In last two decades three prospective randomized studies have addressed the management of regional lymph nodes in CM patients [2, 5, 6]. The result of the first, MSLT-I, confirmed the critical role of the SLN biopsy although it did not demonstrate the melanoma specific survival (MSS) benefit. Despite that, the results did show that early removal of lymph node metastases in intermediate thickness CM could improve survival. 10-year distant disease free survival was 54.8% in the group with intermediate thickness CM following CLND after positive SLN biopsy and 35.6% in the case of observation and nodal recurrence. According to our analysis 10-year OS was 45% in CLND group compared to the 29% OS of the MLNM group which had the characteristics similar to the true observational group. The survival difference was slightly smaller in our population in comparison to MSLT-1trial which can be explained by population differences. MSLT-I included 81.6% of patients with intermediate thickness CM with median thickness of 1.8 mm in biopsy group, while median thickness in our population was 3 mm. One third of patients had SLN tumour burden > 1 mm [2, 11]. In our population the percentage was 48.8%. The observed differences in survival indicate that the benefit of the CLND is not limited only to patients with intermediate thickness CM.
Studies following MSLT-I and addressing the question of improved OS survival after the CLND included small proportion of patients with SLN tumour burden > 1 mm (two thirds of patients in each DeCOG study arm had SLN tumour burden ≤ 1 mm) which would, together with exclusion of patients with head and neck CM and those with extracapsular extension, indicate selection bias during study accrual [5, 6, 11]. One interesting notion comparing our results to the results of the MSLT-II is, that they have include approximately 6% less patients with ulceration (37.0% of CLND compared to our 43.3%) and 20% less patients with thick melanoma (21.8% MSLT-II vs. 41.8%). The percentage of patients with SLN tumour burden > 1 mm was 21.7% in MSLT-II CLND group and 48.8% in our study respectively. The comparison imposes a question whether one can rely on the prospective randomized trials while facing a specific real life population? Differences in our national results indicate that direct implementation of the conclusions of randomised trials may not always be suitable. Results of DeCOG and MSLT-II studies failed to prove the OS survival benefit of the CLND. In case of our cohort the 5-year OS of patients following CLND was improved by 11% compared to the MLNM group (58% vs. 47%, p = 0.003) with no signifficant difference in the Breslow thicknes or presence of ulceration between the two groups.
Another interesting relationship between Breslow thickness and nodal burden was observed. In our study the worst OS survival was associated with SLNM group with only 21% alive after 5 years. The group of SLNM patients had substantially thicker CM yet their nodal burden was smaller compared to MLNM group (35.3 ± 30.7 mm MLNM vs. 20.8 ± 14.2 mm) indicating different primary tumour biology but also indicating the effect of the delayed lymphadenectomy on the size of the nodal burden. If the timing of lymphadenectomy is a vital part of treatment the concern about possible loss of regional control during observation after SLN biopsy is raised. Many clinicians are aware that unresectable regional disease is a very serious clinical problem in CM. At the moment it is not known in how many cases observation and sequential regional relapse would actually cause loss of regional control [11]. But not only regional control, there could be also other results influenced by timing, as indicated in the Delgado meta-analysis. They concluded that there appears to be a time-dependent disease specific survival advantage related to early or immediate surgery regardless of the extent of the procedure compared to delayed or none in the case of nodal metastases [15].
Can we reassure our patient that it is safe to leave the possible CM metastases in lymph node basin in cases where SLN biopsy is not followed by CLND? Many would argue that in the case of high risk for disease progression, small tumour burden in lymph node basin makes no change [6, 11]. Interestingly that is in contrast to some basic research showing that especially in CM models stem-like tumour cells have been found to reside in the vessels in the vicinity of lymphatic nodes, suggesting that there is a kind of ‘lymphovascular’ stem cell niche which is not removed without CLND. It is speculated that these stem-like tumour cells might ‘hibernate’ for a long time span within the lymphovascular niche, and may form new tumours even years after surgical removal of the primary tumour. Similarly, the persistence of metastatic tumour cells in non-SLN subcapsular sinuses might also relate to a tumour cell survival supporting function of lymphatic vessels, which could play a role in premetastatic lymphatic niches as well [16]. On the other hand, lymphatic endothelial cells (LEC) are expressing PD-L1 surface receptors that directly interface with leukocytes and causes dysfunctional T cell activation, so one would speculate that the risk of tumour progression can be minimized with adjuvant immune therapy. Studies aimed at adjuvant therapy in CM patients did show less relapses compared to placebo group and indicated that adjuvant therapy can lead to sustained and durable survival benefit. However additional validation of this approach with extended follow-up in patients receiving adjuvant therapy for CM is warranted, including correlation with OS data [17]. It is important to note that trials that influenced our understanding of stage III melanoma treatment (MSLT-1, MSLT-2, DeCOG) included patients with completely resected CM and SLN burden > 1 mm [11].
With results of MSLT-II and underpowered DeCOG trial indicating no benefit from CLND after positive SLN we can expect, that only a small number of patients will be advised to have CLND in the future. It will be up to clinicians to decide, who with stage III disease should receive adjuvant systemic treatment and the decision will be based only on information gathered from SLN biopsy instead on information gathered from CLND available for adjuvant trials. Unfortunately, until new trial results are available, conclusions from previous adjuvant trials cannot be simply extrapolated to patients who had only SLN biopsy even more so if many of those patients are not candidates for adjuvant treatment according to current recommendations. The information about the non-SLN status might be lacking [18]. Our own results show that 17.4% of patients (79/455) had positive non-SLN and with that possible decision influencing information.
The issue of additional information gained from CLND was addressed by Verver and colleagues. They used a retrospective cohort of SN-positive patients previously collected and described to construct a model of risk stratification based solely on primary CM and SLN biopsy information. Their model is based on presence or absence of the ulceration and SLN burden of > 1 mm or ≤ 1 mm. They concluded that CLND upstaged 19% of patients in the N-category and 5% of patients in AJCC stage 8Th edition (6% AJCC stage upstaging in the 7th edition). The survival analysis showed significant difference between low risk group (absent ulceration and SLN burden ≤ 1 mm) with 5-year MSS of 82.4% and intermediate risk (ulceration present and SLN ≤ 1 mm or ulceration absent and SLN > 1 mm) with survival around 67.6% and substantial gap between intermediate and high risk group (ulceration present and SLN > 1 mm) with 44% 5-year MSS in the later [18]. Verver’s model is a significant step to understanding the stage III survival heterogeneity but if tumor burden is an important prognostic indicator, four group prognostication sounds somehow crude. In our analysis we defined four different groups according to SLN burden. The OS survival analysis done according to the four group stratification caused previously described CLND curve to fan out. The analysis proved that group of patients with SLN burden > 1 mm are high risk patients with 5-year OS of 49%. In fact, their survival did not differ statistically from the MLNM group. On the other side of the spectrum are patients with SLN burden < 0.3 mm with excellent prognosis and 5-year OS of 86% similar to the group with negative SLN. In the middle are those with SLN burden > 0.3 mm and ≤ 1 mm with 60–70% 5-year OS. Additional analysis showed that 9.4% of these patients had metastases in non-SLN. Based on current recommendations those patients would not receive any additional adjuvant treatment. Would some of those patients still benefit from CLND if low rate of postoperative morbidity can be assured, seems to be a question of many surgeons.