Dermatology: Practical and Conceptual Review | Dermatol Pract Concept. 2024;14(1):e2024038 1 The Role of Sentinel Node Biopsy in the Era of Adjuvant Therapy for Melanoma Gabriella Brancaccio1, Giulia Briatico1, Camila Scharf1, Giuseppe Colella2, Giovanni Docimo3, Ludovico Docimo3, Mario Faenza4, Francesco Iovino3, Salvatore Tolone3, Pasquale Verolino2, Stefania Napolitano5, Teresa Troiani5, Andrea Ronchi6, Renato Franco6, Giuseppe Argenziano1 1 Dermatology Unit, University of Campania “Luigi Vanvitelli”, Naples, Italy 2 Multidisciplinary Department of Medical, Surgical and Dental Specialties, Oral and Maxillofacial Surgery Unit, University of Campania “Luigi Vanvitelli”, Naples, Italy 3 Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy 4 Multidisciplinary Department of Medical, Surgical and Dental Sciences, Plastic Surgery Unit, University of Campania “Luigi Vanvitelli”, Naples, Italy 5 Department of Precision Medicine, Medical Oncology Unit, University of Campania “Luigi Vanvitelli”, Naples, Italy 6 Division of Pathology, Department of Mental Health and Preventive Medicine, “Luigi Vanvitelli” University of Campania, Naples, Italy Key words: melanoma, adjuvant therapy, sentinel node biopsy Citation: Brancaccio G, Briatico G, Scharf C, et al. The Role of Sentinel Node Biopsy in the Era of Adjuvant Therapy for Melanoma. Dermatol Pract Concept. 2024;14(1):e2024038. DOI: https://doi.org/10.5826/dpc.1401a38 Accepted: October 9, 2023; Published: January 2024 Copyright: ©2024 Brancaccio et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: All authors have contributed significantly to this publication. Sentinel lymph node biopsy (SLNB) is a surgical procedure aimed to detect nodal metastases in pa- tients with clinically occult disease. Since the advent of new systemic therapies, its role in melanoma has been extensively debated over the last years. In this article, three possible scenarios are discussed, considering the SLNB impact on the management of melanoma patients. First, pT1b and pT2a pa- tients with negative SLNB (stages IA and IB) and those with positive SLNB (stage IIIA) would all not benefit from adjuvant treatment. Therefore, SLNB might be avoided in these categories of patients. Second, in IIB and IIC, melanoma patients are already candidates for adjuvant treatment; therefore, SLNB in patients with T3b, T4a, or T4b melanoma would not change treatment decisions. On the other end of the spectrum, patients with pT2b and pT3a melanomas (clinical stage IIA) represent the only two groups whose management would be significantly affected by the SLNB status, being adju- vant therapy only indicated for SLN-positive patients. Further studies are needed to investigate which melanoma patient deserves SLNB. ABSTRACT 2 Review | Dermatol Pract Concept. 2024;14(1):e2024038 Corresponding Author: Giuseppe Argenziano, MD, PhD, University of Campania “Luigi Vanvitelli”, Dermatology Unit, Viale Pansini 5, 9C, 80131, Naples, Italy. Phone: 0039335415093 Email: g.argenziano@gmail.com Introduction Sentinel lymph node biopsy (SLNB) is a surgical procedure aimed to detect nodal metastases in patients with clinically occult disease. The role of SLNB in melanoma has been extensively debated over the last years. SLNB intended as a therapeutic technique evolved from the observation that most primary cutaneous melanomas spread initially through the intradermal lymphatics to the regional nodes and then move to distant sites [1]. This sequential model of melanoma metastasis has been lately disproved [2,3] and sentinel node is now considered an “indicator” of disease as its status il- lustrates metastatic potential, but its removal cannot prevent further spread. Although SLNB does not impact survival, it is associated with a benefit in terms of rate of recurrence within the primary tumor region [4]. Currently SLNB is recommended as a staging procedure that can help identify those patients with at least pT1b mel- anoma (Tables 1 and 2) who may benefit from adjuvant Table 1. Melanoma stage I and II (SLNB -) according to the AJCC classification system 8th Edition. Breslow thickness Ulceration T Category N category Stage <0.8 mm no T1a N0 IA <0.8 mm yes T1b N0 IB 0.8-1.0 mm Yes/no T1b N0 IB >1.0-2.0 mm no T2a N0 IB >1.0-2.0 mm yes T2b N0 IIA >2.0-4.0 mm no T3a N0 IIA >2.0-4.0 mm yes T3b N0 IIB >4.0 mm no T4a N0 IIB >4.0 mm yes T4b N0 IIC Adapted from: Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017; doi:10.3322/caac.21409. Table 2. Melanoma stage III subgroups according to the AJCC classification system 8th Edition. T Category N Category T0 Occult primary tumor T1a < 0.8 T1b < 0.8 U or 0.8-1.0 T2a >1.0-2.0 T2b >1.0-2.0 U T3a >2.0-4.0 T3b >2.0-4.0 U T4a >4.0 T4b >4.0 U N1a 1 node c.o. N/A A A A B B C C C N1b 1 node c.d B B B B B B C C C N1c only S/T mets B B B B B B C C C N2a 2/3 node c.o. N/A A A A B B C C C N2b 2/3 node, at least 1 c.d. C B B B B B C C C N2c S/T mets + 1 nodea C C C C C C C C C N3a ≥4 node c.o. N/A C C C C C C C D N3b ≥4 node, at least 1 c.d. or matted nodes C C C C C C C C D N3c S/T mets + ≥2 nodea or matted nodes C C C C C C C C D c.o. = clinically occult (diagnosed by sentinel node biopsy); c.d. = clinically detected (by palpation or imaging); N/A = not applicable. S/T mets  = satellite and/or in-transit metastases. T category is expressed in mm.U = ulceration; a in N2c and N3c subcategories involved nodes may be either clinically occult or clinically detected. Adapted from: Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017; doi:10.3322/caac.21409. therapy [3,5,6]. SLNB positivity rates vary depending on histopathological procedures, with a reported false nega- tive rate up to 10% [7]. Adjuvant treatment in stage III melanoma patients is the standard of care from 2018, when both immunotherapy (PD-1 inhibitors) and molecular tar- geted therapy were worldwide approved thanks to the ex- cellent results obtained from Checkmate 238, Keynote-054 and COMBI-AD trials [8-10]. These clinical trials recruited Review | Dermatol Pract Concept. 2024;14(1):e2024038 3 only high-risk stage III patients, meaning that patients with stage IIIA (Table 2) melanoma could only be included if the metastasis in the SLN were larger than 1 mm. How- ever, adjuvant therapies are approved in all stage III sub- groups [11]. Adjuvant treatment in stage II melanoma patients is the current focus of oncology research [12]. Despite the ab- sence of identified lymph node involvement, patients with stage IIB and IIC (Table 1) melanoma have a greater risk of recurrence/death than those with stage IIIA disease and sim- ilar to those with stage IIIB disease. Pembrolizumab 200 mg for one year was compared against placebo in more than 900  patients with stage IIB and IIC melanoma in KEYNOTE 716 trial resulting in a 18-months recurrence-free-survival rate of 86% (95% CI 82-89) in the treatment group versus 77% (95% CI 73-81) in the placebo group, which led to approval by the FDA and EMA [13]. Final results from the CheckMate -76K trial (expected soon) seem to confirm the efficacy of Nivolumab in stage IIB and IIC melanoma pa- tients [14]. With regards to target therapy, a phase III trial comparing Encorafenib plus Binimetinib versus placebo in these subsets of patients is currently enrolling (Columbus-Ad study, NCT05270044). Objectives With the access of negative-SLN patients to adjuvant treat- ment a question rises accordingly: is SLNB still needed [15]? Which melanoma patient does deserve it? Results Impact of SLNB on Staging Workup: Potential Scenarios Af- ter the Indication of Adjuvant Therapy in Stage IIB and IIC Patients In Table 3 the staging workups with indication to SLNB are reported. According to NCCN guidelines, SLNB should be discussed in patients with microsatellites, as SLN status does have prognostic significance, with a positive SLN up- staging a patient from at least N1c and at least stage IIIB dis- ease, to at least N2c, which corresponds to stage IIIC disease (Table 2) [5]. However, although this may have a prognostic Table 3. Staging workup and consequent indication to adjuvant therapy. Subcategory T SNB results Pathological stage 5-year survival (%) 10-year survival (%) Indication to adjuvant therapy pT1b N0 1A 99 96 No N1a, N2ba 3A* 93 88 Questionable pT2a N0 1B 97 94 No N1a, N2aa 3A* 93 88 Questionable pT2b N0 2A 94 88 No N1a, N2a, N3a 3B-3C 83-69 77-60 Yes pT3a N0 2A 97 88 No N1a, N2a, N3a 3B-3C 83-69 77-60 Yes pT3b N0 2B 87 82 Yes N1a, N2a, N3a 3C 69 60 Yes pT4a N0 2B 87 82 Yes N1a, N2a, N3a 3C 69 60 Yes pT4b N0 2C 82 75 Yes N1a, N2a, N3a 3C-3D 69-32 60-24 Yes Two different scenarios are provided for each pT subcategory. The staging and the workup in case of a negative SNB result are outlined in light green, while those in case of a positive SNB in light red. pT subcategories in which performing SNB changes the indication to adjuvant therapy are highlighted by a yellow square. aN3a results are deliberately omitted. The probability to find four or more metastatic nodes (N3a) through SLNB in pT1b and pT2a melano- mas, which would be upgraded to stage IIIC, can be considered not relevant (0.1%). Adapted from: Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017; doi:10.3322/caac.21409. 4 Review | Dermatol Pract Concept. 2024;14(1):e2024038 MSS. Stage IIA melanoma patients were not included in ad- juvant therapy registration trial due to their rather favorable prognosis. In contrast, the presence of a metastatic node de- tected through SLNB upgrades pT2b and pT3a melanoma patients to stage IIIB or IIIC according to the number of nodes involved (Table 3). The prognosis of stages IIIB and IIIC justifies adjuvant treatment as 5-year MSS ranges from 83% to 69% and 10-year MSS ranges from 77% to 60%, re- spectively. Thus, performing SLNB in this group of patients does actually change the management by selecting those pa- tients who may benefit from adjuvant therapy. pT3b, pT4a and pT4b Melanomas Patients with pT3b or pT4a N0 melanoma are included in stage IIB, while those with pT4b N0 melanoma in stage IIC. 5- and 10-year MSS resulted to be 87% and 82% for stage IIB and 82% and 75% for stage IIC. In case of a metastatic node these subsets of patients are upgraded to stages IIIC- IIID according to the number of nodes involved. As men- tioned before, IIB and IIC melanoma patients are already candidates for adjuvant treatment, therefore, SLNB in pa- tients with T3b, T4a, or T4b melanoma would not change treatment decisions and the procedure may be omitted. Conclusions SLNB is a surgical staging procedure aimed at identifying patient who may benefit from adjuvant treatment. Since the approval of adjuvant therapy in negative SLN patients, namely stages IIB and IIC, its role may be reappraised. Pa- tients with pT3b, pT4a and pT4b melanomas and negative SLNB (stages IIB–IIC) and those with positive SLNB (stages IIIC–IIID) would all be candidates for adjuvant therapy for a duration of 1 year. In these patients SLNB might be avoided since it does not alter the therapeutic management. On the other side of the spectrum, pT1b and pT2a patients with neg- ative SLNB (stages IA and IB) and those with positive SLNB (stage IIIA) would all not benefit from adjuvant treatment. Therefore, SLNB might be avoided also in these categories of patients. Patients with pT2b and pT3a melanomas (clinical stage IIA) represent the only two groups whose management would be significantly affected by the SLNB status, being adjuvant therapy only indicated for SLN positive patients. More studies are needed to improve evidence around SLNB and its potential role in only a limited number of patients. References 1. Morton D. Overview and update of the phase III Multicenter Selec- tive Lymphadenectomy Trials (MSLT-I and MSLT-II) in melanoma. impact (from 83% to 69% and from 77% to 60% 5-year and 10-year melanoma specific survival [MSS] respectively), the upgrade from stage IIIB to stage IIIC does not change the therapeutic management of this subgroup of patients, which would all be candidates for adjuvant therapy [16,17]. pT1b and pT2a Melanomas Patients with pT1b melanoma and a negative SLNB (N0) are included in pathological stage IA, which exhibit an excellent 5- and 10-year MSS (99% and 96% respectively). Similarly, patients with pT2a N0 melanoma are characterized by an excellent survival (97% and 94% 5- and 10-year MSS) [17] although are belonging to stage IB. Consequently, they do not require adjuvant therapy. In the literature the probability of finding a metastatic node in pT1b and pT2a melanomas, meaning N1a subcat- egory, ranges from 2.3% and 8.4% to 7.5% and 14.6% [18,19], respectively. 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