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Diagnosis and treatment of Merkel cell carcinoma: European consensus-based interdisciplinary guideline – Update 2022

Open AccessPublished:June 19, 2022DOI:https://doi.org/10.1016/j.ejca.2022.03.043

      Highlights

      • Major progress in the diagnosis of Merkel cell carcinoma by immunohistochemistry/molecular pathogenesis.
      • The management of primary tumour was mostly based on retrospective studies.
      • Breakthrough in advance disease management with the approval of immunotherapy.

      Abstract

      Merkel cell carcinoma (MCC) is a rare skin cancer, accounting for less than 1% of all cutaneous malignancies. It is found predominantly in white populations and risk factors include advanced age, ultraviolet exposure, male sex, immunosuppression, such as AIDS/HIV infection, haematological malignancies or solid organ transplantation, and Merkel cell polyomavirus infection.
      MCC is an aggressive tumour with 26% of cases presenting lymph node involvement at diagnosis and 8% with distant metastases. Five-year overall survival rates range between 48% and 63%. Two subsets of MCC have been characterised with distinct molecular pathogenetic pathways: ultraviolet-induced MCC versus virus-positive MCC, which carries a better prognosis. In both subtypes, there are alterations in the retinoblastoma protein and p53 gene structure and function. MCC typically manifests as a red nodule or plaque with fast growth, most commonly on sun exposed areas. Histopathology (small-cell neuroendocrine appearance) and immunohistochemistry (CK20 positivity and TTF-1 negativity) confirm the diagnosis. The current staging systems are the American Joint Committee on Cancer/Union for international Cancer control 8th edition. Baseline whole body imaging is encouraged to rule out regional and distant metastasis.
      For localised MCC, first-line treatment is surgical excision with postoperative margin assessment followed by adjuvant radiation therapy (RT). Sentinel lymph node biopsy is recommended in all patients with MCC without clinically detectable lymph nodes or distant metastasis. Adjuvant RT alone, eventually combined with complete lymph nodes dissection is proposed in case of micrometastatic nodal involvement. In case of macroscopic nodal involvement, the standard of care is complete lymph nodes dissection potentially followed by post-operative RT. Immunotherapy with anti-PD-(L)1 antibodies should be offered as first-line systemic treatment in advanced MCC. Chemotherapy can be used when patients fail to respond or are intolerant for anti-PD-(L)1 immunotherapy or clinical trials.

      Keywords

      Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer, accounting for less than 1% of all cutaneous malignancies which particularly touches old and/or immunosuppressed patients. Two subsets of MCC have been characterized with distinct molecular pathogenetic pathways based on mutational burden due to ultraviolet (UV) exposure and Merkel cell polyomavirus (MCPyV) infection. Five-year overall survival (OS) rates range between 48% and 63%. A collaboration of multidisciplinary experts from the European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO) and the European Organisation of Research and Treatment of Cancer (EORTC) was formed to update the information and recommendations on MCC European guidelines based on scientific evidence and to provide an expert consensus.
      The current staging systems are the American Joint Committee on Cancer (AJCC)/Union for international Cancer control (UICC) 8th edition. Whole body baseline imaging is encouraged to rule out regional and distant metastasis.
      For localised MCC, first-line treatment is surgical excision with postoperative margin assessment followed by adjuvant radiation therapy (RT). Sentinel lymph node biopsy (SLNB) is recommended in all patients with MCC and without clinically detectable lymph nodes or distant metastasis. Adjuvant RT alone, eventually combined with complete lymph nodes dissection (CLNDs), is proposed in case of micrometastatic nodal involvement. In case of macroscopic nodal involvement, the standard of care is CLND, potentially followed by post-operative RT. Anti-PD-(L)1 antibodies should be offered as first-line systemic treatment in advanced MCC. Several clinical trials are ongoing with new therapies or new combinations of therapies for advanced MCC, and immunotherapy is also currently under evaluation in the adjuvant and neoadjuvant setting. Patients should be involved in shared decision-making regarding their management and should be provided with best supportive care in optimising symptoms’ management and improving quality of life. The frequency of follow-up visits and investigations are based on disease stage, treatment given and individual patient needs.

      1. Propose

      1.1 Societies in charge

      These guidelines were developed on behalf of the EDF. The EADO coordinated the authors’ contributions under the leadership of Céleste Lebbé. Paul Lorigan was responsible for the collaboration with the EORTC to ensure the interdisciplinary quality of the guideline. Twenty-six experts from 13 countries, all of whom were delegates of national and/or international medical societies, collaborated in the development of these guidelines.

      1.2 Financing of these guidelines

      The authors did this work on a voluntary basis and did not receive any honorarium or reimbursements. Guideline task-force group members stated their conflicts of interest in the relevant section.

      1.3 Disclaimer

      The field of medicine is subject to a continuous evolutionary process. This entails that all statements, especially with regard to diagnostic and therapeutic procedures, can only reflect scientific knowledge at the time of printing these guidelines. The attending physician invoking these guidelines recommendations must take into account scientific progress since the publication of the guidelines. In the selection and dosage of the drugs, attention was paid to compliance with the therapeutic recommendations given. Nevertheless, users are requested to use package inserts and technical information from the manufacturers as a backup, and in case of doubt, consult a specialist. The user remains responsible for all diagnostic and therapeutic applications, drugs and doses.
      This work is protected by copyrights in all its parts. Any use outside the provision of the copyright act without the written permission by the guideline program in oncology GPO of the EADO is prohibited and punishable by law. No part of this work may be reproduced in any way without written permission by the GPO. This applies, in particular, to duplications, translations, microfilming and the storage, application and utilisation in electronic systems, intranets and internet.

      1.4 Scope

      These guidelines were written in order to assist clinicians in the diagnosis, treatment and follow-up of MCC. This update was initiated mainly due to advances in systemic treatments and a new AJCC staging system for patients with MCC, which justify a newer approach to definitions, risk classification and multidisciplinary therapeutic strategies. The use of these guidelines in clinical routine should improve patient care.

      1.5 Target population

      These guidelines give recommendations for the diagnosis, treatment and follow-up of patients with MCC. They are aimed at attending physicians and the medical nursing staff.

      1.6 Objectives and formulation of questions

      The guidelines are produced for all clinicians who care for patients with all stages of MCC. Particular emphasis is given to the definition, epidemiology, molecular pathogenesis, clinical and histopathological diagnosis, staging, management, and include a specific section on immunosuppressed patients, supportive care and follow-up. The formulation of clear sections has been made to support clinicians in their practice.

      1.7 Audience and period of validity

      This set of guidelines will assist healthcare providers in managing their patients according to the current standards of care and evidence-based medicine. It is not intended to replace the accepted national guidelines. The guidelines published here reflect the best published data available at the time the report was prepared. Caution should be exercised in interpreting the data; the results of future studies may modify the conclusions or recommendations in this report. In addition, it may be necessary to deviate from these guidelines for individual patients or under special circumstances. Just as adherence to the guidelines may not constitute defence against a claim of negligence (malpractice), deviation from them should not necessarily be deemed negligent. These guidelines will require updating approximately every 2 years (expiration date: May 2023) but advances in medical sciences may demand an earlier update.

      2. Methods

      The European Interdisciplinary Guidelines on MCC are written as a uniform text.
      The guidelines published here are an update of the existing European consensus-based (EDF/EADO/EORTC) interdisciplinary guidelines for the management of MCC (former version 2015) [
      • Lebbe C.
      • Becker J.C.
      • Grob J.-J.
      • Malvehy J.
      • del Marmol V.
      • Pehamberger H.
      • et al.
      Diagnosis and treatment of Merkel Cell Carcinoma. European consensus-based interdisciplinary guideline.
      ] and based on other up-to-date guidelines, including the German S2k guidelines (2019) [
      • Becker J.C.
      • Eigentler T.
      • Frerich B.
      • Gambichler T.
      • Grabbe S.
      • Höller U.
      • et al.
      S2k guidelines for Merkel cell carcinoma (MCC, neuroendocrine carcinoma of the skin) – update 2018.
      ] and the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for MCC (version 1.2021) [
      • Schmults Chrysalyne D.
      • Blitzblau Rachel
      • Aasi Sumaira Z.
      • Alam Murad
      • Andersen James S.
      • Baumann Brian C.
      • et al.
      Merkel Cell Carcinoma Version 1.2021.
      ]. De novo literature search was conducted by the authors with Medline search in English language publications with last search date on 23rd April 2021. Search terms included: ‘MCC’ combined with ‘epidemiology, incidence, mortality, survival’, ‘diagnosis, prognosis, staging, imaging, guidelines, treatment, surgical excision, SLNB, lymph node dissection, radiotherapy, neoadjuvant, adjuvant, systemic, anti-PD-(L)1 antibody, avelumab, pembrolizumab, nivolumab, chemotherapy, clinical trials, immunosuppression, solid organ transplant, haematological malignancy, human immunodeficiency virus, acquired immunodeficiency syndrome, follow-up. The references cited in selected papers were also searched for further relevant publications. The methodology of these updated guidelines was based on the standards of the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument [
      • Brouwers M.C.
      • Kho M.E.
      • Browman G.P.
      • Burgers J.S.
      • Cluzeau F.
      • Feder G.
      • et al.
      AGREE II: Advancing guideline development, reporting and evaluation in health care.
      ].
      Recommendations are based on the level of best quality available evidence and good clinical practice.
      The levels of evidence were graded according to the Oxford classification (Table 1) [
      • Paul Glasziou
      • Greenhalgh Trish
      • Heneghan Carl
      • Alessandro Liberati I.M.
      • Phillips Bob
      • Hazel Thornton O.G.
      • et al.
      OCEBM Table of Evidence Working Group = Jeremy Howick, Iain Chalmers (James Lind Library)OCEBM Levels of Evidence Working Group∗
      “The Oxford 2011 levels of evidence”.
      ].
      Table 1Oxford centre for evidence-based medicine 2011: Levels of evidence [
      • Paul Glasziou
      • Greenhalgh Trish
      • Heneghan Carl
      • Alessandro Liberati I.M.
      • Phillips Bob
      • Hazel Thornton O.G.
      • et al.
      OCEBM Table of Evidence Working Group = Jeremy Howick, Iain Chalmers (James Lind Library)OCEBM Levels of Evidence Working Group∗
      “The Oxford 2011 levels of evidence”.
      ].
      QuestionStep 1 (Level 1
      Level may be graded down on the basis of study quality, imprecision, indirectness (study PICO does not match questions PICO) because of inconsistency between studies, or because the absolute effect size is very small; Level may be graded up if there is a large or very large effect size.
      )
      Step 2 (Level 2
      Level may be graded down on the basis of study quality, imprecision, indirectness (study PICO does not match questions PICO) because of inconsistency between studies, or because the absolute effect size is very small; Level may be graded up if there is a large or very large effect size.
      )
      Step 3 (Level 3
      Level may be graded down on the basis of study quality, imprecision, indirectness (study PICO does not match questions PICO) because of inconsistency between studies, or because the absolute effect size is very small; Level may be graded up if there is a large or very large effect size.
      )
      Step 4 (Level 4
      Level may be graded down on the basis of study quality, imprecision, indirectness (study PICO does not match questions PICO) because of inconsistency between studies, or because the absolute effect size is very small; Level may be graded up if there is a large or very large effect size.
      )
      Step 5 (Level 5)
      How common is the problem?Local and current random sample surveys (or censuses)Systematic review of surveys that allow matching to local circumstances
      As always, a systematic review is generally better than an individual study.
      Local non-random sample
      As always, a systematic review is generally better than an individual study.
      Case-series
      As always, a systematic review is generally better than an individual study.
      n/a
      Is this diagnostic or monitoring test accurate? (Diagnosis)Systematic review of cross-sectional studies with consistently applied reference standard and blindingIndividual cross-sectional studies with consistently applied reference standard and blindingNon-consecutive studies or studies without consistently applied reference standards
      As always, a systematic review is generally better than an individual study.
      Case-control studies, or poor or non-independent reference standard
      As always, a systematic review is generally better than an individual study.
      Mechanism-based reasoning
      What will happen if we do not add a therapy? (Prognosis)Systematic review of inception cohort studiesInception cohort studiesCohort study or control arm of randomised trial
      Level may be graded down on the basis of study quality, imprecision, indirectness (study PICO does not match questions PICO) because of inconsistency between studies, or because the absolute effect size is very small; Level may be graded up if there is a large or very large effect size.
      Case-series or case-control studies, or poor quality prognostic cohort study
      As always, a systematic review is generally better than an individual study.
      n/a
      Does this intervention help? (Treatment Benefits)Systematic review of randomised trials or n-of-1 trialsRandomised trial or observational study with dramatic effectNon-randomised controlled cohort/follow-up study
      As always, a systematic review is generally better than an individual study.
      Case-series, case-control studies or historically controlled studies
      As always, a systematic review is generally better than an individual study.
      Mechanism-based reasoning
      What are the COMMON harms? (Treatment Harms)Systematic review of randomised trials, systematic review of nested case–control studies, nof-1 trial with the patient you are raising the question about or observational study with dramatic effectIndividual randomised trial or (exceptionally) observational study with dramatic effectNon-randomised controlled cohort/follow-up study (post-marketing surveillance) provided there are sufficient numbers to rule out a common harm. (For long-term harms, the duration of follow-up must be sufficient.)
      As always, a systematic review is generally better than an individual study.
      Case-series, case-control or historically controlled studies
      As always, a systematic review is generally better than an individual study.
      Mechanism-based reasoning
      What are the RARE harms? (Treatment Harms)Systematic review of randomised trials or n-of-1 trialRandomised trial or (exceptionally) observational study with dramatic effect
      Is this (early detection) test worthwhile? (Screening)Systematic review of randomised trialsRandomised trialNon -randomised controlled cohort/follow-up study
      As always, a systematic review is generally better than an individual study.
      Case-series, case-control or historically controlled studies
      As always, a systematic review is generally better than an individual study.
      Mechanism-based reasoning
      a Level may be graded down on the basis of study quality, imprecision, indirectness (study PICO does not match questions PICO) because of inconsistency between studies, or because the absolute effect size is very small; Level may be graded up if there is a large or very large effect size.
      b As always, a systematic review is generally better than an individual study.
      The grades of recommendation were classified as follows:
      • A: Strong recommendation. Syntax: ‘shall’.
      • B: Recommendation. Syntax: ‘should’.
      • C: Weak recommendation. Syntax: ‘may/can’.
      • X: Should not be recommended.
      • 0: Recommendation pending. Currently not available or not sufficient evidence to make a recommendation in favour or against.
      Expert consensus was provided wherever adequate evidence was not available.

      2.1 Consensus building process

      The consensus building process was conducted as follows:
      In the first round, medical experts who participated in their national guideline development processes were involved in producing an initial draft. The EORTC selected experts from different specialties to contribute to these first drafts.
      In a second round, a consensus meeting was held on 13th July 2021 with final outcomes: (1) the approval of the text and (2) a consensus rate of agreement of at least 80% for recommendations provided in structured boxes. Voting for the recommendations included the selection of ‘Agree’, ‘Disagree’ or ‘Abstain’ vote and the possibility of providing comments in case of disagree/abstain. Consensus voting on recommendations and finalisation of the draft was conducted among coauthors through emailing between August 15 th September 2021 and the 18th January 2022. There were 3 recommendations that had a lower than 80% consensus rate: the recommendation for 14, 15 and 16. Comments were received from coauthors, the recommendations were revised, and a second round of voting was conducted for these tree recommendations.

      3. Definition (inclusion – exclusion)

      MCC is a highly aggressive primary cutaneous carcinoma with epithelial and endocrine features. Its origin is still disputed: Merkel cell precursors (potentially derived from epidermal stem cells or hair follicle stem cells), pre-B cells, pro-B cells or dermal fibroblasts have been suggested [
      • Samimi M.
      • Kervarrec T.
      • Touze A.
      Immunobiology of Merkel cell carcinoma.
      ].

      4. Epidemiology – risk factors

      MCC is a rare skin cancer, accounting for less than 1% of all cutaneous malignancies [
      • Holterhues C.
      • Vries E De
      • Louwman M.W.
      • Koljenović S.
      • Nijsten T.
      Incidence and trends of cutaneous malignancies in The Netherlands, 1989-2005.
      ,
      • Eisemann N.
      • Waldmann A.
      • Geller A.C.
      • Weinstock M.A.
      • Volkmer B.
      • Greinert R.
      • et al.
      Non-melanoma skin cancer incidence and impact of skin cancer screening on incidence.
      ]. The highest incidence of MCC has been reported in Australia (annual age-standardised incidence rate ranging from 0.82 to 2.5 per 100 000 population) [
      • Garbutcheon-Singh K.B.
      • Curchin D.J.
      • McCormack C.J.
      • Smith S.D.
      Trends in the incidence of Merkel cell carcinoma in Victoria, Australia, between 1986 and 2016.
      ,
      • Youlden D.R.
      • Soyer H.P.
      • Youl P.H.
      • Fritschi L.
      • Baade P.D.
      Incidence and survival for Merkel cell carcinoma in Queensland, Australia, 1993-2010.
      ,
      • Girschik J.
      • Thorn K.
      • Beer T.W.
      • Heenan P.J.
      • Fritschi L.
      Merkel cell carcinoma in Western Australia: a population-based study of incidence and survival.
      ], followed by New Zealand (0.88–0.96) [
      • Robertson J.P.
      • Liang E.S.
      • Martin R.C.W.
      Epidemiology of Merkel cell carcinoma in New Zealand: a population-based study.
      ,
      • Lee Y.
      • Chao P.
      • Coomarasamy C.
      • Mathy J.A.
      Epidemiology and survival of Merkel cell carcinoma in New Zealand: a population-based study between 2000 and 2015 with international comparison.
      ] and the United States (0.66–0.79) [
      • Jacobs D.
      • Huang H.
      • Olino K.
      • Weiss S.
      • Kluger H.
      • Judson B.L.
      • et al.
      Assessment of age, period, and birth cohort effects and trends in merkel cell carcinoma incidence in the United States.
      ,
      • Paulson K.G.
      • Park S.Y.
      • Vandeven N.A.
      • Lachance K.
      • Thomas H.
      • Chapuis A.G.
      • et al.
      Merkel cell carcinoma: current US incidence and projected increases based on changing demographics.
      ,
      • Fitzgerald T.L.
      • Dennis S.
      • Kachare S.D.
      • Vohra N.A.
      • Wong J.H.
      • Zervos E.E.
      Dramatic increase in the incidence and mortality from Merkel cell carcinoma in the United States.
      ]. Among European countries, incidence rates are fairly similar across the continent: 0.25/100 000 person-years in France [
      • Fondain M.
      • Dereure O.
      • Uhry Z.
      • Guizard A.V.
      • Woronoff A.S.
      • Colonna M.
      • et al.
      Merkel cell carcinoma in France: a registries-based, comprehensive epidemiological survey.
      ], 0.31 in Spain [
      • Rubió-Casadevall J.
      • Hernandez-Pujol A.M.
      • Ferreira-Santos M.C.
      • Morey-Esteve G.
      • Vilardell L.
      • Osca-Gelis G.
      • et al.
      Trends in incidence and survival analysis in non-melanoma skin cancer from 1994 to 2012 in Girona, Spain: a population-based study.
      ], 0.3 in Scotland [
      • Samuel R.J.
      • Matthews A.G.
      • Holme S.A.
      Merkel cell carcinoma in Scotland 2000-10.
      ] and 0.35 in the Netherlands [
      • Reichgelt B.A.
      • Visser O.
      Epidemiology and survival of Merkel cell carcinoma in The Netherlands. A population-based study of 808 cases in 1993-2007.
      ]. However, the incidence rate appears slightly lower in Scandinavian countries: 0.19 in Sweden [
      • Zaar O.
      • Gillstedt M.
      • Lindelöf B.
      • Wennberg-Larkö A.M.
      • Paoli J.
      Merkel cell carcinoma incidence is increasing in Sweden.
      ] and 0.12 in Finland [
      • Kukko H.
      • Böhling T.
      • Koljonen V.
      • Tukiainen E.
      • Haglund C.
      • Pokhrel A.
      • et al.
      Merkel cell carcinoma - a population-based epidemiological study in Finland with a clinical series of 181 cases.
      ].
      More importantly, the incidence appears to be rising significantly over time in most areas, by as much as a factor 3 to 5 from 1985 to 2013 and could be due to the aging population [
      • Kieny A.
      • Cribier B.
      • Meyer N.
      • Velten M.
      • Jégu J.
      • Lipsker D.
      Epidemiology of Merkel cell carcinoma. A population-based study from 1985 to 2013, in northeastern of France.
      ,
      • Goon P.K.C.
      • Greenberg D.C.
      • Igali L.
      • Levell N.J.
      Merkel cell carcinoma: rising incidence in the east of england.
      ,
      • Lyhne D.
      • Lock-Andersen J.
      • Dahlstrøm K.
      • Drzewiecki K.T.
      • Balslev E.
      • Muhic A.
      • et al.
      Rising incidence of Merkel cell carcinoma.
      ], particularly in individuals over 70 years old and non-Hispanic whites [
      • Paulson K.G.
      • Park S.Y.
      • Vandeven N.A.
      • Lachance K.
      • Thomas H.
      • Chapuis A.G.
      • et al.
      Merkel cell carcinoma: current US incidence and projected increases based on changing demographics.
      ,
      • Freeman M.B.B.
      • Holman D.M.
      • Qin J.
      • Lunsford N.B.
      Merkel cell carcinoma incidence, trends, and survival rates among adults aged ≥50 years from United States Cancer Statistics.
      ]. This could be due to a true increased incidence related to an increase in risk factors, as well as to upgraded diagnostic immunohistochemical tools and improved registration.
      Known risk factors for MCC are the following:
      MCC is an aggressive tumour [
      • Reichgelt B.A.
      • Visser O.
      Epidemiology and survival of Merkel cell carcinoma in The Netherlands. A population-based study of 808 cases in 1993-2007.
      ,
      • Kieny A.
      • Cribier B.
      • Meyer N.
      • Velten M.
      • Jégu J.
      • Lipsker D.
      Epidemiology of Merkel cell carcinoma. A population-based study from 1985 to 2013, in northeastern of France.
      ]. Five-year relative survival rates range between 48% and 63%. Better prognosis has been reported for women and in younger ages [
      • Garbutcheon-Singh K.B.
      • Curchin D.J.
      • McCormack C.J.
      • Smith S.D.
      Trends in the incidence of Merkel cell carcinoma in Victoria, Australia, between 1986 and 2016.
      ,
      • Kieny A.
      • Cribier B.
      • Meyer N.
      • Velten M.
      • Jégu J.
      • Lipsker D.
      Epidemiology of Merkel cell carcinoma. A population-based study from 1985 to 2013, in northeastern of France.
      ,
      • Tam M.
      • Luu M.
      • Barker C.A.
      • Gharavi N.M.
      • Hamid O.
      • Shiao S.L.
      • et al.
      Improved survival in women versus men with Merkel cell carcinoma.
      ].

      5. Molecular pathogenesis

      The main risk factors for developing MCC – chronic UV-exposure and immunosuppression – point to its molecular pathogenesis. Indeed, one subset of MCCs (virus negative) – prevailing in white patients living in areas with high UV exposure – is characterised by a high tumour mutational burden with a strong UV-signature. Retinoblastoma protein (RB) and p53 are among the most significantly mutated genes. However, the other major MCC subgroup – more common in the Northern hemisphere – has a very low tumour mutational burden and instead harbours clonal integration of the MCPyV (virus positive) [
      • Starrett G.J.
      • Thakuria M.
      • Chen T.
      • Marcelus C.
      • Cheng J.
      • Nomburg J.
      • et al.
      Clinical and molecular characterization of virus-positive and virus-negative Merkel cell carcinoma.
      ]. Notably, MCPyV-encoded early transforming genes also interfere with RB and p53. Indeed, viral integration leads to the expression of a truncated MCPyV large T (LT) antigen that contains the LXCXE motif, capable of binding to RB protein and inactivating its tumour suppression function [
      • DeCaprio J.A.
      Merkel cell polyomavirus and Merkel cell carcinoma.
      ]. LT plays a major role in tumour maintenance and cell growth. Virus-positive MCC tumours also express MCPyV small T antigen (sT) which, upon binding Fbxw7 (F-Box And WD Repeat Domain Containing 7, a critical tumour suppressor and one of the most commonly deregulated ubiquitin-proteasome system proteins in human cancer), leads to the accumulation of oncogenic proteins such as cyclin-E, c-Jun, mTOR and truncated LT-Ag [
      • Verhaegen M.E.
      • Mangelberger D.
      • Harms P.W.
      • Vozheiko T.D.
      • Weick J.W.
      • Wilbert D.M.
      • et al.
      Merkel cell polyomavirus small T antigen is oncogenic in transgenic mice.
      ]. sT is considered the main transforming driver gene with a major role in metastasis [
      • Samimi M.
      • Kervarrec T.
      • Touze A.
      Immunobiology of Merkel cell carcinoma.
      ,
      • DeCaprio J.A.
      Molecular pathogenesis of merkel cell carcinoma.
      ,
      • Pietropaolo V.
      • Prezioso C.
      • Moens U.
      Merkel cell polyomavirus and merkel cell carcinoma.
      ].
      Because of the presence of either multiple neoepitopes or viral proteins, both UV-associated and viral carcinogenesis result in highly immunogenic tumours, which only become clinically evident when they either acquire immune escape mechanisms or cannot be controlled in immunocompromised patients. While there are several phenotypic similarities between both forms of MCC, there are increasing reports indicating histopathologic differences [
      • Kervarrec T.
      • Samimi M.
      • Guyétant S.
      • Sarma B.
      • Chéret J.
      • Blanchard E.
      • et al.
      Histogenesis of Merkel cell carcinoma: a comprehensive review.
      ]. The cell of origin of MCC remains unknown; suggested candidates include pro/pre-B cells and epidermal stem cells. However, there are increasing lines of evidence pointing towards interfollicular and hair bulge basal keratinocytes for UV- and viral-associated MCC, respectively [
      • Samimi M.
      • Kervarrec T.
      • Touze A.
      Immunobiology of Merkel cell carcinoma.
      ].

      6. Diagnostic approach

      6.1 Clinical diagnosis

      6.1.1 Clinical presentation and dermatoscopic features

      MCC typically manifests as a firm, asymptomatic, non-tender flesh-coloured or red nodule or plaque (Fig. 1). The lesion often rapidly increases in size over a period of weeks or months. Ulceration and bleeding are infrequent at first presentation but they might occur at an advanced stage [
      • Lebbe C.
      • Becker J.C.
      • Grob J.-J.
      • Malvehy J.
      • del Marmol V.
      • Pehamberger H.
      • et al.
      Diagnosis and treatment of Merkel Cell Carcinoma. European consensus-based interdisciplinary guideline.
      ,
      • Albores-Saavedra J.
      • Batich K.
      • Chable-Montero F.
      • Sagy N.
      • Schwartz A.M.
      • Henson D.E.
      Merkel cell carcinoma demographics, morphology, and survival based on 3870 cases: a population based study.
      ,
      • Heath M.
      • Jaimes N.
      • Lemos B.
      • Mostaghimi A.
      • Wang L.C.
      • Peñas P.F.
      • et al.
      Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features.
      ]. The most frequent anatomic sites of MCC are the sun-exposed areas of head and neck (29–43.9%) and the extremities (36.9–45%), whereas less than 5–10% of MCCs develop on partially sun-protected areas (abdomen, thighs and hair-bearing scalp) or highly sun-protected areas (buttocks). Extra-cutaneous sites such as vulva, vagina, oral mucosa [
      • Islam M.N.
      • Chehal H.
      • Smith M.H.
      • Islam S.
      • Bhattacharyya I.
      Merkel cell carcinoma of the buccal mucosa and lower lip.
      ], parotid gland, submandibular gland or nasal cavity are very rarely involved (around 0.5%) [
      • Albores-Saavedra J.
      • Batich K.
      • Chable-Montero F.
      • Sagy N.
      • Schwartz A.M.
      • Henson D.E.
      Merkel cell carcinoma demographics, morphology, and survival based on 3870 cases: a population based study.
      ,
      • Heath M.
      • Jaimes N.
      • Lemos B.
      • Mostaghimi A.
      • Wang L.C.
      • Peñas P.F.
      • et al.
      Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features.
      ,
      • Emge D.A.
      • Cardones A.R.
      Updates on merkel cell carcinoma.
      ,
      • Coggshall K.
      • Tello T.L.
      • North J.P.
      • Yu S.S.
      Merkel cell carcinoma: an update and review.
      ]. In some cases, the primary tumour (pT) site is unknown and the disease presents metastatic disease to lymph nodes or distant organs (0.8–14%) [
      • Albores-Saavedra J.
      • Batich K.
      • Chable-Montero F.
      • Sagy N.
      • Schwartz A.M.
      • Henson D.E.
      Merkel cell carcinoma demographics, morphology, and survival based on 3870 cases: a population based study.
      ]. A few cases of intraepidermal MCC manifesting a slightly scaly erythematous patch or violaceous nodule have also been described in the literature [
      • Jour G.
      • Aung P.P.
      • Rozas-Muñoz E.
      • Curry J.L.
      • Prieto V.
      • Ivan D.
      Intraepidermal Merkel cell carcinoma: a case series of a rare entity with clinical follow up.
      ,
      • Navarrete-Dechent C.
      • Cordova M.
      • Aleissa S.
      • Battle L.R.
      • Ganly I.
      • Pulitzer M.
      • et al.
      Dermoscopy and reflectance confocal microscopy of intraepidermal Merkel cell carcinoma.
      ]. The pT can vary in size. One series reported that 21.2% measured less than 1 cm in the largest diameter, 43.3% between 1 and 2 cm and 35.3% more than 2 cm [
      • Heath M.
      • Jaimes N.
      • Lemos B.
      • Mostaghimi A.
      • Wang L.C.
      • Peñas P.F.
      • et al.
      Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features.
      ].
      Fig. 1
      Fig. 1Clinical manifestations of MCC: (a) a slightly elevated red plaque on the thigh of a 68 year-old man. (b) A well-demarcated nodule on the nose of a 70 year-old woman mimicking a basal cell carcinoma, with clinically visible linear branching vessels and an area of pigmentation. (c) A poorly demarcated amelanotic nodule with central ulceration on the temporal area of a 75 year-old man. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article). MCC, Merkel cell carcinoma.
      MCC is frequently misdiagnosed initially, contributing to diagnostic delay; MCC may be confused with an inflammatory lesion such as acne or other folliculitis or with a benign tumour such as epidermal cyst, lipoma, dermatofibroma, fibroma and angioma. In many other cases, MCC is misinterpreted as another malignant tumour, mainly basal or squamous cell carcinoma and less frequently lymphoma, metastatic carcinoma, nodular or amelanotic melanoma or sarcoma, with low impact on prognosis since these tumours are usually rapidly biopsied or removed and the correct diagnosis is established. A clinically useful recommendation is that any nodule with non-specific morphology, lack of tenderness and fast growing should be biopsied rather than monitored.
      The dermatoscopy of MCC reveals a predominant red colour corresponding either to numerous vessels or generalised erythema (Fig. 2). Milky-red or pink structureless colour is an additional dermatoscopic characteristic of MCC [
      • Dalle S.
      • Parmentier L.
      • Moscarella E.
      • Phan A.
      • Argenziano G.
      • Thomas L.
      Dermoscopy of merkel cell carcinoma.
      ,
      • Lallas A.
      • Moscarella E.
      • Argenziano G.
      • Longo C.
      • Apalla Z.
      • Ferrara G.
      • et al.
      Dermoscopy of uncommon skin tumors.
      ]. It might be seen either as a pink background or as smaller roundish areas (milky red areas or globules or clods). Several morphologic types of vessels may be present, including dotted, glomerular, arborising and linear irregular vessels [
      • Dalle S.
      • Parmentier L.
      • Moscarella E.
      • Phan A.
      • Argenziano G.
      • Thomas L.
      Dermoscopy of merkel cell carcinoma.
      ,
      • Lallas A.
      • Moscarella E.
      • Argenziano G.
      • Longo C.
      • Apalla Z.
      • Ferrara G.
      • et al.
      Dermoscopy of uncommon skin tumors.
      ]. Usually, more than one morphologic type of vessel co-exist, resulting in the so-called polymorphous vascular pattern, although lesions with monomorphous vessels have also been described. White areas are also frequently described (Fig. 2) [
      • Jalilian C.
      • Chamberlain A.J.
      • Haskett M.
      • Rosendahl C.
      • Goh M.
      • Beck H.
      • et al.
      Clinical and dermoscopic characteristics of Merkel cell carcinoma.
      ].
      Fig. 2
      Fig. 2Dermatoscopic images of MCC: (a) pink structureless colour combined with white structureless areas and white shiny lines. (b) Red and white structureless areas, multiple ulcerations, dotted and short linear vessels. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article). MCC, Merkel cell carcinoma.
      Overall, the dermatoscopic pattern of MCC cannot be considered as specific since it overlaps with other non-pigmented cutaneous tumours such as poorly differentiated squamous cell carcinoma and amelanotic melanoma. However, the detection of polymorphous vessels and/or milky red colour raises the suspicion of malignancy since both are exceedingly rare in benign tumours. This justifies the diagnostic value of dermatoscopy from a clinical perspective.

      6.2 Histological diagnosis: characteristics and differential diagnosis, pathology report

      6.2.1 Characteristics and differential diagnosis

      Though histopathologic assessment is essential to diagnose and further differentiate this clinically non-specific tumour. Depending on size and location, tissue sampling in suspicious lesions should be accomplished by punch, incisional or excisional biopsy [
      • Becker J.C.
      • Stang A.
      • DeCaprio J.A.
      • Cerroni L.
      • Lebbé C.
      • Veness M.
      • et al.
      Merkel cell carcinoma.
      ,
      • Tello T.L.
      • Coggshall K.
      • Yom S.S.
      • Yu S.S.
      Merkel cell carcinoma: an update and review: current and future therapy.
      ]. MCC generally consists of a solid nodular lesion in the dermis and subcutis. On haematoxylin eosin stains, the tumour typically exhibits sheets and nests of uniform small round blue undifferentiated cells with scant cytoplasm, a ‘salt and pepper’ chromatin pattern, large lobulated nucleoli, high mitotic rate and occasional necrotic cells. A small cell variant displays overlapping features with cutaneous lymphoma. Important differential diagnoses include melanoma, Ewing sarcoma, neuroblastoma, leukaemia cutis or poorly differentiated carcinoma metastatic to the skin (e.g. small cell lung cancer). Superficial or in-situ types may be mistaken for other intraepithelial malignancies.
      Given the broad differential diagnosis, immunohistochemistry is mandatory to confirm the diagnosis and to distinguish MCC from potential histopathologic imitators (Table 2). MCC is characterised by the expression of both epithelial markers such as cytokeratin 20 with a characteristic paranuclear dot-like staining AE1/AE3 and CAM5.2, and neuro-endocrine markers such as neuron-specific enolase (very sensitive but expressed by other neuroendocrine tumours), synaptophysin, CD56 and chromogranin A (more specific for MCC). The latter is the most commonly-used marker with a diffuse cytoplasmic staining pattern. By contrast, the following markers are generally negative: thyroid transcription factor1 (TTF-1) important for differential diagnosis with small-cell lung cancer particularly when the primary is unknown, S-100 and HMB-45 expressed by melanoma, leukocyte common antigen and other lymphocyte markers expressed by lymphomas, CK7 and carcinoembryonic antigen expressed by sweat gland carcinomas (see Table 2). However, an aberrant profile with positive CK7 and TTF-1 expression can occur in CK20- and MCPyV-negative cases [
      • Pasternak S.
      • Carter M.D.
      • Ly T.Y.
      • Doucette S.
      • Walsh N.M.
      Immunohistochemical profiles of different subsets of Merkel cell carcinoma.
      ]; in these cases, a lower expression of neurofilament and AT-rich sequence-binding protein SATB2 can also be observed [
      • Kervarrec T.
      • Tallet A.
      • Miquelestorena-Standley E.
      • Houben R.
      • Schrama D.
      • Gambichler T.
      • et al.
      Diagnostic accuracy of a panel of immunohistochemical and molecular markers to distinguish Merkel cell carcinoma from other neuroendocrine carcinomas.
      ].
      Table 2Immunohistochemistry profile of MCC (adapted from Becker et al. [
      • Becker J.C.
      • Eigentler T.
      • Frerich B.
      • Gambichler T.
      • Grabbe S.
      • Höller U.
      • et al.
      S2k guidelines for Merkel cell carcinoma (MCC, neuroendocrine carcinoma of the skin) – update 2018.
      ]).
      MCCLymphomaMelanomaSCLC
      SCLC small cell lung cancer.
      CK 20+
      Neuron-specific-enolase+#+/−
      Chromogranin A (CgA)+/−+/−
      Huntingtin interacting protein 1 (HIP1)++/−
      Vimentin++
      Melan-A/MART-1+
      Leukocyte common Antigen (LCA)+
      Thyroid transcription factor-1 (TTF-1)+
      a SCLC small cell lung cancer.

      6.2.2 Pathology report

      In clinical practice, a typical histology complemented with positive CK-20 and negative TTF-1 immunostaining is usually considered sufficient for the diagnosis of MCC. Depending on the individual histomorphological features and in special variants (e.g. CK-20 negative tumours), further immunohistochemical analysis should be performed to confirm diagnosis and differentiate MCC from potential mimics. Apart from tumour-thickness, infiltrative growth pattern and lymphovascular invasion can also be documented as potential features of more aggressive tumour behaviour.

      7. Tumour staging – prognosis and risk classification – staging work up

      7.1 Prognostic classification (Table S1)

      7.1.1 AJCC/UICC 8 staging [

      AJCC Cancer staging manual. 8th ed.. In: Amin MB, Edge, S., Greene, F., Byrd, D.R., Brookland, R.K., Washington, M.K., Gershenwald, J.E., Compton, C.C., Hess, K.R., Sullivan, D.C., Jessup, J.M., Brierley, J.D., Gaspar, L.E., Schilsky, R.L., Balch, n.d.

      ]

      AJCC/UICC 8 classification are recommended for staging. It is based on an updated analysis of 9387 cases of MCC from the National Cancer Data Base. In these classifications, there are no differences between the pathological pT assessment and clinical pT assessment (Table 3).
      Table 3TNM classification and staging (8th edition) for Merkel cell carcinoma of the skin (Union for International Cancer Control (UICC). TNM Classification of malignant tumours, Eighth edition. Merkel cell carcinoma. Oxford: WILEY Blackwell; 2017.)/AJCC 8th edition 2017 (AJCC Cancer Staging Manual. Eighth Edition. In: Amin MB et al., 2017).
      Clinical stage groups (cTNM)
      Clinical staging is defined by microstaging the primary Merkel cell carcinoma (MCC) with clinical and/or radiological evaluation for metastasis.
      Pathological stage groups (pTNM)
      Pathological staging is defined by microstaging the primary MCC and pathological nodal evaluation of the regional lymph node basin with sentinel lymph node biopsy or complete lymphadenectomy or pathologic confirmation of distant metastasis.
      TNMTNM
      0TisN0M00TisN0M0
      IT1N0M0IT1N0M0
      IIAT2, T3N0M0IIAT2, T3N0M0
      IIBT4N0M0IIBT4N0M0
      IIIAny TN1-3M0IIIAT0N1bM0
      T1-T4N1a, N1a (sn)M0
      IIIBT1-T4N1b, N2, N3M0
      IVAny TAny NM1IVAny TAny NM1
      c/pT – Primary tumour
      TXPrimary tumour cannot be assessed
      T0No evidence of primary tumour
      TisCarcinoma in situ
      T12 cm or less in greatest dimension
      T2More than 2 cm but not more than 5 cm in greatest dimension
      T3More than 5 cm in greatest dimension
      T4Tumour invades deep extra dermal structures, i.e. cartilage, skeletal muscle, fascia or bone
      cN- Regional lymph nodes
      NXRegional lymph nodes cannot clinically be assessed
      N0No clinically or radiologically detected regional lymph node metastasis
      N1Clinically or radiologically detected regional lymph node metastasis
      N2In-transit metastasis
      In transit metastasis: a discontinuous tumour distinct from the primary lesion and located between the primary lesion and the draining regional lymph nodes or distal to the primary lesion.
      without lymph node metastasis
      N3In-transit metastasis
      In transit metastasis: a discontinuous tumour distinct from the primary lesion and located between the primary lesion and the draining regional lymph nodes or distal to the primary lesion.
      with lymph node metastasis
      pN – Regional lymph nodes
      NXRegional lymph nodes cannot be assessed
      N0No regional lymph node metastasis
      N1Regional lymph node metastasis
      N1a (sn)Clinically occult (microscopic) metastasis detected on sentinel node biopsy
      N1aClinically occult (microscopic) metastasis detected on node dissection
      N1bClinically and/or radiologically detected (macroscopic) regional lymph node metastasis, microscopically confirmed
      N2In-transit metastasis
      In transit metastasis: a discontinuous tumour distinct from the primary lesion and located between the primary lesion and the draining regional lymph nodes or distal to the primary lesion.
      without lymph node metastasis
      N3In-transit metastasis
      In transit metastasis: a discontinuous tumour distinct from the primary lesion and located between the primary lesion and the draining regional lymph nodes or distal to the primary lesion.
      with lymph node metastasis
      cM – Distant metastasis
      M0No distant metastasis
      M1Distant metastasis
      M1aSkin, subcutaneous tissues or non-regional lymph node(s)
      M1bLung
      M1cOther site(s)
      pM- Distant metastasis
      M0No distant metastasis
      M1Distant metastasis microscopically confirmed
      M1aSkin, subcutaneous tissues or non-regional lymph node(s), microscopically confirmed
      M1bLung, microscopically confirmed
      M1cOther site(s), microscopically confirmed
      c: clinical, p: pathological.
      a Clinical staging is defined by microstaging the primary Merkel cell carcinoma (MCC) with clinical and/or radiological evaluation for metastasis.
      b Pathological staging is defined by microstaging the primary MCC and pathological nodal evaluation of the regional lymph node basin with sentinel lymph node biopsy or complete lymphadenectomy or pathologic confirmation of distant metastasis.
      c In transit metastasis: a discontinuous tumour distinct from the primary lesion and located between the primary lesion and the draining regional lymph nodes or distal to the primary lesion.
      For the N categories, the clinical stage where lymph node involvement is identified by clinical or radiological evaluation, and the pathological stage where lymph node involvement is histologically proven either by SLNB or lymphadenectomy or fine biopsy are distinguished (see Table 3).
      There are 3 categories of distant metastatic disease (M status) as in melanoma staging: M1a-distant skin, distant subcutaneous tissues or distant lymph nodes; M1b-lung; and M1c-all other visceral sites. The clinical/radiological and pathological assessment of metastasis are also distinguished (Table 3).
      The stage groups with corresponding prognostic values are summarised in Table 4.
      Table 4AJCC 8th edition, 2017 clinical and pathological staging for Merkel cell carcinoma [

      AJCC Cancer staging manual. 8th ed.. In: Amin MB, Edge, S., Greene, F., Byrd, D.R., Brookland, R.K., Washington, M.K., Gershenwald, J.E., Compton, C.C., Hess, K.R., Sullivan, D.C., Jessup, J.M., Brierley, J.D., Gaspar, L.E., Schilsky, R.L., Balch, n.d.

      ] with the prognosis of stage groups (adapted from Harms et al., 2016 [
      • Harms K.L.
      • Healy M.A.
      • Nghiem P.
      • Sober A.J.
      • Johnson T.M.
      • Bichakjian C.K.
      • et al.
      Analysis of prognostic factors from 9387 merkel cell carcinoma cases forms the basis for the new 8th edition AJCC staging system.
      ]).
      StageTNM5-year OS (%)
      0Tis N0 M0
      cIT1 N0 M045
      pIT1 N0 M062.8
      cIIAT2/T3 N0 M030.9
      pIIAT2/T3 N0 M054.6
      cIIBT4 N0 M027.3
      pIIBT4 N0 M034.8
      cIIIAnyT N1-3 M026.8
      pIII39.7
      IIIAAnyT N1a (sn) or N1a M040.3
      T0 N1b M026.8
      IIIBT1-4 N1b-3 M0
      cIVAnyT AnyN M1
      pIVAnyT AnyN M113.5
      c: clinical, p: pathological, T0: no primary tumour, Tis: in situ, OS: overall survival.
      Other abbreviations are detailed in the text.

      7.1.2 Clinical features (demography, pT)

      MCC has a high rate of local recurrence, regional recurrence and distant metastasis. Clinical factors related to an adverse outcome are older age, male sex, location in head and neck or trunk compared to upper limbs, size of the pT and the presence of immunosuppression, which is described in a dedicated section below [
      • Björn Andtback H.
      • Björnhagen-Säfwenberg V.
      • Shi H.
      • Lui W.-O.
      • Masucci G.V.
      • Villabona L.
      Sex differences in overall survival and the effect of radiotherapy in merkel cell carcinoma—a retrospective analysis of A Swedish cohort.
      ,
      • Yusuf M.B.
      • Gaskins J.
      • Wall W.
      • Tennant P.
      • Bumpous J.
      • Dunlap N.
      Immune status and the efficacy of radiotherapy on overall survival for patients with localized Merkel cell carcinoma: an analysis of the National Cancer Database.
      ,
      • Bleicher J.
      • Asare E.A.
      • Flores S.
      • Bowles T.L.
      • Bowen G.M.
      • Hyngstrom J.R.
      Oncologic outcomes of patients with Merkel Cell Carcinoma (MCC): a multi-institutional cohort study.
      ,
      • Smith V.A.
      • Camp E.R.
      • Lentsch E.J.
      Merkel cell carcinoma: Identification of prognostic factors unique to tumors located in the head and neck based on analysis of SEER data.
      ]. The maximum tumour diameter, which is included in AJCC8 staging, is also an important clinical predictor. In the 2021 NCCN guidelines 2021, unfavourable prognostic factors include tumour size >2 cm, chronic immunosuppression and head/neck primary site (Table 5) [
      • Schmults Chrysalyne D.
      • Blitzblau Rachel
      • Aasi Sumaira Z.
      • Alam Murad
      • Andersen James S.
      • Baumann Brian C.
      • et al.
      Merkel Cell Carcinoma Version 1.2021.
      ].
      Table 5Clinical and histological features associated with high-risk MCC versus low-risk MCC.
      Risk of recurrenceClinical features
      High-risk MCC: any of the criteria is sufficient to classify as high-risk tumour
      • -
        Tumour size ≥2 cm,
      • -
        Chronic immunosuppression
      • -
        Head/neck primary site
      • -
        Pathologically positive lymph nodes or no correct assessment of the lymph node status
      • -
        Lymphovascular invasion
      Tumour size is strongly correlated with lymph node metastasis which is, in turn, a very strong prognostic indicator. The risk of regional nodal involvement (micro or macroscopic) increased from 14% for 0.5-cm diameter tumours to 25% for 1.7-cm (median-sized) tumours and to more than 36% for tumours 6 cm or larger [
      • Iyer J.G.
      • Storer B.E.
      • Paulson K.G.
      • Lemos B.
      • Phillips J.L.
      • Bichakjian C.K.
      • et al.
      Relationships among primary tumor size, number of involved nodes, and survival for 8044 cases of Merkel cell carcinoma.
      ].

      7.1.3 Histological prognostic markers of the pTs

      Although several prognostic markers have been studied in MCC, to date there is no convincing demonstration of any histological or immunohistochemical prognostic marker. However, several prognostic markers have been studied and some deserve further evaluation:
      Increasing pT thickness was significantly associated with poorer disease-free survival (69% 5-year disease-free survival in tumours ≤10 mm thick compared to 18% for patients with tumours >10 mm thick, p = 0.002) and disease-specific survival (97% 5-year survival in tumours ≤10 mm thick compared to 74% for patients with tumours ≥10 mm thick, p = 0.006) [
      • Lim C.S.
      • Whalley D.
      • Haydu L.E.
      • Murali R.
      • Tippett J.
      • Thompson J.F.
      • et al.
      Increasing tumor thickness is associated with recurrence and poorer survival in patients with merkel cell carcinoma.
      ,
      • Smith F.O.
      • Yue B.
      • Marzban S.S.
      • Walls B.L.
      • Carr M.
      • Jackson R.S.
      • et al.
      Both tumor depth and diameter are predictive of sentinel lymph node status and survival in Merkel cell carcinoma.
      ]. However, it is well known from clinical practice that even a superficial MCC can metastasize, and in the AJCC classification, tumour depth is not regarded as a high-risk feature [
      • Harms K.L.
      • Healy M.A.
      • Nghiem P.
      • Sober A.J.
      • Johnson T.M.
      • Bichakjian C.K.
      • et al.
      Analysis of prognostic factors from 9387 merkel cell carcinoma cases forms the basis for the new 8th edition AJCC staging system.
      ].
      • -
        Lymphovascular invasion is also a prognostic factor for poor outcome [
        • Fields R.C.
        • Busam K.J.
        • Chou J.F.
        • Panageas K.S.
        • Pulitzer M.P.
        • Allen P.J.
        • et al.
        Five hundred patients with merkel cell carcinoma evaluated at a single institution.
        ]. Although it is not included in the AJCC staging system, it is included in the 2021 NCCN guidelines as a baseline risk factor [
        • Schmults Chrysalyne D.
        • Blitzblau Rachel
        • Aasi Sumaira Z.
        • Alam Murad
        • Andersen James S.
        • Baumann Brian C.
        • et al.
        Merkel Cell Carcinoma Version 1.2021.
        ].
      • -
        Tumour infiltrating immune cells have been suggested as having a positive prognostic value although their presence deserves further evaluation [
        • Smith F.O.
        • Yue B.
        • Marzban S.S.
        • Walls B.L.
        • Carr M.
        • Jackson R.S.
        • et al.
        Both tumor depth and diameter are predictive of sentinel lymph node status and survival in Merkel cell carcinoma.
        ,
        • Sihto H.
        • Böhling T.
        • Kavola H.
        • Koljonen V.
        • Salmi M.
        • Jalkanen S.
        • et al.
        Tumor infiltrating immune cells and outcome of merkel cell carcinoma: a population-based study.
        ,
        • Feldmeyer L.
        • Hudgens C.W.
        • Ray-Lyons G.
        • Nagarajan P.
        • Aung P.P.
        • Curry J.L.
        • et al.
        Density, distribution, and composition of immune infiltrates correlate with survival in Merkel cell carcinoma.
        ].
      • -
        Deep tumour invasion of fascia, muscle, cartilage or bone defines T4 in AJCC8 [

        AJCC Cancer staging manual. 8th ed.. In: Amin MB, Edge, S., Greene, F., Byrd, D.R., Brookland, R.K., Washington, M.K., Gershenwald, J.E., Compton, C.C., Hess, K.R., Sullivan, D.C., Jessup, J.M., Brierley, J.D., Gaspar, L.E., Schilsky, R.L., Balch, n.d.

        ].
      • -
        The prognostic value of MCPyV status has been debated in the past years. Several small studies have shown that MCPyV-negative tumours have a worse prognosis and two recent studies showed that MCPyV-positive tumours are associated with a more favourable prognosis. A Swedish study found an increased risk of death for men with a virus-negative MCC (HR 3.6 [
        • Björn Andtback H.
        • Björnhagen-Säfwenberg V.
        • Shi H.
        • Lui W.-O.
        • Masucci G.V.
        • Villabona L.
        Sex differences in overall survival and the effect of radiotherapy in merkel cell carcinoma—a retrospective analysis of A Swedish cohort.
        ]). A second study showed that MCPyV-positive tumours display longer disease-specific and recurrence-free survival in both univariate and multivariate analysis [
        • Harms K.L.
        • Zhao L.
        • Johnson B.
        • Wang X.
        • Carskadon S.
        • Palanisamy N.
        • et al.
        Virus-positive merkel cell carcinoma is an independent prognostic group with distinct predictive biomarkers.
        ]. Therefore, the diagnostic value of MCPyV detection using either molecular or immunohistochemical techniques is currently under investigation. However, there is as yet no routine method available to accurately distinguish between both types. In particular, immune-staining for MCPyV large T antigen cannot reliably discriminate virus-positive from the more aggressive virus-negative MCC [
        • Starrett G.J.
        • Thakuria M.
        • Chen T.
        • Marcelus C.
        • Cheng J.
        • Nomburg J.
        • et al.
        Clinical and molecular characterization of virus-positive and virus-negative Merkel cell carcinoma.
        ,
        • Coggshall K.
        • Tello T.L.
        • North J.P.
        • Yu S.S.
        Merkel cell carcinoma: an update and review.
        ,
        • Becker J.C.
        • Stang A.
        • DeCaprio J.A.
        • Cerroni L.
        • Lebbé C.
        • Veness M.
        • et al.
        Merkel cell carcinoma.
        ].
      The favourable prognostic values of lower mast cell counts, reduced vascular density, absence of p53 and p63 and phosphorylated CRE-binding protein P-CREB deserve also further evaluation [
      • Smith F.O.
      • Yue B.
      • Marzban S.S.
      • Walls B.L.
      • Carr M.
      • Jackson R.S.
      • et al.
      Both tumor depth and diameter are predictive of sentinel lymph node status and survival in Merkel cell carcinoma.
      ,
      • Sihto H.
      • Böhling T.
      • Kavola H.
      • Koljonen V.
      • Salmi M.
      • Jalkanen S.
      • et al.
      Tumor infiltrating immune cells and outcome of merkel cell carcinoma: a population-based study.
      ,
      • Feldmeyer L.
      • Hudgens C.W.
      • Ray-Lyons G.
      • Nagarajan P.
      • Aung P.P.
      • Curry J.L.
      • et al.
      Density, distribution, and composition of immune infiltrates correlate with survival in Merkel cell carcinoma.
      ,
      • González-Vela M. del C.
      • Curiel-Olmo S.
      • Derdak S.
      • Beltran S.
      • Santibañez M.
      • Martínez N.
      • et al.
      Shared oncogenic pathways implicated in both virus-positive and UV-induced merkel cell carcinomas.
      ].

      7.1.4 Regional and distant involvement

      The main prognostic factors are related to regional and distant involvement. The localised MCC tumours carry the best prognosis (50.6% 5-year OS rate) [
      • Harms K.L.
      • Healy M.A.
      • Nghiem P.
      • Sober A.J.
      • Johnson T.M.
      • Bichakjian C.K.
      • et al.
      Analysis of prognostic factors from 9387 merkel cell carcinoma cases forms the basis for the new 8th edition AJCC staging system.
      ]. In regional and distant disease, 5-year OS was estimated to be 35.4% and 13.5%, respectively, from a National Cancer Database study of 2856 cases [
      • Harms K.L.
      • Healy M.A.
      • Nghiem P.
      • Sober A.J.
      • Johnson T.M.
      • Bichakjian C.K.
      • et al.
      Analysis of prognostic factors from 9387 merkel cell carcinoma cases forms the basis for the new 8th edition AJCC staging system.
      ]. Nodal MCC with unknown pT have a higher 5-year OS of 42.2% [
      • Harms K.L.
      • Healy M.A.
      • Nghiem P.
      • Sober A.J.
      • Johnson T.M.
      • Bichakjian C.K.
      • et al.
      Analysis of prognostic factors from 9387 merkel cell carcinoma cases forms the basis for the new 8th edition AJCC staging system.
      ]. Remarkably, a recent study showed substantially higher OS rates than predicted in the AJCC8 study: 5-year OS of 72.6% for local disease and 62.7% for nodal disease [
      • Farley C.R.
      • Perez M.C.
      • Soelling S.J.
      • Delman K.A.
      • Harit A.
      • Wuthrick E.J.
      • et al.
      Merkel cell carcinoma outcomes: does AJCC8 underestimate survival?.
      ].
      Lymph node status is the most important independent prognostic predictor including occult microscopic nodal involvement which occurs in around one-third of patients [
      • Gupta S.G.
      • Wang L.C.
      • Peñas P.F.
      • Gellenthin M.
      • Lee S.J.
      • Nghiem P.
      Sentinel lymph node biopsy for evaluation and treatment of patients with merkel cell carcinoma.
      ,
      • Lemos B.D.
      • Storer B.E.
      • Iyer J.G.
      • Phillips J.L.
      • Bichakjian C.K.
      • Fang L.C.
      • et al.
      Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823 cases as the basis of the first consensus staging system.
      ,
      • Gunaratne D.A.
      • Howle J.R.
      • Veness M.J.
      Sentinel lymph node biopsy in Merkel cell carcinoma: a 15-year institutional experience and statistical analysis of 721 reported cases.
      ]. SLNB is therefore considered as an important procedure in MCC management as it allows the detection of nodal micro-metastasis (metastatic involvement of clinically or radiologically negative nodes) [
      • Becker J.C.
      • Stang A.
      • DeCaprio J.A.
      • Cerroni L.
      • Lebbé C.
      • Veness M.
      • et al.
      Merkel cell carcinoma.
      ]. Tumour burden in the regional nodal basin was predictive of survival, with 40% and 27% 5-year OS for clinically occult and clinically detected nodal disease, respectively [
      • Harms K.L.
      • Healy M.A.
      • Nghiem P.
      • Sober A.J.
      • Johnson T.M.
      • Bichakjian C.K.
      • et al.
      Analysis of prognostic factors from 9387 merkel cell carcinoma cases forms the basis for the new 8th edition AJCC staging system.
      ]. Moreover, the number of involved nodes proved to be strongly predictive of 5-year relative survival: 0 nodes, 76%; 1 node, 50%; 2 nodes, 47%; 3–5 nodes, 42% and ≥6 nodes, 24% [
      • Iyer J.G.
      • Storer B.E.
      • Paulson K.G.
      • Lemos B.
      • Phillips J.L.
      • Bichakjian C.K.
      • et al.
      Relationships among primary tumor size, number of involved nodes, and survival for 8044 cases of Merkel cell carcinoma.
      ]. This was also confirmed in a recently published large study showing that each additional metastatic node conferred an increased risk of death, even after adjusting for a variety of tumour- and patient-associated factors [
      • Nguyen A.T.
      • Luu M.
      • Lu D.J.
      • Hamid O.
      • Mallen-St
      • Clair J.
      • et al.
      Quantitative metastatic lymph node burden and survival in Merkel cell carcinoma.
      ]. This effect was found to be most pronounced for the first 3 metastatic LNs, with an added 17% risk of death for each metastasis-positive LN. Beyond 3 LNs, the risk of death continued to increase at a reduced rate of 3% per each additional LN [
      • Nguyen A.T.
      • Luu M.
      • Lu D.J.
      • Hamid O.
      • Mallen-St
      • Clair J.
      • et al.
      Quantitative metastatic lymph node burden and survival in Merkel cell carcinoma.
      ].
      Patterns for first-site metastasis have reported regional lymph nodes in 87% and distant metastasis in 13% of patients (most commonly abdominal viscera and distant lymph nodes) [
      • Song Y.
      • Azari F.S.
      • Tang R.
      • Shannon A.B.
      • Miura J.T.
      • Fraker D.L.
      • et al.
      Patterns of metastasis in merkel cell carcinoma.
      ]. In a study among elderly patients with MCC, liver metastasis proved to be an independent unfavourable prognostic factor [
      • Xia Y.
      • Cao D.
      • Zhao J.
      • Zhu B.
      • Xie J.
      Clinical features and prognosis of merkel cell carcinoma in elderly patients.
      ].
      Clinical and histological features associated with high-risk MCC (versus low risk MCC) are summarised in Table 5 below.

      7.2 Preoperative/baseline staging work up

      Initial staging includes full body skin examination with a clinical examination of all main nodal basins with particular consideration to the locoregional nodes.
      MCC is clinically localised in 65% of cases and presents with nodal and distant metastasis in 26% and 8% of patients, respectively [
      • Harms K.L.
      • Healy M.A.
      • Nghiem P.
      • Sober A.J.
      • Johnson T.M.
      • Bichakjian C.K.
      • et al.
      Analysis of prognostic factors from 9387 merkel cell carcinoma cases forms the basis for the new 8th edition AJCC staging system.
      ,
      • Albores-Saavedra J.
      • Batich K.
      • Chable-Montero F.
      • Sagy N.
      • Schwartz A.M.
      • Henson D.E.
      Merkel cell carcinoma demographics, morphology, and survival based on 3870 cases: a population based study.
      ]. Imaging is encouraged to rule out regional and distant metastasis. Baseline cross-sectional imaging such as CT, PET-CT or magnetic resonance imaging (MRI)) including at least the chest-abdomen-pelvis and draining node bed upstaged 13.2% of patients with MCC and with non-palpable regional lymph nodes (8.9% to radiographic nodal involvement and 4.3% to distant metastatic involvement). PET-CT appears more sensitive than CT alone. In a recent study, 16.8% of patients who underwent PET-CT imaging had their disease up-staged compared to 6.9% of those who received CT scans only (p = 0.0006) [
      • Singh N.
      • Alexander N.A.
      • Lachance K.
      • Lewis C.W.
      • McEvoy A.
      • Akaike G.
      • et al.
      Clinical benefit of baseline imaging in merkel cell carcinoma: analysis of 584 patients.
      ].
      The value of somatostatin receptor (SSTR) PET in the diagnosis of MCC metastatic spread cannot be definitively assessed yet. A clear advantage over 18 F FDG PET has not yet been demonstrated [
      • Taralli S.
      • Sollini M.
      • Milella M.
      • Perotti G.
      • Filice A.
      • Menga M.
      • et al.
      18F-FDG and 68Ga-somatostatin analogs PET/CT in patients with Merkel cell carcinoma: a comparison study.
      ]. However, a potential additional benefit of SSTR PET lies in a better detection of brain metastases as well as the assessment of the possibility of radionuclide therapy with SSTR-specific radiotherapeutics (i.e. peptide receptor radionuclide therapy, yPRRT) [
      • Buder K.
      • Lapa C.
      • Kreissl M.C.
      • Schirbel A.
      • Herrmann K.
      • Schnack A.
      • et al.
      Somatostatin receptor expression in Merkel cell carcinoma as target for molecular imaging.
      ,
      • Akaike T.
      • Qazi J.
      • Anderson A.
      • Behnia F.S.
      • Shinohara M.M.
      • Akaike G.
      • et al.
      High somatostatin receptor expression and efficacy of somatostatin analogues in patients with metastatic Merkel cell carcinoma.
      ].
      Brain metastases occur only in 5% of patients with initial metastatic disease [
      • Lewis C.W.
      • Qazi J.
      • Hippe D.S.
      • Lachance K.
      • Thomas H.
      • Cook M.M.
      • et al.
      Patterns of distant metastases in 215 Merkel cell carcinoma patients: Implications for prognosis and surveillance.
      ]. Therefore, brain MRI is not indicated in asymptomatic stage I-II patients.
      The most reliable staging tool to identify subclinical nodal disease is SLNB. Thus, SLNB is recommended in all patients with MCC without clinically detectable lymph nodes, when feasible, if baseline imaging is negative [
      • Schmults Chrysalyne D.
      • Blitzblau Rachel
      • Aasi Sumaira Z.
      • Alam Murad
      • Andersen James S.
      • Baumann Brian C.
      • et al.
      Merkel Cell Carcinoma Version 1.2021.
      ,
      • Singh N.
      • Alexander N.A.
      • Lachance K.
      • Lewis C.W.
      • McEvoy A.
      • Akaike G.
      • et al.
      Clinical benefit of baseline imaging in merkel cell carcinoma: analysis of 584 patients.
      ]. Before SLNB, regional lymph node ultrasonography (US) is recommended. In case of clinical/radiological suspicion of regional lymph nodes involvement, fine-needle aspiration or core biopsy is recommended.
      Tabled 1
      Recommendation 1
      Preoperative staging procedureEvidence-based recommendation
      Level of recommendation BClinical examination:

      Full body skin examination with the clinical examination of all main lymph node basins

      Imaging:
      • -
        8–14 megaherz Ultrasound of regional nodal basin should be performed
      • -
        Whole body imaging should be performed. If available, FDG PET/CT whole-body is preferable over contrast-enhanced CT-scan of neck/thorax/abdomen/pelvis [
        • Singh N.
        • Alexander N.A.
        • Lachance K.
        • Lewis C.W.
        • McEvoy A.
        • Akaike G.
        • et al.
        Clinical benefit of baseline imaging in merkel cell carcinoma: analysis of 584 patients.
        ]
      • -
        Routine brain imaging is not recommended in asymptomatic stage I-II patients
      Level of evidence: 3-4Guidelines adaptation [
      • Schmults Chrysalyne D.
      • Blitzblau Rachel
      • Aasi Sumaira Z.
      • Alam Murad
      • Andersen James S.
      • Baumann Brian C.
      • et al.
      Merkel Cell Carcinoma Version 1.2021.
      ]

      Retrospective small sample study [
      • Singh N.
      • Alexander N.A.
      • Lachance K.
      • Lewis C.W.
      • McEvoy A.
      • Akaike G.
      • et al.
      Clinical benefit of baseline imaging in merkel cell carcinoma: analysis of 584 patients.
      ]
      Strength of consensus: 93%

      8. Management

      8.1 Surgical therapy of the pT (Table S2)

      Surgical excision is the first-line treatment for MCC; the goal is to achieve the removal of the primary lesion with histologically clear margins. This outcome, however, should be balanced with the morbidity of the surgical procedure and with a possible delay in adjuvant RT to the pT site, if a skin graft or a flap is needed for surgical closure. The optimal surgical margins have not been well defined yet since no randomised clinical trial has attempted to address this issue and most studies do not separately consider whether patients subsequently received adjuvant RT. Also, studies frequently include node negative and loco-regional disease in the same data analysis.
      Two large retrospective studies (>6000 patients) reported significant differences in survival outcome measures between patients treated with narrow margins and those treated with wide surgical margins [
      • Yan L.
      • Sun L.
      • Guan Z.
      • Wei S.
      • Wang Y.
      • Li P.
      Analysis of cutaneous Merkel cell carcinoma outcomes after different surgical interventions.
      ,
      • Andruska N.
      • Fischer-Valuck B.W.
      • Mahapatra L.
      • Brenneman R.J.
      • Gay H.A.
      • Thorstad W.L.
      • et al.
      Association between surgical margins larger than 1 cm and overall survival in patients with merkel cell carcinoma.
      ]. Andruska et al. [
      • Andruska N.
      • Fischer-Valuck B.W.
      • Mahapatra L.
      • Brenneman R.J.
      • Gay H.A.
      • Thorstad W.L.
      • et al.
      Association between surgical margins larger than 1 cm and overall survival in patients with merkel cell carcinoma.
      ] recently showed that clinical margins >1.0 cm improve OS (HR, 0.88; 95% CI, 0.81–0.95; P < .001) compared with margins of 1.0 cm or smaller, regardless of tumour subsite, whereas no difference in OS was observed between margins of 1.1 cm–2.0 cm and margins larger than 2.0 cm (HR, 0.99; 95% CI, 0.83–1.19; P = .79). This study was underpowered to evaluate the benefit of margins larger than 1.0 cm in the subgroup of patients with negative SNLB. Receiving adjuvant RT improved OS in patients in all excision margin groups [
      • Andruska N.
      • Fischer-Valuck B.W.
      • Mahapatra L.
      • Brenneman R.J.
      • Gay H.A.
      • Thorstad W.L.
      • et al.
      Association between surgical margins larger than 1 cm and overall survival in patients with merkel cell carcinoma.
      ]. According to Yan et al. [
      • Yan L.
      • Sun L.
      • Guan Z.
      • Wei S.
      • Wang Y.
      • Li P.
      Analysis of cutaneous Merkel cell carcinoma outcomes after different surgical interventions.
      ], large excision margins do not significantly impact on survival rates in patients aged >75 years or with stage III MCC.
      These results above, albeit based on a moderate level of evidence, support complete excision with clinical safety margins of 1 cm followed by adjuvant RT as the preferred treatment. If no adjuvant RT is possible, safety margins of up to 2 cm should be performed. Excision of the tumour with clinical margins <1 cm followed by adjuvant RT can be acceptable in situations when obtaining wide surgical resection margins may be difficult or impossible due to patient or tumour-related factors or would postpone RT.
      Tabled 1
      Recommendation 2
      Treatment of primary MCC tumourEvidence-based recommendation
      Grade of recommendation B• Complete excision of the tumour with clinical safety margins of 1 cm followed by post-operative adjuvant RT on the tumour bed is the preferred treatment
      Level of evidence: 3Retrospective large sample studies [
      • Yan L.
      • Sun L.
      • Guan Z.
      • Wei S.
      • Wang Y.
      • Li P.
      Analysis of cutaneous Merkel cell carcinoma outcomes after different surgical interventions.
      ,
      • Andruska N.
      • Fischer-Valuck B.W.
      • Mahapatra L.
      • Brenneman R.J.
      • Gay H.A.
      • Thorstad W.L.
      • et al.
      Association between surgical margins larger than 1 cm and overall survival in patients with merkel cell carcinoma.
      ,
      • Tarabadkar E.S.
      • Fu T.
      • Lachance K.
      • Hippe D.S.
      • Pulliam T.
      • Thomas H.
      • et al.
      Narrow excision margins are appropriate for Merkel cell carcinoma when combined with adjuvant radiation: analysis of 188 cases of localized disease and proposed management algorithm.
      ,
      • Harrington C.
      • Kwan W.
      Radiotherapy and conservative surgery in the locoregional management of merkel cell carcinoma: the British columbia cancer agency experience.
      ,
      • Jaouen F.
      • Kervarrec T.
      • Caille A.
      • Le Corre Y.
      • Dreno B.
      • Esteve E.
      • et al.
      Narrow resection margins are not associated with mortality or recurrence in patients with Merkel cell carcinoma: a retrospective study.
      ,
      • Perez M.C.
      • de Pinho F.R.
      • Holstein A.
      • Oliver D.E.
      • Naqvi S.M.H.
      • Kim Y.
      • et al.
      Resection margins in merkel cell carcinoma: is a 1-cm margin wide enough?.
      ,
      • Allen P.J.
      • Bowne W.B.
      • Jaques D.P.
      • Brennan M.F.
      • Busam K.
      • Coit D.G.
      Merkel cell carcinoma: prognosis and treatment of patients from a single institution.
      ,
      • Sattler E.
      • Geimer T.
      • Sick I.
      • Flaig M.J.
      • Ruzicka T.
      • Berking C.
      • et al.
      Sentinel lymph node in Merkel cell carcinoma: to biopsy or not to biopsy?.
      ]
      Strength of consensus: 92%

      8.2 Sentinel lymph node biopsy, clinically-identified lymph node metastases and indication to subsequent complete lymph node dissection

      In patients with MCC, SLNB has shown a rate of microscopic metastases between 24% and 48% in the different available studies (Table S3). This supports the recommendation to use SLNB as routine staging in patients with primary clinical stage I/II MCC .
      Results from the SEER Database show a better disease-specific survival in patients with a negative SLNB versus a positive SLNB (84.5% versus 64.6%) [
      • Kachare S.D.
      • Wong J.H.
      • Vohra N.A.
      • Zervos E.E.
      • Fitzgerald T.L.
      Sentinel lymph node biopsy is associated with improved survival in merkel cell carcinoma.
      ]. Undergoing a SLNB was also borderline significantly associated with an improved survival [
      • Kachare S.D.
      • Wong J.H.
      • Vohra N.A.
      • Zervos E.E.
      • Fitzgerald T.L.
      Sentinel lymph node biopsy is associated with improved survival in merkel cell carcinoma.
      ]; however, selection bias of younger, less frail patients is a likely cause for this observation due to the retrospective design of the study and lack of therapeutic effect of SLNB for other cancers [
      • Kachare S.D.
      • Wong J.H.
      • Vohra N.A.
      • Zervos E.E.
      • Fitzgerald T.L.
      Sentinel lymph node biopsy is associated with improved survival in merkel cell carcinoma.
      ].
      Furthermore, when considering the potential therapeutic advantage of having a SLNB, it's likely, that patients who had a positive SLNB were selected for further adjuvant RT and that this might confer a benefit [
      • Conic R.R.Z.
      • Ko J.
      • Saridakis S.
      • Damiani G.
      • Funchain P.
      • Vidimos A.
      • et al.
      Sentinel lymph node biopsy in Merkel cell carcinoma: predictors of sentinel lymph node positivity and association with overall survival.
      ,
      • Kachare S.D.
      • Wong J.H.
      • Vohra N.A.
      • Zervos E.E.
      • Fitzgerald T.L.
      Sentinel lymph node biopsy is associated with improved survival in merkel cell carcinoma.
      ].
      In summary, positive SLNB has been associated with decreased overall and disease-specific survival in large database analyses and is thus recognised as a prognostic factor for poor outcome [
      • Allen P.J.
      • Bowne W.B.
      • Jaques D.P.
      • Brennan M.F.
      • Busam K.
      • Coit D.G.
      Merkel cell carcinoma: prognosis and treatment of patients from a single institution.
      ,
      • Sattler E.
      • Geimer T.
      • Sick I.
      • Flaig M.J.
      • Ruzicka T.
      • Berking C.
      • et al.
      Sentinel lymph node in Merkel cell carcinoma: to biopsy or not to biopsy?.
      ,
      • Conic R.R.Z.
      • Ko J.
      • Saridakis S.
      • Damiani G.
      • Funchain P.
      • Vidimos A.
      • et al.
      Sentinel lymph node biopsy in Merkel cell carcinoma: predictors of sentinel lymph node positivity and association with overall survival.
      ,
      • Kachare S.D.
      • Wong J.H.
      • Vohra N.A.
      • Zervos E.E.
      • Fitzgerald T.L.
      Sentinel lymph node biopsy is associated with improved survival in merkel cell carcinoma.
      ]. These findings were also observed in shorter cases series, whilst other reports failed to find a significant relationship between SLNB status and recurrence or survival [
      • Sridharan V.
      • Muralidhar V.
      • Margalit D.N.
      • Tishler R.B.
      • DeCaprio J.A.
      • Thakuria M.
      • et al.
      Merkel cell carcinoma: a population analysis on survival.
      ,
      • Fields R.C.
      • Busam K.J.
      • Chou J.F.
      • Panageas K.S.
      • Pulitzer M.P.
      • Kraus D.H.
      • et al.
      Recurrence and survival in patients undergoing sentinel lymph node biopsy for merkel cell carcinoma: analysis of 153 patients from a single institution.
      ] (Table S3).
      Tabled 1
      Recommendation 3
      Sentinel lymph node biopsyEvidence-based recommendation
      Grade of recommendation BSentinel lymph node biopsy should be offered in the absence of clinical or imaging evidence for nodal or distant metastases.
      Level of evidence: 2-3Prospective large simple study [
      • Conic R.R.Z.
      • Ko J.
      • Saridakis S.
      • Damiani G.
      • Funchain P.
      • Vidimos A.
      • et al.
      Sentinel lymph node biopsy in Merkel cell carcinoma: predictors of sentinel lymph node positivity and association with overall survival.
      ]

      Retrospective large sample studies [
      • Kachare S.D.
      • Wong J.H.
      • Vohra N.A.
      • Zervos E.E.
      • Fitzgerald T.L.
      Sentinel lymph node biopsy is associated with improved survival in merkel cell carcinoma.
      ,
      • Sridharan V.
      • Muralidhar V.
      • Margalit D.N.
      • Tishler R.B.
      • DeCaprio J.A.
      • Thakuria M.
      • et al.
      Merkel cell carcinoma: a population analysis on survival.
      ,
      • Servy A.
      • Maubec E.
      • Sugier P.E.
      • Grange F.
      • Mansard S.
      • Lesimple T.
      • et al.
      Merkel cell carcinoma: value of sentinel lymph-node status and adjuvant radiation therapy.
      ]

      Systemic review [
      • Sadeghi R.
      • Adinehpoor Z.
      • Maleki M.
      • Fallahi B.
      • Giovanella L.
      • Treglia G.
      Prognostic significance of sentinel lymph node mapping in merkel cell carcinoma: systematic review and meta-analysis of prognostic studies.
      ]
      Strength of consensus: 96%

      8.3 CLND

      No prospective studies have analysed the outcome of completion lymph node dissection in patients with MCC and nodal involvement, either microscopically or clinically detected. In a monocentric prospective study enrolling 163 patients, there was no significant difference in 5-year disease specific survival, disease-free survival and nodal recurrence-free survival between patients with microscopic nodal disease detected by SLNB undergoing CLND versus RT [
      • Lee J.S.
      • Durham A.B.
      • Bichakjian C.K.
      • Harms P.W.
      • Hayman J.A.
      • McLean S.A.
      • et al.
      Completion lymph node dissection or radiation therapy for sentinel node metastasis in merkel cell carcinoma.
      ] (Table S4). However, patients with non-sentinel lymph node (SLN) involvement showed a significantly worse disease-specific and disease-free survival compared to patients without non-SLN metastases after CLND [
      • Lee J.S.
      • Durham A.B.
      • Bichakjian C.K.
      • Harms P.W.
      • Hayman J.A.
      • McLean S.A.
      • et al.
      Completion lymph node dissection or radiation therapy for sentinel node metastasis in merkel cell carcinoma.
      ].
      A retrospective analysis of the National Cancer Database on 447 MCC with positive SNLB did not find a significant improved OS after CLND compared to observation (HR 0.62, CI 0.33–1.16), but the study was clearly underpowered. In the same study, adjuvant RT increased significantly survival (HR 0.48, CI 0.28–0.82). Moreover, both observation (HR 3.54, CI 1.36–9.18) and CLND alone (HR 2.54, CI 1.03–6.27) were associated with worse OS compared to CLND and adjuvant RT [
      • Cramer J.D.
      • Suresh K.
      • Sridharan S.
      Completion lymph node dissection for Merkel cell carcinoma.
      ]. A retrospective case series based on only 71 SLNB-positive MCC did not find significant improvement of recurrence-free survival, overall and disease-specific survival with respect to CLND and RT alone [
      • Perez M.C.
      • Oliver D.E.
      • Weitman E.S.
      • Boulware D.
      • Messina J.L.
      • Torres-Roca J.
      • et al.
      Management of sentinel lymph node metastasis in merkel cell carcinoma: completion lymphadenectomy, radiation, or both?.
      ] (Table S4). These results, albeit based on a moderate-to-low level of evidence, along with the high risk of lymphatic spread of MCC support the recommendation of RT alone or eventually combined with CLND in patients with microscopic metastasis to the sentinel node (recommendation 4a).
      Tabled 1
      Recommendation 4a
      Management of microscopic nodal metastasesConsensus-based recommendation
      GCPIn patients with microscopic nodal disease (positive SLNB), adjuvant RT alone (50–55 Gy see RT section) or eventually combined with CLND is preferred over CLND alone, which could constitute an option in case adjuvant RT is not possible
      Strength of consensus: 81%
      Tabled 1
      Recommendation 4 b
      Management of nodal metastases identified clinically or by imagingConsensus-based recommendation
      GCPTherapeutic lymph node dissection should be performed in patients with nodal metastases identified clinically or by imaging.
      Strength of consensus: 92%

      8.4 Radiotherapy: primary and regional disease (Table S5, S6)

      As MCC cells are highly sensitive to radiation [
      • Leonard J.H.
      • Ramsay J.R.
      • Kearsley J.H.
      • Birrell G.W.
      Radiation sensitivity of Merkel cell carcinoma cell lines.
      ], RT is a major therapeutic tool at diverse disease stages.
      Since MCC is a rare disease, no data are available from randomised controlled studies. Several large registry studies and retrospective case series strongly suggest that, after surgical excision, adjuvant RT to the pT bed improves local and regional relapse-free survival [
      • Tarabadkar E.S.
      • Fu T.
      • Lachance K.
      • Hippe D.S.
      • Pulliam T.
      • Thomas H.
      • et al.
      Narrow excision margins are appropriate for Merkel cell carcinoma when combined with adjuvant radiation: analysis of 188 cases of localized disease and proposed management algorithm.
      ,
      • Ghadjar P.
      • Kaanders J.H.
      • Poortmans P.
      • Zaucha R.
      • Krengli M.
      • Lagrange J.L.
      • et al.
      The essential role of radiotherapy in the treatment of merkel cell carcinoma: a study from the rare cancer Network.
      ], disease-free survival [
      • Kukko H.
      • Böhling T.
      • Koljonen V.
      • Tukiainen E.
      • Haglund C.
      • Pokhrel A.
      • et al.
      Merkel cell carcinoma - a population-based epidemiological study in Finland with a clinical series of 181 cases.
      ,
      • Servy A.
      • Maubec E.
      • Sugier P.E.
      • Grange F.
      • Mansard S.
      • Lesimple T.
      • et al.
      Merkel cell carcinoma: value of sentinel lymph-node status and adjuvant radiation therapy.
      ,
      • Kang S.H.
      • Haydu L.E.
      • Goh R.Y.
      • Fogarty G.B.
      Radiotherapy is associated with significant improvement in local and regional control in Merkel cell carcinoma.
      ,
      • Strom T.
      • Carr M.
      • Zager J.S.
      • Naghavi A.
      • Smith F.O.
      • Cruse C.W.
      • et al.
      Radiation therapy is associated with improved outcomes in merkel cell carcinoma.
      ], distant metastasis-free survival and OS [
      • Servy A.
      • Maubec E.
      • Sugier P.E.
      • Grange F.
      • Mansard S.
      • Lesimple T.
      • et al.
      Merkel cell carcinoma: value of sentinel lymph-node status and adjuvant radiation therapy.
      ,
      • Bhatia S.
      • Storer B.E.
      • Iyer J.G.
      • Moshiri A.
      • Parvathaneni U.
      • Byrd D.
      • et al.
      Adjuvant radiation therapy and chemotherapy in merkel cell carcinoma: survival analyses of 6908 cases from the national cancer data base.
      ] when compared to surgery alone without adjuvant RT. RT effects could particularly impact on large tumours [
      • Mojica P.
      • Smith D.
      • Ellenhorn J.D.I.
      Adjuvant radiation therapy is associated with improved survival in merkel cell carcinoma of the skin.
      ] and MCC of the head and neck [
      • van Veenendaal L.M.
      • van Akkooi A.C.J.
      • Verhoef C.
      • Grünhagen D.J.
      • Klop W.M.C.
      • Valk G.D.
      • et al.
      Merkel cell carcinoma: clinical outcome and prognostic factors in 351 patients.
      ]. Adjuvant RT should be performed within the first 8 weeks following surgery [
      • Tarabadkar E.S.
      • Fu T.
      • Lachance K.
      • Hippe D.S.
      • Pulliam T.
      • Thomas H.
      • et al.
      Narrow excision margins are appropriate for Merkel cell carcinoma when combined with adjuvant radiation: analysis of 188 cases of localized disease and proposed management algorithm.
      ].
      Omitting adjuvant RT was recently suggested for small (<2 cm, stage I), margin-free tumours in patients with the following features: pathologically negative lymph nodes and no risk factors, such as lymphatic-vascular invasion, pT in the head and neck area [
      • Takagishi S.R.
      • Marx T.E.
      • Lewis C.
      • Tarabadkar E.S.
      • Juhlin I.D.
      • Blom A.
      • et al.
      Postoperative radiation therapy is associated with a reduced risk of local recurrence among low risk Merkel cell carcinomas of the head and neck.
      ], absence of a correct pathological assessment of the lymph node status, immunosuppression and lymphoproliferative diseases. As the study is small sized and all the unfavourable factors were not precisely defined, decision-making on this option needs to be shared by the multidisciplinary team [
      • Petrelli F.
      • Ghidini A.
      • Torchio M.
      • Prinzi N.
      • Trevisan F.
      • Dallera P.
      • et al.
      Adjuvant radiotherapy for Merkel cell carcinoma: a systematic review and meta-analysis.
      ] (Table S5).
      Due to the introduction of SLNB as the standard approach in clinically node-negative patients, an underpowered randomised trial was prematurely closed. It did, however, demonstrate that prophylactic RT to the regional nodes was associated with increased regional relapse-free survival but not an improved OS [
      • Jouary T.
      • Leyral C.
      • Dreno B.
      • Doussau A.
      • Sassolas B.
      • Beylot-Barry M.
      • et al.
      Adjuvant prophylactic regional radiotherapy versus observation in stage I Merkel cell carcinoma: a multicentric prospective randomized study.
      ]. As stated in Recommendation 4a, in patients with microscopic nodal disease (positive SLNB), 50–55 Gy adjuvant RT is the preferred choice.
      No differences in OS emerged whether patients with nodal metastases (stage III) received adjuvant RT or not [
      • Bhatia S.
      • Storer B.E.
      • Iyer J.G.
      • Moshiri A.
      • Parvathaneni U.
      • Byrd D.
      • et al.
      Adjuvant radiation therapy and chemotherapy in merkel cell carcinoma: survival analyses of 6908 cases from the national cancer data base.
      ]. In some series, adjuvant RT significantly improved regional control [
      • Hui A.C.
      • Stillie A.L.
      • Seel M.
      • Ainslie J.
      Merkel cell carcinoma: 27-year experience at the peter MacCallum cancer Centre.
      ,
      • Strom T.
      • Naghavi A.O.
      • Messina J.L.
      • Kim S.
      • Torres-Roca J.F.
      • Russell J.
      • et al.
      Improved local and regional control with radiotherapy for Merkel cell carcinoma of the head and neck.
      ] and disease-free or -specific survival [
      • Sridharan V.
      • Muralidhar V.
      • Margalit D.N.
      • Tishler R.B.
      • DeCaprio J.A.
      • Thakuria M.
      • et al.
      Merkel cell carcinoma: a population analysis on survival.
      ,
      • Kang S.H.
      • Haydu L.E.
      • Goh R.Y.
      • Fogarty G.B.
      Radiotherapy is associated with significant improvement in local and regional control in Merkel cell carcinoma.
      ]. Definitive conclusions are hard to reach as data on the irradiated volumes were sometimes lacking and patients were enrolled at different stages of disease and with clinical and pathological nodal involvement.
      In patients not eligible to SLNB in the head and neck region, radical RT can be suggested (SLNB is not performed and the only treatment is RT with a radical and curative intent.) [
      • Schmults Chrysalyne D.
      • Blitzblau Rachel
      • Aasi Sumaira Z.
      • Alam Murad
      • Andersen James S.
      • Baumann Brian C.
      • et al.
      Merkel Cell Carcinoma Version 1.2021.
      ].
      In macroscopic stage III disease, adjuvant RT is generally recommended after regional CLND, particularly in cases of multiple node involvement and/or extracapsular extension. In a retrospective study of stage III patients, lymph node irradiation alone to positive regional lymph nodes conferred an excellent regional control rate that was comparable to CLND for both microscopic and palpable lymph node disease, without improving OS [
      • Fang L.C.
      • Lemos B.
      • Douglas J.
      • Iyer J.
      • Nghiem P.
      Radiation monotherapy as regional treatment for lymph node-positive Merkel cell carcinoma.
      ] (Table S6).
      Data from a large registry study suggested doses from 40 to fewer than 50 Gy adjuvant RT are adequate in stage I–III MCC of the trunk or extremities. Compared with the group who received 50–55 Gy, OS was equivalent in groups receiving 40 to <50 Gy or >55–70 Gy. It was worse in the group that received >30 to <40 Gy [
      • Patel S.A.
      • Qureshi M.M.
      • Sahni D.
      • Truong M.T.
      Identifying an optimal adjuvant radiotherapy dose for extremity and trunk merkel cell carcinoma following resection.
      ]. Data also showed that optimal adjuvant RT doses are 50–55 Gy in head and neck MCC [
      • Patel S.A.
      • Qureshi M.M.
      • Mak K.S.
      • Sahni D.
      • Giacalone N.J.
      • Ezzat W.
      • et al.
      Impact of total radiotherapy dose on survival for head and neck Merkel cell carcinoma after resection.
      ]. Regardless of the tumour site, higher doses are required when margins are positive, up to 60 and 66 Gy for microscopically and macroscopically positive margins, respectively [
      • Schmults Chrysalyne D.
      • Blitzblau Rachel
      • Aasi Sumaira Z.
      • Alam Murad
      • Andersen James S.
      • Baumann Brian C.
      • et al.
      Merkel Cell Carcinoma Version 1.2021.
      ]. Fractionation is conventional, with 2 Gy single dose. A bolus should be considered to ensure an adequate skin dose [
      • Schmults Chrysalyne D.
      • Blitzblau Rachel
      • Aasi Sumaira Z.
      • Alam Murad
      • Andersen James S.
      • Baumann Brian C.
      • et al.
      Merkel Cell Carcinoma Version 1.2021.
      ].
      Tabled 1
      Recommendations 5
      Adjuvant radiotherapy on the primary tumour bedEvidence-based recommendation
      Grade of recommendation BAdjuvant RT (doses: see text) to the primary tumour bed should be performed within 8 weeks of surgical excision.
      Level of evidence 3Retrospective large sample studies [
      • Servy A.
      • Maubec E.
      • Sugier P.E.
      • Grange F.
      • Mansard S.
      • Lesimple T.
      • et al.
      Merkel cell carcinoma: value of sentinel lymph-node status and adjuvant radiation therapy.
      ,
      • Ghadjar P.
      • Kaanders J.H.
      • Poortmans P.
      • Zaucha R.
      • Krengli M.
      • Lagrange J.L.
      • et al.
      The essential role of radiotherapy in the treatment of merkel cell carcinoma: a study from the rare cancer Network.
      ,
      • Kang S.H.
      • Haydu L.E.
      • Goh R.Y.
      • Fogarty G.B.
      Radiotherapy is associated with significant improvement in local and regional control in Merkel cell carcinoma.
      ,
      • Strom T.
      • Carr M.
      • Zager J.S.
      • Naghavi A.
      • Smith F.O.
      • Cruse C.W.
      • et al.
      Radiation therapy is associated with improved outcomes in merkel cell carcinoma.
      ,
      • Bhatia S.
      • Storer B.E.
      • Iyer J.G.
      • Moshiri A.
      • Parvathaneni U.
      • Byrd D.
      • et al.
      Adjuvant radiation therapy and chemotherapy in merkel cell carcinoma: survival analyses of 6908 cases from the national cancer data base.
      ] [
      • Kukko H.
      • Böhling T.
      • Koljonen V.
      • Tukiainen E.
      • Haglund C.
      • Pokhrel A.
      • et al.
      Merkel cell carcinoma - a population-based epidemiological study in Finland with a clinical series of 181 cases.
      ]
      Strength of consensus: 93%
      Tabled 1
      Recommendation 6
      Adjuvant radiotherapy after lymphadenectomy for clinically involved nodal basinConsensus-based recommendation
      GCPAdjuvant RT (doses: see text) should be discussed in a multidisciplinary board after complete lymph node dissection for clinical or radiological nodal disease
      Strength of consensus: 93%
      Tabled 1
      Recommendation 7
      Palliative radiation therapy for primary tumours or clinically involved lymph node basin diseaseEvidence-based recommendation
      Grade of recommendation CPalliative radiotherapy alone can be suggested in frail patients to treat primary tumours and/or nodal involvement when surgery is not feasible
      Level of evidence 3-4Retrospective small sample studies [
      • Veness M.
      • Howle J.
      Radiotherapy alone in patients with Merkel cell carcinoma: the Westmead Hospital experience of 41 patients.
      ,
      • Dubois M.
      • Rached H.A.
      • Escande A.
      • Dezoteux F.
      • Darloy F.
      • Jouin A.
      • et al.
      Outcome of early stage Merkel carcinoma treated by exclusive radiation : a study of 53 patients.
      ]
      Strength of consensus: 85%

      8.5 Treatment of locally advanced and metastatic MCC

      In metastatic disease, the historical 5-year survival is at 13.5% [
      • Harms K.L.
      • Healy M.A.
      • Nghiem P.
      • Sober A.J.
      • Johnson T.M.
      • Bichakjian C.K.
      • et al.
      Analysis of prognostic factors from 9387 merkel cell carcinoma cases forms the basis for the new 8th edition AJCC staging system.
      ]. Until 2017, recommendations for systemic therapy of advanced MCC were based on data usually obtained by single-centre and oligo-centre, mostly retrospective analyses as well as on data inferred from other tumour entities such as small-cell lung carcinomas and personal experience.
      Based on an increased understanding of the biology of MCC in recent years and the development of immunotherapy with check-point inhibitors in other tumour types, prospective phase I/II immunotherapy trials have demonstrated encouraging results. While there are no randomised clinical trials available to guide the recommendations for advanced MCC treatment on a high level of evidence, the superiority in the mid-term outcomes of these immunotherapy phase I/II trials compared to historic data on cytotoxic therapies makes such a study design ethically difficult and out of date. However, as combination therapies will likely enter the field of MCC, participation in clinical trials, if available, should be encouraged.
      Multidisciplinary tumour board consultations (dermatologist, surgeon and radiotherapist) for patients with advanced MCC are needed to consider all options for the management of advanced MCC cases.

      8.5.1 Immunotherapy

      8.5.1.1 Rationale

      There are clinical and scientific data available implying that MCC is an immunosensitive solid malignancy. MCC often develops in immunodeficient patients, and spontaneous regression of pTs has been observed occasionally. Both MCPyV-negative MCC, which is known to harbour a high burden of UV-induced somatic tumour mutations which can serve as neo-antigens and MCPyV-positive MCC, which expresses viral oncogenes, can provide a basis for the immune recognition of MCC [
      • Terheyden P.
      • Becker J.C.
      New developments in the biology and the treatment of metastatic Merkel cell carcinoma.
      ]. Approximately 50% of MCC cells express PD-L1 on their surface, while tumour-infiltrating lymphocytes and circulating MCPyV-specific T cells express PD-1 [
      • Lipson E.J.
      • Vincent J.G.
      • Loyo M.
      • Kagohara L.T.
      • Luber B.S.
      • Wang H.
      • et al.
      PD-L1 expression in the Merkel cell carcinoma microenvironment: association with inflammation, Merkel cell polyomavirus and overall survival.
      ]. This PD-1/PD-L1 pathway is known to contribute to local immune evasion by inhibiting T-cell activation and impairing the CD8/Treg ratio. In MCC, like in many other tumours, PD-1 and PD-L1 inhibitors are thus expected to restore T-cell-dependent antitumour response. Anti-PD-L1 antibodies could also play a role through NK-cell-dependent ADCC [
      • Boyerinas B.
      • Jochems C.
      • Fantini M.
      • Heery C.R.
      • Gulley J.L.
      • Tsang K.Y.
      • et al.
      Antibody-dependent cellular cytotoxicity activity of a Novel Anti-PD-L1 antibody avelumab (MSB0010718C) on human tumor cells.
      ] against PD-L1 positive malignant cells and cells of the tumour microenvironment [
      • Boyerinas B.
      • Jochems C.
      • Fantini M.
      • Heery C.R.
      • Gulley J.L.
      • Tsang K.Y.
      • et al.
      Antibody-dependent cellular cytotoxicity activity of a Novel Anti-PD-L1 antibody avelumab (MSB0010718C) on human tumor cells.
      ,
      • D'Angelo S.P.
      • Bhatia S.
      • Brohl A.S.
      • Hamid O.
      • Mehnert J.M.
      • Terheyden P.
      • et al.
      Avelumab in patients with previously treated metastatic Merkel cell carcinoma: long-term data and biomarker analyses from the single-arm phase 2 JAVELIN Merkel 200 trial.
      ].

      8.5.1.2 Anti-PD-1/PD-L1 agents in MCC

      PD-1/PD-L1 inhibition has been investigated in advanced MCC in phase-1/2 trials. The results of three phase −2 [
      • D'Angelo S.P.
      • Russell J.
      • Lebbé C.
      • Chmielowski B.
      • Gambichler T.
      • Grob J.J.
      • et al.
      Efficacy and safety of first-line avelumab treatment in patients with stage IV metastatic Merkel cell carcinoma a preplanned interim analysis of a clinical trial.
      ]) [
      • Nghiem P.
      • Bhatia S.
      • Lipson E.J.
      • Sharfman W.H.
      • Kudchadkar R.R.
      • Brohl A.S.
      • et al.
      Durable tumor regression and overall survival in patients with advanced Merkel cell carcinoma receiving pembrolizumab as first-line therapy.
      ,
      • Nghiem P.T.
      • Bhatia S.
      • Lipson E.J.
      • Kudchadkar R.R.
      • Miller N.J.
      • Annamalai L.
      • et al.
      PD-1 blockade with pembrolizumab in advanced merkel-cell carcinoma.
      ], and 1 phase I trial [
      • Topalian S.L.
      • Bhatia S.
      • Hollebecque A.
      • Awada A.
      • Boer JP De
      • Kudchadkar R.R.
      • et al.
      Abstract CT074: Non-comparative, open-label, multiple cohort, phase 1/2 study to evaluate nivolumab (NIVO) in patients with virus-associated tumors (CheckMate 358): Efficacy and safety in Merkel cell carcinoma (MCC).
      ] have been published and are summarised in Table 6.
      Table 6Summary of 4 Phase II anti PD-1/PD-L1 trials.
      TrialPembrolizumab [
      • Nghiem P.
      • Bhatia S.
      • Lipson E.J.
      • Sharfman W.H.
      • Kudchadkar R.R.
      • Brohl A.S.
      • et al.
      Durable tumor regression and overall survival in patients with advanced Merkel cell carcinoma receiving pembrolizumab as first-line therapy.
      ]
      Avelumab [
      • D'Angelo S.P.
      • Russell J.
      • Lebbé C.
      • Chmielowski B.
      • Gambichler T.
      • Grob J.J.
      • et al.
      Efficacy and safety of first-line avelumab treatment in patients with stage IV metastatic Merkel cell carcinoma a preplanned interim analysis of a clinical trial.
      ] updated in SITC2019
      Nivolumab [
      • Topalian S.L.
      • Bhatia S.
      • Hollebecque A.
      • Awada A.
      • Boer JP De
      • Kudchadkar R.R.
      • et al.
      Abstract CT074: Non-comparative, open-label, multiple cohort, phase 1/2 study to evaluate nivolumab (NIVO) in patients with virus-associated tumors (CheckMate 358): Efficacy and safety in Merkel cell carcinoma (MCC).
      ]
      Avelumab [
      • D'Angelo S.P.
      • Bhatia S.
      • Brohl A.S.
      • Hamid O.
      • Mehnert J.M.
      • Terheyden P.
      • et al.
      Avelumab in patients with previously treated metastatic Merkel cell carcinoma: long-term data and biomarker analyses from the single-arm phase 2 JAVELIN Merkel 200 trial.
      ]

      Updated in ASCO2021
      N501162588
      Line1st1st1st, 2nd and 3rd>2nd
      ORR (CR)56% (24%)39.7 (16.4%)68% (14%)33.0% (11.4%)
      Median PFS (months) (95%CI)16.8 (4.6 – NR)4.1 (1.4–6.1)NA2.7 (1.4,6.9)
      Median OS (months) (95%CI)NR (26-NR)20 (12.4-NR)NA12.6 (7.5–17.1)
      1-year OS %, (95%CI)∼73 (NA)60 (50–68)NA50 (39–60)
      2-year OS %, (95%CI)68.7% (NA)NANA36 (26–46)
      3-year OS %, (95%CINANANA32 (23–42)
      5-year OS % (95%CI)NANANA26 (17–36)
      Follow-up (months) (range)14.9 (0.4–36.4+)21.2 (14.9–36.6)6.5 (1.3–8.8)65.1 (60.8–74.1)
      Table 7Recommended follow-up for patients with MCC.
      StageClinNodal sonographyContrast-enhanced neck/thorax/abdomen/pelvis CT or FDG PET/CT whole-body, Brain MRI
      Year1–34–56–101–34–56–101–34–56–10
      BaselineFull body clinical examination

      8-14 megaherz ultrasound of regional nodal basin

      Whole body imaging FDG PET/CT (preferred)/contrast-enhanced neck/thorax/abdomen/pelvis CT

      Brain MRI for stage ≥ III or symptomatic patients
      stage Tis-II3–6 mo12 moX3–6 moxxxxx
      ≥III3mo6 mo12 mo3mo6 mox3–6 mo6–12 mox
      IV∗∗Adapt clinical visits, laboratory examinations and imaging according to treatment and symptoms

      8.5.1.2.1 Avelumab

      Avelumab is a fully human anti-PD-L1 antibody [
      • Boyerinas B.
      • Jochems C.
      • Fantini M.
      • Heery C.R.
      • Gulley J.L.
      • Tsang K.Y.
      • et al.
      Antibody-dependent cellular cytotoxicity activity of a Novel Anti-PD-L1 antibody avelumab (MSB0010718C) on human tumor cells.
      ], which was first evaluated in a phase II trial on 88 previously treated patients (JAVELIN Merkel 200 trial) [
      • D'Angelo S.P.
      • Bhatia S.
      • Brohl A.S.
      • Hamid O.
      • Mehnert J.M.
      • Terheyden P.
      • et al.
      Avelumab in patients with previously treated metastatic Merkel cell carcinoma: long-term data and biomarker analyses from the single-arm phase 2 JAVELIN Merkel 200 trial.
      ,
      • Kaufman Howard L.
      • Russell Jeffery
      • Hamid Omid
      • Bhatia Shailender
      • Terheyden Patrick
      • D'Angelo Sandra P.
      • et al.
      Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial.
      ,
      • Kaufman H.L.
      • Russell J.S.
      • Hamid O.
      • Bhatia S.
      • Terheyden P.
      • D'Angelo S.P.
      • et al.
      Updated efficacy of avelumab in patients with previously treated metastatic Merkel cell carcinoma after ≥1 year of follow-up: JAVELIN Merkel 200, a phase 2 clinical trial.
      ] at 10 mg/kg every 2 weeks with a median follow-up of 65.1 months (range 60.8–74.1 months). The overall response rate (ORR) was 33.0% (95% CI 23.3%–43.8%), including a complete response (CR) of 11.4% (10 patients) [
      • D'Angelo S.P.
      • Bhatia S.
      • Brohl A.S.
      • Hamid O.
      • Mehnert J.M.
      • Terheyden P.
      • et al.
      Avelumab in patients with previously treated metastatic Merkel cell carcinoma: long-term data and biomarker analyses from the single-arm phase 2 JAVELIN Merkel 200 trial.
      ]. The median progression-free survival (PFS) was 2.7 months (95% CI, 1.4–6.9). However [
      • Kaufman H.L.
      • Russell J.S.
      • Hamid O.
      • Bhatia S.
      • Terheyden P.
      • D'Angelo S.P.
      • et al.
      Updated efficacy of avelumab in patients with previously treated metastatic Merkel cell carcinoma after ≥1 year of follow-up: JAVELIN Merkel 200, a phase 2 clinical trial.
      ], the median duration of responses was 40.5 months (95% CI 18.0 months not estimable), showing that responding patients benefit in the long-term, which was not seen with conventional chemotherapies. The median OS was 12.6 months (95% CI 7.5–17.1 months), the 3-year OS rate was 32% (95% CI 23%–42%,) and the most recent update at ASCO2021 showed a 5-year OS rate of 26% (95%CI 17%–36%), thus confirming durable responses and a potential survival benefit in an indirect comparison to chemotherapies (Abstract No. 9517 ASCO 2021). Of long-term survivors (OS > 36 months) evaluable for PD-L1 expression status (n = 22), 81.8% had PD-L1+ tumours [
      • D'Angelo S.P.
      • Bhatia S.
      • Brohl A.S.
      • Hamid O.
      • Mehnert J.M.
      • Terheyden P.
      • et al.
      Avelumab in patients with previously treated metastatic Merkel cell carcinoma: long-term data and biomarker analyses from the single-arm phase 2 JAVELIN Merkel 200 trial.
      ]. Moreover, longer median OS (12.9 months [95% CI, 8.7–29.6 months] versus 7.3 months [95% CI, 3.4–14.0 months], respectively) and a higher 5-year OS rate (28% [95% CI, 17%–40%] versus 19% [95% CI, 5%–40%]) were observed in patients with PD-L1+ versus PD-L1– tumours. Patients who experienced irAEs seem to have better outcome (HR 0.71, 95% CI, 0.59 to 0.85) using the time-dependent Cox model. The JAVELIN Merkel 200 part B was recently updated at the Society for Immunotherapy of Cancer congress 2019 and focused on 116 treatment-naïve patients, also using avelumab 10 mg/kg every two weeks. After a median follow-up of only 21.2 months (range: 14.9–36.6), response was higher than in the second-line cohort with an ORR of 39.7% (95% CI, 30.7%–49.2%). The median PFS was 4.1 months (95% CI, 1.4–6.1), higher than previous retrospective reports for chemotherapy in the same population for which median PFS ranged from 3 to 5 months. The median OS reached 20 months (95% CI, 12.4-NR). The avelumab flat dose of 800 mg IV every 2 weeks is currently recommended for all cancer entities.
      After approval, a real-world experience with avelumab in patients with mMCC from an expanded access program was published [
      • Walker J.W.
      • Lebbé C.
      • Grignani G.
      • Nathan P.
      • Dirix L.
      • Fenig E.
      • et al.
      Efficacy and safety of avelumab treatment in patients with metastatic Merkel cell carcinoma: experience from a global expanded access program.
      ] and confirmed efficacy and safety data of the registrational study, 494 patients received avelumab in the expanded access program . Among 240 evaluable patients, the objective response rate was 46.7%. The median duration of treatment in evaluable patients with response was 7.9 months (range, 1.0–41.7) overall and 5.2 months (range, 3.0–13.9) in immunocompromised patients. No new safety signals were identified.

      8.5.1.2.2 Pembrolizumab

      Pembrolizumab is a humanised IgG4 antibody directed against PD-1. A multicentre phase-2 trial (Keynote-017) evaluated pembrolizumab 2 mg/kg every 3 weeks for up to 2 years in 50 patients with treatment-naïve advanced MCC. The median follow-up time was 14.9 months (range, 0.4 to 36.4+ months). ORR was 56% (95% CI, 41.3%–70.0%) with CR and PR rates of 24% and 32%, respectively. The median duration of response was not reached and median PFS was 16.8 months (95% CI, 4.6 months to not estimable). The 2-year OS was 68.7% and median OS was not reached [
      • Nghiem P.
      • Bhatia S.
      • Lipson E.J.
      • Sharfman W.H.
      • Kudchadkar R.R.
      • Brohl A.S.
      • et al.
      Durable tumor regression and overall survival in patients with advanced Merkel cell carcinoma receiving pembrolizumab as first-line therapy.
      ]. These data confirm the high efficacy of anti-PD-1/PD-L1 blockade in treatment-naïve patients.

      8.5.1.2.3 Nivolumab

      Nivolumab, a fully human IgG4 antibody against PD-1 was evaluated in patients with previously untreated advanced MCC (60%) or in previously treated patients (1–2 previous systemic therapies; 40%) in the Checkmate 358 trial, that includes patients with virus-associated malignancies. Nivolumab was given at 240 mg every 2 weeks with a median follow-up of 26 weeks (range, 5–35 weeks). Twenty-five patients were enrolled. ORR was 68% for the overall population: 71% for treatment-naïve patients and 63% for pre-treated patients. With a very short follow-up, at 3 months, PFS and OS rates were 82% and 92%, respectively [
      • Topalian S.L.
      • Bhatia S.
      • Hollebecque A.
      • Awada A.
      • Boer JP De
      • Kudchadkar R.R.
      • et al.
      Abstract CT074: Non-comparative, open-label, multiple cohort, phase 1/2 study to evaluate nivolumab (NIVO) in patients with virus-associated tumors (CheckMate 358): Efficacy and safety in Merkel cell carcinoma (MCC).
      ].

      8.5.1.3 Safety profile of anti-PD-(L)1 agent

      The safety profile of anti PD-(L)1 immune check point inhibitors in MCC showed that these drugs were generally well-tolerated and that their side-effects were comparable to known side-effects in other indications for solid tumours. Grade 3-4 adverse events did occur in 11.4–28% of treated patients and treatment-related adverse event leading to treatment discontinuation in 9.1–15.4%. Only one treatment-related death occurred during these trials [
      • D'Angelo S.P.
      • Bhatia S.
      • Brohl A.S.
      • Hamid O.
      • Mehnert J.M.
      • Terheyden P.
      • et al.
      Avelumab in patients with previously treated metastatic Merkel cell carcinoma: long-term data and biomarker analyses from the single-arm phase 2 JAVELIN Merkel 200 trial.
      ,
      • D'Angelo S.P.
      • Russell J.
      • Lebbé C.
      • Chmielowski B.
      • Gambichler T.
      • Grob J.J.
      • et al.
      Efficacy and safety of first-line avelumab treatment in patients with stage IV metastatic Merkel cell carcinoma a preplanned interim analysis of a clinical trial.
      ,
      • Nghiem P.
      • Bhatia S.
      • Lipson E.J.
      • Sharfman W.H.
      • Kudchadkar R.R.
      • Brohl A.S.
      • et al.
      Durable tumor regression and overall survival in patients with advanced Merkel cell carcinoma receiving pembrolizumab as first-line therapy.
      ,
      • Topalian S.L.
      • Bhatia S.
      • Hollebecque A.
      • Awada A.
      • Boer JP De
      • Kudchadkar R.R.
      • et al.
      Abstract CT074: Non-comparative, open-label, multiple cohort, phase 1/2 study to evaluate nivolumab (NIVO) in patients with virus-associated tumors (CheckMate 358): Efficacy and safety in Merkel cell carcinoma (MCC).
      ].

      8.5.1.4 Biomarkers associated with response

      Clinical benefit was not consistently predicted by any single biomarker [
      • D'Angelo S.P.
      • Bhatia S.
      • Brohl A.S.
      • Hamid O.
      • Mehnert J.M.
      • Terheyden P.
      • et al.
      Avelumab in patients with previously treated metastatic Merkel cell carcinoma: long-term data and biomarker analyses from the single-arm phase 2 JAVELIN Merkel 200 trial.
      ].

      8.5.1.4.1 PD-L1 status

      Although statistical significance was not reached [
      • Nghiem P.
      • Bhatia S.
      • Lipson E.J.
      • Sharfman W.H.
      • Kudchadkar R.R.
      • Brohl A.S.
      • et al.
      Durable tumor regression and overall survival in patients with advanced Merkel cell carcinoma receiving pembrolizumab as first-line therapy.
      ], PD-L1 positive tumours were more likely MCPyV-positive [
      • Nghiem P.
      • Bhatia S.
      • Lipson E.J.
      • Sharfman W.H.
      • Kudchadkar R.R.
      • Brohl A.S.
      • et al.
      Durable tumor regression and overall survival in patients with advanced Merkel cell carcinoma receiving pembrolizumab as first-line therapy.
      ]. A trend for higher OS rates was observed in patients with PD-L1 positive versus PD-L1 negative tumours but did not reach statistical significance [
      • D'Angelo S.P.
      • Bhatia S.
      • Brohl A.S.
      • Hamid O.
      • Mehnert J.M.
      • Terheyden P.
      • et al.
      Avelumab in patients with previously treated metastatic Merkel cell carcinoma: long-term data and biomarker analyses from the single-arm phase 2 JAVELIN Merkel 200 trial.
      ,
      • Nghiem P.
      • Bhatia S.
      • Lipson E.J.
      • Sharfman W.H.
      • Kudchadkar R.R.
      • Brohl A.S.
      • et al.
      Durable tumor regression and overall survival in patients with advanced Merkel cell carcinoma receiving pembrolizumab as first-line therapy.
      ]. PD-L1 was also positive in most long-term survivors suggesting that patients with PD-L1 positive tumours may have a higher probability of long-term survival [
      • D'Angelo S.P.
      • Bhatia S.
      • Brohl A.S.
      • Hamid O.
      • Mehnert J.M.
      • Terheyden P.
      • et al.
      Avelumab in patients with previously treated metastatic Merkel cell carcinoma: long-term data and biomarker analyses from the single-arm phase 2 JAVELIN Merkel 200 trial.
      ].

      8.5.1.4.2 Tumour mutational burden

      High tumour mutational burden was generally associated with MCPyV negativity. There was a trend for increasing efficacy (PFS and OS) in patient with high mutational burden tumours.

      8.5.1.4.3 Tumour MCPyV status

      Virus-positive or virus-negative status was evaluated in several trials and no strong association with anti-PD(L)1 efficacy was shown [
      • D'Angelo S.P.
      • Bhatia S.
      • Brohl A.S.
      • Hamid O.
      • Mehnert J.M.
      • Terheyden P.
      • et al.
      Avelumab in patients with previously treated metastatic Merkel cell carcinoma: long-term data and biomarker analyses from the single-arm phase 2 JAVELIN Merkel 200 trial.
      ,
      • Nghiem P.
      • Bhatia S.
      • Lipson E.J.
      • Sharfman W.H.
      • Kudchadkar R.R.
      • Brohl A.S.
      • et al.
      Durable tumor regression and overall survival in patients with advanced Merkel cell carcinoma receiving pembrolizumab as first-line therapy.
      ].
      The response rate was particularly high in tumours combining 3 factors: high mutational burden, MCPyV negative and high CD8+ T cell density at the invasive margin [
      • D'Angelo S.P.
      • Bhatia S.
      • Brohl A.S.
      • Hamid O.
      • Mehnert J.M.
      • Terheyden P.
      • et al.
      Avelumab in patients with previously treated metastatic Merkel cell carcinoma: long-term data and biomarker analyses from the single-arm phase 2 JAVELIN Merkel 200 trial.
      ].
      Additional work is needed to further investigate these biomarker findings.

      8.5.1.5 Immunotherapy discontinuation

      Tabled 1
      Recommendation 8
      First-line treatment for inoperable locally advanced or metastatic MCCEvidence-based recommendation
      Grade of recommendation: AImmunocompetent patients with locally advanced or metastatic MCC (surgery no feasible) shall receive anti PD-(L)1 -based immunotherapy as first line treatment.
      Level of evidence: 2Phase II study of avelumab∗ [
      • D'Angelo S.P.
      • Bhatia S.
      • Brohl A.S.
      • Hamid O.
      • Mehnert J.M.
      • Terheyden P.
      • et al.
      Avelumab in patients with previously treated metastatic Merkel cell carcinoma: long-term data and biomarker analyses from the single-arm phase 2 JAVELIN Merkel 200 trial.
      ,
      • D'Angelo S.P.
      • Russell J.
      • Lebbé C.
      • Chmielowski B.
      • Gambichler T.
      • Grob J.J.
      • et al.
      Efficacy and safety of first-line avelumab treatment in patients with stage IV metastatic Merkel cell carcinoma a preplanned interim analysis of a clinical trial.
      ]

      Phase II study of pembrolizumab [
      • Nghiem P.
      • Bhatia S.
      • Lipson E.J.
      • Sharfman W.H.
      • Kudchadkar R.R.
      • Brohl A.S.
      • et al.
      Durable tumor regression and overall survival in patients with advanced Merkel cell carcinoma receiving pembrolizumab as first-line therapy.
      ]

      Phase I/II study of nivolumab [
      • Topalian S.L.
      • Bhatia S.
      • Hollebecque A.
      • Awada A.
      • Boer JP De
      • Kudchadkar R.R.
      • et al.
      Abstract CT074: Non-comparative, open-label, multiple cohort, phase 1/2 study to evaluate nivolumab (NIVO) in patients with virus-associated tumors (CheckMate 358): Efficacy and safety in Merkel cell carcinoma (MCC).
      ]
      Strength of consensus: 100%

      8.5.2 Chemotherapy

      Tabled 1
      Recommendation 9
      Chemotherapy for locally advanced or metastatic MCCEvidence-based recommendation
      Grade of recommendation: CChemotherapy can be used when patients fail to respond, are intolerant or present contraindication to anti-PD-(L)1 immunotherapy, or when immunotherapy or clinical trials are not available
      Level of evidence: 3-4Systematic review of 35 studies including retrospective studies and cases series [
      • Nghiem P.
      • Kaufman H.L.
      • Bharmal M.
      • Mahnke L.
      • Phatak H.
      • Becker J.C.
      Systematic literature review of efficacy, safety and tolerability outcomes of chemotherapy regimens in patients with metastatic Merkel cell carcinoma.
      ]
      Strength of consensus: 100%

      8.5.3 Immunotherapy in the adjuvant setting

      Adjuvant treatment with ipilimumab versus observation was tested in a randomised DeCOG phase-2 trial (‘ADMEC’) in Germany, but prematurely closed due to a futility analysis. After the inclusion of just 40 patients, no difference in PFS had been observed and ipilimumab caused significant toxicities [
      • Becker J.C.
      • Hassel J.C.
      • Menzer C.
      • Kähler K.C.
      • Eigentler T.K.
      • Meier F.E.
      • et al.
      Adjuvant ipilimumab compared with observation in completely resected Merkel cell carcinoma (ADMEC): a randomized, multicenter DeCOG/ADO study.
      ]. The subsequent randomised phase-2 trial of the DeCOG (“ADMEC-O’) compares the efficacy of nivolumab versus observation alone in 180 patients randomised in a 2:1 ratio, but data are not yet available [

      Nivolumab adjuvant (NCT02196961); ADMEC (DeCOG); Ph-II, open, randomized vs observation; www.clinicaltrials.gov [n.d].

      ]. A few clinical trials are ongoing (NCT04291885, NCT03271372, NCT03712605) and results are awaited.

      8.5.4 Immunotherapy in the neoadjuvant setting

      In a neo-adjuvant cohort of CheckMate 358, patients with resectable MCC received nivolumab 240 mg intravenously on days 1 and 15. Surgery was planned on day 29.39 patients with AJCC stage IIA-IV resectable MCC received ≥1 nivolumab dose. Three patients (7.7%) did not undergo surgery because of tumour progression (n = 1) or adverse events (n = 2). Any-grade treatment-related adverse events occurred in 18 patients (46.2%) and grade 3–4 events in 3 patients (7.7%), with no unexpected toxicities. Among 36 patients who underwent surgery, 17 (47.2%) patients achieved a complete pathologic response (pCR). Among 33 radiographically evaluable patients who underwent surgery, 18 (54.5%) patients had tumour reductions ≥30%. Responses were observed regardless of tumour MCPyV, PD-L1 or TMB status. At a median follow-up of 20.3 months, median recurrence-free survival (RFS) and OS were not reached. RFS significantly correlated with pCR and radiographic response at the time of surgery. No patient with a pCR had tumour relapse during observation [
      • Topalian S.L.
      • Bhatia S.
      • Amin A.
      • Kudchadkar R.R.
      • Sharfman W.H.
      • Lebbé C.
      • et al.
      Neoadjuvant nivolumab for patients with resectable Merkel cell carcinoma in the CheckMate 358 trial.
      ].

      8.5.5 Ongoing clinical trials with a novel approach

      Despite very encouraging results obtained with PD-1/PD-L1 blockade, approximately 50% of patients with advanced MCC do not have a durable benefit due to the primary and secondary resistances of unknown mechanisms, highlighting the need for further clinical trials.
      Tabled 1
      Recommendation 10
      Clinical trials for locally advanced or metastatic MCCConsensus-based recommendation
      GCPIf available and appropriate, inclusion in clinical trial should be encouraged
      Strength of consensus: 100%

      8.5.6 Locoregional control and palliative radiotherapy

      The place of isolated hyperthermic limb perfusion with alkeran and actinomycin D or isolated limb perfusion with TNF and alkeran combination therapy remains uncertain despite some favourable results in case reports or small retrospective and prospective cohort studies [
      • van Veenendaal L.M.
      • Madu M.F.
      • Tesselaar M.E.T.
      • Verhoef C.
      • Grünhagen D.J.
      • van Akkooi A.C.J.
      Efficacy of isolated limb perfusion (ILP) in patients with Merkel cell carcinoma (MCC): a multicenter experience.
      ,
      • O'Donoghue C.
      • Perez M.C.
      • Mullinax J.E.
      • Hardman D.
      • Sileno S.
      • Naqvi S.M.H.
      • et al.
      Isolated limb infusion: a single-center experience with over 200 infusions.
      ].
      In advanced patients with MCC, RT is routinely performed with palliative intent for symptomatic lesions either alone or combined to systemic therapies: 8 Gy in one session may be enough to reduce tumour burden providing durable palliation [
      • Iyer J.G.
      • Parvathaneni U.
      • Gooley T.
      • Miller N.J.
      • Markowitz E.
      • Blom A.
      • et al.
      Single-fraction radiation therapy in patients with metastatic Merkel cell carcinoma.
      ]. Other hypo-fractionated schedules can be used in the palliative treatment setting, such as 20 Gy in five fractions [
      • Veness M.
      • Howle J.
      Radiotherapy alone in patients with Merkel cell carcinoma: the Westmead Hospital experience of 41 patients.
      ]. Stereotactic RT (i.e. a local ablative treatment which delivers over 5 Gy per fraction in 1–5 fractions) is suitable for oligometastatic disease i.e. up to 5 small metastatic lesions in the brain or extracranial organs. RT is indicated for in-transit metastases which cannot be resected surgically. External beam RT or brachytherapy, although not in widespread use, are both valid options [
      • Cotter S.E.
      • Devlin P.M.
      • Sahni D.
      • Hansen J.L.
      • O'Farrell D.A.
      • Ng A.K.
      • et al.
      Treatment of cutaneous metastases of merkel cell carcinoma with surface-mold computer-optimized high-dose-rate brachytherapy.
      ,
      • Garibyan L.
      • Cotter S.E.
      • Hansen J.L.
      • Noell C.
      • Dorosario A.
      • O'Farrell D.A.
      • et al.
      Palliative treatment for in-transit cutaneous metastases of merkel cell carcinoma using surface-mold computer-optimized high-dose-rate brachytherapy.
      ].

      9. Quality of life, Palliative, Best supportive care

      The mean age of patients diagnosed with MCC is 77 years. Whilst the prognosis for patients with MCC is overall poor, advanced age worsens the prognosis [

      Schadendorf D, Larkin J, Postow M, Chiarion-sileni V, Gonzalez R, Rutkowski P, et al. Efficacy and safety outcomes in patients with advanced melanoma (MEL) who discontinued treatment with nivolumab (NIVO) plus ipilimumab (IPI) due to toxicity Disclosures : Dirk Schadendorf , MD • Research funding from Merck and Bristol-Myers Squibb • n.d.:1–18.

      ]. Older age is associated with increased comorbidity burden and frailty [
      • Sarfati D.
      • Koczwara B.
      • Jackson C.
      The impact of comorbidity on cancer and its treatment.
      ]. But chronological age alone provides limited information to physicians. Therefore, incorporating geriatric assessments, such as a comprehensive geriatric assessment allows a better understanding of the patients' functional status, as well as planning interventions to optimise and/or better support vulnerable/frail patients [
      • Mohile S.G.
      • Dale W.
      • Somerfield M.R.
      • Schonberg M.A.
      • Boyd C.M.
      • Burhenn P.S.
      • et al.
      Practical assessment and management of Vulnerabilities in older patients receiving chemotherapy: ASCO guideline for geriatric oncology.
      ]. But beyond that, this provides important information regarding the patient's individual risk and prognosis which supports the shared decision-making process when determining the best treatment plan. However, these assessments are not necessary for all older patients. Therefore, implementing validated screening tools, such as Geriatric 8 (G8), is a strategy to identify those older patients who may benefit the most from more in-depth assessments and support [
      • Decoster L.
      • Van Puyvelde K.
      • Mohile S.
      • Wedding U.
      • Basso U.
      • Colloca G.
      • et al.
      Screening tools for multidimensional health problems warranting a geriatric assessment in older cancer patients: an update on SIOG recommendations.
      ].
      The impact of the vulnerability of many of these patients with MCC was highlighted in an observational study with 500 patients with MCC and with a median age at diagnosis of 71 years who had been treated at a single centre. It found that half of the patients died during a median follow-up of 3 years. Yet, whilst 25% died due to MCC, the other 24% died of other causes [
      • Fields R.C.
      • Busam K.J.
      • Chou J.F.
      • Panageas K.S.
      • Pulitzer M.P.
      • Allen P.J.
      • et al.
      Five hundred patients with merkel cell carcinoma evaluated at a single institution.
      ].
      Health-related quality of life (HRQoL) is another important consideration when determining the best treatment plan. Older patients with cancer often value quality of life more than survival outcomes. Therefore, incorporating this information at decision timepoints is paramount [
      • Scotté F.
      • Bossi P.
      • Carola E.
      • Cudennec T.
      • Dielenseger P.
      • Gomes F.
      • et al.
      Addressing the quality of life needs of older patients with cancer: a SIOG consensus paper and practical guide.
      ]. Furthermore, assessing HRQoL at baseline and monitoring throughout a treatment pathway is a key to intervene time and meet the patients’ needs. This is particularly important when a curative-intent treatment is not appropriate, and the prognosis is poor. Several HRQoL tools have been developed and are widely used, such as the EORTC QLQ-C30 [
      • Scotté F.
      • Bossi P.
      • Carola E.
      • Cudennec T.
      • Dielenseger P.
      • Gomes F.
      • et al.
      Addressing the quality of life needs of older patients with cancer: a SIOG consensus paper and practical guide.
      ].
      Patients and their carers often suffer from both physical and psychological distress which fluctuates throughout the cancer journey, being at times worsened by the treatments provided. Therefore, similarly to what is advocated in other cancer types, an early integration with palliative and supportive care should be promoted.
      Apart from the potential side-effects and toxicity caused by the MCC treatments, which may require targeted interventions, the tumour itself is a frequent cause of symptoms which can have a great impact in the HRQoL and the well-being of patients. The key symptoms related to the pT and local cancer involvement are pain, ulceration, exudate and odour.
      Pain should be assessed regularly using validated pain scales [
      • Fallon M.
      • Giusti R.
      • Aielli F.
      • Hoskin P.
      • Rolke R.
      • Sharma M.
      • et al.
      Management of cancer pain in adult patients: ESMO Clinical Practice Guidelines.
      ]. The visual analogue scale, the verbal rating scale and the numerical rating scale (NRS) are most frequently used. When the score exceeds 2, a conversation about pain is required. Analgesics for chronic pain are best taken orally and should be prescribed on a regular basis instead of an ‘as required’ schedule [
      • Fallon M.
      • Giusti R.
      • Aielli F.
      • Hoskin P.
      • Rolke R.
      • Sharma M.
      • et al.
      Management of cancer pain in adult patients: ESMO Clinical Practice Guidelines.
      ]. The WHO proposes a sequential three-step analgesic ladder strategy, from non-opioids (paracetamol, anti-inflammatory drugs (NSAIDs)) to weak opioids to strong opioids according to pain scores [
      ]. However, in case a patient already suffers from intermediate (NRS ≥4) to severe (NRS ≥7) pain, weak opioids (e.g. tramadol, dihydrocodeine and codeine) might be best added to the mild analgesics immediately.
      Regarding ulcerating wounds, surgery and RT are effective palliative treatments but this is not always possible. The first step in odor prevention is daily rinsing with tap water or sodium chloride cleaning fluid. In a large review, evidence was found for topical metronidazole (gel or solution of metronidazole in concentrations of 0.75%–0.8% once daily for at least 14 days), sodium chloride dressing, activated carbon dressing and curcumin ointment [
      • da Costa Santos C.M.
      • de Mattos Pimenta C.A.
      • Nobre M.R.C.
      A systematic review of topical treatments to control the odor of malignant fungating wounds.