Can Completion Lymph Node Dissection Be Avoided for a Positive Sentinel Node in Melanoma?
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- Morton, D.L., Scheri, R.P. & Balch, C.M. Ann Surg Oncol (2007) 14: 2437. doi:10.1245/s10434-007-9474-9
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Sentinel node biopsy (SNB) in melanoma was developed as a minimally invasive technique to identify the 20% of patients who have occult lymph node metastases and therefore could benefit from completion lymph node dissection (CLND). Recently published interim results from the first Multicenter Selective Lymphadenectomy Trial (MSLT-I) have validated the accuracy and reliability of SNB in melanoma.1,2 Interestingly, results revealed that nearly 80–90% of patients who underwent CLND after a positive SNB had no other lymph node metastases; the percentage varies with the thickness of the primary melanoma and the amount of tumor in the sentinel node (SN).3,4 Does this mean that CLND may not be indicated for all patients with SN metastasis? Many studies have attempted to answer this question, but as yet none have identified a reliable and accurate method to distinguish patients whose SN metastasis does not require CLND.
The article by Govindarajan et al.5 in the February 2007 issue used microanatomic assessment of SN metastases as a basis for prediction of nonsentinel node (NSN) metastasis or disease recurrence. They retrospectively studied all patients at their institution who had a tumor-positive SNB between 1999 and 2004. SNB was performed in a standard fashion using both radioisotope and blue dye; SNs were stained with hematoxyin and eosin (H&E) and with immunohistochemistry using antibodies to S-100 and HMB-45. NSNs were bivalved and examined only by H&E, which probably led to underestimation of the incidence of NSN metastasis. Data on patient demographics and primary tumor pathological features were collected, and the SNs were microanatomically staged for zone of metastatic involvement, number of tumor-involved zones, size of metastases, and number of metastatic foci. Of 127 patients with positive SNs, 20 (15.8%) had NSN metastasis, and the recurrence rate was 30.7% at a median follow-up of 31.2 months. Multivariate analysis revealed that size of largest metastatic focus was predictive of NSN metastasis (P < .05); patients with SN metastases less than 0.2 mm had no evidence of nodal involvement in the CLND specimen. Unlike many prior studies,4,6–8 this study did not identify the histological location of SN metastasis as predictive of NSN involvement, which suggests that patients with subcapsular SN metastasis cannot avoid CLND. The size of the largest SN metastasis and the involvement of all three histological zones (subcapsular, parenchymal, and sinusoidal), which like SN effacement is a surrogate for burden of disease, were predictive of recurrence, as reported in other studies.3,9–12
Several studies have evaluated microanatomic SN staging as a predictor of NSN metastasis and recurrence.3,4,6–12 These studies identified Breslow thickness, primary ulceration, gender, SN penetration, size and area of SN metastases, SN effacement, extranodal extension, >3 positive SNs, and dendritic cell density as predictive of NSN involvement. Factors predictive of recurrence were Breslow thickness, SN penetration, area of metastases, and dendritic cell density. No factor was consistently predictive, but Breslow thickness, SN penetration, and area of metastases were observed most commonly. Not surprisingly these factors are surrogates for burden of disease, a factor that has been long appreciated in melanoma.
The study from Govindarajan et al.5 is quite similar to the previous studies in its size and its rates of NSN metastasis and recurrence. The microanatomic evaluation uniquely classified SN metastases by the type and number of histologic zones involved; the authors hypothesized that the anatomical pattern of SN metastasis might be predictive of NSN metastasis and recurrence. Unfortunately, this study shares many weaknesses with its predecessors. Because it is relatively small, the number of NSN metastases correlates to low statistical power. Although none of the 13 patients with SN metastases <0.2 mm had NSN metastases, the wide confidence intervals could occur by chance alone. All six patients with three histologic zones of SN metastasis had NSN metastasis, but again the numbers are too small for any conclusion—except the need for a larger prospective study with greater power.
The authors note the absence of recurrence in patients with a low burden of disease in the SN and wonder if these SN metastases might be considered false positives. However, their study is too small and its follow-up too short to answer this question, especially since the rate of recurrence should be lower and the onset of recurrence should be later in patients with low-volume disease. Furthermore, several large studies with long follow-up have reported higher recurrence rates for patients whose regional node involvement is limited to polymerase chain reaction (PCR) evidence of SN metastasis, compared with patients whose SN is tumor-free.13,14 Even submicroscopic evidence of SN involvement might be linked to dysfunction of the regional immune environment, leaving a patient more susceptible to local regional recurrence.
A recent study by Wong et al.15 examined the survival of 134 melanoma patients who did not undergo CLND after identification of SN metastasis. At a median follow-up of only 20 months, nodal recurrence rate was 15%, similar to the rate of NSN involvement in a contemporary cohort of patients who underwent CLND for SN metastasis. There was no difference in disease-specific survival between the two groups. Multivariate analysis revealed that only patient age and primary thickness were independently predictive of survival. Authors of this 16-center study concluded that the therapeutic benefit of CLND versus observation for SN metastasis can only be determined by randomized trials.
Govindarajan et al.5 suggest that within the population of patients with SN metastasis it may be possible to identify a small group that does not require CLND and another small group that may require CLND, but the limited follow-up and low power of their study do not support these conclusions. A more definitive conclusion must await results of the second MSLT (MSLT-II), in which patients with a positive SN are randomized to CLND or to nodal observation with ultrasound monitoring. Until then, all patients with a positive SN should undergo CLND as standard of care since there is presently no other reliable means of determining which patients with SN metastasis also have NSN metastasis.