Guideline sources The following summarized guidelines for the evaluation and management of cutaneous melanoma (CM) are prepared by our editorial team based on guidelines from the U.S. Preventive Services Task Force (USPSTF 2023), the American Society of Plastic Surgeons (ASPS 2021), the European Society of Medical Oncology (ESMO 2020; 2019), the American Society of Clinical Oncology (ASCO 2020), and the American Academy of Dermatology (AAD 2019). 1 2 3 4 5 7 Calculator Calculator Calculator 7-point dermoscopy checklist fo Eastern Cooperative Oncology G Karnofsky Guidelines https://web.pathway.md/diseases/recGM7euHf4Lsuh55 1/8 6/23/23, 3:36 AM Cutaneous melanoma Pathway 1. Screening and diagnosis Indications for screening: insufficient evidence to assess the balance of benefits and harms of visual skin examination by a clinician to screen for skin cancer in adolescents and adults. I 2. Diagnostic investigations Physical examination: Obtain dermatoscopy by an experienced physician to enhance the diagnostic accuracy. B Perform physical examination with special attention to other suspicious pigmented lesions, tumor satellites, in-transit metastases, regional lymph nodes, and distant metastases. B Baseline imaging: As per AAD 2019 guidelines, do not obtain baseline imaging in asymptomatic patients with newly diagnosed stage 0-II primary CM. D Show 2 more As per ESMO 2019 guidelines, do not obtain additional investigations in patients with low-risk melanomas (pT1a). D Show 2 more Baseline laboratory tests: Do not obtain baseline laboratory studies in asymptomatic patients with newly diagnosed stage 0-II primary CM. D Obtain baseline laboratory studies only for the evaluation of specific signs or symptoms of synchronous metastasis (regional nodal or distant) in patients with CM. E 3. Diagnostic procedures Skin biopsy: As per AAD 2019 guidelines, perform narrow excisional/complete biopsy with 1-3 mm margins encompassing the entire breadth of lesion and of sufficient depth to prevent transection at the base as the preferred biopsy technique. Perform excisional biopsy by any of the following methods: fusiform/elliptical excision punch excision around the clinical lesion deep shave/saucerization removal to depth below the anticipated plane of the lesion. E Show 2 more As per ESMO 2019 guidelines: Perform full thickness excisional biopsy with a minimal side margin for the diagnosis of CM. B Follow the eighth edition of the AJCC tumor, node, metastasis classification for histology reporting and include the following in the report: https://web.pathway.md/diseases/recGM7euHf4Lsuh55 2/8 6/23/23, 3:36 AM Cutaneous melanoma Pathway the maximum thickness in millimetres (Breslow) reported to the nearest 0.1 mm (rounding up starting at 0.05) presence of ulceration information on mitotic rate presence and extent of regression actinic damage clearance of the surgical margins. B Sentinel lymph node biopsy: As per ESMO 2020 guidelines, perform sentinel lymph node biopsy for staging of melanomas of stage pT2a or higher (> 1.0 mm Breslow thickness). A Show 3 more As per AAD 2019 guidelines, discuss carefully the risks and benefits of the procedure involving surgical oncology input with all patients eligible for sentinel lymph node biopsy. E Show 5 more As per ESMO 2019 guidelines, perform sentinel lymph node biopsy for precise staging of melanoma in patients with stage pT1b or higher, with a tumor thickness > 0.8 mm or with a tumor thickness with < 0.8 mm with ulceration. B Molecular testing: As per AAD 2019 guidelines, consider obtaining ancillary diagnostic molecular tests, such as comparative genomic hybridization, FISH, gene expression profiling, in patients with equivocal melanocytic neoplasms. E Show 2 more As per ESMO 2019 guidelines, obtain mutation testing for actionable mutations (including BRAF) in patients with: resectable or unresectable stage III or stage IV disease high-risk resected stage IIC disease. A Show 4 more 4. Medical management Neoadjuvant therapy: As per ASCO 2020 guidelines, insufficient evidence to recommend for or against the routine use of neoadjuvant therapy in adult patients with resectable regional or distant metastatic CM. Offer neoadjuvant therapy or refer patients for enrollment in clinical trials where possible. I As per ESMO 2020 guidelines: Consider offering neoadjuvant therapy in patients with easily resectable stage III disease with acceptable surgical morbidity only in the context of a clinical trial. C Consider offering neoadjuvant therapy outside of the context of a clinical trial in patients with technically resectable but bulky nodal and/or in-transit disease when surgery will be https://web.pathway.md/diseases/recGM7euHf4Lsuh55 3/8 6/23/23, 3:36 AM Cutaneous melanoma Pathway associated with significant morbidity, likely to result in positive resection margin status or necessitate the need for postoperative radiotherapy. C Adjuvant therapy: Do not offer adjuvant pembrolizumab, nivolumab, or combination dabrafenib and trametinib therapy in patients with resected stage II melanoma outside of enrollment in a clinical trial. D Show 6 more Consider continuing treatment after surgery based on the pathological response evaluation of the surgical specimen. C Show 9 more Consider offering topical imiquimod 5% cream as second-line therapy in patients with melanoma in situ, lentigo maligna type, after optimal surgery (adjuvant setting). E Offer anti-PD-1 adjuvant therapy or dabrafenib/trametinib as the preferred treatment options in patients with local/locoregional melanoma. A Recognize that the European Medicines Agency has approved nivolumab, pembrolizumab, and the combination of dabrafenib/trametinib for melanoma in the adjuvant setting. A Management of unresectable/metastatic disease: As per ASCO 2020 guidelines, offer the following regimens (in no particular order) in patients with BRAF wild-type unresectable/metastatic CM: ipilimumab plus nivolumab followed by nivolumab nivolumab pembrolizumab. A Show 7 more As per AAD 2019 guidelines, consider offering topical imiquimod 5% cream as second-line therapy in patients with melanoma in situ, lentigo maligna type, if surgery is not possible at the outset (primary setting). E As per ESMO 2019 guidelines, offer programmed cell death protein-1 blockade as first-line standard of care in all patients, regardless of BRAF status. A Show 11 more 5. Therapeutic procedures Radiotherapy: Reserve radiotherapy for patients with recurrent disease. B Consider offering adjuvant radiotherapy in high-risk patients if regional control is a major issue and/or systemic therapy is not possible. C Consider offering radiotherapy as second-line therapy in non-surgical candidates with melanoma in situ, lentigo maligna type. E Show 2 more Do not perform primary elective irradiation in patients with locoregional disease. D https://web.pathway.md/diseases/recGM7euHf4Lsuh55 4/8 6/23/23, 3:36 AM Cutaneous melanoma Pathway Show 3 more 6. Surgical interventions Wide-local excision: As per ESMO 2020 guidelines: Remove primary melanomas with clear margins to ensure local control in the context of resectable clinical stage III disease. Consider performing wide local excision with primary closure to avoid reconstruction whenever possible, ideally with a clinical 1 cm margin, with reconstruction avoided whenever possible. B Do not resect the primary tumor in the absence of symptoms or need for diagnostic tissue in the context of clinical stage IV disease. Resect with clear margins but without additional safety margins if there is an indication to resect the primary lesion. D As per AAD 2019 guidelines, perform surgical excision with histologically negative margins as first-line treatment in patients with CM of any thickness and melanoma in situ. Decide on surgical margins based on tumor thickness. E Show 5 more Lymph node dissection: Perform radical lymph node dissection in patients with clinically-detected lymph node metastases in resectable stage III disease after pathological assessment (cytology or histology of lesion preoperatively) and adequate staging. B Show 5 more Ensure interdisciplinary collaboration involving surgical and medical oncologists for discussion of possible completion of lymph node dissection or obtaining regional nodal ultrasound surveillance in patients with positive sentinel lymph node biopsy. E Do not perform elective lymph node dissection in patients with locoregional disease. D Show 2 more Resection of metastases: Perform resection with clear margins, but without additional safety margins, in patients with in- transit metastases regarded as few, small and non-rapidly recurrent lesions. Avoid performing extensive and multiple repeated resections and reconstructions. B Consider performing surgical removal of locoregional recurrence or single distant metastasis in fit patients, as a therapeutic option for long-term disease control. C 7. Specific circumstances Pregnant patients: ensure a tailored, multidisciplinary approach of care for pregnant patients with CM, involving obstetrician and CM specialist relevant to the patient's stage of disease. Recognize that the diagnosis of CM during pregnancy does not alter prognosis or outcome for the patient, however take the safety of the fetus into consideration for work-up and treatment. E https://web.pathway.md/diseases/recGM7euHf4Lsuh55 5/8 6/23/23, 3:36 AM Cutaneous melanoma Pathway Show 2 more Concurrent use of exogenous hormones: recognize that exogenous hormones (such as oral contraceptives and hormone-containing contraceptive devices/implants, postmenopausal HRT, or hormones associated with assisted reproductive technology) may be used in female patients diagnosed with CM. E 8. Patient education General counseling: As per AAD 2019 guidelines: Discuss carefully the associated risks, benefits and uncertainties of non-surgical treatment with the patient and family. E Educate patients on self-examination of the skin and lymph node for the detection of recurrent disease or new primary CM. E As per ESMO 2019 guidelines: Provide patients with CM with instructions in avoidance of sunburns, extended unprotected solar or artificial UV exposure, and in lifelong regular self-examinations of the skin and peripheral lymph nodes. B Inform patients that their family members have an increased risk of melanoma. B Genetic counseling: as per AAD 2019 guidelines, provide cancer risk counseling by a qualified genetic counselor in patients with CM with any of the following: a family history of invasive CM or pancreatic cancer ( 3 affected members on one side of the family) multiple primary invasive CM ( 3), including one early-onset tumor (at age < 45 years) 1 melanocytic BAP1-mutated atypical intradermal tumor and a family history of mesothelioma, meningioma, and/or uveal melanoma 2 melanocytic BAP1-mutated atypical intradermal tumors. E 9. Follow-up and surveillance Assessment for cutaneous toxicity: ensure collaboration between dermatologists and oncologists for the management of cutaneous toxicity during BRAF/MEK kinase or immune checkpoint inhibitor therapy because appropriate recognition and control of skin side effects may improve the quality of life of patients with CM and avoid unnecessary interruption of medication. E Show 4 more Skin reconstruction after tumor resection (timing): consider performing reconstructive surgery in a delayed (asynchronous) fashion in adult patients after skin cancer resection. C Skin reconstruction after tumor resection (perioperative antibiotics): consider discussing the management of antibiotics with adult patients undergoing reconstruction after skin cancer https://web.pathway.md/diseases/recGM7euHf4Lsuh55 6/8 6/23/23, 3:36 AM Cutaneous melanoma Pathway resection when relevant. C Show 3 more Skin reconstruction after tumor resection (perioperative antithrombotics): consider discussing the management of anticlotting agents with adult patients undergoing reconstruction after skin cancer resection when relevant. C Show 2 more Skin reconstruction after tumor resection (perioperative analgesics): consider discussing the management of pain with adult patients undergoing reconstruction after skin cancer resection when relevant. C Show 2 more Skin reconstruction after tumor resection (follow-up): consider obtaining postoperative follow- up assessment in adult patients undergoing reconstruction after skin cancer resection. C Follow-up: As per AAD 2019 guidelines, obtain regular clinical follow-up as the most important means of detecting CM recurrence. Include history (review of systems) and physical examination in the follow-up assessment to direct the need for further radiologic or laboratory studies to detect local, regional, and distant metastatic disease. E Show 4 more As per ESMO 2019 guidelines: Monitor patients with CM to detect a relapse and to recognize additional skin tumors, especially secondary melanomas as early as possible. B Obtain serum S100 protein rather than LDH, if any blood test is required, as the most accurate blood test for monitoring disease progression in patients with CM. B Likelihood Ratios Pertinent positives The following findings increase the probability of cutaneous melanoma in adults. -1 Finding LR+ Value History of lesion enlargement 11 (8.5-14) Presence of lesion greater than 6 mm in diameter 2.3 (2.1-2.5) Presence of asymmetric lesion 2.1 (1.9-2.5) Presence of uneven or ragged borders of lesion 2.1 (1.8-2.4) Show 2 more Pertinent negatives The following findings decrease the probability of cutaneous melanoma in adults. -1 Finding LR- Value Absence of ABCDE score (< 1) 0.07 (0.04-0.13) https://web.pathway.md/diseases/recGM7euHf4Lsuh55 7/8 6/23/23, 3:36 AM Cutaneous melanoma Pathway Absence of lesion greater than 6 mm in diameter No history of lesion enlargement 0.17 (0.13-0.22) 0.18 (0.15-0.22) Absence of more than 1 shade of pigment in lesion 0.59 (0.52-0.68) Show 2 more References 1. Swetter SM, Tsao H, Bichakjian CK et al. Guidelines of care for the management of primary cutaneous melanoma. J Am Acad Dermatol. 2019 Jan;80 1 208 250. Open 2. O Michielin, A C J van Akkooi, P A Ascierto et al. Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019 Dec 1;30 12 1884 1901. Open 3. Andrew Chen, John G Albertini, Jeremy S Bordeaux et al. Evidence-Based Clinical Practice Guideline: Reconstruction after Skin Cancer Resection. Plast Reconstr Surg. 2021 May 1;147 5 812e-829e. Open 4. O Michielin, A van Akkooi, P Lorigan et al. ESMO consensus conference recommendations on the management of locoregional melanoma: under the auspices of the ESMO Guidelines Committee. Ann Oncol. 2020 Nov;31 11 1449 1461. Open 5. Rahul Seth, Hans Messersmith, Varinder Kaur et al. Systemic Therapy for Melanoma: ASCO Guideline. J Clin Oncol. 2020 Nov 20;38 33 3947 3970. Open 6. Wong SL, Faries MB, Kennedy EB et al. Sentinel Lymph Node Biopsy and Management of Regional Lymph Nodes in Melanoma: American Society of Clinical Oncology and Society of Surgical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2018 Feb 1;36 4 399 413. Open 7. US Preventive Services Task Force, Carol M Mangione, Michael J Barry et al. Screening for Skin Cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2023 Apr 18;329 15 1290 1295. Open 8. Dummer R, Hauschild A, Guggenheim M et al. Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012 Oct;23 Suppl 7:vii86 91. Open 9. Giulia C Leonardi, Luca Falzone, Rossella Salemi et al. Cutaneous melanoma: From pathogenesis to therapy Review). Int J Oncol. 2018 Apr;52 4 1071 1080. Open 10. David E Elder, Boris C Bastian, Ian A Cree et al. The 2018 World Health Organization Classification of Cutaneous, Mucosal, and Uveal Melanoma: Detailed Analysis of 9 Distinct Subtypes Defined by Their Evolutionary Pathway. Arch Pathol Lab Med. 2020 Apr;144 4 500 522. Open 11. G Argenziano, G Fabbrocini, P Carli et al. Epiluminescence microscopy for the diagnosis of doubtful melanocytic skin lesions. Comparison of the ABCD rule of dermatoscopy and a new 7-point checklist based on pattern analysis. Arch Dermatol. 1998 Dec;134 12 1563 70. Open 12. G Argenziano, C Catrical , M Ardigo et al. Seven-point checklist of dermoscopy revisited. Br J Dermatol. 2011 Apr;164 4 785 90. Open 13. Rahul Seth, Hans Messersmith, Pauline Funchain et al. Systemic Therapy for Melanoma: ASCO Guideline Rapid Recommendation Update. J Clin Oncol. 2022 Jul 20;40 21 2375 2377. Open https://web.pathway.md/diseases/recGM7euHf4Lsuh55 8/8