10.5826/dpc.1304a304
The incidence of melanoma has been dramatically increasing over the last decades. Melanoma is considered to have a high metastatic potential and it can progress due to hematogenous metastasis or via lymphatic vessels. Different patterns of recurrence have been described, namely, local, satellite, and in transit metastasis (LCIT), lymphatic, and systemic metastasis. With a more advanced melanoma stage at diagnosis, there is a higher risk for systemic metastasis in comparison to LCIT; in contrast, early-stage melanoma tends to recur more frequently as LCIT and less commonly as systematic metastasis. The aim of this review was to summarize the patterns of recurrence of cutaneous melanoma, giving the clinician a practical summary for diagnosis, prognosis, and surveillance. There is a knowledge gap of the common patterns of recurrence that needs to be addressed to better identify patients at high risk of disease recurrence and personalize surveillance strategies as well as patient counseling.
text/xml
2160-9381
3474
en
Cristian Patricio Navarrete-Dechent
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
screening
Patterns of Recurrence of Cutaneous Melanoma: A Literature Review
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Review
2023-10-31
2023-04-28
2023-10-31
2024-01-16
e2023304
Dermatol Pract Concept
The incidence of melanoma has been dramatically increasing over the last decades. Melanoma is considered to have a high metastatic potential and it can progress due to hematogenous metastasis or via lymphatic vessels. Different patterns of recurrence have been described, namely, local, satellite, and in transit metastasis (LCIT), lymphatic, and systemic metastasis. With a more advanced melanoma stage at diagnosis, there is a higher risk for systemic metastasis in comparison to LCIT; in contrast, early-stage melanoma tends to recur more frequently as LCIT and less commonly as systematic metastasis. The aim of this review was to summarize the patterns of recurrence of cutaneous melanoma, giving the clinician a practical summary for diagnosis, prognosis, and surveillance. There is a knowledge gap of the common patterns of recurrence that needs to be addressed to better identify patients at high risk of disease recurrence and personalize surveillance strategies as well as patient counseling.
Cristian Patricio Navarrete-Dechent
2023/10/31
10.5826/dpc.1304a304
e2023304
Department of Dermatology, Facultad de Medicina; Melanoma and Skin Cancer Unit, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
2160-9381
screening
en
e2023304
Rueth NM, Cromwell KD, Cormier JN. Long-term follow-up for melanoma patients: is there any evidence of a benefit? Surg Oncol Clin N Am. 2015;24(2):359-77. DOI: 10.1016/j.soc.2014.12.012. PMID: 25769718.
Patterns of Recurrence of Cutaneous Melanoma: A Literature Review
https://dpcj.org/index.php/dpc/article/download/3474/2400
    Patterns of Recurrence of Cutaneous Melanoma:
                  A Literature Review
Dominga Peirano1, Francisca Donoso1, Sebastián Vargas1, Leonel Hidalgo1, Rosario Agüero1,
           Pablo Uribe1,2, Sebastían Mondaca2,3, Cristian Navarrete-Dechent1,2


1 Department of Dermatology, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
2 Melanoma and Skin Cancer Unit, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
3 Department of Medical Oncology, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile



Key words: melanoma, staging, metastasis, recurrence, skin cancer, immune checkpoint inhibitors, screening
Citation: Peirano D, Donoso F, Vargas S, et al. Patterns of Recurrence on Cutaneous Melanoma: A Literature Review. Dermatol Pract
Concept. 2023;13(4):e2023304. DOI: https://doi.org/10.5826/dpc.1304a304
Accepted: October 10, 2023; Published: October 2023
Copyright: ©2023 Peirano 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: Partial funding was obtained from La Fondation La Roche Possay Research Awards. The funding source had no role in the study.
Competing Interests: None.
Authorship: All authors have contributed significantly to this publication.
Corresponding Author: Cristian Navarrete-Dechent, MD, Department of Dermatology, Escuela de Medicina, Pontificia Universidad
Católica de Chile, Diagonal Paraguay 362, 6th floor, Santiago, Chile 8330077. Phone: +56-2-2435 3574 E-mail: ctnavarr@gmail.com




  ABSTRACT             The incidence of melanoma has been dramatically increasing over the last decades. Melanoma is
                       considered to have a high metastatic potential and it can progress via lymphatic vessels or through
                       hematogenous metastasis. Different patterns of recurrence have been described, namely, local, ­satellite,
                       and in transit metastasis (LCIT), lymphatic metastasis, and systemic metastasis. With a more advanced
                       melanoma stage at diagnosis, there is a higher risk for systemic metastasis in comparison to LCIT;
                       in contrast, early-stage melanoma tends to recur more frequently as LCIT and less commonly as
                       ­systematic metastasis. The aim of this review was to summarize the patterns of recurrence of cuta-
                        neous melanoma, giving the clinician a practical summary for diagnosis, prognosis, and surveillance.
                        There is a knowledge gap of the common patterns of recurrence that needs to be addressed to better
                        identify patients at high risk of disease recurrence and personalize surveillance strategies as well as
                        patient counseling.




Review | Dermatol Pract Concept. 2023;13(4):e2023304                                                                                1
                                                                  Objective
Introduction
                                                                  The aim of this review was to evaluate the recurrence patterns
The incidence of melanoma has been dramatically increas-          of cutaneous melanoma, regarding the time of follow-up,
ing worldwide over the last two decades [1,2]. It is the fifth    time of detection of the recurrence, and the most frequent
most common cancer in the U.S. and the ninth in Europe[3].        site of recurrence, giving the clinician a practical summary
In 2023, it was estimated that there would be 89,070 new          for diagnosis, prognosis, and surveillance.
melanoma cases in the United States (US) with 7,990 pa-
tients dying of the disease [2]. Patients with ­early-stage
cutaneous melanoma (i.e. stages I and II) are generally con-      Methods
sidered to have an excellent prognosis. Data from the Sur-
                                                                  A literature narrative review of articles published in PubMed
veillance, ­Epidemiology, and End Results (SEER) Program
                                                                  between the years 2000 to 2022 was conducted. The key-
suggests that 99.5% of patients with l­ocalized melanoma,
                                                                  words were “Melanoma” OR “Cutaneous melanoma” AND
70.6% regional melanoma, and 31.9% of those with dis-
                                                                  “Recurrence” OR “Relapse” AND/OR “Patterns”. We in-
tant metastases, will be alive at 5 years [4]. Cutaneous mel-
                                                                  cluded all studies in English and/or Spanish. Exclusion cri-
anoma is considered to have a high metastatic potential
                                                                  teria were non-skin melanomas, stage IV melanoma only,
and it can have lymphatic metastasis or hematogenous
                                                                  studies published before the year 2000, studies reporting
metastasis [5]. Specifically, it can metastasize as local, sat-
                                                                  the local and regional recurrence together as one group, and
ellite, and in transit metastasis (LCIT), on lymph nodes,
                                                                  case reports and case series with less than 10 patients. From
or as distant metastasis [5–8]. The presence of regional
                                                                  the remaining results, study type, number of patients, stage
lymph node metastatic disease is a significant predictor
                                                                  of melanoma at diagnosis and substage if they reported (e.g
of outcome in melanomas as it is associated with a 50%
                                                                  IA, IIB, IIC), median follow-up, mean recurrence time (in
reduction in survival compared to patients without nodal
                                                                  months), recurrence site, recurrence predictors, and survival
involvement [3,9].
                                                                  rate were recorded. For the study purposes, ‘recurrence’ was
    There is limited research analyzing the patterns of re-
                                                                  defined as the return of the melanoma after initial treatment
currence in patients with primary localized cutaneous mel-
                                                                  and after a period of time during which the cancer was not
anoma. Meier et al study in 2002 traced the metastatic
                                                                  detected. ‘Progression’ was defined as melanoma growing or
pathways of 3,001 patients with primary cutaneous mel-
                                                                  spreading without ever having gone away completely. The
anoma from 1976-1996. Of the patients who had disease
                                                                  recurrence sites were divided into local, satellite, and in tran-
confined to the primary tumor at diagnosis (i.e. stages I
                                                                  sit metastasis (LCIT), lymph nodes/nodal, and systemic me-
and II), 15.5% developed metastasis during the study pe-
                                                                  tastasis. We also described the sites of systemic metastasis,
riod [6]. Another study conducted in 1999 by Cohn et al.
                                                                  if reported. The recurrence detection method was classified
identified 569 of 2493 patients with recurrent melanoma
                                                                  into patient symptoms (i.e. detected by the patient), physical
and d
    ­ emonstrated a 5-year survival rate of 82% and 30%
                                                                  examination (e.g. palpation, visual examination), and images
among those with a primary local versus regional recurrence,
                                                                  (e.g. PET-CT). Overall survival (OS) was presented as a per-
respectively [10]. Furthermore, current guidelines are fairly
                                                                  centage rate at 3 or 5 years.
vague as to how aggressively we should follow up patients
with localized disease (i.e. stage I and II), with most advo-
cating only routine skin examinations at various intervals        Results
for the first 5 years. Surveillance guidelines, in general, and
melanoma patients specifically, are often follow-up based on      The overall information is summarized in Tables 1-4.
low-level evidence. Additionally, despite clinical guidelines,
practice patterns tend to vary across different institutions      Follow-up and Recurrence Type
and countries [11–14].                                            The rate of melanoma recurrence was determined by the me-
    Given the increasing incidence of cutaneous malig-            dian follow-up time reported in different studies. Most stud-
nant melanoma and the recent changes in the treatment             ies have shown similar recurrence timing patterns. Across all
landscape, it is important to understand stage-specific re-       stages, Meyers et al reported a recurrence rate of 36%, with
currence patterns [15]. In the current era of immune check-       a median time of recurrence of 14 months [16]. O ‘Connell
point inhibitors and targeted therapies, early detection of       et al and Berger et al reported lower recurrence rates of 24%
melanoma recurrences is important, as it can lead to more         and 29.5%, respectively [1,3]. Barbour et al reported the
effective and manageable treatment options.                       highest rate of recurrence of 45% in their series [17].




2                                                                             Review | Dermatol Pract Concept. 2023;13(4):e2023304
                                                       Table 1. Patients’ demographics and melanoma diagnosis details.
                                                                               Year of         Summary                        Number of patients of           Mean Age                                               Mean ­follow
                                                              Study          publication      of the study      Country          the study (n)             (y, range or SD)     Gender (Male/ Female)        Stage   up (months)
                                                       Meier F, et al.          2002       Retrospective       Germany                 3001                       -                        -            I-II             120
                                                       Meyers O, et al.         2008       Retrospective       USA                     118                      63,5            41 (35%) Female         II-III           44
                                                                                                                                                                                77 (65%) Male
                                                       Barbour S, et al.        2015       Prospective         Australia               173               Group 1: 61 (15–92)    19 (18%) Female         IIIB-IIIC        32
                                                                                                                                                         Group 2: 61 (20–88)    88 (82%) Male
                                                       O Connell E, et al.      2015       Retrospective       Ireland                 164                   51.2 (±14.1)       88 (53.7%) Female       I-II             75
                                                                                                                                                                                76 (46.3%) Male
                                                       Svedman F , et al.       2016       Systematic Review . Multicenter           152.422                      -                        -            I-III             -
                                                       Sparks DS, et al.        2016       Retrospective       Australia               107                   72.1 (58–80)       25 (23.4%) Female       I-III            30,5
                                                                                                                                                                                82 (76.6%) Male




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                                                       Berger AC, et al.        2017       Retrospective       USA                     581                   63.5 (11–91)       221 (38%) Female        II                -
                                                                                                                                                                                360 (62%) Male
                                                       Lee AY, et al.           2017       Retrospective       USA                     738                   62 (17–91)         284 (38.5%) Female      II               52
                                                                                                                                                                                454 (61.5%) Male
                                                       Namin AW, et al.         2018       Retrospective       USA                     168                       62             42 (25%) Female         I-II              -
                                                                                                                                                                                126 (75%) Male
                                                       Leeneman B, et al.       2019       Retrospective       Netherlands             1397               Stage I 54 (43–64)    1754 (56.7%) Female     I-III            65
                                                                                                                                                         Stage II 63 (50–74)    1339 (43.2%) Male
                                                                                                                                                         Stage III 58 (45–69)
                                                       Thomas DC, et al.        2019       Retrospective       Multicenter   6305 (5351 SLN negative)             -             2310 ( 43%) Female.     I-II             32,1
                                                                                                                                                                                3041 (57%) Male
                                                       Bartlett EK, et al.      2020       Prospective         USA                     370                    61 (5–95)         145 (39%) Female        III              33
                                                                                                                                                                                225 (61%) Male
                                                       Bleicher J, et al.       2020       Retrospective       USA                     580                   62 (48–74)         228 (39.3%) Female      II               59
                                                                                                                                                                                352 (60.7%) Male
                                                       Oh Y, et al.             2020       Retrospective       Corea                   340                      57,94           195 (57.4%) Female      I-II             46,2
                                                                                                                                                                                142 (42.6%) Male
                                                       Eggermont M, et al.      2021       Clinical Trial      Multicenter   1019 ( 514 pembrolizumab,   251 (25%) > 65 years   Female 391 ( 38%)       III              42,3
                                                                                                                                    505 placebo)                                Male 628 (62%)
                                                       Ertekin S, et al.        2021       Retrospective       Spain                   3786                58.27 (± 16.75)      330 (42.1%) Female      I-III             -
                                                                                                                                                                                454 (57.9%) Male
                                                       Luke J, et al.           2022       Clinical Trial      Multicenter       976 (487 group 1,               61             Female 387 (40%)        IIB-IIC          20,9




3
                                                                                                                                   489 group 2)                                 Male 589 (60%)
4
                                                       Table 2. Melanoma recurrence details and method of detection.
                                                                                     Recurrence           Mean time of             Mean time of LCIT      Mean time of LN         Mean time of systemic
                                                              Study              of melanoma n(%)      recurrence (months)        recurrence (months)   recurrence (months)        recurrence (months)         Detection of recurrence
                                                       Meier F, et al.       466/3001 (15%)                       -                       17                      16                         25                             -
                                                       Meyers O, et al.      43/118 (36%)                        14                        -                       -                          -               Patient self-report (67%)
                                                                                                                                                                                                              Physical examination (26%)
                                                                                                                                                                                                              Images (7%)
                                                       Barbour S, et al.     78/173 (45%)                         -                        -                       -                          -                             -
                                                       O Connell E, et al.   40/164 (24%)                       39,5                       -                       -                          -                             -
                                                       Svedman F , et al.    -                                    -                        -                       -                          -                             -
                                                       Sparks DS, et al.     38/107 (35.5%)                     11,8                       -                       -                          -                             -
                                                       Berger AC, et al.     171/581 (29.4%)                      -                        -                       -                          -               Patient self-report (39%)
                                                                                                                                                                                                              Physical examination (32%)
                                                                                                                                                                                                              Images (21%)
                                                       Lee AY, et al.        219/738 (29.6%)              IIA (195.1) IIB                  -                       -                          -               Patient self-report (59%)
                                                                                                       (unknown) IIC (85.9)
                                                       Namin AW, et al.      33/168 (20%)                        17                       8                     13,5                        18,3                            -
                                                       Leeneman B, et al.    275/1397 (20%)            IB (34) II (18) III (12)            -            IB 36) II (9.6) III (6)    IB (37) II (26) III (13)                 -
                                                       Thomas DC, et al.     558/5351 (10.4%)                     -                      16,7                   18,6                        31,2                            -
                                                       Bartlett EK, et al.   158/370 (42.7%)                     12                        -                       -                          -               Patient self-report (29%),
                                                                                                                                                                                                              Physical examination
                                                                                                                                                                                                              (20.3%), Images (39.9%).
                                                       Bleicher J, et al.    158/580 (27.2%)                      -                        -                       -                          -               Patient self-report (60.1%)
                                                                                                                                                                                                              Physical examination
                                                                                                                                                                                                              (12.0%) Images (27.3%)
                                                       Oh Y, et al.          92/340 ( 27.1%)                    16,3                       -                       -                          -                             -
                                                       Eggermont M, et al. 199/514 (39%) Group 1                  -                        -                       -                          -                             -
                                                                           287/505 (53%) Group 2.
                                                                           Total 47.6%
                                                       Ertekin S, et al.     Total: 784/3786 (20.7%)   Total: 21 Stage I (40)            17,5                   25,5                         25                             -
                                                                             Stage I (21%)                 Stage II (22)
                                                                             Stage II (33%)                Stage III (14)
                                                                             Stage III (45%)
                                                       Luke J, et al.        187/976 (19%)                        -                        -                       -                          -                             -




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                                                       Table 3. Melanoma recurrence location details and predictors of recurrence.
                                                                                                                        Recurrence   Recurrence   Recurrence
                                                               Study                   Location of recurrence            LCIT (n)      LN (n)     Systemic (n)                      Predictors of recurrence
                                                       Meier F, et al.       LCIT (21.7%) LN (50.2%) Systemic (28.1%)      101          234           131        Location of initial tumor (p<0.001) Tumor thickness (p=0.028)
                                                       Meyers O, et al.      LCIT (49%) LN (16%) Systemic: (35%)           21            7            15                                        -
                                                       Barbour S, et al.     LCIT (14%) LN (8%) Systemic (78%)          Group 1: 5   Group 1: 5   Group 1: 33                                   -
                                                                                                                        Group 2: 6   Group 2: 1   Group 2: 28
                                                       O Connell E, et al.   LCIT (30%) LN (30%) Systemic: (40%)           12           12            16         Nodular Subtype (p<0.05) Tumor thickness (p<0.001)
                                                       Svedman F, et al.     -                                              -            -             -                                        -
                                                       Sparks DS, et al.     LCIT (16%) LN (12%) Systemic (15%)            17           13            16                                        -




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                                                       Berger AC, et al.                         -                         56           52            63         Male sex (p=0.0018) T classification (p=0.0049) Ulceration
                                                                                                                                                                 (p=0.0016)
                                                       Lee AY, et al.                            -                         80           50            81                                        -
                                                       Namin AW, et al.      LCIT (18%) LN (18%) Systemic (49%)             6            6            21                                        -
                                                       Leeneman B, et al.                        -                         59           100           116                                       -
                                                       Thomas DC, et al.                         -                         221          109           220        For LCIT recurrence: age, anatomic location, thickness
                                                                                                                                                                 (all p<0.05) For LN recurrence: age and thickness (all p<0.05)
                                                                                                                                                                 For systemic recurrence: anatomic locations, thickness,
                                                                                                                                                                 ulceration, and lymphovascular invasion (all p<0.05)
                                                       Bartlett EK, et al.                       -                         45           62            51                                        -
                                                       Bleicher J, et al.    LCIT (19.6%) LN (29.8%) Systemic (50.6%)      31           47            80         Age (p< 0.05) Stage (p<0.05) Breslow (p< 0.01)
                                                       Oh Y, et al.                              -                         29           49            28         Male sex (p=0.030) Breslow >1 mm (p=0.008)
                                                       Eggermont M, et al.                       -                          -            -        Group 1 126                                   -
                                                                                                                                                  (25%) Group
                                                                                                                                                   2 194 (38%)
                                                       Ertekin S, et al.     LCIT. (50.1%) LN - Systemic (49.9%)           393          98            293                                       -
                                                       Luke J, et al.                            -                          -            -        Group 1:31                                    -
                                                                                                                                                  Group 2 : 60




5
6
                                                       Table 4. Melanoma survival and additional details.
                                                                                                      Overall Survival    Overall survival % at     Disease free survival   Disease free survival
                                                              Study               Survival          (months at 5 years)         5 years                 (n) at 5 years         (%) at 5 years                Additional details
                                                       Meier F, et al.                -             -                                -                        -                       -
                                                       Meyers O, et al.               -             22 (LN and LCIT)                 -                        -                       -
                                                                                                    7 (Systemic)
                                                       Barbour S, et al.              -                       -                     53                       80                     46%                                -
                                                       O Connell E, et al.     23.5% from the       6                                -                        -                       -                                -
                                                                                  diagnosis
                                                       Svedman F , et al.             -                       -            Stage I (95%–100%)                 -                       -                                -
                                                                                                                          Stage II (65%–92.8%)
                                                                                                                           Stage III (41%–71%)
                                                                                                                           Stage IV (9%–28%)
                                                       Sparks DS, et al.              -                       -                     47                        -                      47             First site being lungs (4), brain (3),
                                                                                                                                                                                                    liver (2), subcutaneous (1), bone (1),
                                                                                                                                                                                                    and synchronous metastases to
                                                                                                                                                                                                    multiple sites (6)
                                                       Berger AC, et al.     IIA (57%) IIB (57%)              -                      -                        -                       -                                -
                                                                             IIC (40%) at 5 years
                                                       Lee AY, et al.                 -             Stage IIA (87%)                  -                        -                       -             Lung was the most frequent site
                                                                                                    Stage IIB (78%)                                                                                 of systemic relapse in all substages
                                                                                                    Stage IIC (69%)                                                                                 (n = 11, 11, and 13 for stage IIA, IIB,
                                                                                                                                                                                                    and IIC, respectively). The second
                                                                                                                                                                                                    most frequent site was brain for IIA
                                                                                                                                                                                                    (n = 9) and IIC (n = 5), and liver for
                                                                                                                                                                                                    IIB (n = 4). Three IIA patients had a
                                                                                                                                                                                                    rare site of distant metastasis— two
                                                                                                                                                                                                    to the larynx, and one to the heart.
                                                       Namin AW, et al.             92%                       -                      .                      135                      85                                -
                                                       Leeneman B, et al.             -             Stage IB 1.9 years    Stage IB (41%) Stage II             -                       -                                -
                                                                                                    (95% CI: 0.8-3.2)     (42%) Stage III (43%)
                                                                                                    Stage II 1.5 years           at 2 years
                                                                                                    (95% CI: 1.1-2.1)
                                                                                                    Stage III 1.1 years
                                                                                                    (95% CI: 0.6-2.2).




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                                                       Thomas DC, et al.     -   -           86.9%                      .                         -                                 -
                                                       Bartlett EK, et al.   -   -              -                       -                         -                                 -
                                                       Bleicher J, et al.    -   -   Stage IIA (82.6%) Stage            -                         -               Distant recurrence, 29 (36.3%)
                                                                                       IIB (71.5) Stage IIC                                                       patients had pulmonary metastases,
                                                                                             (60.3%)                                                              17 (21.3%) had brain
                                                                                                                                                                  metastases, 9 (11.3%) had
                                                                                                                                                                  intraabdominal metastases, 6 (7.5%)
                                                                                                                                                                  had bone metastases, 7 (8.8%) had
                                                                                                                                                                  multiple sites of primary recurrence,
                                                                                                                                                                  and 12 (15.0%) had distant




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                                                                                                                                                                  metastasis at another location.
                                                       Oh Y, et al.          -   -              -                       -                         -               The most common site of distant
                                                                                                                                                                  metastasis was the lung, and the
                                                                                                                                                                  median latency of lung metastasis
                                                                                                                                                                  was 19.7 months.
                                                       Eggermont M,          -   -              -                  Stage III A 62          Stage IIIA: 80.8%                        -
                                                       et al.                                                      (group 1) 54          (95% CI 69.7–88.2)
                                                                                                               (group 2). Stage III     in group 1 and 70.8%
                                                                                                                 B 164 (group 1)         (58.7–79.9) in group
                                                                                                               123 (group 2) Stage        2 Stage IIIB disease,
                                                                                                               III C 115 (group 1)        68.1% (61.6–73.8)
                                                                                                                   83 (group 2)        in group 1 and 51.0%
                                                                                                                                       (44·2–57·4) in group 2.
                                                                                                                                      Stage IIIC disease 55,8%
                                                                                                                                         (48.1–62.8) in group
                                                                                                                                         1 and 39.2% (32.2–
                                                                                                                                         46.1) in the group 2.
                                                       Ertekin S, et al.     -   -              -                       -                         -                                 -
                                                       Luke J, et al.        -   -              -                       -                         -                                 -




7
    Frequency and patterns of melanoma recurrence were             group [6]. Also, Namin et al study showed a mean time to re-
highly stage dependent. Studies grouping stage I and II mela-      currence of 8 months in the LCIT group, 13.5 months in the
noma patients have estimated 1 and 10‐year recurrence rates        LN group, and 18.3 in the systemic recurrence group [31].
at approximately 9% and 23% respectively, with increas-
ing risk dependent on stage [8,18,19]. When stratified by          Type and Site of Recurrence
AJCC 7th substage, a large retrospective study conducted at        In all (without accounting for melanoma stage at diagnosis),
Memorial Sloan Kettering Cancer Center found the 5‐year            the most common melanoma recurrence type was systemic
risk of recurrence for stage IIA, IIB, and IIC to be 21.6%,        recurrence in all studies [1,3,17,22,24,29–31]. O’Connell
35.1%, and 45.3%, respectively. Substratification of stage III     et al reported that 40% of melanoma recurrences were
patients in a large retrospective analysis reported an overall     ­systemic [3]; for Namin et al and Bleicher et al, recurrences
5‐year risk of recurrence for stages IIIA, IIIB, and IIIC to be    were systemic in 49% and 50.6%, respectively. In prospec-
approximately 48%, 71%, and 85%, respectively [8,20]. A            tive randomized studies evaluating melanoma surgical mar-
recent study from Finland examined the PET/CT follow-up            gins, LCIT recurrence rates (or surgical site recurrence) were
utility, the recurrence rate was 49% in stage IIB and IIC pa-      as low as 2-5%, despite wide or narrow surgical margins
tients. A total of 38% of the melanoma recurrences were            used [36]. Overall, LCIT recurrences are low compared to
loco-regional recurrences (9% LCIT and 29% in lymph                systemic or nodal recurrences.
nodes) and 61% were systemic recurrences [1,21]. Stage IIC            When systemic recurrence occurs, the most common site
disease behaved similarly to Stage IIIB and IIIC melanoma          of distant metastasis was the lung followed by the brain,
with the highest risk of recurrence in the first 2–3 years fol-    liver, and bone [22,24,27,28,31]. The second most frequent
lowing diagnosis [8,22,23].                                        recurrence site was LCIT [6,32]. This is also in line with
                                                                   studies evaluating systemic therapies where systemic recur-
Time for Recurrence                                                rences were the most frequent [37]. In 2020, the Checkmate
The timing for metastasis development in patients with pri-        238 trial concluded that the lung, liver, and brain were the
mary cutaneous melanoma must be considered within the              most common sites of first distant metastasis (seen in 24%,
context of the above-mentioned melanoma TNM stages.                13%, and 10% of patients, respectively) for patients with
Most of the studies did not report the onset or timing of the      resected stage IIIB-C disease [38].
recurrence from diagnosis. For those studies that mention it,         When evaluating recurrence based on melanoma stage,
the majority of metastasis occurs within 3 years of diagnosis      recurrences were more likely to be systemic and less likely
[8,20,22,24-26] and recurrence rates were earlier with more        to be nodal or LCIT, as the AJCC stage increases [39]. A
advanced stages [3,6,16,21,28-32]. Fusi et al in their study       ­retrospective study of 466 patients, detected the proportion
of 250 patients with stage I-II melanoma, reported that 67%        of recurrences to be systemic in 48% of stage II, 68% of stage
of recurrences arose within 2 years and 81% within 3 years of      III, and 77% of resected stage IV patients [40]. This trend
disease [33]. Dicker et al in their study of 1,568 patients with   was also related to substage as patients with stage IIA and
stage I melanoma reported that 80% of recurrences occurred         IIC had a systemic recurrence rate of 34% and 52%, respec-
in the first 3 years [26]. Behave et al in their study reported    tively [40,41]. A study by Romano et al concluded that as
that time to first recurrence occurred at a median time of 17.7    substages increased from IIIA to IIIB to IIIC, the proportion
months (range 1.7–53.6) [34]. However, a recent study with         of LCIT recurrence as the site of first relapse ­progressively
long-term follow-up showed that only 82% of recurrences oc-        decreased from 32%, 30%, and 22%, respectively [20]. Sim-
curred in the first 5 years, 91% in the first 7 years, and some    ilarly, the proportion of initial relapse in lymph nodes de-
occurring even after 10 years from melanoma diagnosis [35].        creased (28%, 19%, and 17%) and the proportion of initial
Similarly, the mean time for recurrence in Lee et al series        relapse as a systemic recurrence increased as substage pro-
was shorter in later stages when compared to early stages          gressed (40%, 51%, and 61%) [20]. Leeneman et al, how-
(34 months in stage IB vs. 12 months in stage III) [24]. Ertekin   ever, showed that lymph nodes were the most frequent site
et al reported a mean time of recurrence of 40 months in           of recurrence [29] and in Lee et al study, LCIT was the most
stage I melanoma, 22 months in stage II melanoma, and              common recurrence site (12%) [24]. These differences might
14 months in stage III melanoma [32]. Even more, some stud-        be explained by different inclusion criteria and different rep-
ies reported the time to recurrence according to the initial       resentation of melanoma stages as well as specific clinical
type of recurrence (e.g. LCIT vs. lymph nodes vs. systemic).       and histopathological details.
Systemic recurrences tend to appear later when compared to
local recurrences. The mean time to recurrence in Meier et al      Recurrence Detection Method
study was 17 months for the LCIT group, 16 months for the          There is relevance to the modalities for melanoma recur-
lymph node group, and 25 months for the systemic recurrence        rence detection (i.e. clinical examination vs imaging). Some



8                                                                             Review | Dermatol Pract Concept. 2023;13(4):e2023304
studies have reported the melanoma recurrence detection           1.1 years (95% CI:0.6-2.2) for patients initially diagnosed
modality: a) symptoms/self-reported by the patient, b) by         with stage III that recurred [29].
physician examination (i.e. physical examination), or c)              Sparks et al reported an OS of 47% at 5 years and Thomas
by imaging (e.g. ultrasound, PET-CT, among others). The           et al an OS of 86.9% at 5 years after recurrence [27,42].
most frequent modality for detection of recurrence was pa-        O’Connell et al reported an OS of 6 months (range of 1-126
tient self-report across most studies (mainly by symptoms)        months) at 5 years in the recurrent melanoma group when
[1,16,22,24]. Meyers et al study reported that melanoma           compared to the non-recurrent group [3]. Leeneman et al
recurrence detection was by patient self-reports in 67%, by       also found a two-year post-recurrence survival rate of 41%,
clinical examination in 26%, and by imaging in only 7%            42%, and 43% for patients initially diagnosed with stages IB,
of cases [16]. In Lee et al series, 59% of recurrences were       II, and III, respectively. By the type of first recurrence, m
                                                                                                                              ­ edian
detected by patient self-report (symptoms) and similarly, in      post-recurrence OS was longer for patients with lymph node
Bleicher et al series, 60% of recurrences were detected by        metastasis (3.9 years; 95% CI: 2.5-Not Reached) than for
patient self-report [22,24]. Based on this data, it appears       patients with LCIT (2.8 years; 95% CI: 1.9-4.6) and distant
to be mandatory to directly question patients for specific        metastasis (0.5 years; 95% CI: 0.3-0.6)[29].
symptoms (e.g. headache, dyspnea, pain, bumps, or asthenia)
during follow-up after melanoma treatment. This should be
                                                                  Conclusions
in addition to melanoma guidelines-directed imaging and
other complementary testing and should not be overlooked          In this review, we have summarized the patterns of recur-
or underestimated.                                                rence of primary cutaneous melanoma in various studies
                                                                  and populations. The overall recurrence rate ranged from
Recurrence Predictors                                             approximately 20% to 40%, with systemic recurrence, par-
Several risk factors are associated with or predict the risk of   ticularly to the lungs, being the most frequent pattern. The
melanoma recurrence. The most frequent predictors of re-          primary predictors of recurrence were Breslow thickness and
currence were Breslow thickness and male sex [1,3,6,22,42].       male sex. Notably, patient self-report, primarily based on
Meier et al showed that the location of the initial tumor         symptoms, was the most frequent method of recurrence de-
(trunk in men and lower extremities in women) and Breslow         tection. This particular finding underscores the importance
thickness were the main predictors of recurrence [6]. O’Con-      of patient education regarding signs and symptoms for the
nell et al reported that recurrence predictors were nodu-         early detection of melanoma recurrence or progression. Di-
lar histologic subtype and Breslow thickness [3]. Similarly,      rectly questioning about specific signs and symptoms during
­Bleicher et al showed that age, male sex, stage, and Breslow     each visit is highly relevant. This simple strategy should not
thickness as important recurrence factors [22]. Berger et al      be underestimated.
series included recurrent factors: Male sex, T- classification,       Current Melanoma guidelines lack precision regarding
and ulceration as predictors [1]. Thomas et al series evalu-      optimal follow-up modalities and when to order specific
ated risk factors for specific recurrence patterns. For LCIT      cross-sectional imaging studies (e.g. computed tomogra-
recurrence: age, anatomic location, Breslow thickness; for        phy, PET-CT). Moreover, there is also a wide variation in
lymph node recurrence: age and Breslow thickness; and for         recommendations among different melanoma guidelines
systemic recurrence: anatomic location (head and neck or          [12,13,43,44]. For example, the National Comprehensive
trunk), Breslow thickness, ulceration, and lymphovascular         Cancer Network (NCCN) does not recommend imaging in
invasion [42].                                                    stages I and II in the absence of symptoms. For asymptomatic
                                                                  patients with stages IIB and IIC, NCCN guidelines do not
Overall Survival: Role of Recurrent Disease                       strongly recommend cross-sectional imaging. In contrast, Eu-
The patterns of recurrence tend to impact melanoma overall        ropean guidelines recommend cross-sectional imaging from
survival (OS); therefore, careful understanding of recurrence     stage IIC onwards but recommend nodal ultrasound from
type can help with patient management and counseling:             stage IB and above [43]. Given these variations in the specific
The sole occurrence of recurrent disease (irrespective of         recommendations, a comprehensive understanding of recur-
type) is associated with a worse prognosis. Meyers et al          rence patterns is paramount when deciding a detailed and
study showed that the median survival was 22 months for           individualized follow-up plan for specific patients [1]. Ad-
melanoma recurrences in the LCIT-lymph node group and             ditionally, a detailed understanding of melanoma recurrence
7 months for the systemic recurrence group [16]. Leeneman         patterns might have a role in adjuvant treatment selection.
et al showed a mean OS of 1.9 years (95% CI: 0.8- 3.2) for        Recently, the approval of adjuvant treatment with immune
patients initially diagnosed with stage IB, 1.5 years (95% CI:    checkpoint inhibitors and targeted therapies by both the US
1.1-2.1) for patients initially diagnosed with stage II, and      Food and Drug Administration (FDA) and the European



Review | Dermatol Pract Concept. 2023;13(4):e2023304                                                                               9
Medicine Agency (EMA) have significantly changed mela-                  10. Cohn-Cedermark G, Månsson-Brahme E, Rutqvist LE, Lars-
noma management [37]. The projected increase in the use                     son O, Singnomklao T, Ringborg U. Metastatic patterns, clini-
                                                                            cal outcome, and malignant phenotype in malignant cutaneous
of adjuvant systemic therapy might also lead to changes in
                                                                            melanoma. Acta Oncol Stockh Swed. 1999;38(5):549-57. DOI:
melanoma recurrence patterns among treated patients when
                                                                            10.1080/028418699431122. PMID: 10427942.
compared to those described in this study.                              11. Cromwell KD, Ross MI, Xing Y, et al. Variability in mela-
     Strict follow-up and patient education play a critical                 noma post-treatment surveillance practices by country and
role in detecting melanoma recurrences. Due to the higher                   physician specialty: A systematic review. Melanoma Res.
prevalence of regional lymph node recurrences in early-stage                2012;22(5):376-85. DOI: 10.1097/CMR.0b013e328357d796.
                                                                            PMID: 22914178
melanoma, ultrasound may prove to be a valuable and
                                                                        12. Garbe C, Amaral T, Peris K, et al. European consensus-based
cost-effective strategy for recurrence detection in early-stage
                                                                            interdisciplinary guideline for melanoma. Part 2: Treatment -
melanoma [1]. Conversely, for patients with more advanced                   Update 2022. Eur J Cancer. 2022;170:256-84. DOI: 10.1016/j.
disease at diagnosis, cross-sectional full-body imaging (e.g.               ejca.2022.04.018. PMID: 35623961.
PET-CT) might be of benefit due to the more frequent sys-               13. Swetter SM, Tsao H, Bichakjian CK, et al. Guidelines of care
temic metastasis. This knowledge gap needs to be addressed                  for the management of primary cutaneous melanoma. J Am
                                                                            Acad Dermatol. 2019;80(1):208-50. DOI: 10.1016/j.jaad
in order to better identify patients at high risk of disease re-
                                                                            .2018.08.055. PMID: 30392755.
currence and personalize surveillance strategies [11,24,45].
                                                                        14. Cancer Council Australia Melanoma Guidelines. Clinical prac-
Recognizing melanoma recurrence patterns can aid in the de-                 tice guidelines for the diagnosis and management of melanoma.
sign of active surveillance strategies that have the potential              Accessed February 7, 2023. https://wiki.cancer.org.au/australia
to modify clinical follow-up plans.                                         /Guidelines:Melanoma
                                                                        15. Svedman FC, Pillas D, Taylor A, Kaur M, Linder R, Hansson J.
                                                                              Stage-specific survival and recurrence in patients with cutane-
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Review | Dermatol Pract Concept. 2023;13(4):e2023304                                                                                       11
