoma.
Incorporation of preoperative lymphoscintigraphy
Sappey, in 1864, described injecting mercury into human cadaver dermis and observing its migration to regional lymph nodes. The use of radioactive particles to map lymphatic spread was introduced in 1953 by Sherman and Ter-Pogossian using radioactive gold. Radioactive gold was later replaced by 99m Tc-sulfur colloid (termed radiocolloid) in the late 1960s and 1970s. The agents used for lymphatic mapping should be compounds that have a small enough particle size to allow their translocation from the dermal location into the lymphatics. In addition, the agents should have a short radioactive half-life. Both of these requirements are met by 99m Tc-labeled sulfur colloids, which travel to local lymph nodes relatively rapidly, emit γ-rays that image well, and have a half-life of only 6 hours and decay entirely after 2.5 days.
Preoperative lymphatic mapping serves several important functions. First, it identifies all the nodal basins at risk for metastatic spread, allowing each nodal basin so identified to be evaluated with an SLN biopsy. Second, the number of sentinel nodes in a particular basin can also be estimated, allowing the surgeon to be more vigilant in the search for all nodes at risk for nodal disease. Third, preoperative mapping may identify in-transit nodes, such as the popliteal and epitrochlear sites, that would normally not be identified and removed, to detect nodal metastases. Such interval nodes have the same incidence of harboring metastatic disease as an SLN retrieved from the neighboring nodal basin. The incidence of in-transit nodes ranges between 0.5% in the legs and up to 12% in the posterior trunk primaries. Although extremity melanomas have been relatively easy to identify in lymphatic drainage basins, lymphatic mapping using radiocolloids has been especially valuable in identifying draining lymphatic basins, especially when the primary tumor is located in areas with ambiguous drainage pathways. This situation holds true particularly over the entire head and neck area, as well as over the shoulders and midline trunk regions (see later discussion).
On the day of the wide local excision and the SLN biopsy, preoperative lymphoscintigraphy typically is performed in the department of nuclear medicine, using 250 to 600 μCi of cold-filtered technetium-99m sulfur colloid injected intradermally in equal quadrants around the site of the primary tumor. On occasion the lymphoscintigram may be performed up to 24 hours before operative treatment to accommodate the nuclear medicine schedule or if an early start time is requested for the melanoma operation. The absolute counts are reduced by this maneuver; however, the SLNs are still able to be easily identified with the hand-held gamma probe and removed. Anterior-posterior and lateral radiographic views are then taken at 1 minute, 10 minutes, and 2 hours after injection using a large field-of-view gamma detection camera ( Fig. 1 ). When lymphoscintigraphy was initially introduced in the treatment of melanoma, many cancer centers were performing the preoperative lymphoscintigram several days before the SLN harvest. Radioactive sulfur colloid was again injected intradermally at the tumor site just before the wide local excision (WLE) to ensure high readings. This procedure is rarely performed today as the hand-held gamma probes are very sensitive at detecting even minute amounts of radioactive material, and the lymphoscintigrams are scheduled to occur on the day before or on the day of the operation and not days in advance. 99m Tc-sulfur colloid has its greatest nodal concentration between 2 and 4 hours after injection, making localization of the SLN(s) on the day of the preoperative lymphoscintigram the most logical. The images produced by the preoperative lymphoscintigram are somewhat “fuzzy” and may be hard to interpret for the novice SLN surgeon ( Fig. 2 ). Discussing the findings with the nuclear radiologist may prove to be helpful in interpreting the images and planning the operative approach to harvesting the SLN(s). Current lymphoscintigraphic imaging provides a 2-dimensional imaging of the nodes to be removed but cannot localize their exact location in 3 dimensions. Newer scanners are being introduced that can provide images in “3D” by allowing the images to be manipulated and rotated 360°. Any markings made by the radiologist or the nuclear medicine technicians pertaining to the location of the SLNs should be confirmed by the surgeon with the hand-held gamma probe before final patient positioning and prepping.
Incorporation of vital blue dye in the sentinel lymph node biopsy
Morton and colleagues described using blue dye injected directly intradermally at the melanoma biopsy site to identify the afferent lymphatics and stain the SLN a brilliant blue color. Several dyes were initially investigated for their lymphatic transit times and staining patterns including fluorescein, patent blue-V, Cyalume, isosulfan blue, and methylene blue. Isosulfan blue 1% aqueous solution proved to perform the best in terms of visualization with the unassisted eye in ambient operating room lighting; it has minimal collateral tissue diffusion, and has a rapid speed of migration to and retention within regional nodal basins ( Fig. 3 ).
The use of intraoperative blue dye to identify an SLN is relatively safe; however, certain adverse effects are known to occur. Momeni and Ariyan, in a series of 84 patients undergoing an SLN for melanoma, reported that 20% experienced a significant decline (≥2%) in pulse oximetry oxygen saturations, reaching a nadir at about 23 minutes after the injection. Although the decline in oxygenation in erroneous, it could lead to unnecessary interventions and concern over the patients’ well-being. The injection of isosulfan blue dye is associated with rare incidences of allergic reactions, ranging between 0.7% and 2.0%. Montgomery and colleagues described 3 grades of allergic reactions: grade 3 reactions are anaphylactoid with associated cardiovascular collapse and a systolic blood pressure of less than 70 mm Hg; grade 2 reactions are transient hypotension with blood pressure being maintained at greater than 70 mm Hg; and grade 1 reactions are defined as “blue hives” and as a generalized rash. Deaths associated with blue dye injections are very rare and probably reflect that the injections are done in a hospital/operating room setting with immediate availability of full resuscitative services. It is good practice to announce to the anesthesiologist exactly when the blue dye is being injected and to mention the rare risk of adverse effects on the blood pressure and pulse oximeter readings.
The intradermal injection of blue dye also imparts a blue tattoo at the injection site that, if not excised, can persist for many months postoperatively. This stain is mainly an issue when an SLN biopsy is done for breast cancer, and the blue dye is injected in an area of skin that is not subsequently resected with the mastectomy/lumpectomy procedure ( Fig. 4 ). Over the distal legs, feet, and back where the lymphatic flow is relatively slow, the blue hue may persist for a prolonged time and may actually never completely clear. In the head and neck region, the lymphatic washout rates are typically high, making the retention on blue dye short-lived. The blue dye is absorbed and cleared by the renal system, imparting a greenish tint to the urine that may persist for several hours after the procedure ( Fig. 5 ). To avoid needless phone calls and the need to provide words of reassurance, it is best to inform patients about the color change in their urine preoperatively.
The rate of lymph flow is dependent on several factors including skin temperature, movement of the body part, body location, and the presence of external pressure. Under ideal conditions, the blue dye travels through the lymphatics relatively quickly at a rate ranging between 10 cm per minute in the lower extremity and foot to 1.5 cm per minute in the head and neck. When the dye is injected before doing the surgical prep, enough time usually passes to allow the dye to reach a sufficient concentration in the nodal basin, making visual identification of the SLN simple; this is especially true in distal extremity primary sites. Massaging the injection site after the introduction of the dye also promotes dermal blood flow and associated lymph production, speeding the washout of the dye toward the nodal basin(s).
Intraoperative gamma probe sentinel lymph node localization
Without question, the introduction of the hand-held gamma probe has had a significant impact on the ease of use of SLN technology, and has made the technique more widely applicable to multiple tumor types. The gamma probe has also made the technique less technically demanding and thereby has opened up SLN mapping to a greater number of surgeons in academic as well as community practices. The first use of intraoperative lymphatic mapping to identify sentinel nodal tissue using a hand-held gamma detector was reported by Alex and colleagues and Krag and colleagues in 1993 and 1995, and by Van der Veen and colleagues in 1994. Gamma probe localization was pursued because using blue dye alone as a sole modality to identify an SLN was often difficult, if not impossible, with only about 85% of SLN overall and considerably fewer in the head and neck region being retrieved. Combining blue dye with intradermal 99m Tc-labled sulfur colloid has increased the overall retrieval rate from approximately 84% to 96% to 99% ( Table 2 ). Therefore, approximately 16% of melanoma patients who were treated with SLN biopsies using blue dye alone would have had an unsuccessful SLN biopsy, and would be at risk for having occult nodal disease undiagnosed and potentially undertreated. In this scenario, the option would be to adopt a “wait and watch” approach or proceed to an ELND. With the combined modalities, the need to default to an ELND has been significantly reduced, as the successful retrieval rates are close to 100%.
| Improved localization of SLN using blue dye and radiolabeled colloid | |||
|---|---|---|---|
| Basin | Dye Alone | Dye & Colloid | P Value |
| Cervical | 56% | 97% | 0.002 |
| Axillary | 84% | 98% | <0.00001 |
| Inguinal | 95% | 100% | <0.03 |
| Total | 87% | 99% | <0.00001 |
Standardization of pathologic evaluation
With the advent of SLN biopsy techniques, the amount of nodal tissue delivered to the pathologist has become increasingly small. The ability to accurately determine nodal involvement has also become increasingly more complex. Initially, SLNs were often examined using frozen section analysis while the surgeon waited to perform either a full nodal basin dissection for stage 3 disease if the SLN was positive, or to end the nodal portion of the operation if the SLN was negative. In the ensuing years it was shown that frozen section analysis of the SLN has a low sensitivity, due to the inferior quality of frozen sections compared with permanent section analysis and also because of the low tumor burden present in most positive SLNs (typically <2 mm focus). Preparing tissue for frozen section evaluation may also destroy small quantities of diagnostic tissue that would potentially be used to identify metastases by more sophisticated methods. At present, frozen section analysis should be performed only as a confirmatory maneuver for grossly positive lymph nodes that contain large quantities of metastatic disease ( Fig. 6 ). Clinically benign nodes should be submitted to fixative for more intensive evaluation and not examined using frozen section techniques.
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
