Guideline sources The following summarized guidelines for the evaluation and management of merkel cell carcinoma are prepared by our editorial team based on guidelines from the German Society of Dermatology (DDG 2023), the U.S. Preventive Services Task Force (USPSTF 2023; 2018), and the European Association of Dermato-Oncology (EADO/EDF/EORTC 2022). 1 2 3 4 Calculator TNM classification for Merkel cel Guidelines 1. Screening and diagnosis https://web.pathway.md/diseases/recqIj04bYj75VU1Z 1/6 6/30/23, 1:01 AM Merkel cell carcinoma Pathway Indications for screening: As per USPSTF 2023 guidelines, 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 As per USPSTF 2018 guidelines, insufficient evidence to assess the balance of benefits and harms of counseling adult persons about skin self-examination to prevent skin cancer. I 2. Classification and risk stratification Staging: use the current AJCC TNM classification for postoperative staging. A 3. Diagnostic investigations Clinical assessment: As per DDG 2023 guidelines: Inspect the entire skin and palpate the surrounding skin and regional lymph nodes in addition to inspection of the tumor. A Use appropriate questionnaires, such as the Quality of Life in Late-Stage Dementia questionnaire or the Cognitively Impaired Life Quality scale, in patients with cognitive impairment or dementia. B As per EDF 2022 guidelines, perform full body skin inspection and examination of all main lymph node basins in patients with suspected MCC. B Show 2 more Imaging for staging: As per DDG 2023 guidelines, obtain imaging of the draining lymph nodes to evaluate for locoregional metastases. A Show 2 more As per EDF 2022 guidelines: Obtain an ultrasound of the regional nodal basin and whole-body imaging, preferably with FDG-positron emission tomography/CT over contrast-enhanced CT of neck/chest/abdomen/pelvis, in patients with MCC. B Do not obtain routine brain imaging in asymptomatic patients with stage I-II disease. D 4. Diagnostic procedures Biopsy and histopathology: Perform complete excision of cutaneous neoplasms of uncertain biological behavior and obtain a histological examination. Perform biopsy with histological analysis if complete excision is not feasible. A https://web.pathway.md/diseases/recqIj04bYj75VU1Z 2/6 6/30/23, 1:01 AM Merkel cell carcinoma Pathway Obtain stepwise immunohistochemical studies to confirm the histological diagnosis of MCC and exclude differential diagnoses. A Sentinel lymph node biopsy: As per DDG 2023 guidelines: Perform sentinel node biopsy in patients without clinical or imaging evidence of metastasis (N0/M0), given the high frequency of lymphogenic spread. A Perform diagnostic lymph node dissection or aspiration cytology (if appropriate) following diagnostic imaging in patients with clinical suspicion of lymph node metastases. B As per EDF 2022 guidelines, perform sentinel lymph node biopsy in patients without clinical or imaging evidence of nodal or distant metastases. B 5. Medical management Systemic therapy: As per DDG 2023 guidelines: Assess for indications for systemic therapy, including PD-L1 inhibitors as first-line therapy, B in patients with locally advanced disease or distant metastases unsuitable for surgery or radiotherapy. A Assess for indications for chemotherapy in case of disease progression on immunotherapy or contraindications for immunotherapy. B As per EDF 2022 guidelines, offer anti-PD-L1-based immunotherapy as first-line therapy in immunocompetent patients with locally advanced or metastatic MCC (surgery not feasible). B Show 2 more Palliative care: As per DDG 2023 guidelines, offer palliative therapy, regardless of whether systemic treatment is administered or not, in all patients with advanced MCC. A As per EDF 2022 guidelines: Refer patients, particularly with symptomatic locally advanced or metastatic disease, to supportive care and a palliative care team early. B Consider offering palliative radiotherapy for the management of primary tumors and/or nodal involvement in frail patients, if surgery is not feasible. C 6. Therapeutic procedures Adjuvant radiotherapy: As per DDG 2023 guidelines: Offer adjuvant radiotherapy of the tumor bed even after complete resection. Administer a total dose of 50 Gy (single dose 2 Gy). Irradiate the tumor bed with a safety margin of 3 cm allowing for an adequate dose to be delivered to the skin (bolus). B https://web.pathway.md/diseases/recqIj04bYj75VU1Z 3/6 6/30/23, 1:01 AM Merkel cell carcinoma Pathway Offer irradiation of the affected lymph node basin in patients with positive sentinel node biopsy (micrometastasis). Consider offering irradiation of the affected lymph node basin in patients with negative sentinel node biopsy with increased risk of false negative results or recurrence (maximum tumor diameter > 2 cm). Administer a total dose of 50-56 Gy in subclinical tumors and 56 Gy in macroscopic/clinically manifest tumors. B As per EDF 2022 guidelines, offer postoperative adjuvant radiotherapy to the primary tumor bed within 8 weeks after complete tumor excision. B Show 2 more 7. Surgical interventions Surgical resection: As per DDG 2023 guidelines, perform complete excision with adequate surgical margins in patients with primary tumors without evidence of organ metastases. A As per EDF 2022 guidelines, perform complete excision of the tumor with clinical safety margins of 1 cm, followed by postoperative adjuvant radiotherapy on the tumor bed. B Lymph node dissection: As per DDG 2023 guidelines: Perform therapeutic lymphadenectomy or offer irradiation of the affected lymph node basin in patients with a positive sentinel lymph node (micrometastasis). B Perform therapeutic lymphadenectomy or consider offering irradiation of the affected lymph node basin in patients with clinically confirmed lymph node metastases and M0 situation. Consider offering a combination of both in situations with an increased risk of recurrence (such as capsule breach). B As per EDF 2022 guidelines: Perform therapeutic lymph node dissection in patients with nodal metastases identified clinically or by imaging. B Consider performing central lymph node dissection combined with adjuvant radiotherapy (preferred over central lymph node dissection alone) in patients with microscopic nodal disease (positive sentinel lymph node biopsy). Consider performing central lymph node dissection if adjuvant radiotherapy is not possible. C Resection of distant metastases: consider performing surgical removal of distant metastases on an individual basis if it appears feasible that the entire tumor mass can be removed (R0) without exposing the patient to undue measures. B 8. Follow-up and surveillance Follow-up: As per DDG 2023 guidelines: https://web.pathway.md/diseases/recqIj04bYj75VU1Z 4/6 6/30/23, 1:01 AM Merkel cell carcinoma Pathway Obtain close follow-up at 3-month intervals in patients with MCC, given the increased risk of locoregional recurrence within the first 2 years after the initial diagnosis. Consider continuing follow-up at 6-month intervals for another 3 years after 2 years. A Consider obtaining additional close follow-up with cross-sectional imaging (18-FDG-positron emission tomography/CT or a combination of ultrasound, CT, and MRI) in the first 2 years in patients with stage III disease or in case of lacking sentinel lymph node status. C As per EDF 2022 guidelines, obtain regular clinical visits coupled with ultrasound of the scar of the primary, draining area, and lymph nodes every 3-6 months for the first 3 years, followed by clinical visits every 12 months until 5 years in patients without additional high-risk factors. B Show 2 more Management of recurrent disease: perform complete surgical excision (R0) in patients with local recurrences. A Clinical findings Patient demographics Past medical history Elderly Cerebellar degeneration Human immunodeficiency virus infection Social history Immunocompromising condition Exposure to excessive sun Lambert-eaton myasthenic syndrome Lab findings Merkel cell polyomavirus infection Hyponatremia Solid organ transplantation Integument exam Skin nodule Serological findings merkel cell polyomavirus oncoprotein antibodies References 1. J rgen C Becker, Ambros J Beer, Viola K DeTemple et al. S2k Guideline Merkel cell carcinoma MCC, neuroendocrine carcinoma of the skin) Update 2022. J Dtsch Dermatol Ges. 2023 Mar;21 3 305 320. Open 2. Marie-L a Gauci, Cynthia Aristei, Jurgen C Becker et al. Diagnosis and treatment of Merkel cell carcinoma: European consensus-based interdisciplinary guideline Update 2022. Eur J Cancer. 2022 Aug;171 203 231. Open https://web.pathway.md/diseases/recqIj04bYj75VU1Z 5/6 6/30/23, 1:01 AM Merkel cell carcinoma Pathway 3. US Preventive Services Task Force, Grossman DC, Curry SJ et al. Behavioral Counseling to Prevent Skin Cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2018 Mar 20;319 11 1134 1142. Open 4. 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 5. Vazquez Doval J, Llombart Cussac B, Perez Bustillo A et al. Diagnosis and Treatment of Merkel Cell Carcinoma in Specialized Dermatology Units: A Clinical Practice Guideline of the Spanish Academy of Dermatology and Venereology. Actas Dermosifiliogr. 2019 Jul Aug;110 6 460 468. Open https://web.pathway.md/diseases/recqIj04bYj75VU1Z 6/6