Melanoma Today DPC Journal Special Issue table of contents Epidemiology and Risk Factors of Melanoma: A Review Claudio Conforti, Iris Zalaudek Evolution of the Clinical, Dermoscopic and Pathologic Diagnosis of Melanoma Harald Kittler Melanoma: Staging and Follow-Up Chryssoula Papageorgiou, Zoe Apalla, Sofia-Magdalini Manoli, Konstantinos Lallas, Efstratios Vakirlis, Aimilios Lallas Current Landscape and Open Questions on Adjuvant Therapies in Melanoma Vincenzo De Falco, Stefania Napolitano, Luigi Pio Guerrera, Teresa Troiani Treatment of Advanced Metastatic Melanoma Pietro Quaglino, Paolo Fava, Luca Tonella, Marco Rubatto, Simone Ribero, Maria Teresa Fierro Mattioli 1885 www.mattioli1885.com CHIEF EDITOR Prof. Giuseppe Argenziano, MD Dermatology Unit, University of Campania Luigi Vanvitelli, Naples GUEST EDITORS Prof. H. Peter Soyer, MD, FACD, FAHMS Chair in Dermatology. Director, Dermatology Research Centre, The University of Queensland Diamantina Institute; Director, Dermatology Department, Princess Alexandra Hospital Prof. Paola Queirolo, MD Director of the “Divisione di Oncologia Medica del Melanoma, Sarcoma e Tumori Rari” - Istituto Europeo di Oncologia, IEO Grazie al contributo di Melanoma Today DPC Journal Special Issue table of contents Epidemiology and Risk Factors of Melanoma: A Review Claudio Conforti, Iris Zalaudek The Evolution of the Clinical, Dermoscopic and Pathologic Diagnosis of Melanoma Harald Kittler Melanoma: Staging and Follow-Up Chryssoula Papageorgiou, Zoe Apalla, Sofia-Magdalini Manoli, Konstantinos Lallas, Efstratios Vakirlis, Aimilios Lallas Current Landscape and Open Questions on Adjuvant Therapies in Melanoma Vincenzo De Falco, Stefania Napolitano, Luigi Pio Guerrera, Teresa Troiani Treatment of Advanced Metastatic Melanoma Pietro Quaglino, Paolo Fava, Luca Tonella, Marco Rubatto, Simone Ribero, Maria Teresa Fierro Mattioli 1885 www.mattioli1885.com CHIEF EDITOR Prof. Giuseppe Argenziano, MD Dermatology Unit, University of Campania Luigi Vanvitelli, Naples GUEST EDITORS Prof. H. Peter Soyer, MD, FACD, FAHMS Chair in Dermatology. Director, Dermatology Research Centre, The University of Queensland Diamantina Institute; Director, Dermatology Department, Princess Alexandra Hospital Prof. Paola Queirolo, MD Director of the “Divisione di Oncologia Medica del Melanoma, Sarcoma e Tumori Rari” - Istituto Europeo di Oncologia, IEO Grazie al contributo di Melanoma Today DPC Journal Special Issue TABLE OF CONTENTS Epidemiology and Risk Factors of Melanoma: A Review Claudio Conforti, Iris Zalaudek The Evolution of the Clinical, Dermoscopic and Pathologic Diagnosis of Melanoma Harald Kittler Melanoma: Staging and Follow-Up Chryssoula Papageorgiou, Zoe Apalla, Sofia-Magdalini Manoli, Konstantinos Lallas, Efstratios Vakirlis, Aimilios Lallas Current Landscape and Open Questions on Adjuvant Therapies in Melanoma Vincenzo De Falco, Stefania Napolitano, Luigi Pio Guerrera, Teresa Troiani Treatment of Advanced Metastatic Melanoma Pietro Quaglino, Paolo Fava, Luca Tonella, Marco Rubatto, Simone Ribero, Maria Teresa Fierro Guest Editors Prof. H. Peter Soyer, MD, FACD, FAHMS Chair in Dermatology. Director, Dermatology Research Centre, The University of Queensland Diamantina Institute; Director, Dermatology Department, Princess Alexandra Hospital Prof. Paola Queirolo, MD Director of the “Divisione di Oncologia Medica del Melanoma, Sarcoma e Tumori Rari” - Istituto Europeo di Oncologia, IEO. Thanks to Dermatology Practical & Conceptual Review | Dermatol Pract Concept. 2021; 11(S1): e2021162S 1 Melanoma: Staging and Follow-Up Chryssoula Papageorgiou1, Zoe Apalla1, Sofia-Magdalini Manoli2, Konstantinos Lallas2, Efstratios Vakirlis2, Aimilios Lallas2 1. Second Dermatology Department, Medical School, Faculty of Health Sciences, Aristotle University of Thessaloniki, Greece 2. First Dermatology Department, Medical School, Faculty of Health Sciences, Aristotle University of Thessaloniki, Greece Key words: Melanoma; staging; follow-up Citation: Papageorgiou C, Apalla Z, Manoli SM, Lallas K, Vakirlis E, Lallas A. Melanoma: staging and follow-up. Dermatol Pract Concept. 2021; 11(S1): e2021162S. DOI: https://doi.org/10.5826/dpc.11S1a162S Accepted: May 17, 2021; Published: July 2021 Copyright: ©2021 Papageorgiou et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License BY-NC-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing interests: The authors have no conflict of interest to disclose. Authorship: All authors have contributed significantly to this publication Corresponding author: Aimilios Lallas, Associate Professor of Dermatology, First Department of Dermatology, Medical School, Faculty of Health Sciences, Aristotle University of Thessaloniki, Greece. Email: alallas@auth.gr. Cancer staging is the process determining to which extent a cancer has spread and where it is located in the body. A thorough staging is of utmost importance, not only because it provides the most accu- rate prognostic estimation, but also because several crucial decisions, such as the treatment choice and the follow-up strategy, vary according to the tumor’s stage. The current staging system for melanoma is based on the 8th edition of TNM classification issued by the American Joint Committee on Cancer (AJCC) in 2017. It includes a clinical and a pathological staging, both consisting of 5 stages (0-IV). The stage of a melanoma is determined by several factors, among which the Breslow thickness, the pathological presence or absence of ulceration in the primary tumor, the presence and the number of tumor-involved regional lymph nodes, the presence or absence of in-transit, satellite and/or mi- crosatellite metastases, and the presence of distant metastases. Following melanoma diagnosis, an accurate medical workup, in line with the stage and the physical examination, should be performed. ABSTRACT This article is part of the DPC Journal Special Issue Melanoma Today Guest Editors Prof. H. Peter Soyer, MD, FACD, FAHMS Chair in Dermatology. Director, Dermatology Research Centre, The University of Queensland Diamantina Institute; Director, Dermatology Department, Princess Alexandra Hospital Prof. Paola Queirolo, MD Director of the “Divisione di oncologia Medica del Melanoma, sarcoma e Tumori Rari” - Istituto Europeo di Oncologia, IEO. 2 Review | Dermatol Pract Concept. 2021; 11(S1): e2021162S Introduction Staging is a process determining the extent to which a cancer has spread in a person’s body and where it is located. Can- cer stage is categorized from 0 to IV, with stage IV cancer corresponding to a cancer that has metastasized at distant locations. The most used system to stage solid tumors, includ- ing melanoma, is the universally accepted TNM (Tumor, Node, Metastasis) staging system. Cancer staging can be divided into clinical and pathological staging. Clinical and pathological stages are defined by different criteria and may differ but are generally considered as complementary to each other. In general, clinical staging is based on all the available information obtained before surgical excision of the tumor (eg by physical examination, blood tests, and imaging), while pathological staging is performed by a pathologist and relies on the information provided by microscopic examination of the tumor following surgical resection. The clinical stage of a melanoma can be determined only following a complete excision of the primary tumor, a clinical examination of the skin and lymph nodes, and a radiologic assessment for regional and distant metastases’ detection. Pathological staging of a melanoma takes into account not only the microstaging of the primary tumor and the wide excision but also considers the information on regional lymph nodes after partial or complete lymphadenectomy, when performed. A proper staging is extremely important, because it provides the most accurate prognostic estimation and allows to take several crucial decisions, such as the treatment choice and the follow-up strategy, that are based on clinical tumor stage. A continuous patient monitoring is fundamental to detect a potential relapse or a second primary melanoma and should be lifelong. However, there is still no universally adopted follow-up strategy program and different follow-up schemes have been suggested. Future prospective studies are needed to evaluate different follow-up protocols according to the adopted therapy, as novel recent therapies (targeted and immunotherapies) are being increasingly used. Key Messages • Proper staging is of utmost importance because it provides accurate prognostic estimation. Sev- eral crucial decisions, such as the treatment choice and the follow up strategy, are based on the tumor stage. • Physical examination during staging procedure and follow-up visits are important to avoid unneces- sary imaging and laboratory tests that could increase the patients’ anxiety. A personalized approach taking into consideration the patient’s risk factors, is strongly recommended. • Melanoma patients should be kept under surveillance lifelong due to an increased risk of developing a second primary melanoma and the risk of recurrence. Higher intensity follow-up strategies during the first 5 years are recommended due to higher rates of regional or distant relapse. Table 1. Clinical staging according to AJCC 8th edition [1]. T N M Stage 0 Tis N0 M0 Stage IA T1a N0 M0 Stage IB T1b N0 M0 T2a N0 M0 Stage IIA T2b N0 M0 T3a N0 M0 Stge IIB T3b N0 M0 T4a N0 M0 Stage IIC T4b N0 M0 Stage III Any t, Tis ≥ N1 M0 Stage IV Any T Any N M1 Melanoma Staging System The current staging system is based on the 8th edition of TNM classification for staging of melanoma issued by the AJCC in 2017 and is summarized in Tables 1-5 [1]. This relatively new system has been broadly accepted after its publication and is considered the cornerstone for classifying melanomas [2,3]. There is both a clinical and a pathological staging, both consisting of 5 stages as follows: Clinical Staging: • 0: in situ disease • I and II: localized disease Stage I is further divided into substage IA and IB, while stage II includes substages IIA, IIB and IIC. The determining Review | Dermatol Pract Concept. 2021; 11(S1): e2021162S 3 factors for staging and substaging are the Breslow thickness and the presence or absence of ulceration after the pathologi- cal assessment of the primary tumor (Tables 1 and 2). Of note, mitotic rate and Clark’s level of invasion, previously used for sub-classification, no longer influence melanoma staging. Table 2. Pathological staging according to AJCC 8th edition [1]. T N M Stage 0 Tis N0 M0 Stage IA T1a N0 M0 T1b N0 M0 Stage IB T2a N0 M0 Stage IIA T2b N0 M0 T3a N0 M0 Stage IIB T3b N0 M0 T4a N0 M0 Stage IIC T4b N0 M0 Stage IIIA T1a/b, T2a N1a, N2a M0 Stage IIIB T0 N1b, N1c M0 T1a/b, T2a N1b/c, N2b M0 T2b, T3a N1a/b/c, N2a/b M0 Stage IIIC T0 N2b/c, N3b/c M0 T1a/b, T2a/b, T3a N2c, N3a/b/c M0 T3b, T4a Any N ≥ N1 M0 T4b N1a/b/c, N2a/b/c M0 Stage IIID T4b N3a/b/c M0 Stage IV Any T, Tis Any N M1 Table 3. Definition of T according to AJCC 8th edition [1]. Category Thickness Ulceration TX: Primary tumor cannot be assessed N/A N/A T0: No evidence of primary tumor N/A N/A Tis (in situ) N/A N/A T1 T1a T1b ≤1 mm <0.8 mm Without ulceration <0.8 0.8- 1.0 mm With ulceration With or without ulceration T2 T2a T2b >1.0- 2.0 mm >1.0- 2.0 mm Without ulceration >1.0- 2.0 mm With ulceration T3 T3a T3b >2.0- 4.0 mm >2.0- 4.0 mm Without ulceration >2.0- 4.0 mm With ulceration T4 T4a T4b >4.0 mm >4.0 mm Without ulceration >4.0 mm With ulceration • III: regional disease Regional disease is defined by the presence of metastases in regional lymph nodes and/or “in transit metastases”, “satellite metastases”, and microsatellite metastases. Satellite metastases are defined as cutaneous or subcutaneous met- astatic lesions up to 2 cm from the margin of the primary tumor. In-transit metastases are defined as cutaneous or subcutaneous lesions located between 2 cm from the primary tumor and the regional nodal basin. Microsatellite metastases are defined as tumor nests larger than 0.05 mm in diameter in the reticular dermis, subcutis, or vessels beneath the primary invasive tumor, but separated from it by at least 0.3 mm of normal tissue on the section in which the Breslow measure- ment was taken. Regional lymph nodes metastases are defined as metasta- ses in the lymph node basin that drains lymph from the region around the tumor. Involvement of regional lymph nodes is confirmed by their pathological examination after sentinel lymph node (SLN) biopsy (for clinically occult lymph node metastases) or therapeutic lymph node dissection when per- formed (for clinically evident regional lymph node disease). Involvement of regional lymph nodes may be also detected by clinical, radiologic examination and/or diagnostic biopsies (clinical staging). Therefore, there is only 1 stage group for clinical stage III. In contrast, pathological stage III is divided into A, B, C, and D stage groups depending on Breslow thick- ness, the pathological presence or absence of ulceration in the primary tumor, the number of tumor-involved regional lymph nodes, and the presence or absence of in-transit, satellite and/ or microsatellite metastases (Table 4). 4 Review | Dermatol Pract Concept. 2021; 11(S1): e2021162S Table 4. Definition of N according to AJCC 8th edition [1]. Category Number of Tumor-Involved Regional Lymph Node Presence of In-transit, Satellite, and/or Microsatellite Metastases NX: Patients in whom the regional nodes cannot be assessed N/A No N0: No regional metastases detected N/A No N1 1 tumor-involved node or in-transit, satellite, and/or microsatellite metastases with no tumor-involved node N1a 1 clinically occult (ie, detected by SLN biopsy) No N1b 1 clinically detected No N1c No regional lymph node disease Yes N2 2 or 3 tumor-involved nodes or in-transit, satellite, and/or microsatellite metastases with 1 tumor-involved node N2a 2 or 3 clinically occult (ie, detected by SLN biopsy) No N2b 2 or 3, at least 1 of which was clinically detected No N2c 1 clinically occult or clinically detected Yes N3 4 or more tumor-involved nodes or in-transit, satellite, and/or microsatellite metastases with 2 or more tumor-involved nodes, or any number of matted nodes without or with in-transit, satellite, and/or microsatellite metastases N3a 4 or more clinically occult (ie, detected by SLN biopsy) No N3b 4 or more, at least one of which was clinically detected, or presence of any number of matted nodes No N3c 2 or more clinically occult or clinically detected and/or presence of any number of matted nodes Yes • IV: distant metastatic disease This stage includes distant metastases to lung, central nervous system (CNS) or other organs as well as to skin, soft tissue and nonregional lymph nodes. Although there is no further division to substages, a sub-classification according to the number of organs involved, which organs are involved, and serum levels of lactate dehydrogenase (LDH) is essential for prognostic reasons (Table 5). Staging workup Histopathologic Examination When a suspicious lesion is detected, a biopsy should be performed. A narrow-margin (1-3 mm) excisional biopsy is strongly preferred. In case of primary melanoma, the his- topathological features along with clinical examination are determining factors for staging and further management. Therefore, the pathology report should include the Breslow thickness, the ulceration status, the dermal mitotic rate, the margin status, the presence, or absence of microsatellitosis, and the presence or not of pure desmoplasia. Physical Examination Special attention should be paid to the physical examination of the entire skin surface to look for satellites or in-transit metas- tases but also for a second primary melanoma. Physical exam- ination of the regional lymph node basin should be included. Sentinel Lymph Node Biopsy and Imaging Patients with a melanoma in situ and a clinical stage IA melanoma with normal physical examination and no other symptoms need no further imaging or laboratory tests. They also are not candidates for SLN biopsy at baseline. The stag- ing procedure is completed with the performance of wide excision [1]. Patients with clinical stage IB melanoma with normal physical examination and no other symptoms need no fur- ther imaging or laboratory tests at baseline. Concerning SLN biopsy, this should be considered in patients with T1b melanoma. The decision depends on several factors, such as comorbidities, age, mitotic rate or lymphovascular invasion [1]. Patients with a T2a melanoma, should undergo SLN biopsy. Review | Dermatol Pract Concept. 2021; 11(S1): e2021162S 5 Patients with clinical stage II melanoma with normal physical examination and no other symptoms need no further imaging or lab tests at baseline, but a SLN biopsy should be offered [1,4,5]. In melanoma patients of any stage, if an equivocal regional lymph node is detected during clinical examina- tion, an ultrasound (US) should be considered prior to SLN biopsy. However, a negative nodal basin US is not a substitute for biopsy of clinically suspicious lymph nodes and histopathology should be warranted. Moreover, abnor- malities or suspicious lesions on nodal basin US should be histopathologically confirmed. The presence of lymph node metastasis can be confirmed either with core biopsy or fine-needle aspiration (FNA) [6-8]. Similarly, if clinical or microscopic satellite/in-transit metastases are suspected, a biopsy is mandatory. If a SLN biopsy is indicated, it should be performed at the same time with the wide excision of the primary melanoma. Noteworthy, SLN biopsy was shown to have only prognostic (and not therapeutic) significance [9-13]. A positive SLN biopsy would directly upstage a patient to stage III, which highlights its significance as a staging proce- dure, especially after the introduction of adjuvant systemic therapy for stage III. A complete lymph node dissection is not anymore recommended in case of positive SLN biopsy, since it does not offer any therapeutic benefit, it has little prognostic value, and is associated with surgical morbidity [14-17]. It is, however, indicated for the treatment of lymph node metastases diagnosed clinically or by imaging, in the absence of distant metastases. Imaging for baseline staging should be considered in patients with pathological stage IIIA melanoma and should be performed in all patients with stage IIIB/C/D [1]. Imaging modalities include chest/abdominal/pelvic CT with intrave- nous (iv) contrast or whole-body PET/CT, with or without brain MRI with iv contrast. Moreover, if clinically indicated, neck region should be also checked with CT with iv contrast. Finally, stage IV melanoma patients need careful total body medical imaging (CT or PET/CT, brain MRI). Moreover, plasma LDH should also be assessed [1]. Follow-Up After melanoma diagnosis, the role of ongoing surveil- lance of disease-free patients is of paramount importance. The main goals of the follow-up are the following: 1. Early identification of relapse (local, distant) and subse- quent guidance for adjuvant treatment, where appropriate. 2. Early detection of a second primary melanoma and/or non-melanoma skin cancer. 3. Recognition and management of side-effects, in case of adjuvant systemic treatment. Early detection of relapse is associated with a higher survival rate, highlighting the importance of an adequate follow-up. The likelihood of recurrence varies according to melanoma stage at first presentation. Patients with melanoma in situ, are very unlikely to recur following wide excision. There are a few exceptions though, such as lentigo maligna type [18-20]. In general, patients with earlier stage melanoma at first presentation are less likely to recur compared to Table 5. Definition of M according to AJCC 8th edition [1]. Category Anatomic Site LDH level M0: No evidence of distant metastasis N/A N/A M1 Evidence of distant metastases See below M1a Distant metastasis to skin, soft tissue including muscle, and/or nonregional lymph node Not recorded or unspecified M1a(0) Not elevated M1a(1) Elevated M1b Distant metastasis to lung with or without M1a sites of disease Not recorded or unspecified M1b(0) Not elevated M1b(1) Elevated M1c Distant metastasis to non-CNS visceral sites with or without M1a or M1b sites of disease Not recorded or unspecified M1c(0) Not elevated M1c(1) Elevated M1d Distant metastasis to CNS with or without M1a, M1b, or M1c sites of disease Not recorded or unspecified M1d(0) Normal M1d(1) Elevated 6 Review | Dermatol Pract Concept. 2021; 11(S1): e2021162S those with more advanced stages. Accordingly, the timing of relapse varies according to the stage. Patients with advanced melanoma tend to recur more quickly compared to those with earlier stage [21-23]. Nonetheless, the vast majority of relapses are recorded in the first 5 years and most of them within 2- 3 years following surgery. Moreover, the risk of recurrence tends to decrease over time for melanoma stages, but late recurrence (more than 10 years after the initial diag- nosis) cannot be excluded [21,22,24-26] Patients with a personal history of melanoma are at high risk of developing a second primary melanoma. Concerning the risk of developing a second primary melanoma, data reported in the literature is very heterogenous. The reported percentage of melanoma patients developing a second pri- mary melanoma ranges between 2% and 20% [23, 27-30]. In a cohort of prospectively monitored melanoma patients, the cumulative 5-year risk of second primary melanoma was 8% [30]. Interestingly, the risk appears to be higher within the first year after the diagnosis of the first melanoma, but it remains considerable for at least 5 years and very possibly even more [23, 27-30]. Therefore, individuals with melanoma history should rather be considered at a life-long increased risk of developing a new primary melanoma. Although the need for a follow-up in patients with mela- noma is not a matter of debate, surveillance recommendations vary widely in terms of methods and frequency of visits, and examinations. As there is currently lack of evidence regard- ing the efficacy of follow-up strategies, different follow-up schemes have been proposed and are mainly based on expert opinions. The suggested follow-up schemes consider the mela- noma stage and the presence or not of additional risk factors. As mentioned above, the first 5 years following the exci- sion of the primary tumor are the most crucial due to high rates of relapse. This is why current guidelines suggest adopt- ing higher intensity follow up strategies during this period. Still, because of the lifetime increased risk of a second primary melanoma or a non-melanoma skin cancer, as well as the risk for late recurrence, monitoring programs for mela- noma patients should go beyond 5 years, including at least 1 strongly recommended annual skin exam lifelong [31]. The modalities used to monitor melanoma patients include whole body skin examination, physical examination of the regional lymph nodes, blood tests, and imaging exams, such as chest X-ray, ultrasound, CT, PET/CT, and MRI. More analytically, a clinical evaluation performed by a dermatolo- gist is mandatory at any stage and includes a total body skin examination (with or without a total body clinical and der- moscopic digital documentation) to identify local recurrences (scar, satellite/in-transit recurrence) and subsequent primary melanoma or other skin cancers. Clinical evaluation should also include the examination of the regional lymph nodes and the evaluation of patients’ symptoms and/or signs that would direct appropriate imaging if needed. Ultrasound of the lymph nodes is the most accurate method to detect nodal disease and is generally recommended in patients with equivocal lymph node during physical examination, in patients with AJCC T1b stage and above, in patients who were offered SLN biopsy but it was not performed or in patients with positive SLN biopsy who did not undergo complete lymph node dissection [32]. Other imaging modalities (CT, PET/CT, MRI, chest x-ray) should be considered for monitoring asymptomatic patients in more advanced stages or when signs and symptoms may suggest distant metastasis [33]. In any clinical scenario, if there is a recurrence suspect, this should be confirmed by histopathologic analysis whenever possible. Finally, routine blood testing (LDH, S100 protein) to detect recurrence is generally not recommended as low positive predictive values have been demonstrated. Ongoing research focuses on liquid biopsies, namely the detection of molecular alterations in plasma and serum of melanoma patients by characterization of circulating tumor cells and cell-free circulating tumor DNA [34,35]. This may provide Table 6. Example of follow up schedule examinations based on melanoma stage proposed by European consensus-based interdisciplinary guidelines [2]. Stage Clinical- dermatological examination Lymph node sonography Laboratory examination: LDH, S-100 CT neck, thorax, abdominal, pelvic or PET/ CT - MRI head Year 1 to 3 4 to 10 >10 1 to 3 4 to 10 1 to 3 4 to 10 1 to 3 4 to 10 IA 6 m 12 m 12 m - - - - - - IB-IIB 3-6 m 6 m 12 m 6 m - - - - - IIC-IIIC 3 m 6 m 12 m 3-6 m - 3-6 m - 6 m - IIID 3 m 6 m 12 m 3-6 m - 3-6 m - 3-6 m - IV NED (resected, CR under therapy) 3 m 6 m 12 m 3-6 m - 3-6 m - 3 m - IV (M1a- M1d) (distant metastasis) Individualized; otherwise staging every 12 weeks * NED= No evidence disease, CR= Complete response Review | Dermatol Pract Concept. 2021; 11(S1): e2021162S 7 valuable information on prognostic outcomes and assessment of treatment response or resistance in the future. The National Comprehensive Cancer Network (NCCN), an alliance of 31 cancer centers in the United States, has released follow up recommendations per melanoma stage [1]. Accord- ing to them, no routine imaging is recommended for stage 0 (in situ) melanoma. For patients with stage IA to IIA with no evidence of disease, routine imaging to screen for asymptomatic recurrence or metastatic disease is not recommended. Clinical visits should be scheduled every 6 to 12 months for 5 years and annually thereafter, as clinically indicated. Clinical examination in these visits should emphasize on the regional nodes and skin. For patients with stage IIB to IV (with no evidence of disease), scheduled visits should be conducted every 3 to 6 months for the first 2 years, every 3 to 12 months for the next 3 years and annually thereafter, as clinically indicated again emphasizing on the regional nodes and skin. Moreover, in these stages, imaging (chest x-ray, CT and/or PET/CT) every 3 to 12 months could be considered to screen for asymptomatic recurrence. Regarding central nervous system (CNS), a periodic brain MRI should be performed for up to 3 years to screen for asymptomatic brain metastases in high-risk patients with stage IIIC or higher mel- anoma, while more frequent surveillance is recommended for patients with prior brain metastases. However, routine imaging is not recommended after 3 to 5 years. Nonetheless, in any case and at any time of follow-up period, when clinically indicated, an appropriate imaging should be offered to evaluate specific signs or symptoms. Finally, if relapse occurs, imaging is recommended to assess the extent of the disease. In addition, when complete surgical resection of relapse is not feasible and active non-sur- gical treatment is initiated, clinical examination and/or imaging may be appropriate throughout treatment to assess treatment response. In Europe, follow up schemes vary among countries, rang- ing in frequency from 2 to 4 times per year for 5-10 years, again with higher-intensity strategies in more advanced stages and during the first years. Current European consensus-based interdisciplinary guidelines for melanoma have proposed an example of follow-up schedule examinations based on stage and is shown in Table 6 [2]. Irrespectively of the selected follow-up scheme, an indi- vidualized approach taking into consideration patient’s risk factors, such as risk for recurrence, prior primary melanoma, family history of melanoma and atypical mole syndrome, is optimal. Moreover, patients’ education must be an integral part of the surveillance strategy and should include: a. Communication on what to expect from follow-up exam- inations and why it is important to be compliant with the regular follow-ups. b. Awareness that family members often have an increased melanoma risk. c. Guidance on how to perform regular self-examination of the skin and peripheral lymph nodes. d. Information regarding correct sun exposure behavior. Conclusion In conclusion, although there is still no universally adopted follow-up strategy program to monitor melanoma patients, current recommendations, as described above, could serve as a guide for clinicians while future prospective studies are necessary to better standardize this follow-up protocols. References 1. Gershenwald JE, Scolyer RA, Hess KR, Sondak VK, Long GV, Ross MI, et al. Melanoma staging: Evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(6):472-492. DOI: 10.3322/caac.21409. PMID: 29028110. 2. Garbe C, Amaral T, Peris K, Hauschild A, Arenberger P, Bastholt L, et al. European consensus-based interdisciplinary guideline for melanoma. Part 1: Diagnostics - Update 2019. Eur J Cancer. 2020;126:141-158. DOI: 10.1016/j.ejca.2019.11.014. PMID: 31928887. 3. Michielin O, van Akkooi ACJ, Ascierto PA, Dummer R, Keil- holz U. Cutaneous melanoma: ESMO Clinical Practice Guide- lines for diagnosis, treatment and follow-up†. Ann Oncol. 2019;30(12):1884-1901. DOI: 10.1093/annonc/mdz411. PMID: 31566661. 4. Balch CM, Soong SJ, Gershenwald JE, Thompson JF, Reintgen DS, Cascinelli N, et al. Prognostic factors analysis of 17,600 melano- ma patients: validation of the American Joint Committee on Can- cer melanoma staging system. J Clin Oncol. 2001;19(16):3622- 3634. DOI: 10.1200/JCO.2001.19.16.3622. 5. Morton DL, Thompson JF, Cochran AJ, Mozzillo N, Nieweg OE, Roses DF, et al. MSLT Group. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med. 2014;370(7):599-609. DOI: 10.1056/NEJMoa1310460. PMID: 24521106. 6. Hall BJ, Schmidt RL, Sharma RR, Layfield LJ. Fine-needle aspira- tion cytology for the diagnosis of metastatic melanoma: systemat- ic review and meta-analysis. Am J Clin Pathol. 2013;140(5):635- 642. DOI: 10.1309/AJCPWSDDHLLW40WI. PMID: 24124141. 7. Oude Ophuis CMC, Verhoef C, Grünhagen DJ, Siegel P, Scho- engen A, Röwert-Huber J, et al. Long-term results of ultrasound guided fine needle aspiration cytology in conjunction with sentinel node biopsy support step-wise approach in melanoma. Eur J Surg Oncol. 2017;43(8):1509-1516. DOI: 10.1016/j.ejso.2017.02.009. PMID: 28262276. 8. Bohelay G, Battistella M, Pages C, de Margerie-Mellon C, Bas- set-Seguin N, Viguier M, et al. Ultrasound-guided core needle biopsy of superficial lymph nodes: an alternative to fine-needle aspiration cytology for the diagnosis of lymph node metastasis in cutaneous melanoma. Melanoma research. 2015;25:519-527. DOI: 10.1097/CMR.0000000000000161. PMID: 25933210. 9. Statius Muller MG, van Leeuwen PA, de Lange-De Klerk ES, van Diest PJ, Pijpers R, Ferwerda CC, et al. The sen- tinel lymph node status is an important factor for pre- 8 Review | Dermatol Pract Concept. 2021; 11(S1): e2021162S dicting clinical outcome in patients with Stage I or II cu- taneous melanoma. Cancer. 2001;91(12):2401-2408. DOI: 10.1002/1097-0142(20010615)91:12<2401::AID-CN- CR1274>3.0.CO;2-I. 10. Wright BE, Scheri RP, Ye X, Faries MB, Turner RR, Essner R, et al. Importance of sentinel lymph node biopsy in patients with thin melanoma. Arch Surg. 2008;143(9):892-899; discussion 899-900. DOI: 10.1001/archsurg.143.9.892. PMID: 18794428. 11. Lima Sánchez J, Sánchez Medina M, García Duque O, Fiúza Pérez M, Carreteri Hernández G, Fernández Palácios J. Sentinel lymph node biopsy for cutaneous melanoma: a 6 years study. Indian J Plast Surg. 2013;46(1):92-97. DOI: 10.4103/0970-0358.113717. PMID: 23960312. 12. Ranieri JM, Wagner JD, Wenck S, Johnson CS, Coleman JJ 3rd. The prognostic importance of sentinel lymph node biopsy in thin melanoma. Ann Surg Oncol. 2006;13(7):927-932. DOI: 10.1245/ ASO.2006.04.023. PMID: 16788753. 13. Mozzillo N, Pennacchioli E, Gandini S, Caracò C, Crispo A, Botti G, et al. Sentinel node biopsy in thin and thick melanoma. Ann Surg Oncol. 2013;20(8):2780-2786. DOI: 10.1245/s10434-012- 2826-0. PMID. 23720068. 14. Leiter U, Stadler R, Mauch C, Hohenberger W, Brockmeyer NH, Berking C, et al. Final Analysis of DeCOG-SLT Trial: No Sur- vival Benefit for Complete Lymph Node Dissection in Patients With Melanoma With Positive Sentinel Node. J Clin Oncol. 2019; 37(32): 3000–3008. DOI: 10.1200/JCO.18.02306. PMID: 31557067. 15. Faries MB, Thompson JF, Cochran AJ, Andtbacka RH, Mozzillo N, Zager JS, et al. (2017). Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma. N Eng J Med. 2017; 376(23): 2211–2222. 16. Kyrgidis A, Tzellos T, Mocellin S, Apalla Z, Lallas A, Pilati P, Stratigos A. Sentinel lymph node biopsy followed by lymph node dissection for localised primary cutaneous melanoma. Cochrane Database Syst Rev. 2015; 16(5): CD010307. DOI 10.1002/14651858.CD010307.pub2. PMID: 25978975. 17. Verver D, Rekkas A, Garbe C, van Klaveren D, van Akkooi ACJ, Rutkowski P, et al. The EORTC-DeCOG nomogram adequately predicts outcomes of patients with sentinel node-positive melano- ma without the need for completion lymph node dissection. Eur J Cancer. 2020; 134: 9–18. DOI: 10.1016/j.ejca.2020.04.022. PMID: 32454396. 18. Joyce KM, Joyce CW, Jones DM, Donnellan P, Hussey AJ, Re- gan PJ, et al. An assessment of histological margins and recur- rence of melanoma in situ. Plast Reconstr Surg Glob Open. 2015;3(2):e301. DOI:10.1097/GOX.0000000000000272. PMID: 25750840. 19. Duffy KL, Truong A, Bowen GM, Andtbacka RH, Hyngstrom J, Bowles T, et al. Adequacy of 5-mm surgical excision margins for non-lentiginous melanoma in situ. J Am Acad Dermatol. 2014;71(4):835-838. DOI: 10.1016/j.jaad.2014.06.044. PMID: 25219711. 20. de Vries K, Greveling K, Prens LM, Munte K, Koljenović S, van Doorn MB, et al. Recurrence rate of lentigo maligna after micrographically controlled staged surgical excision. Br J Der- matol. 2016;174(3):588-593. DOI: 10.1111/bjd.14325. PMID: 26616840. 21. Romano E, Scordo M, Dusza SW, Coit DG, Chapman PB. Site and timing of first relapse in stage III melanoma patients: implications for follow-up guidelines. J Clin Oncol. 2010;28(18):3042-3047. DOI: 10.1200/JCO.2009.26.2063. PMID: 20479405. 22. Salama AK, de Rosa N, Scheri RP, Pruitt SK, Herndon JE 2nd, Marcello J, et al. Hazard-rate analysis and patterns of recur- rence in early stage melanoma: moving towards a rationally de- signed surveillance strategy. PLoS One. 2013;8(3):e57665. DOI: 10.1371/journal.pone.0057665. PMID: 23516415. 23. Gassenmaier M, Stec T, Keim U, Leiter U, Eigentler TK, Metzler G, Garbe C. Incidence and characteristics of thick second primary melanomas: a study of the German Central Malignant Melanoma Registry. J Eur Acad Dermatol Venereol. 2019 Jan;33(1):63-70. DOI: 10.1111/jdv.15194. PMID: 30051517. 24. Hofmann U, Szedlak M, Rittgen W, Jung EG, Schadendorf D. Primary staging and follow-up in melanoma patients--monocenter evaluation of methods, costs and patient survival. Br J Cancer. 2002;87(2):151-157. DOI: 10.1038/sj.bjc.6600428. PMID: 12107834. 25. Osella-Abate S, Ribero S, Sanlorenzo M, Maule MM, Richiardi L, Merletti F, et al. Risk factors related to late metastases in 1,372 melanoma patients disease free more than 10 years. Int J Cancer. 2015;136(10):2453-2457. DOI: 10.1002/ijc.29281. PMID: 25331444. 26. Crowley NJ, Seigler HF. Late recurrence of malignant melanoma. Analysis of 168 patients. Ann Surg. 1990;212(2):173-177. DOI: 10.1097/00000658-199008000-00010. PMID: 2375648. 27. Jones MS, Torisu-Itakura H, Flaherty DC, et al. Second Primary Melanoma: Risk Factors, Histopathologic Features, Survival, and Implications for Follow-Up. Am Surg 2016;82:1009-1013. DOI: 10.1177/000313481608201034. PMID: 27779995. 28. Schuurman MS, de Waal AC, Thijs EJM, van Rossum MM, Kiemeney LALM, Aben KKH. Risk factors for second primary melanoma among Dutch patients with melanoma. Br J Dermatol. 2017;176:971-978. DOI: 10.1111/bjd.15024. PMID: 27596937. 29. Youlden DR, Youl PH, Soyer HP, Aitken JF, Baade PD. Distri- bution of subsequent primary invasive melanomas following a first primary invasive or in situ melanoma Queensland, Austra- lia, 1982-2010. JAMA Dermatol. 2014;150(5):526-534. DOI: 10.1001/jamadermatol.2013.9852. PMID: 25093216. 30. Lallas A, Apalla Z, Kyrgidis A, Papageorgiou C, Boukovinas I, Bobos M, et al. Second primary melanomas in a cohort of 977 melanoma patients within the first 5 years of monitoring. J Am Acad Dermatol. 2020;82(2):398-406. DOI: 10.1016/j. jaad.2019.08.074. PMID: 31499156. 31. Youlden DR, Baade PD, Soyer HP, Youl PH, Kimlin MG, Aitken JF, Green AC, Khosrotehrani K. Ten-Year Survival after Multiple In- vasive Melanomas Is Worse than after a Single Melanoma: a Pop- ulation-Based Study. J Invest Dermatol. 2016 Nov;136(11):2270- 2276. DOI: 10.1016/j.jid.2016.03.014. PMID: 27019458. 32. Xing Y, Bronstein Y, Ross MI, Askew RL, Lee JE, Gershenwald JE, et al. Contemporary diagnostic imaging modalities for the staging and surveillance of melanoma patients: a meta-analysis. J Natl Cancer Inst. 2011;103(2):129-142. DOI: 10.1093/jnci/ djq455. PMID: 21081714. 33. Riquelme-Mc Loughlin C, Podlipnik S, Bosch-Amate X, Ri- era-Monroig J, Barreiro A, Espinosa N, et al. Diagnostic ac- curacy of imaging studies for initial staging of T2b-T4b mela- noma patients. A cross-sectional study. J Am Acad Dermatol. 2019;81(6):1330-1338. DOI: 10.1016/j.jaad.2019.05.076. PMID: 31163236. Review | Dermatol Pract Concept. 2021; 11(S1): e2021162S 9 34. Marczynski GT, Laus AC, Dos Reis MB, Reis RM, Vazquez VL. Circulating tumor DNA (ctDNA) detection is associated with shorter progression-free survival in advanced melanoma patients. Sci Rep. 2020;10(1):18682. DOI: 10.1038/s41598-020-75792-1. PMID: 33122747. 35. Huynh K, Hoon DS. Liquid Biopsies for Assessing Metastatic Melanoma Progression. Crit Rev Oncog. 2016;21(1-2):141-154. DOI: 10.1615/CritRevOncog.2016016075. PMID: 27481010. 1-Indice 4-1795