Dermatology: Practical and Conceptual Review | Dermatol Pract Concept. 2023;13(4):e2023304 1 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 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. ABSTRACT 2 Review | Dermatol Pract Concept. 2023;13(4):e2023304 Introduction The incidence of melanoma has been dramatically increas- ing worldwide over the last two decades [1,2]. It is the fifth most common cancer in the U.S. and the ninth in Europe[3]. In 2023, it was estimated that there would be 89,070 new 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- sidered to have an excellent prognosis. Data from the Sur- veillance, Epidemiology, and End Results (SEER) Program suggests that 99.5% of patients with localized melanoma, 70.6% regional melanoma, and 31.9% of those with dis- tant metastases, will be alive at 5 years [4]. Cutaneous mel- anoma is considered to have a high metastatic potential and it can have lymphatic metastasis or hematogenous metastasis [5]. Specifically, it can metastasize as local, sat- ellite, and in transit metastasis (LCIT), on lymph nodes, or as distant metastasis [5–8]. The presence of regional lymph node metastatic disease is a significant predictor of outcome in melanomas as it is associated with a 50% reduction in survival compared to patients without nodal involvement [3,9]. There is limited research analyzing the patterns of re- currence in patients with primary localized cutaneous mel- anoma. Meier et al study in 2002 traced the metastatic pathways of 3,001 patients with primary cutaneous mel- anoma from 1976-1996. Of the patients who had disease confined to the primary tumor at diagnosis (i.e. stages I and II), 15.5% developed metastasis during the study pe- riod [6]. Another study conducted in 1999 by Cohn et al. identified 569 of 2493 patients with recurrent melanoma and demonstrated a 5-year survival rate of 82% and 30% among those with a primary local versus regional recurrence, respectively [10]. Furthermore, current guidelines are fairly 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 for the first 5 years. Surveillance guidelines, in general, and melanoma patients specifically, are often follow-up based on low-level evidence. Additionally, despite clinical guidelines, practice patterns tend to vary across different institutions and countries [11–14]. Given the increasing incidence of cutaneous malig- nant melanoma and the recent changes in the treatment landscape, it is important to understand stage-specific re- currence patterns [15]. In the current era of immune check- point inhibitors and targeted therapies, early detection of melanoma recurrences is important, as it can lead to more effective and manageable treatment options. Objective The aim of this review was to evaluate the recurrence patterns of cutaneous melanoma, regarding the time of follow-up, time of detection of the recurrence, and the most frequent site of recurrence, giving the clinician a practical summary for diagnosis, prognosis, and surveillance. Methods A literature narrative review of articles published in PubMed between the years 2000 to 2022 was conducted. The key- words were “Melanoma” OR “Cutaneous melanoma” AND “Recurrence” OR “Relapse” AND/OR “Patterns”. We in- cluded all studies in English and/or Spanish. Exclusion cri- teria were non-skin melanomas, stage IV melanoma only, studies published before the year 2000, studies reporting the local and regional recurrence together as one group, and case reports and case series with less than 10 patients. From the remaining results, study type, number of patients, stage of melanoma at diagnosis and substage if they reported (e.g IA, IIB, IIC), median follow-up, mean recurrence time (in months), recurrence site, recurrence predictors, and survival rate were recorded. For the study purposes, ‘recurrence’ was defined as the return of the melanoma after initial treatment and after a period of time during which the cancer was not detected. ‘Progression’ was defined as melanoma growing or spreading without ever having gone away completely. The recurrence sites were divided into local, satellite, and in tran- sit metastasis (LCIT), lymph nodes/nodal, and systemic me- tastasis. We also described the sites of systemic metastasis, if reported. The recurrence detection method was classified into patient symptoms (i.e. detected by the patient), physical examination (e.g. palpation, visual examination), and images (e.g. PET-CT). Overall survival (OS) was presented as a per- centage rate at 3 or 5 years. Results The overall information is summarized in Tables 1-4. Follow-up and Recurrence Type The rate of melanoma recurrence was determined by the me- dian follow-up time reported in different studies. Most stud- ies have shown similar recurrence timing patterns. Across all stages, Meyers et al reported a recurrence rate of 36%, with a median time of recurrence of 14 months [16]. O ‘Connell et al and Berger et al reported lower recurrence rates of 24% and 29.5%, respectively [1,3]. Barbour et al reported the highest rate of recurrence of 45% in their series [17]. Review | Dermatol Pract Concept. 2023;13(4):e2023304 3 Ta b le 1 . P at ie nt s’ d em og ra ph ic s an d m el an om a di ag no si s de ta ils . St u d y Ye ar o f p u b lic at io n Su m m ar y o f  th e  st u d y C o u n tr y N u m b er o f p at ie n ts o f th e st u d y (n ) M ea n A g e (y , r an g e o r SD ) G en d er ( M al e/ F em al e) St ag e M ea n f o llo w u p ( m o n th s) M ei er F , e t al . 20 02 R et ro sp ec ti ve G er m an y 30 01 - - I- II 12 0 M ey er s O , e t al . 20 08 R et ro sp ec ti ve U SA 11 8 63 ,5 41 ( 35 % ) Fe m al e 77 ( 65 % ) M al e II -I II 44 B ar bo ur S , e t al . 20 15 Pr os pe ct iv e A us tr al ia 17 3 G ro up 1 : 6 1 (1 5– 92 ) G ro up 2 : 6 1 (2 0– 88 ) 19 ( 18 % ) Fe m al e 88 ( 82 % ) M al e II IB -I II C 32 O C on ne ll E , e t al . 20 15 R et ro sp ec ti ve Ir el an d 16 4 51 .2 ( ±1 4. 1) 88 ( 53 .7 % ) Fe m al e 76  ( 46 .3 % ) M al e I- II 75 Sv ed m an F , et a l. 20 16 Sy st em at ic R ev ie w . M ul ti ce nt er 15 2. 42 2 - - I- II I - Sp ar ks D S, e t al . 20 16 R et ro sp ec ti ve A us tr al ia 10 7 72 .1 ( 58 –8 0) 25 ( 23 .4 % ) Fe m al e 82 ( 76 .6 % ) M al e I- II I 30 ,5 B er ge r A C , e t al . 20 17 R et ro sp ec ti ve U SA 58 1 63 .5 ( 11 –9 1) 22 1 (3 8% ) Fe m al e 36 0 (6 2% ) M al e II - L ee A Y , e t al . 20 17 R et ro sp ec ti ve U SA 73 8 62 ( 17 –9 1) 28 4 (3 8. 5% ) Fe m al e 45 4 (6 1. 5% ) M al e II 52 N am in A W , e t al . 20 18 R et ro sp ec ti ve U SA 16 8 62 42 ( 25 % ) Fe m al e 12 6 (7 5% ) M al e I- II - L ee ne m an B , e t al . 20 19 R et ro sp ec ti ve N et he rl an ds 13 97 St ag e I 54 ( 43 –6 4) St ag e II 6 3 (5 0– 74 ) St ag e II I 58 ( 45 –6 9) 17 54 ( 56 .7 % ) Fe m al e 13 39  ( 43 .2 % ) M al e I- II I 65 T ho m as D C , e t al . 20 19 R et ro sp ec ti ve M ul ti ce nt er 63 05 ( 53 51 S L N n eg at iv e) - 23 10 ( 4 3% ) Fe m al e. 30 41 ( 57 % ) M al e I- II 32 ,1 B ar tl et t E K , e t al . 20 20 Pr os pe ct iv e U SA 37 0 61 ( 5– 95 ) 14 5 (3 9% ) Fe m al e 22 5 (6 1% ) M al e II I 33 B le ic he r J, e t al . 20 20 R et ro sp ec ti ve U SA 58 0 62 ( 48 –7 4) 22 8 (3 9. 3% ) Fe m al e 35 2 (6 0. 7% ) M al e II 59 O h Y , e t al . 20 20 R et ro sp ec ti ve C or ea 34 0 57 ,9 4 19 5 (5 7. 4% ) Fe m al e 14 2  (4 2. 6% ) M al e I- II 46 ,2 E gg er m on t M , e t al . 20 21 C lin ic al T ri al M ul ti ce nt er 10 19 ( 5 14 p em br ol iz um ab , 50 5 pl ac eb o) 25 1 (2 5% ) > 65 y ea rs Fe m al e 39 1 ( 38 % ) M al e  62 8 (6 2% ) II I 42 ,3 E rt ek in S , e t al . 20 21 R et ro sp ec ti ve Sp ai n 37 86 58 .2 7 (± 1 6. 75 ) 33 0 (4 2. 1% ) Fe m al e 45 4  (5 7. 9% ) M al e I- II I - L uk e J, e t al . 20 22 C lin ic al T ri al M ul ti ce nt er 97 6 (4 87 g ro up 1 , 48 9  gr ou p 2) 61 Fe m al e 38 7 (4 0% ) M al e 58 9 (6 0% ) II B -I IC 20 ,9 4 Review | Dermatol Pract Concept. 2023;13(4):e2023304 Ta b le 2 . M el an om a re cu rr en ce d et ai ls a nd m et ho d of d et ec ti on . St u d y R ec u rr en ce o f  m el an o m a n (% ) M ea n t im e o f re cu rr en ce ( m o n th s) M ea n t im e o f LC IT re cu rr en ce ( m o n th s) M ea n t im e o f LN re cu rr en ce ( m o n th s) M ea n t im e o f sy st em ic re cu rr en ce ( m o n th s) D et ec ti o n o f re cu rr en ce M ei er F , e t al . 46 6/ 30 01 ( 15 % ) - 17 16 25 - M ey er s O , e t al . 43 /1 18 ( 36 % ) 14 - - - Pa ti en t se lf -r ep or t (6 7% ) Ph ys ic al e xa m in at io n (2 6% ) Im ag es ( 7% ) B ar bo ur S , e t al . 78 /1 73 ( 45 % ) - - - - - O C on ne ll E , e t al . 40 /1 64 ( 24 % ) 39 ,5 - - - - Sv ed m an F , et a l. - - - - - - Sp ar ks D S, e t al . 38 /1 07 ( 35 .5 % ) 11 ,8 - - - - B er ge r A C , e t al . 17 1/ 58 1 (2 9. 4% ) - - - - Pa ti en t se lf -r ep or t (3 9% ) Ph ys ic al e xa m in at io n (3 2% ) Im ag es ( 21 % ) L ee A Y , e t al . 21 9/ 73 8 (2 9. 6% ) II A ( 19 5. 1) I IB (u nk no w n) I IC ( 85 .9 ) - - - Pa ti en t se lf -r ep or t (5 9% ) N am in A W , e t al . 33 /1 68 ( 20 % ) 17 8 13 ,5 18 ,3 - L ee ne m an B , e t al . 27 5/ 13 97 ( 20 % ) IB ( 34 ) II ( 18 ) II I (1 2) - IB 3 6) I I (9 .6 ) II I (6 ) IB ( 37 ) II ( 26 ) II I (1 3) - T ho m as D C , e t al . 55 8/ 53 51 ( 10 .4 % ) - 16 ,7 18 ,6 31 ,2 - B ar tl et t E K , e t al . 15 8/ 37 0 (4 2. 7% ) 12 - - - Pa ti en t se lf -r ep or t (2 9% ), Ph ys ic al e xa m in at io n (2 0. 3% ), Im ag es ( 39 .9 % ). B le ic he r J, e t al . 15 8/ 58 0 (2 7. 2% ) - - - - Pa ti en t se lf -r ep or t (6 0. 1% ) Ph ys ic al e xa m in at io n (1 2. 0% ) Im ag es ( 27 .3 % ) O h Y , e t al . 92 /3 40 ( 2 7. 1% ) 16 ,3 - - - - E gg er m on t M , e t al . 19 9/ 51 4 (3 9% ) G ro up 1 28 7/ 50 5 (5 3% ) G ro up 2 . To ta l 4 7. 6% - - - - - E rt ek in S , e t al . To ta l: 78 4/ 37 86 ( 20 .7 % ) St ag e I (2 1% ) St ag e II ( 33 % ) St ag e  II I  (4 5% ) To ta l: 21 S ta ge I ( 40 ) St ag e II ( 22 ) St ag e  II I  (1 4) 17 ,5 25 ,5 25 - L uk e J, e t al . 18 7/ 97 6 (1 9% ) - - - - - Review | Dermatol Pract Concept. 2023;13(4):e2023304 5 Ta b le 3 . M el an om a re cu rr en ce lo ca ti on d et ai ls a nd p re di ct or s of r ec ur re nc e. St u d y Lo ca ti o n o f re cu rr en ce R ec u rr en ce LC IT ( n ) R ec u rr en ce LN ( n ) R ec u rr en ce Sy st em ic ( n ) Pr ed ic to rs o f re cu rr en ce M ei er F , e t al . L C IT ( 21 .7 % ) L N ( 50 .2 % ) Sy st em ic ( 28 .1 % ) 10 1 23 4 13 1 L oc at io n of in it ia l t um or ( p< 0. 00 1) T um or t hi ck ne ss ( p= 0. 02 8) M ey er s O , e t al . L C IT ( 49 % ) L N ( 16 % ) Sy st em ic : ( 35 % ) 21 7 15 - B ar bo ur S , e t al . L C IT ( 14 % ) L N ( 8% ) Sy st em ic ( 78 % ) G ro up 1 : 5 G ro up 2 : 6 G ro up 1 : 5 G ro up 2 : 1 G ro up 1 : 3 3 G ro up 2 : 2 8 - O C on ne ll E , e t al . L C IT ( 30 % ) L N ( 30 % ) Sy st em ic : ( 40 % ) 12 12 16 N od ul ar S ub ty pe ( p< 0. 05 ) T um or t hi ck ne ss ( p< 0. 00 1) Sv ed m an F , e t al . - - - - - Sp ar ks D S, e t al . L C IT ( 16 % ) L N ( 12 % ) Sy st em ic ( 15 % ) 17 13 16 - B er ge r A C , e t al . - 56 52 63 M al e se x (p =0 .0 01 8) T c la ss ifi ca ti on ( p= 0. 00 49 ) U lc er at io n (p =0 .0 01 6) L ee A Y , e t al . - 80 50 81 - N am in A W , e t al . L C IT ( 18 % ) L N ( 18 % ) Sy st em ic ( 49 % ) 6 6 21 - L ee ne m an B , e t al . - 59 10 0 11 6 - T ho m as D C , e t al . - 22 1 10 9 22 0 Fo r L C IT r ec ur re nc e: a ge , a na to m ic lo ca ti on , t hi ck ne ss (a ll p< 0. 05 ) Fo r L N r ec ur re nc e: a ge a nd t hi ck ne ss ( al l p <0 .0 5) Fo r sy st em ic r ec ur re nc e: a na to m ic lo ca ti on s, t hi ck ne ss , ul ce ra ti on , a nd ly m ph ov as cu la r in va si on ( al l p <0 .0 5) B ar tl et t E K , e t al . - 45 62 51 - B le ic he r J, e t al . L C IT ( 19 .6 % ) L N ( 29 .8 % ) Sy st em ic ( 50 .6 % ) 31 47 80 A ge ( p< 0 .0 5) S ta ge ( p< 0. 05 ) B re sl ow ( p< 0 .0 1) O h Y , e t al . - 29 49 28 M al e se x (p =0 .0 30 ) B re sl ow > 1 m m ( p= 0. 00 8) E gg er m on t M , e t al . - - - G ro up 1 1 26 (2 5% ) G ro up 2  19 4 (3 8% ) - E rt ek in S , e t al . L C IT . ( 50 .1 % ) L N - S ys te m ic ( 49 .9 % ) 39 3 98 29 3 - L uk e J, e t al . - - - G ro up 1 :3 1 G ro up 2 : 60 - 6 Review | Dermatol Pract Concept. 2023;13(4):e2023304 Ta b le 4 . M el an om a su rv iv al a nd a dd it io na l d et ai ls . St u d y Su rv iv al O ve ra ll Su rv iv al (m o n th s at 5  y ea rs ) O ve ra ll su rv iv al % a t 5 ye ar s D is ea se f re e su rv iv al (n ) at 5 y ea rs D is ea se f re e su rv iv al (% ) at 5 y ea rs A d d it io n al d et ai ls M ei er F , e t al . - - - - - M ey er s O , e t al . - 22 ( L N a nd L C IT ) 7  (S ys te m ic ) - - - B ar bo ur S , e t al . - - 53 80 46 % - O C on ne ll E , e t al . 23 .5 % f ro m t he di ag no si s 6 - - - - Sv ed m an F , et a l. - - St ag e I (9 5% –1 00 % ) St ag e II ( 65 % –9 2. 8% ) St ag e II I (4 1% –7 1% ) St ag e IV ( 9% –2 8% ) - - - Sp ar ks D S, e t al . - - 47 - 47 Fi rs t si te b ei ng lu ng s (4 ), br ai n (3 ), liv er ( 2) , s ub cu ta ne ou s (1 ), bo ne ( 1) , an d sy nc hr on ou s m et as ta se s to m ul ti pl e si te s (6 ) B er ge r A C , e t al . II A ( 57 % ) II B ( 57 % ) II C ( 40 % ) at 5 y ea rs - - - - - L ee A Y , e t al . - St ag e II A ( 87 % ) St ag e II B ( 78 % ) St ag e II C ( 69 % ) - - - L un g w as t he m os t fr eq ue nt s it e of s ys te m ic r el ap se in a ll su bs ta ge s (n = 1 1, 1 1, a nd 1 3 fo r st ag e II A , I IB , an d II C , r es pe ct iv el y) . T he s ec on d m os t fr eq ue nt s it e w as b ra in f or I IA (n = 9 ) an d II C ( n = 5) , a nd li ve r fo r II B ( n = 4) . T hr ee I IA p at ie nt s ha d a ra re s it e of d is ta nt m et as ta si s— t w o to t he la ry nx , a nd o ne t o th e he ar t. N am in A W , e t al . 92 % - . 13 5 85 - L ee ne m an B , e t al . - St ag e IB 1 .9 y ea rs (9 5% C I: 0 .8 -3 .2 ) St ag e II 1 .5 y ea rs (9 5% C I: 1 .1 -2 .1 ) St ag e II I 1. 1 ye ar s (9 5% C I: 0 .6 -2 .2 ). St ag e IB ( 41 % ) St ag e II (4 2% ) St ag e II I (4 3% ) at 2 y ea rs - - - Review | Dermatol Pract Concept. 2023;13(4):e2023304 7 T ho m as D C , e t al . - - 86 .9 % . - - B ar tl et t E K , e t al . - - - - - - B le ic he r J, e t al . - - St ag e II A ( 82 .6 % ) St ag e II B ( 71 .5 ) St ag e II C (6 0. 3% ) - - D is ta nt r ec ur re nc e, 2 9 (3 6. 3% ) pa ti en ts h ad p ul m on ar y m et as ta se s, 17 ( 21 .3 % ) ha d br ai n m et as ta se s, 9 ( 11 .3 % ) ha d in tr aa bd om in al m et as ta se s, 6 ( 7. 5% ) ha d bo ne m et as ta se s, 7 ( 8. 8% ) ha d m ul ti pl e si te s of p ri m ar y re cu rr en ce , an d 12 ( 15 .0 % ) ha d di st an t m et as ta si s at a no th er lo ca ti on . O h Y , e t al . - - - - - T he m os t co m m on s it e of d is ta nt m et as ta si s w as t he lu ng , a nd t he m ed ia n la te nc y of lu ng m et as ta si s w as 1 9. 7 m on th s. E gg er m on t M , et a l. - - - St ag e II I A 6 2 (g ro up  1 ) 54 (g ro up 2 ). St ag e II I B 1 64 ( gr ou p 1) 12 3  (g ro up 2 ) St ag e II I C 1 15 ( gr ou p 1) 83  ( gr ou p 2) St ag e II IA : 8 0. 8% (9 5% C I 69 .7 –8 8. 2) in g ro up 1 a nd 7 0. 8% (5 8. 7– 79 .9 ) in g ro up 2 St ag e II IB d is ea se , 68 .1 % ( 61 .6 –7 3. 8) in  g ro up 1  a nd 5 1. 0% (4 4· 2– 57 ·4 ) in g ro up 2 . St ag e II IC d is ea se 5 5, 8% (4 8. 1– 62 .8 ) in g ro up 1  an d 39 .2 % ( 32 .2 – 46 .1 ) in t he g ro up 2 . - E rt ek in S , e t al . - - - - - - L uk e J, e t al . - - - - - - 8 Review | Dermatol Pract Concept. 2023;13(4):e2023304 group [6]. Also, Namin et al study showed a mean time to re- currence of 8 months in the LCIT group, 13.5 months in the LN group, and 18.3 in the systemic recurrence group [31]. Type and Site of Recurrence In all (without accounting for melanoma stage at diagnosis), the most common melanoma recurrence type was systemic recurrence in all studies [1,3,17,22,24,29–31]. O’Connell et al reported that 40% of melanoma recurrences were systemic [3]; for Namin et al and Bleicher et al, recurrences were systemic in 49% and 50.6%, respectively. In prospec- tive randomized studies evaluating melanoma surgical mar- gins, LCIT recurrence rates (or surgical site recurrence) were as low as 2-5%, despite wide or narrow surgical margins used [36]. Overall, LCIT recurrences are low compared to systemic or nodal recurrences. When systemic recurrence occurs, the most common site of distant metastasis was the lung followed by the brain, liver, and bone [22,24,27,28,31]. The second most frequent recurrence site was LCIT [6,32]. This is also in line with studies evaluating systemic therapies where systemic recur- rences were the most frequent [37]. In 2020, the Checkmate 238 trial concluded that the lung, liver, and brain were the most common sites of first distant metastasis (seen in 24%, 13%, and 10% of patients, respectively) for patients with resected stage IIIB-C disease [38]. When evaluating recurrence based on melanoma stage, recurrences were more likely to be systemic and less likely to be nodal or LCIT, as the AJCC stage increases [39]. A retrospective study of 466 patients, detected the proportion of recurrences to be systemic in 48% of stage II, 68% of stage III, and 77% of resected stage IV patients [40]. This trend was also related to substage as patients with stage IIA and IIC had a systemic recurrence rate of 34% and 52%, respec- tively [40,41]. A study by Romano et al concluded that as substages increased from IIIA to IIIB to IIIC, the proportion of LCIT recurrence as the site of first relapse progressively decreased from 32%, 30%, and 22%, respectively [20]. Sim- ilarly, the proportion of initial relapse in lymph nodes de- creased (28%, 19%, and 17%) and the proportion of initial relapse as a systemic recurrence increased as substage pro- gressed (40%, 51%, and 61%) [20]. Leeneman et al, how- ever, showed that lymph nodes were the most frequent site of recurrence [29] and in Lee et al study, LCIT was the most common recurrence site (12%) [24]. These differences might be explained by different inclusion criteria and different rep- resentation of melanoma stages as well as specific clinical and histopathological details. Recurrence Detection Method There is relevance to the modalities for melanoma recur- rence detection (i.e. clinical examination vs imaging). Some Frequency and patterns of melanoma recurrence were highly stage dependent. Studies grouping stage I and II mela- noma patients have estimated 1 and 10‐year recurrence rates at approximately 9% and 23% respectively, with increas- ing risk dependent on stage [8,18,19]. When stratified by AJCC 7th substage, a large retrospective study conducted at Memorial Sloan Kettering Cancer Center found the 5‐year risk of recurrence for stage IIA, IIB, and IIC to be 21.6%, 35.1%, and 45.3%, respectively. Substratification of stage III patients in a large retrospective analysis reported an overall 5‐year risk of recurrence for stages IIIA, IIIB, and IIIC to be approximately 48%, 71%, and 85%, respectively [8,20]. A recent study from Finland examined the PET/CT follow-up utility, the recurrence rate was 49% in stage IIB and IIC pa- tients. A total of 38% of the melanoma recurrences were loco-regional recurrences (9% LCIT and 29% in lymph nodes) and 61% were systemic recurrences [1,21]. Stage IIC disease behaved similarly to Stage IIIB and IIIC melanoma with the highest risk of recurrence in the first 2–3 years fol- lowing diagnosis [8,22,23]. Time for Recurrence The timing for metastasis development in patients with pri- mary cutaneous melanoma must be considered within the context of the above-mentioned melanoma TNM stages. Most of the studies did not report the onset or timing of the recurrence from diagnosis. For those studies that mention it, the majority of metastasis occurs within 3 years of diagnosis [8,20,22,24-26] and recurrence rates were earlier with more advanced stages [3,6,16,21,28-32]. Fusi et al in their study of 250 patients with stage I-II melanoma, reported that 67% of recurrences arose within 2 years and 81% within 3 years of disease [33]. Dicker et al in their study of 1,568 patients with stage I melanoma reported that 80% of recurrences occurred in the first 3 years [26]. Behave et al in their study reported that time to first recurrence occurred at a median time of 17.7 months (range 1.7–53.6) [34]. However, a recent study with long-term follow-up showed that only 82% of recurrences oc- curred in the first 5 years, 91% in the first 7 years, and some occurring even after 10 years from melanoma diagnosis [35]. Similarly, the mean time for recurrence in Lee et al series was shorter in later stages when compared to early stages (34 months in stage IB vs. 12 months in stage III) [24]. Ertekin et  al reported a mean time of recurrence of 40  months in stage I melanoma, 22 months in stage II melanoma, and 14 months in stage III melanoma [32]. Even more, some stud- ies reported the time to recurrence according to the initial type of recurrence (e.g. LCIT vs. lymph nodes vs. systemic). Systemic recurrences tend to appear later when compared to local recurrences. The mean time to recurrence in Meier et al study was 17 months for the LCIT group, 16 months for the lymph node group, and 25 months for the systemic recurrence Review | Dermatol Pract Concept. 2023;13(4):e2023304 9 1.1 years (95% CI:0.6-2.2) for patients initially diagnosed with stage III that recurred [29]. Sparks et al reported an OS of 47% at 5 years and Thomas et  al an OS of 86.9% at 5 years after recurrence [27,42]. O’Connell et al reported an OS of 6 months (range of 1-126 months) at 5 years in the recurrent melanoma group when compared to the non-recurrent group [3]. Leeneman et al also found a two-year post-recurrence survival rate of 41%, 42%, and 43% for patients initially diagnosed with stages IB, II, and III, respectively. By the type of first recurrence, median post-recurrence OS was longer for patients with lymph node metastasis (3.9 years; 95% CI: 2.5-Not Reached) than for patients with LCIT (2.8 years; 95% CI: 1.9-4.6) and distant metastasis (0.5 years; 95% CI: 0.3-0.6)[29]. Conclusions In this review, we have summarized the patterns of recur- rence of primary cutaneous melanoma in various studies and populations. The overall recurrence rate ranged from approximately 20% to 40%, with systemic recurrence, par- ticularly to the lungs, being the most frequent pattern. The primary predictors of recurrence were Breslow thickness and male sex. Notably, patient self-report, primarily based on symptoms, was the most frequent method of recurrence de- tection. This particular finding underscores the importance of patient education regarding signs and symptoms for the early detection of melanoma recurrence or progression. Di- rectly questioning about specific signs and symptoms during each visit is highly relevant. This simple strategy should not be underestimated. Current Melanoma guidelines lack precision regarding optimal follow-up modalities and when to order specific cross-sectional imaging studies (e.g. computed tomogra- phy, PET-CT). Moreover, there is also a wide variation in recommendations among different melanoma guidelines [12,13,43,44]. For example, the National Comprehensive Cancer Network (NCCN) does not recommend imaging in stages I and II in the absence of symptoms. For asymptomatic patients with stages IIB and IIC, NCCN guidelines do not strongly recommend cross-sectional imaging. In contrast, Eu- ropean guidelines recommend cross-sectional imaging from stage IIC onwards but recommend nodal ultrasound from stage IB and above [43]. Given these variations in the specific recommendations, a comprehensive understanding of recur- rence patterns is paramount when deciding a detailed and individualized follow-up plan for specific patients [1]. Ad- ditionally, a detailed understanding of melanoma recurrence patterns might have a role in adjuvant treatment selection. Recently, the approval of adjuvant treatment with immune checkpoint inhibitors and targeted therapies by both the US Food and Drug Administration (FDA) and the European studies have reported the melanoma recurrence detection modality: a) symptoms/self-reported by the patient, b) by physician examination (i.e. physical examination), or c) by imaging (e.g. ultrasound, PET-CT, among others). The most frequent modality for detection of recurrence was pa- tient self-report across most studies (mainly by symptoms) [1,16,22,24]. Meyers et al study reported that melanoma recurrence detection was by patient self-reports in 67%, by clinical examination in 26%, and by imaging in only 7% of cases [16]. In Lee et al series, 59% of recurrences were detected by patient self-report (symptoms) and similarly, in Bleicher et al series, 60% of recurrences were detected by patient self-report [22,24]. Based on this data, it appears to be mandatory to directly question patients for specific symptoms (e.g. headache, dyspnea, pain, bumps, or asthenia) during follow-up after melanoma treatment. This should be in addition to melanoma guidelines-directed imaging and other complementary testing and should not be overlooked or underestimated. Recurrence Predictors Several risk factors are associated with or predict the risk of melanoma recurrence. The most frequent predictors of re- currence were Breslow thickness and male sex [1,3,6,22,42]. Meier et al showed that the location of the initial tumor (trunk in men and lower extremities in women) and Breslow thickness were the main predictors of recurrence [6]. O’Con- nell et al reported that recurrence predictors were nodu- lar histologic subtype and Breslow thickness [3]. Similarly, Bleicher et al showed that age, male sex, stage, and Breslow thickness as important recurrence factors [22]. Berger et al series included recurrent factors: Male sex, T- classification, and ulceration as predictors [1]. Thomas et al series evalu- ated risk factors for specific recurrence patterns. For LCIT recurrence: age, anatomic location, Breslow thickness; for lymph node recurrence: age and Breslow thickness; and for systemic recurrence: anatomic location (head and neck or trunk), Breslow thickness, ulceration, and lymphovascular invasion [42]. Overall Survival: Role of Recurrent Disease The patterns of recurrence tend to impact melanoma overall survival (OS); therefore, careful understanding of recurrence type can help with patient management and counseling: The sole occurrence of recurrent disease (irrespective of type) is associated with a worse prognosis. Meyers et al study showed that the median survival was 22 months for melanoma recurrences in the LCIT-lymph node group and 7 months for the systemic recurrence group [16]. Leeneman et al showed a mean OS of 1.9 years (95% CI: 0.8- 3.2) for patients initially diagnosed with stage IB, 1.5 years (95% CI: 1.1-2.1) for patients initially diagnosed with stage II, and 10 Review | Dermatol Pract Concept. 2023;13(4):e2023304 10. Cohn-Cedermark G, Månsson-Brahme E, Rutqvist LE, Lars- son O, Singnomklao T, Ringborg U. Metastatic patterns, clini- cal outcome, and malignant phenotype in malignant cutaneous melanoma. Acta Oncol Stockh Swed. 1999;38(5):549-57. 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Recurrence patterns in patients with Stage II melanoma: The evolving role of routine imaging for surveillance. J Surg Oncol. 2020;122(8):1770-7. DOI:10.1002/jso.26214. PMID: 33098702. Medicine Agency (EMA) have significantly changed mela- noma management [37]. The projected increase in the use of adjuvant systemic therapy might also lead to changes in melanoma recurrence patterns among treated patients when compared to those described in this study. Strict follow-up and patient education play a critical role in detecting melanoma recurrences. Due to the higher prevalence of regional lymph node recurrences in early-stage melanoma, ultrasound may prove to be a valuable and cost-effective strategy for recurrence detection in early-stage melanoma [1]. Conversely, for patients with more advanced disease at diagnosis, cross-sectional full-body imaging (e.g. PET-CT) might be of benefit due to the more frequent sys- temic metastasis. 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