10.5826/dpc.1401a38
Sentinel lymph node biopsy (SLNB) is a surgical procedure aimed to detect nodal metastases in patients 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 patients 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 adjuvant therapy only indicated for SLN-positive patients. Further studies are needed to investigate which melanoma patient deserves SLNB.
text/xml
2160-9381
3378
en
Giuseppe Argenziano
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
sentinel node biopsy
The Role of Sentinel Node Biopsy in the Era of Adjuvant Therapy for Melanoma
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Review
2024-01-31
2023-03-28
2024-01-31
2024-02-21
e2024038
Dermatol Pract Concept
Sentinel lymph node biopsy (SLNB) is a surgical procedure aimed to detect nodal metastases in patients 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 patients 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 adjuvant therapy only indicated for SLN-positive patients. Further studies are needed to investigate which melanoma patient deserves SLNB.
Giuseppe Argenziano
2024/01/31
10.5826/dpc.1401a38
e2024038
Dermatology Unit, University of Campania "Luigi Vanvitelli", Naples, Italy
2160-9381
sentinel node biopsy
en
e2024038
Michielin O, van Akkooi A, Lorigan P, et al. ESMO consensus conference recommendations on the management of locoregional melanoma: under the auspices of the ESMO Guidelines Committee. Ann Oncol. 2020;31(11):1449-1461. DOI: 10.1016/j.annonc.2020.07.005. PMID: 32763452.
The Role of Sentinel Node Biopsy in the Era of Adjuvant Therapy for Melanoma
https://dpcj.org/index.php/dpc/article/download/3378/2440
           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.




  ABSTRACT             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.




Review | Dermatol Pract Concept. 2024;14(1):e2024038                                                                                        1
Corresponding Author: Giuseppe Argenziano, MD, PhD, University          therapy [3,5,6]. SLNB positivity rates vary depending on
of Campania “Luigi Vanvitelli”, Dermatology Unit, Viale Pansini
                                                                        histopathological procedures, with a reported false nega-
5, 9C, 80131, Naples, Italy. Phone: 0039335415093 Email:
g.argenziano@gmail.com                                                  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-

Introduction                                                            cellent results obtained from Checkmate 238, Keynote-054
                                                                        and COMBI-AD trials [8-10]. These clinical trials recruited
Sentinel lymph node biopsy (SLNB) is a surgical procedure
aimed to detect nodal metastases in patients with clinically               Table 1. Melanoma stage I and II (SLNB -)
occult disease. The role of SLNB in melanoma has been                      according to the AJCC classification system
extensively debated over the last years. SLNB intended as                                  8th Edition.
a therapeutic technique evolved from the observation that               Breslow                            T            N
most primary cutaneous melanomas spread initially through               thickness        Ulceration    Category     category    Stage
the intradermal lymphatics to the regional nodes and then               <0.8 mm          no            T1a          N0          IA
move to distant sites [1]. This sequential model of melanoma            <0.8 mm          yes           T1b          N0          IB
metastasis has been lately disproved [2,3] and sentinel node            0.8-1.0 mm       Yes/no        T1b          N0          IB
is now considered an “indicator” of disease as its status il-           >1.0-2.0 mm      no            T2a          N0          IB
lustrates metastatic potential, but its removal cannot prevent          >1.0-2.0 mm      yes           T2b          N0          IIA
                                                                        >2.0-4.0 mm      no            T3a          N0          IIA
further spread. Although SLNB does not impact survival, it
                                                                        >2.0-4.0 mm      yes           T3b          N0          IIB
is associated with a benefit in terms of rate of recurrence
                                                                        >4.0 mm          no            T4a          N0          IIB
within the primary tumor region [4].
                                                                        >4.0 mm          yes           T4b          N0          IIC
    Currently SLNB is recommended as a staging procedure
that can help identify those patients with at least pT1b mel-           Adapted from: Gershenwald JE, Scolyer RA, Hess KR, et al.
                                                                        ­Melanoma staging: evidence-based changes in the American Joint
anoma (Tables 1 and 2) who may benefit from adjuvant                     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
                                    T0
                                 Occult                  T1b                        T2b                        T3b                T4b
                                 primary     T1a      < 0.8 U or      T2a         >1.0-2.0        T3a        >2.0-4.0    T4a      >4.0
         N Category               tumor      < 0.8     0.8-1.0      >1.0-2.0         U          >2.0-4.0        U        >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      C            B        B             B            B              B           C            C       C
        1 c.d.
 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       C            C        C             C            C              C           C            C       D
        1 c.d. or matted
        nodes
 N3c    S/T mets                C            C        C             C            C              C           C            C       D
        + ≥2 nodea or
        matted nodes

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.




2                                                                                    Review | Dermatol Pract Concept. 2024;14(1):e2024038
only high-risk stage III patients, meaning that patients with          these subsets of patients is currently enrolling (Columbus-Ad
stage IIIA (Table 2) melanoma could only be included if                study, NCT05270044).
the metastasis in the SLN were larger than 1 mm. How-
ever, adjuvant therapies are approved in all stage III sub-
                                                                       Objectives
groups [11].
   Adjuvant treatment in stage II melanoma patients is the             With the access of negative-SLN patients to adjuvant treat-
current focus of oncology research [12]. Despite the ab-               ment a question rises accordingly: is SLNB still needed [15]?
sence of identified lymph node involvement, patients with              Which melanoma patient does deserve it?
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
                                                                       Results
for one year was compared against placebo in more than                 Impact of SLNB on Staging Workup: Potential Scenarios Af-
900 ­patients with stage IIB and IIC melanoma in KEYNOTE               ter the Indication of Adjuvant Therapy in Stage IIB and IIC
716 trial resulting in a 18-months recurrence-free-survival            Patients
rate of 86% (95% CI 82-89) in the treatment group versus                    In Table 3 the staging workups with indication to SLNB
77% (95% CI 73-81) in the placebo group, which led to                  are reported. According to NCCN guidelines, SLNB should
approval by the FDA and EMA [13]. Final results from the               be discussed in patients with microsatellites, as SLN status
CheckMate -76K trial (expected soon) seem to confirm the               does have prognostic significance, with a positive SLN up-
efficacy of Nivolumab in stage IIB and IIC melanoma pa-                staging a patient from at least N1c and at least stage IIIB dis-
tients [14]. With regards to target therapy, a phase III trial         ease, to at least N2c, which corresponds to stage IIIC disease
comparing Encorafenib plus Binimetinib versus placebo in               (Table 2) [5]. However, although this may have a prognostic




                   Table 3. Staging workup and consequent indication to adjuvant therapy.
                                           Pathological        5-year survival           10-year            Indication to adjuvant
 Subcategory T          SNB results           stage                 (%)                survival (%)                 therapy
 pT1b                 N0                         1A                    99                    96                         No
                      N1a, N2ba                 3A*                    93                    88                   Questionable
 pT2a                 N0                         1B                    97                    94                         No
                                 a
                      N1a, N2a                  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.
a
 N3a 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.




Review | Dermatol Pract Concept. 2024;14(1):e2024038                                                                                     3
impact (from 83% to 69% and from 77% to 60% 5-year               MSS. Stage IIA melanoma patients were not included in ad-
and 10-year melanoma specific survival [MSS] respectively),      juvant therapy registration trial due to their rather favorable
the upgrade from stage IIIB to stage IIIC does not change the    prognosis. In contrast, the presence of a metastatic node de-
therapeutic management of this subgroup of patients, which       tected through SLNB upgrades pT2b and pT3a melanoma
would all be candidates for adjuvant therapy [16,17].            patients to stage IIIB or IIIC according to the number of
                                                                 nodes involved (Table 3). The prognosis of stages IIIB and
pT1b and pT2a Melanomas                                          IIIC justifies adjuvant treatment as 5-year MSS ranges from
Patients with pT1b melanoma and a negative SLNB (N0) are         83% to 69% and 10-year MSS ranges from 77% to 60%, re-
included in pathological stage IA, which exhibit an excellent    spectively. Thus, performing SLNB in this group of patients
5- and 10-year MSS (99% and 96% respectively). Similarly,        does actually change the management by selecting those pa-
patients with pT2a N0 melanoma are characterized by an           tients who may benefit from adjuvant therapy.
excellent survival (97% and 94% 5- and 10-year MSS) [17]
although are belonging to stage IB. Consequently, they do        pT3b, pT4a and pT4b Melanomas
not require adjuvant therapy.                                    Patients with pT3b or pT4a N0 melanoma are included in
    In the literature the probability of finding a metastatic    stage IIB, while those with pT4b N0 melanoma in stage IIC.
node in pT1b and pT2a melanomas, meaning N1a subcat-             5- and 10-year MSS resulted to be 87% and 82% for stage
egory, ranges from 2.3% and 8.4% to 7.5% and 14.6%               IIB and 82% and 75% for stage IIC. In case of a metastatic
[18,19], respectively. Among those, the overall incidence        node these subsets of patients are upgraded to stages IIIC-
of a maximum deposit size greater than 1.0 mm is likewise        IIID according to the number of nodes involved. As men-
slightly above 3% [18,19]. As shown in Table 1, pT1b-N1a,        tioned before, IIB and IIC melanoma patients are already
pT2a-N1a, pT1b-N2a and pT2b-N2a melanomas are in-                candidates for adjuvant treatment, therefore, SLNB in pa-
cluded in stage IIIA. The probability to find four or more       tients with T3b, T4a, or T4b melanoma would not change
metastatic nodes (N3a) through SLNB in pT1b and pT2a             treatment decisions and the procedure may be omitted.
melanomas, which would be upgraded to stage IIIC, can be
considered not relevant (0.1%) [17,19].
                                                                 Conclusions
    Stage IIIA carries a better prognosis of stage IIB and
IIC (5-year MSS: 93% versus 87% and 82%; 10-year                 SLNB is a surgical staging procedure aimed at identifying
MSS: 88% versus 82% and 75%), thus it remains highly             patient who may benefit from adjuvant treatment. Since
questionable whether adjuvant treatment is needed in this        the approval of adjuvant therapy in negative SLN patients,
stage [20,21]. Recent updates on adjuvant therapy survival       namely stages IIB and IIC, its role may be reappraised. Pa-
rates highlighted that the benefit in stage IIIA patients was    tients with pT3b, pT4a and pT4b melanomas and negative
lower than other stage III subgroups [22]. Consequently,         SLNB (stages IIB–IIC) and those with positive SLNB (stages
the ESMO consensus on melanoma management under-                 IIIC–IIID) would all be candidates for adjuvant therapy for a
lined that there is currently insufficient evidence to support   duration of 1 year. In these patients SLNB might be avoided
the routine use of adjuvant therapy in stage IIIA mela-          since it does not alter the therapeutic management. On the
noma [23]. NCCN guidelines states that in patients with a        other side of the spectrum, pT1b and pT2a patients with neg-
low risk of recurrence (for example, stage IIIA with <1 mm       ative SLNB (stages IA and IB) and those with positive SLNB
of nodal tumor burden), the toxicity of adjuvant therapy         (stage IIIA) would all not benefit from adjuvant treatment.
may outweigh the benefit and observation is preferred.           Therefore, SLNB might be avoided also in these categories of
Although adjuvant systemic therapy is approved for these         patients. Patients with pT2b and pT3a melanomas (clinical
patients, they were excluded from the prospective adjuvant       stage IIA) represent the only two groups whose management
therapy trials [5].                                              would be significantly affected by the SLNB status, being
    In this light, weighing the very low frequency of a posi-    adjuvant therapy only indicated for SLN positive patients.
tive SLN (especially greater than 1 mm), the morbidity and           More studies are needed to improve evidence around
costs of the surgical procedure and the benefit–risk ratio       SLNB and its potential role in only a limited number of
of adjuvant therapy, the indication to performing SLNB in        patients.
pT1b and pT2a melanomas can be questioned.

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Review | Dermatol Pract Concept. 2024;14(1):e2024038                                                                                                5
