Biopsy can differentiate risk level for patients, but selectively indicated
Sentinel lymph node biopsy remains one of the most important prognostic tools for patients with early-stage localized melanoma.
“The most important aspect of the procedure is that it allows us to differentiate patients who may be at higher risk for relapse versus those at lower risk,” says Giorgos Karakousis, M.D., an associate professor of surgery at the Hospital of the University of Pennsylvania in Philadelphia.
However, the biopsy is not required or indicated for all patients, such as most patients with very thin melanomas and lacking high-risk features.
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“But patients with intermediate-depth melanoma typically would be recommended for sentinel lymph biopsy, as would patients with thick melanomas for regional control of their disease and also for improved staging,” Dr. Karakousis says.
Common conventional factors to help decide which patients with thin melanoma are at higher risk for sentinel lymph node metastasis have included primarily thickness, ulceration and mitotic rate.
“Some ‘softer’ factors may also play a role in predicting sentinel lymph metastasis, such as age, Clark level, and presence of tumor infiltrating lymphocytes at the primary tumor site,” says Dr. Karakousis, who provided an oncologic surgeon’s perspective on the sentinel lymph node procedure at the summer meeting of the American Academy of Dermatology (AAD) in July in New York City. “These factors will no doubt continue to evolve as more data is accrued with time, and with newer iterations of the American Joint Committee on Cancer (AJCC) staging system.”
Dr. Karakousis shared his perspective on the final report from the first Multicenter Selective Lymphadenectomy Trial (MSLT-I) for patients with melanoma, which randomized patients to either sentinel lymph biopsy or observation.1
“While there was no difference in overall survival in the overall cohort, the study demonstrated a differential recurrence survival rate between the two groups among patients with nodal metastases,” he says.
For study patients with a nodal metastasis and an intermediate-depth melanoma who underwent sentinel lymph biopsy, followed by immediate completion lymph node dissection, “there was about a 20% more favorable survival rate compared to patients who did not have the biopsy, but subsequently developed lymph node metastasis, which were resected at a later date,” Dr. Karakousis says.
One of the controversies of the trial is whether there truly is a therapeutic benefit to the sentinel lymph biopsy. “There are serious limitations to any subgroup analyses of randomized studies,” Dr. Karakousis says. “Still, this trial may provide the best data we have as to the impact of early nodal intervention compared to delayed nodal intervention, because it is not known upfront which patients are going to have a positive node.”
Interestingly, while there was a differential survival rate in the subgroup analysis among patients with intermediate-depth melanoma, “there was not a differential survival noted in patients with thick melanomas who either underwent a sentinel lymph biopsy or were observed,” Dr. Karakousis says. “This suggests that in patients with thicker lesions who are at increased risk for hematogenous spread, early nodal intervention at the nodal level may not significantly impact the natural history of the disease.”
Dr. Karakousis says that while a sentinel lymph biopsy is definitely prognostic for treating patients with melanoma, there potentially may be a therapeutic effect, which is differential across primary tumor thickness
“When counseling patients, it should be noted that the main reason for a sentinel lymph node is for prognosis, but now we have an additional reason: novel immune checkpoint inhibitors,” Dr. Karakousis says. “These inhibitors are being instituted into practice in the adjuvant setting, if patients have been identified as having a positive sentinel lymph node.”
Currently, the only FDA approved immune checkpoint inhibitor in the adjuvant setting is ipilimumab (Yervoy, Bristol-Myers Squibb), which targetsCTLA-4. “This biologic was first approved in 2011 for metastatic stage IV melanoma, but in 2015 was also approved for adjuvant therapy,” Dr. Karakousis says. “Ipilimumab is a drug which can be considered in patients with stage 3 melanoma as an adjunct therapy. Other agents will likely also be approved in the adjuvant setting in the not-too-distant future. The sentinel lymph biopsy allows one to identify stage 3 patients at diagnosis, allowing for earlier access to these therapies, rather than waiting for recurrence.”
Meanwhile, PD-1 inhibitors are being investigated in clinical trials in the adjuvant setting.
Results of the second Multicenter Selective Lymphadenectomy Trial (MSLT-II) for patients with melanoma were published in June in the New England Journal of Medicine.2
“The study showed that melanoma patients with sentinel lymph node metastasis, when randomized to either immediate completion lymph node dissection or observation of the remaining nodes, had no difference in overall survival between the two groups,” Dr. Karakousis says. “This tells us as clinicians that we do not necessarily need to, in a knee-jerk fashion, schedule a dissection on every patient with a positive sentinel lymph node, which might lead to morbidity in the form of lymphedema and other complications.”
Instead, these patients with a positive sentinel lymph node have the option of and may be able to be safely followed with close ultrasound surveillance. “Patients would then require surgery only if the lymph nodes changed radiographically in a concerning way,” Dr. Karakousis says.
However, patients with particularly high risk for non-sentinel lymph node disease may still be considered for completion lymph node dissection for regional control of their disease.
Going forward, Dr. Karakousis is hopeful there will be new technologies that can prognosticate or predict which patients are likely to develop a sentinel lymph node, perhaps through molecular characterization of the primary tumor in a much more precise manner.
“This way, we can spare many patients a biopsy they do not need,” he says.
Advancing imaging technologies to detect subclinical or microscopic disease would also help to identify early micrometastatic disease.
1 Morton DL, Thompson JF, Cochran AJ, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med. 2014;370(7):599-609.
2 Faries MB, Thompson JF, Cochran AJ, et al. Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma. N Engl J Med. 2017;376(23):2211-2222.