Journal of Clinical Medicine Article Sentinel Lymph Node Biopsy vs. Observation in Thin Melanoma: A Multicenter Propensity Score Matching Study Antonio Tejera-Vaquerizo 1,2, *,† , Aram Boada 3,† , Simone Ribero 4 , Susana Puig 5,6 , Sabela Paradela 7 , David Moreno-Ramírez 8 , Javier Cañueto 9 , Blanca de Unamuno-Bustos 10 , Ana Brinca 11 , Miguel A. Descalzo-Gallego 12 , Simona Osella-Abate 13 , Paola Cassoni 13 , Sebastian Podlipnik 5,6 , Cristina Carrera 5,6 , Sergi Vidal-Sicart 14 , Ramón Pigem 5,6 , Agustí Toll 5,6 , Ramón Rull 15 , Llucìa Alos 16 , Celia Requena 17 , Isidro Bolumar 18 , Víctor Traves 19 , Ángel Pla 20 , Almudena Fernández-Orland 8 , Ane Jaka 3 , María Teresa Fernández-Figueras 21 , Nina Anika Richarz 3 , Ricardo Vieira 11 , Rafael Botella-Estrada 10 , Concepción Román-Curto 9,22 , Lara Ferrándiz-Pulido 8 , Nicolás Iglesias-Pena 7 , Carlos Ferrándiz 3 , Josep Malvehy 5,6 , Pietro Quaglino 4 and Eduardo Nagore 17 1 Dermatology Department, Instituto Dermatológico GlobalDerm, 14700 Palma del Río, Spain 2 Cutaneous Oncology Unit, Hospital San Juan de Dios, 14012 Córdoba, Spain 3 Dermatology Department, Hospital Universitari Germans Trials i Pujol, Institut d’Investigació Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain; aramboada@gmail.com (A.B.); iratzia@hotmail.com (A.J.); richarznina@gmail.com (N.A.R.); cferrandizf@gmail.com (C.F.)  4 Medical Sciences Department, Section of Dermatology, University of Turin, 10124 Turin, Italy;  simone.ribero@unito.it (S.R.); pietro.quaglino@unito.it (P.Q.) 5 Melanoma Unit, Dermatology Department, Hospital Clinic, Universitat de Barcelona, Citation: Tejera-Vaquerizo, A.; Boada, A.; Ribero, S.; Puig, S.; Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; spuig@clinic.cat (S.P.); spodlipnik@gmail.com (S.P.); ccarrera@clinic.cat (C.C.); Paradela, S.; Moreno-Ramírez, D.; ramon.pigem@gmail.com (R.P.); atoll@clinic.cat (A.T.); jmalvehy@gmail.com (J.M.) Cañueto, J.; de Unamuno-Bustos, B.; 6 Biomedical Research Networking Center on Rare Diseases (CIBERER), ISCIII, 28029 Barcelona, Spain Brinca, A.; Descalzo-Gallego, M.A.; 7 Departamento de Dermatología, Hospital Universitario de la Coruña, 15006 La Coruña, Spain; et al. Sentinel Lymph Node Biopsy vs. sparmor78@gmail.com (S.P.); niglep@gmail.com (N.I.-P.) Observation in Thin Melanoma: A 8 Melanoma Unit, Medical-&-Surgical Dermatology Department, Hospital Universitario Virgen Macarena, Multicenter Propensity Score 41009 Sevilla, Spain; david.moreno.ramirez.sspa@juntadeandalucia.es (D.M.-R.); Matching Study. J. Clin. Med. 2021, 10, almudenaorland@yahoo.com (A.F.-O.); lferrandiz@e-derma.org (L.F.-P.) 9 Dermatology Department, Complejo Asistencial Universitario de Salamanca, 37007 Salamanca, Spain; 5878. https://doi.org/10.3390/ jcm10245878 javier.canueto@gmail.com (J.C.); cromancurto@gmail.com (C.R.-C.) 10 Dermatology Department, Hospital Universitario La Fe, 46126 Valencia, Spain; blancaunamuno@yahoo.es (B.d.U.-B.); rbotellaes@gmail.com (R.B.-E.) Academic Editor: Pablo 11 Departament of Dermatology, University Hospital of Coimbra, 3000-075 Coimbra, Portugal; Fernandez-Peñas anabrinca@gmail.com (A.B.); ricardo.jdc.vieira@gmail.com (R.V.) 12 Unidad de Investigación, Fundación Piel Sana, Academia Española de Dermatología, 28008 Madrid, Spain; Received: 14 November 2021 miguelangel.descalzo@aedv.es Accepted: 14 December 2021 13 Medical Sciences Department, Section of Surgical Pathology, University of Turin, 10124 Turin, Italy; Published: 15 December 2021 simona.osellaabate@unito.it (S.O.-A.); paola.cassoni@unito.it (P.C.) 14 Nuclear Medicine Department, Hospital Clinic Barcelona, Universitat de Barcelona, Institut d’investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; svidalsicart@gmail.com Publisher’s Note: MDPI stays neutral 15 Surgery Department, Hospital Clinic, Universidad de Barcelona, 08036 Barcelona, Spain; RRULL@clinic.cat with regard to jurisdictional claims in 16 Pathology Department, Hospital Clinic, Universidad de Barcelona, 08036 Barcelona, Spain; lalos@clinic.cat published maps and institutional affil- 17 Dermatology Department, Instituto Valenciano de Oncología, 46009 Valencia, Spain; iations. celiareq@hotmail.com (C.R.); eduardo_nagore@ono.com (E.N.) 18 Surgery Department, Instituto Valenciano de Oncología, 46009 Valencia, Spain; ibolumar@yahoo.es 19 Pathology Department, Instituto Valenciano de Oncología, 46009 Valencia, Spain; victortraves@telefonica.net 20 Otorhinolaringology Department, Instituto Valenciano de Oncología, 46009 Valencia, Spain; apmocholi@gmail.com Copyright: © 2021 by the authors. 21 Pathology Department, Hospital Universitari Germans Trial i Pujol, 08916 Badalona, Spain; Licensee MDPI, Basel, Switzerland. maiteffig@gmail.com This article is an open access article 22 Instituto de Investigación Biomédica de Salamanca, Complejo Asistencial Universitario de Salamanca, distributed under the terms and 37007 Salamanca, Spain conditions of the Creative Commons * Correspondence: antoniotejera@aedv.es; Tel.: +34-957644564 Attribution (CC BY) license (https:// † These authors contributed equally to this study. creativecommons.org/licenses/by/ 4.0/). J. Clin. Med. 2021, 10, 5878. https://doi.org/10.3390/jcm10245878 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 10, 5878 2 of 14 Abstract: The therapeutic value of sentinel lymph node biopsy (SLNB) in thin melanoma remains controversial. The aim of this study is to determine the role of SLNB in the survival of thin melanomas (≤1 mm). A multicenter retrospective observational study was designed. A propensity score match- ing was performed to compare patients who underwent SLNB vs. observation. A multivariate Cox regression was used. A total of 1438 patients were matched by propensity score. There were no sig- nificant differences in melanoma-specific survival (MSS) between the SLNB and observation groups. Predictors of MSS in the multivariate model were age, tumor thickness, ulceration, and interferon treatment. Results were similar for disease-free survival and overall survival. The 5- and 10-year MSS rates for SLN-negative and -positive patients were 98.5% vs. 77.3% (p < 0.001) and 97.3% vs. 68.7% (p < 0.001), respectively. SLNB does not improve MSS in patients with thin melanoma. It also had no impact on DSF or OS. However, a considerable difference in MSS, DFS, and OS between SLN- positive and -negative patients exists, confirming its value as a prognostic procedure and therefore we recommend discussing the option of SLNB with patients. Keywords: melanoma; sentinel lymph node biopsy; survival 1. Introduction Sentinel lymph node biopsy (SLNB) is a commonly used procedure in the management of cutaneous melanoma [1]. Although the Multicenter Selective Lymphadenectomy Trial I (MSTL-I) showed that SLNB does not improve disease-specific survival in melanoma (MSS) [2], it did not include tumors with a Breslow thickness < 1.2 mm in the analysis. The therapeutic effect of SLNB in thin melanoma thus remains to be determined. This is important, particularly in our setting, where tumors with a Breslow thickness < 1 mm are the most common diagnosed melanomas [3]. In addition, SLNB is recommended for patients with stage T1b melanoma and stage T1a melanoma if there are other high- risk factors, such as a mitotic rate > 2 mitoses/mm2 [4], lymphovascular invasion, and young age [5]. The main aim of this study was to determine whether SLNB improves MSS in patients with thin tumors. Secondary objectives were to compare disease-free survival (DFS) and overall survival (OS) between patients who undergo SLNB and those who undergo observation and to examine the effect of SLN positivity on survival. 2. Materials and Methods 2.1. Study Population We designed a multicenter observational study following the Strengthening the Re- porting of Observational Studies in Epidemiology guidelines [6]. Patients were selected from the databases of nine hospitals that form part of the Sentinel Lymph Node Study Group in Melanoma (Sentimel). Seven of the hospitals are in Spain: Instituto Valenciano de Oncología in Valencia, Hospital Universitario de Salamanca in Salamanca, Hospital La Fe in Valencia, Hospital Universitario Virgen Macarena in Seville, Hospital de la Coruña in A Coruña, Hospital Germans Trias i Pujol in Badalona, and Hospital Clínic in Barcelona. The other two hospitals are in Portugal (Centro Hospitalar e Universitário de Coimbra) and Italy (University Hospital “Città della Salute e della Scienza di Torino”). We included all patients aged ≥18 years who were registered in the hospital databases up to 31 December 2017 with a diagnosis of thin melanoma (Breslow thickness ≤ 1 mm) and no evidence of metastasis at diagnosis. 1 January 1998 was chosen as the start date for inclusion, as this is when most hospitals started to use SLNB in the management of melanoma [7]. SLNB is performed using a similar procedure at all the hospitals with any combination of vital blue dye, radioactive tracer, and preoperational lymphography (+/− preoperative PET-CT/CT) for SLN mapping. Thin primary melanomas are excised with a 1-cm margin, as recommended by clinical practice guidelines. The procedure for J. Clin. Med. 2021, 10, 5878 3 of 14 pathologic SLN examination has been described previously [8]. Hospital Clínic in Barcelona has been using the Minitub protocol (EORTC 1208: Minitub registration study) since 2011. The study was approved by the lead ethics committee, located at Hospital Universitario Reina Sofía in Cordoba (reference 3569). 2.2. Study Groups and Outcome Variables The patients were divided into two groups: an SLNB group and an observation-only group. Patients in the SLNB group were further classified as SLN-positive or SLN-negative. The outcome variables were DFS, MSS, and OS. Survival was defined as time in months from excision of the primary tumor to first recurrence (DFS), death due to melanoma (MSS), or death due to any cause (OS). Recurrence was classified as local recurrence or satellite, regional lymph node recurrence, or distant metastasis. In patients with multiple simultaneous recurrences, the most advanced type of recurrence was considered. 2.3. Propensity Score Matching Propensity score matching is a relatively new statistical technique that controls for se- lection biases in non-randomized studies comparing two interventions or treatments [9]. It consists of matching patients according to their likelihood of being assigned to one group or another, in our case: SLNB or observation. The first step was to perform logistic regression with SLNB as the dependent variable and all the other variables as independent variables. The independent variables were chosen because of their potential prognostic value in melanoma [10] and comprised Breslow thickness [11], ulceration [11,12], regression [13,14], Clark level, microscopic satellitosis [15], mitotic rate [16], vascular invasion [16], tumor infiltrating lymphocytes [17], histologic subtype, age, sex, anatomic location [18], hospital, year, and treatment with interferon [19]. Histologic subtypes were “superficial spreading melanoma”, “nodular melanoma” and “other” histological subtypes. For the convergence of the models it was mandatory to reunify the rest of the histologic subgroups (lentigo maligna, acral lentiginous melanoma, . . . ) into a single simple group (other). 2.4. Statistical Analysis Between-group comparisons were made using the Mann–Whitney U test and the t test for qualitative and quantitative variables respectively. Breslow thickness and age were log-transformed to avoid skewed distribution. Separate models were built for DFS, MSS, and OS. Survival times were calculated from excision of the primary tumor to the event in question. Cases with no events up to the date of the last follow-up were treated as censored data. Survival curves estimated using the Kaplan–Meier method were compared using the log-rank test to compare survival between patients in the SLNB and observation- only groups. The same method was used to compare SLN-positive and SLN-negative patients. Univariate Cox regression was used to assess the effect of each variable on survival according to the performance of SLNB or not. A multivariate model was built to analyze the impact on survival of all variables with a significance level of p < 0.2 in the univariate analysis. 2.5. Missing Data Assuming that missing data were missing at random, we generated 20 complete datasets using multivariate imputation by chained equations (mi impute chained procedure in Stata). The procedure included all variables that were to be subsequently analyzed in addition to any variables that could help explain the missing data. Each of 20 imputed datasets was analyzed using Cox regression to fit the model of interest to the outcome variables (DFS, MSS, and OS). Finally, the results of the complete datasets were combined into a single set of estimates using Rubin rules [20]. All analyses were performed in STATA v.14.1 (Stata Corp. 2015. Stata Statistical Software: Release 14). datasets was analyzed using Cox regression to fit the model of interest to the outcome variables (DFS, MSS, and OS). Finally, the results of the complete datasets were combined into a single set of estimates using Rubin rules [20]. All analyses were performed in J. Clin. Med. 2021, 10, 5878 4 of 14 STATA v.14.1 (Stata Corp. 2015. Stata Statistical Software: Release 14). 3. Results 3. Results 3.1. Study Population Characteristics 3.1. Study Population We included Characteristics 5049 patients with thin localized melanoma (≤1 mm) at diagnosis; 1083 We included had undergone 50493966 SLNB and patients with thin observation localized only (Figure melanoma ≤1 mm) 1). In total, (1438 at diagnosis; patients were 1083 had undergone SLNB matched by propensity scores. and 3966 observation only (Figure 1). In total, 1438 patients were matched by propensity scores. Figure 1. Flow chart of the study population. PSM denotes propensity score matching; SLNB, sentinel lymph Figure node 1. Flow biopsy. chart of the study population. PSM denotes propensity score matching; SLNB, sen- tinel lymph node biopsy. Before matching, patients in the observation group were more likely to be women (58% Before 53%, p < 0.001) vs.matching, andin patients to the haveobservation melanoma of the head group wereand neck more (14%to likely vs.be7%, p < 0.001) women and less likely to have ulceration (1% vs. 10%, p < 0.001), regression (26% (58% vs. 53%, p < 0.001) and to have melanoma of the head and neck (14% vs. 7%, p < 0.001)vs. 45%, p < 0.001), and a Clark level IV (6% vs. 26%, p and less likely to have ulceration (1% vs. 10%, p < 0.001), regression (26% vs. 45%, p 4 mm) cutaneous melanoma: An observational study. Eur. J. Dermatol. 2016, 26, 34–48. [CrossRef] [PubMed] 16. Nagore, E.; Oliver, V.; Botella-Estrada, R.; Moreno-Picot, S.; Insa, A.; Fortea, J.M. Prognostic factors in localized invasive cutaneous melanoma: High value of mitotic rate, vascular invasion and microscopic satellitosis. Melanoma Res. 2005, 15, 169–177. [CrossRef] 17. Taylor, R.C.; Patel, A.; Panageas, K.S.; Busam, K.J.; Brady, M.S. 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