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SENTINEL LYMPH NODE BIOPSY: Is it the new standard of care?

T he standard of care for the staging of selected patients with biopsy-proven malignant melanoma without clinical evidence of regional or distant metastases is the performance of sentinel lymph node (SLN) biopsy immediately followed by wide re-excision of the primary tumor. SLN biopsy may also be useful for the surgical staging of Merkel cell cancer, selected high-risk squamous cell cancers and certain breast cancers. In the recent past, there have been debates about the roles of prophylactic verses therapeutic regional lymph node dissection (PRLND versus TRLND); adequate wide re-excision margins of melanoma; and the proper histostaging of melanoma. Dermatological surgeons have often been in the forefront of these debates and these issues have largely been decided in a way that favors the dermatologist. Smaller margins, without the need for PRLND, have allowed dermatological surgeons to treat the vast majority of melanomas in their office procedure rooms. Until recently the only melanoma patients requiring referral to our general surgery colleagues were those with clinically palpable lymph nodes. Now a new debate has arisen — one that threatens to remove the surgical treatment of melanoma from our offices and into outpatient surgery centers. There is no debate that the prognosis for a stage III melanoma patient (node positive) is worse than a stage I/II (node negative) patient’s prognosis. Metastatic melanoma to the regional nodes predicts a significantly worsened prognosis. The debate over PRLND versus TRLND revolves around whether removing histologically positive nodes improves survival compared to performing TRLND after detection of clinically palpable nodes. SLN biopsy obviates this debate because it answers two questions accurately and reproducibly: 1. What node(s)/nodal basin(s) actually drains the melanoma site? 2. Do the regional nodes contain metastatic melanoma? The only unresolved issue, and the focus of the several ongoing studies, is whether removing histologically positive and clinically negative regional lymph nodes improves survival. Some of our derm-surgery colleagues are resisting the wide spread acceptance of SNL biopsy by the general surgical community. Even HMO’s in our community are routinely performing SLN biopsies! So What’s the Debate Regarding SLN Biopsy About? The debate revolves around 5 questions: 1. Is the technology to perform SLN biopsy available and is it mature enough to give accurate and reproducible results in or outside of the research centers where it was developed and tested? 2. Do we know which patients should be offered SLN biopsy? 3. Is there effective treatment for patients who are SLN biopsy positive for metastatic disease and does it matter? 4. Is SLN biopsy a staging technique or a therapy and does it matter? 5. Does removing all nodes in a basin give more accurate staging information than removing only the “sentinel” node(s)? The Technology of SLN Biopsy The technology for doing SLN biopsy for melanoma has steadily improved. The minimum team required for this procedure consists of surgery, nuclear medicine and pathology. After a patient is diagnosed with melanoma, lymphoscintigraphy is performed to determine where the SLNs are located. Drainage patterns are often unexpected and unpredictable. Dynamic studies are essential to determine if nodes are truly “sentinel,” with a direct lymph channel from the area of the tumor to the sentinel node without passing through any intervening node. Timing of lymphoscintigraphy in relation to the surgical procedure must be optimized to prevent significant labeling of non-sentinel nodes. Films need to be taken in two planes, with the patient positioned as he or she would be for surgery, to allow for quick intra-operative localization of the SLN(s). Good quality lymphoscintigraphy is essential to SLN biopsy, and the equipment and expertise to perform it is widely available. Even for patients not undergoing SLN biopsy, lymphoscintigraphy can demonstrate which nodal basins are “at risk” for metastatic disease, thus allowing for a more focused clinical assessment at tumor board visits. Armed with a proper lymphoscintigraphy, the surgeon can use a hand-held, directional gamma probe in combination with deep blue dye (lymphazurine) to easily and quickly remove the sentinel lymph node(s) immediately followed by re-excision of the melanoma. This low-morbidity surgery can be done in an outpatient surgery setting using conscious sedation or general anesthesia. The equipment for this procedure is widely available and not excessively expensive. Frozen sections are generally not done on the SLN(s) removed because this wastes tissue better utilized for H&E and immunohistochemistry evaluation. Immunohistochemistry is widely available. The role of reverse transcriptase-polymerase chain reaction (RT-PCR) is still to be determined, although I predict RT-PCR panel analysis of SLN’s will eventually be standard for SLN biopsy tissue evaluation. Patient Selection For SLN Biopsy Patient selection is based upon multiple criteria and continually changes as new information dictates. In my practice, I include the following types of patients for SLN biopsy: • All patients being stratified for entry into melanoma studies of prognosis and/or therapy. • All patient with primary melanomas of Breslow thickness 1.0 mm or greater. I would not exclude thick melanomas. (Continued on page 40) • Patients whose tumors were transected at the base of the biopsy. • Patients with tumors less than 1 mm Breslow, but with epidermal ulceration histologically or whose tumors extend to Clark’s level IV. • Patients with tumors of uncertain diagnosis (probable but not certain melanoma). • Patients not meeting these criteria but who have invasive melanoma and request the procedure. The criteria should be liberal because SLN biopsy has low morbidity and gives accurate and reproducible prognostic information that will influence both therapy and follow-up. Therapy of Melanoma Patients With SLN Biopsy Proven Micrometastases Many who argue against SLN biopsy use two arguments that revolve around melanoma therapy: 1. No effective therapy presently exists for patients with metastatic melanoma. 2. SLN biopsy should only be done in major centers where SLN biopsy positive patients can then be entered into treatment studies. Standard therapy of lymph nodes basins containing metastatic melanoma has always been to remove the remaining nodes in the basin — TRLND. It is uncertain whether TRLND affects survival or tumor-free interval, but it usually results in the surgical control of the involved nodal basin and is the current standard of care for nodal metastatic disease. While it would be wonderful if currently ongoing studies showed that removal of nodal micrometastatic disease increased tumor-free interval and/or survival, such a result is unnecessary to prove SLN biopsy’s worth as the standard of care for staging melanoma patients. It wasn’t too many years ago that melanoma centers were spending big bucks on CT scans, MRI’s, X-rays, nuclear scans, and various other tests — all for evaluations and staging as opposed to therapy for melanoma patients. None of these proved particularly worthwhile. Studies (ECOG-1684,1690 & 1694) have shown that alpha 2b interferon (Intron A) increases tumor-free interval and survival of stage III melanoma patients. Interleukin-2 (IL-2) has also been FDA-approved for the treatment of metastatic melanoma. Optimal dosing is still under evaluation. Therefore, there is effective/adjuvant treatment for node positive patients. There are numerous therapeutic clinical trials into which the dermatologist can refer patients with micrometastatic nodal disease; conventional adjuvant treatment such as DTIC is also widely available. It is disingenuous to suggest that only major academic study centers be doing SLN biopsy because they have adjuvant therapeutic studies. Is there a suggestion on the table that those unable or unwilling to go to the major centers be punished by not having an available and accurate staging procedure performed? Is it a fact that only patients at major centers may be entered into therapeutic studies or receive available adjuvant therapy? The answer has to be a resounding no. SLN biopsy needs to be widely used within and outside of the major centers; this is true regardless of whether it is diagnostic or therapeutic and regardless of whether the patient desires or is able to participate in therapeutic studies. Removal of All Nodes Versus Removal of Sentinal Nodes Only When discussing the accuracy of SLN biopsy, remember that assessment of the sentinel node(s) provides more accurate evaluation of the nodal basin for metastatic melanoma than would be achieved by completely removing the nodal basin (PRLND/TRLND). Finding micrometastases in a nodal basin is analogous to finding a needle in a haystack. After PRLND/TRLND the surgeon sends the haystack to the pathologist who takes random sections from the nodal tissue he or she can find; path assessment is usually done using standard H&E staining. By contrast, after SLN biopsy, the surgeon sends one to a few lymph nodes to the pathologist who step cuts this tissue and performs H&E and immunohistochemistry evaluation of these nodes. Since the “haystack” is left in the patient, the pathologist can more easily find the “needle.” Learning SLN Biopsy Technique Like Mohs surgery, sentinel node biopsy has a short learning curve for surgery and pathology oriented dermatologists. Several excellent centers are willing and able to train you and your “team” in this procedure. As dermatologists we all see large numbers of melanoma patients. Those interested in continuing to provide treatment for these patients need to form a team to train in this procedure or join an existing team. Melanoma has been a major interest of mine since residency. I’ve run a melanoma tumor board and seen diagnostic and treatment fads come and go and I’ve performed many SLN biopsies with the general surgeon on our team. Sentinel node biopsy is a solid, accurate and reproducible technique that can be performed on an outpatient basis with little morbidity. If a friend or family member developed melanoma, I would strongly recommend SLN biopsy. My patients and your patients deserve the same level of care. The cheese has moved — get with the program.