eMedicine Specialties > Otolaryngology and Facial Plastic Surgery > Head & Neck Surgery
Sentinel Lymph Node Biopsy in Patients With Melanoma: Treatment
Updated: May 22, 2008
Treatment
Preoperative Details
Sentinel lymph node mapping
Lymphatic mapping and sentinel lymphadenectomy are minimally invasive techniques that have been shown to help accurately stage the regional nodal basin with a lower associated rate of complications and costs. These simple and reliable techniques help identify patients with micrometastatic disease who may benefit from complete regional lymphadenectomy.
Some survival benefit has been shown with adjuvant interferon-alfa therapy for patients with node-positive melanoma. The presence of regional lymph node metastasis has commonly been used as an indication for systemic, often invasive, adjuvant therapy. Thus, staging of the disease is important for therapeutic decisions, such as adjuvant interferon-alfa therapy, if indicated in patients with node-positive melanoma. (Interferon-alfa is approved by the US Food and Drug Administration for adjuvant treatment of patients with stage III melanoma.) Numerous experimental trials of vaccines for melanoma require the assessment of regional lymph node involvement.
The impact of the pathologic status of the SLN on relapse-free and disease-specific survival rates is being defined. A multi-institutional outcome analysis of patients with early-stage melanoma has identified micrometastatic disease in the SLN as the most significant independent predictor of tumor-related death. Recent data also suggest that for thick melanomas, SLN status is the most powerful predictor of survival. With previous negative results from a biopsy of the SLN, occurrence in a regional lymph nodal basin is infrequent (1-4%). These low regional failure rates have been partly attributed to improved histopathologic diagnostic techniques, such as nodal serial step-sectioning and immunohistochemistry.
Indication of biopsy of sentinel lymph node
Patients who have untreated melanoma with a thickness of 1 mm or more or Clark level IV (any thickness) are ideally suited for biopsy of the SLN, as are patients who have previously undergone a biopsy for melanoma with a thickness of 1 mm or more or a Clark level IV (any thickness).
Positive nodes are only rarely found in patients with thin melanomas (T1). Positive nodes are found in less than 2% of patients with nonulcerated primary lesions with a thickness of less than 1 mm (T1) and less than a Clark level IV. No lymph node involvement has been reported in lesions of less than 0.73-mm thickness. Thus, SLN mapping does not play a role in these patients. The 2 most significant risk factors for positive nodes in thin primary lesions are ulceration and a Clark level of greater than or equal to IV.
No trial has shown benefit for ELND in subjects with tumors of greater than 4-mm thickness; in fact, ELND was not performed in this group of subjects. However, many centers perform SLN mapping in such patients, perhaps because a subgroup of patients with deep lesions and negative nodes may have an improved survival rate, as compared with patients with stage III cancer, and would be spared adjuvant therapy.
Intraoperative Details
Sentinel lymph node mapping technique
Overall, the success rate of harvesting the SLN is 82% by blue dye alone (blue afferent lymphatics are not always consistent in leading to a blue SLN), 94% by radioactive mapping alone, and 98% by both. An advantage of using the combined approach is that the gamma probe directs the surgeon to the area of greatest radioactivity. Visualization of the blue-dyed lymphatics also helps to decrease the dissection needed to detect the SLN. Thus, the combination of blue dye and radioisotope mapping helps to harvest a SLN with the least dissection and maximum accuracy.
The blue dye technique requires a longer learning curve to achieve success rates of only 80%. Although this technique is helpful in the visual confirmation of a hot node, up to 15% of the blue nodes are not hot, and some of these nodes are the only sites of metastasis. Complications of the blue dye technique are infrequent and minor, including dye-stained urine for a few days (blue dye enters the circulatory system) and prolonged tattooing of the skin that lasts for several months. The rate of anaphylaxis to isosulfan blue is approximately 1%, but the anaphylaxis can be fatal if not recognized and rapidly treated; the anesthetist must be prepared to treat anaphylaxis.
Lymphoscintigraphy can be performed the day before or on the day of surgery at the discretion of the operating physician. Patients scheduled for a biopsy of the SLN undergo a preoperative lymphoscintigraphy to facilitate identifications of all nodal basins at risk and to identify aberrant in-transit SLNs.
The radioisotopes that can be used for lymphatic mapping are technetium Tc 99m human serum albumin,99m Tc colloidal albumin,99m Tc antimony sulfur colloid, and99m Tc sulfur colloid. The choice of the tracer is also important. The ideal radioisotope colloid is one that moves rapidly to the regional lymph node after injection and concentrates in that node without leakage for several hours, which allows the patient to be transported from the nuclear medicine suite to the operating room within a reasonable period of time for successful mapping by the handheld gamma probe, without contaminating the rest of the nodal basin.
The99m Tc sulfur colloid has a particle size in the micrometer range, and the transport may be too slow to be suitable for dynamic imaging. It takes approximately 3-6 hours to concentrate in the SLN. Both the99m Tc colloidal albumin and the99m Tc human serum albumin appear to be the most favorable because the SN becomes positive within 20 minutes in 98% of patients and is maintained for up to 24 hours without an increase in the number of SNs. The99m Tc serum albumin demonstrated faster washout rates from injection sites and better definition of lymph channels than either particulate agent, whereas particulate agents were retained longer in nodes and demonstrated more nodes in delayed images than in early images.
The99m Tc sulfur colloid is made by a hydrogen sulfide technique, which makes the particles much smaller than the standard thiosulfate method. The99m Tc sulfur colloid is passed through a 0.2-mm filter before use, which removes any larger particles. It is intradermally administered to establish lymphatic drainage patterns and to identify those basins at risk for metastatic melanoma. A total dose of 200-400 µCi in 1-2 mL of normal saline is injected intradermally at 4 equal locations around the primary melanoma site or the excisional biopsy scar.
Both the injection and the lymphoscintigraphy are performed in the nuclear medicine suite 1-4 hours before surgery. The advantages are that the preoperative lymphoscintigraphy and the intraoperative mapping can be performed on the same day of surgery, thereby avoiding 2 different injections of radioisotopes and a separate lymphoscintigraphy before surgery. The colloidal isotopes are phagocytosed by the macrophages within the lymph node, keeping the tracer in the draining node and preventing further passage through the nodal basin.
Dynamic scans of all nodal basins at risk are obtained, beginning 5-10 minutes after the injection, using a large field-of-view gamma camera set at 20% window and fitted with a low-energy, high-resolution parallel hole collimator. Anterior and lateral static images are obtained at 5-minute intervals over a period of 20 minutes to 2 hours. The time from radioisotope injection to surgical incision is 60-150 minutes in various studies. Dynamic imaging helps to differentiate between multiple SNs and spillover to nonsentinel nodes.
Early dynamic imaging is important because a SLN cannot be reliably distinguished from a non-SLN in delayed images alone. The radiologist should mark the position of the SLN on the skin, although the surgeon must be aware that relaxation during surgery and positioning may change the position of the lymph node relative to the skin marker. The surgeon should reexamine the lymph node in the operating room with the handheld gamma counter and make the skin incision directly over the most radioactive point. Because only 1% of the injected dose of radioactive colloid reaches the lymph node, a primary site close to the nodal basin may preclude the effective use of the gamma probe, even if the primary site is initially excised. The shadowing becomes important in melanomas of the head and neck, where the nodes and the primary site overlap. After the SLN is removed, explore the lymphatic basin with the gamma probe for additional hot, blue nodes.
The gamma counter is more accurate than vital dyes for locating the SLN, especially in the axilla or deep fatty tissue. Lymphatic basins at risk are identified by the nuclear medicine physician, and the location of the highest radioisotope uptake is marked to indicate the presence of a SLN in each basin. In most cases, the lymphatic channels leading to the SLN are also seen. Sometimes, covering the injection site with lead is necessary to visualize the lymphatic channels, especially if the injection site is in the field of view with the SLN, such as with the head and neck. The patient is then taken to the operating room after the lymphoscintigraphy.
After induction of general anesthesia or sedation with local or regional anesthesia appropriate to the anatomy and at the discretion of the surgeon, 0.5-1 mL (not to exceed 5-7 mL) of 1% isosulfan blue is injected intradermally around the intact tumor or the biopsy site closest to the draining nodal basin detected by lymphoscintigraphy. Lymphatic mapping is performed again by the surgeon in the operating room with the aid of a handheld gamma counter. On average, the colloid or the blue dye travels through the lymphatics to the appropriate SLN within 5-15 minutes. The surgical wounds are then prepared. A SLN is defined as one that localized blue dye and/or concentrated radiolabeled colloid within a regional nodal basin.
After identification of the hot spot, the skin over the site of maximal transcutaneous counts is incised and limited flaps are elevated. An incision of 2-4 cm is made and carried down through the subcutaneous fat, and the superficial fascia is incised. Incisions are fashioned in such a way that they can be incorporated into formal incisions used for nodal dissections in case of a positive node. Both the blue-stained afferent lymphatic channel and the increasing radioactivity counts per second are used to guide dissection and to identify the SLN. The SLN is identified as the lymph node with the afferent blue lymphatic channel staining the node hilus and/or hot node(s). The identified SLN is correlated with the preoperative lymphoscintigram results.
After identification of the SLN, afferent and efferent lymphatics are clipped and divided, and the node is excised. Additional hot nodes are removed from the lymphatic basin until the background radioactivity is less than 10% of the hottest node removed based on ex vivo counts. Thus, after removal of the SLN, the handheld gamma probe is used to search the resection bed to ensure that no residual, elevated radioactivity is remaining.
Further exploration of the basin is performed if the resection bed counts remain high. If only one SLN is present, the resection bed count is almost equal to the background levels. On the other hand, when multiple SLNs are present, the resection bed, after removal of the first SLN, shows persistent elevation of radioactivity until the last SLN is removed. At this time, a decrease in the resection bed count to almost background levels occurs. In general, consider the possibility of residual SLNs in the basin if the ratio of the resection bed to the background remains higher than 3:1.
Currently, a SLN is arbitrarily defined as a node that grossly harbors blue dye or shows radioactive uptake exceeding a 10:1 ratio of ex vivo to resection bed count or a 3:1 ratio of in vivo to resection bed count.
After selective dissection of the SLN is completed, the wound can be approximated in 3-layered closure with interrupted absorbable sutures. Skin can be approximated with skin staples or with absorbable subcuticular stitches. After changing gloves and instruments, the primary site can be excised according to the thickness of the lesion. Again, most commonly, the wound is closed primarily; occasionally, a split-thickness skin graft may be used. When the blue dye is not used, excising the primary site first is not uncommon, especially if the primary site is close to the nodal basin, to avoid the shine effect. Complications are minor, and the patient can be discharged from the hospital on the day of or the day after surgery.
Regarding the timing of excision of the primary tumor, some believe that previous wide excision might affect the ability to map the SLN by changing the local lymphatic drainage pattern. Most surgeons strongly recommend the use of lymphoscintigraphy before wide excision to avoid disruption, artifactual drainage of lymphatic drainage, or both. The primary tumor may be excised after lymphatic mapping is complete or can be performed prior to it. Sometimes, patients have had excisional biopsies performed, and only the surgical scar of excision is seen.
In their study of retrospective analysis, Morton et al concluded that biopsy of the SLN can be cautiously performed in patients who have undergone previous wide local excision if the primary resection margin was no greater than 2 cm and the primary tumor was not in an area of ambiguous drainage.5 Another retrospective review concluded that wide excision does not affect the reliability of a biopsy specimen from the SLN unless a rotation flap has been used. Thus, further studies are needed before firm conclusions can be made on the timing of a biopsy of the SLN.
Pathologic examination
A frozen section analysis is sometimes performed on the SLN, although not routinely because of the low sensitivity. Its role in biopsy of the SLN has not been defined. Controversy still exists over the use of intraoperative frozen section analysis of the SLN. Proponents argue that it allows conversion to regional lymphadenectomy during the same surgical setting, thereby avoiding a second anesthetic. Frozen section may also be relevant in the setting of primary melanomas of the head and the neck, particularly for patients with an intraparotid SLN, in whom avoiding a secondary procedure in a previously operated field is important and safeguards the facial nerve.
The loss of SLN tissue containing small foci of micrometastases during the frozen section processing and a low sensitivity of intraoperative frozen section analysis are possible. Given the low prevalence (20%) of metastases within the SLN and the low sensitivity (59%) of frozen section analysis, the routine use of frozen section in all patients undergoing a biopsy of the SLN is not recommended. Frozen section may be appropriate for patients with melanomas of the head and neck to avoid a secondary procedure that may imperil the facial nerve or the spinal accessory nerve.
The SLN is subjected to routine pathologic evaluation. It is bisected along the longitudinal axis at the hilum. A 4-µm thick, hematoxylin and eosin–stained section is then obtained. When micrometastasis consists of a single cell or a cluster of fewer than 50 cells, immunohistochemistry may be applied for further confirmation.
Immunohistochemistry is performed on the paraffin-embedded sections using the avidin-biotin-peroxidase complex method. The commercially obtained antibodies used are S-100 protein and homatropine methylbromide. The endogenous peroxidase is suppressed by 20 minutes of incubation with 1% hydrogen peroxide. Diaminobenzidine tetrahydrochloride is used as a chromogen. Each assay is run with positive and negative internal controls.
The Multicenter Selective Lymphadenectomy Trial uses strict guidelines in handling nodal tissue. The trial recommends cutting the lymph node in 2 halves through its longest diameter infixing the specimen. Ten serial, 8- to 10-µm sections are then made. Sections 1, 3, 5, and 10 are used for hematoxylin and eosin staining; section 2 is used for S-100 protein; section 4 is used for homatropine methylbromide; and sections 6-7 are negative controls for the immunoperoxidase studies. Sections 8-9 are used to repeat any needed studies. Accuracy is increased because of the multiple sectioning techniques and because only 1-2 SLNs are involved. The cost is reduced, as compared with the application of all these techniques to all the multiple lymph nodes obtained in an ELND.
A diagnosis of metastatic melanoma is made if the pleomorphic tumor cells similar to the primary tumor are present in the lymph node. Immunohistochemical results are interpreted as positive for melanoma if homatropine methylbromide–immunopositive cells are present in the lymph node. For S-100 protein–positive cells, the diagnosis of metastatic melanoma requires careful comparison of the morphology of the immunopositive cells with the primary tumor. If the cells are aggregated similar to the primary tumor or are clearly pleomorphic, a diagnosis of melanoma is made. Individual isolated S-100 protein–positive cells with small cytologically bland nuclei and dendritic processes are interpreted as follicular dendritic cells and regarded as negative for melanoma. If melanocytes are detected in a nested pattern confined to the capsule of the lymph node, a diagnosis of nodal nevus is made.
The use of reverse transcriptase-polymerase chain reaction or the potential future use of the TaqMan analysis to examine the nodes for tyrosinase gene messenger RNA melanosomal proteins may be valuable to increase detection of submicroscopic disease. The advantage of this method is that it examines the entire lymph node, thus eliminating sampling error and increasing sensitivity. However, its extreme sensitivity may result in inappropriate upstaging of patients and overtreatment of patients falsely deemed positive. One melanoma cell in 1 million background cells can be detected. Thus, prospective and long-term follow-up of patients treated with this technique is needed to define the true biology of nodal micrometastasis. One aim of the current Sunbelt Melanoma Trial is to examine the importance of polymerase chain reaction–positive lymph nodes and the effect of adjuvant therapy for patients with histologically negative nodes.
Biopsy of sentinel lymph node in head and neck
Series report a 90-95% success rate in identifying the SLN, which is somewhat less than the success rate for detection of the SLN at other sites. Many differences and variations in the lymphatic drainage patterns, as described above, make biopsy of the SLN more difficult. Whereas most patients with melanomas on the extremities have a median of 1.3-1.8 SLNs, a median of 3.8 SLNs is found in patients with intermediate-thickness lesions on the head and neck. Because of the close proximity of cutaneous melanomas of the head and neck to the regional lymphatic basins, the radioactive signal from the primary tumor may obscure that from the SLNs in nearby nodal basins. Hence, sometimes melanomas of the head and neck may be excised before intraoperative identification of the SLNs in order to decrease the background radioactivity from the primary site.
Difficulties in mapping strategies are observed in nonclassic nodes and especially parotid nodes, which may be shadowed by the radioisotope injected in the primary site. In patients with melanomas of the head and neck, the SLN in the parotid gland is approached by performing a superficial parotidectomy with dissection of the facial nerve. Furthermore, only 67% of lesions stain with the vital dyes. Half the SLNs are located in nonadjacent nodal basins. One fourth are in nonclassic sites, and half the nodes are in the parotid gland. Sometimes, a functional node dissection with ex vivo dissection using the gamma probe is necessary to find small SLNs. Warning patients about the prolonged tattooing that may occur with the blue dye is important.
Advantages of a biopsy of the sentinel lymph node
A negative node reduces the extent of surgery, the cost, and the morbidity for patients who would otherwise undergo ELND; 80% of those undergoing ELND experience the morbidity without any therapeutic benefit. The removal of the positive node followed by a CLND provides better local control of the disease-involved lymphatic basin. Biopsy of the SLN can be considered a staging procedure when results are positive, after which additional surgery (eg, CLND) and adjuvant therapy (eg, interferon alfa-2B) may be given. A negative node may reassure the patient that the likelihood of metastatic disease to the lymph node is low.
Follow-up
The postoperative follow-up evaluation consists of a physical examination, chest radiograph, and determinations of serum alkaline phosphatase and lactate dehydrogenase levels. Further investigations, which include computed tomography, magnetic resonance imaging, and/or nuclear scan, are also performed selectively to confirm abnormal findings suggestive of metastatic melanoma. Routine surveillance is recommended every 3-6 months for the first 2 years, every 6 months for 3-5 years, and annually thereafter.
For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education articles Skin Cancer and Skin Biopsy.
Complications
The rate of regional nodal failure is reportedly approximately 1%. Regional nodal failure may also result from the secondary spread of clinically apparent or occult local or in-transit disease. In this situation, which is termed biologic failure, the negative node that was initially removed accurately reflects the histologic status of the nodal basin at the time of biopsy. Nodal failure subsequently occurs as a consequence of local or in-transit disease not removed by wide local excision or secondary to the interval development of clinical local or in-transit failure
More on Sentinel Lymph Node Biopsy in Patients With Melanoma |
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 Treatment: Sentinel Lymph Node Biopsy in Patients With Melanoma |
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References
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Further Reading
Keywords
sentinel lymph node biopsy in patients with melanoma, sentinel lymph node, melanoma, SN, SLN, SLN biopsy, elective lymph node dissection, ELND, complete lymph node dissection, CLND, SLN mapping, sentinel lymph node mapping, therapeutic lymph node dissection, TLND, skin malignancy, skin cancer, skin melanoma, malignant melanoma, skin cancer diagnosis, skin malignancies, sentinel node
