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ESP, EORTC, and EURACAN Expert Opinion: practical recommendations for the pathological diagnosis and clinical management of intermediate melanocytic tumors and rare related melanoma variants

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Abstract

The recent WHO classification of skin tumors has underscored the importance of acknowledging intermediate grade melanocytic proliferations. A multistep acquisition of oncogenic events drives the progressive transformation of nevi into melanomas. The various pathways described are modulated by the initial oncogenic drivers that define the common, blue, and Spitz nevi groups. Intermediate lesions are most often the result of a clonal evolution within such nevi. Based on this established classification, we have suggested for each pathway a practical diagnostic approach, benefiting from the recently developed molecular tools, both in the setting of general pathology labs and expert centers. Moreover, recommendations regarding the re-excision and clinical follow-up are given to support decision-making in multidisciplinary tumor boards.

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References

  1. Elder DE, Massi D, Scolyer RA, Willemze R, eds (2018) WHO Classification of Skin Tumours. 4th ed. Lyon, France: International Agency for Research on Cancer (IARC), Lyon Cedex 08 (France)

  2. Elder DE, Bastian BC, Cree IA, Massi D, Scolyer RA (2020) The 2018 World Health Organization Classification of cutaneous, mucosal, and uveal melanoma: detailed analysis of 9 distinct subtypes defined by their evolutionary pathway. Arch Pathol Lab Med 144:500–522

    Article  CAS  Google Scholar 

  3. Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, Cho KH, Aiba S, Bröcker EB, LeBoit PE, Pinkel D, Bastian BC (2005) Distinct sets of genetic alterations in melanoma. N Engl J Med 353(20):2135–2147

    Article  CAS  Google Scholar 

  4. Bastian BC (2014) The molecular pathology of melanoma: an integrated taxonomy of melanocytic neoplasia. Annu Rev Pathol 9:239–271

    Article  CAS  Google Scholar 

  5. Shain AH, Bastian BC (2016) From melanocytes to melanomas. Nat Rev Cancer 16(6):345–358

    Article  CAS  Google Scholar 

  6. Guillot B, Dalac S, Denis MG, Dupuy A, Emile JF, De La Fouchardiere A, Hindie E, Jouary T, Lassau N, Mirabel X, Piperno Neumann S, De Raucourt S, Vanwijck R (2017) French updated recommendations in stage I to III melanoma treatment and management. J Eur Acad Dermatol Venereol 31(4):594–602

    Article  CAS  Google Scholar 

  7. Melanoom (2019). https://richtlijnendatabase.nl/richtlijn/melanoom/melanoom_-_startpagina.html

  8. Eigentler TK, Mühlenbein C, Follmann M, Schadendorf D, Garbe C (2017) S3-Leitlinie Diagnostik, Therapie und Nachsorge des Melanoms - update 2015/2016, Kurzversion 2.0. J Dtsch Dermatol Ges 15(6):e1–e41

    Article  Google Scholar 

  9. (2017) Brown ER, Fraser SJ, Quaba O, Simms A, Stein A (2017) Cutaneous melanoma: an updated SIGN guideline. J R Coll Physicians Edinb 47(3):214–217

  10. AIOM (Associazione Italiana Oncologia Medica) - Linee guida melanoma (2019). https://www.aiom.it/wp-content/uploads/2019/10/2019_LG_AIOM_Melanoma.pdf

  11. Berrocal A, Arance A, Castellon VE, de la Cruz L, Espinosa E, Cao MG, Larriba JLG, Márquez-Rodas I, Soria A, Algarra SM (2018) SEOM clinical guideline for the management of malignant melanoma (2017). Clin Transl Oncol 20(1):69–74

    Article  CAS  Google Scholar 

  12. Michielin O, van Akkooi ACJ, Ascierto PA, Dummer R, Keilholz U, Guidelines Committee ESMO (2019) Cutaneous melanoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up†. Ann Oncol 30(12):1884–1901

    Article  CAS  Google Scholar 

  13. Michielin O, van Akkooi A, Lorigan P, Ascierto PA, Dummer R, Robert C, Arance A, Blank CU, Chiarion Sileni V, Donia M, Faries MB, Gaudy-Marqueste C, Gogas H, Grob JJ, Guckenberger M, Haanen J, Hayes AJ, Hoeller C, Lebbé C, Lugowska I, Mandalà M, Márquez-Rodas I, Nathan P, Neyns B, Olofsson Bagge R, Puig S, Rutkowski P, Schilling B, Sondak VK, Tawbi H, Testori A, Keilholz U (2020) ESMO consensus conference recommendations on the management of locoregional melanoma: under the auspices of the ESMO Guidelines Committee. Ann Oncol S0923-7534(20):39940–39943

    Google Scholar 

  14. Garbe C, Amaral T, Peris K, Hauschild A, Arenberger P, Bastholt L, Bataille V, Del Marmol V, Dréno B, Fargnoli MC, Grob JJ, Höller C, Kaufmann R, Lallas A, Lebbé C, Malvehy J, Middleton M, Moreno-Ramirez D, Pellacani G, Saiag P, Stratigos AJ, Vieira R, Zalaudek I, Eggermont AMM; European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO), and the European Organization for Research and Treatment of Cancer (EORTC) (2020). European consensus-based interdisciplinary guideline for melanoma. Part 1: diagnostics - update 2019. Eur J Cancer 126:141-158

  15. Garbe C, Amaral T, Peris K, Hauschild A, Arenberger P, Bastholt L, Bataille V, Del Marmol V, Dréno B, Fargnoli MC, Grob JJ, Höller C, Kaufmann R, Lallas A, Lebbé C, Malvehy J, Middleton M, Moreno-Ramirez D, Pellacani G, Saiag P, Stratigos AJ, Vieira R, Zalaudek I, Eggermont AMM; European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO), and the European Organization for Research and Treatment of Cancer (EORTC) (2020). European consensus-based interdisciplinary guideline for melanoma. Part 2: treatment - update 2019. Eur J Cancer 126:159-177

  16. Swetter SM, Tsao H, Bichakjian CK, Curiel-Lewandrowski C, Elder DE, Gershenwald JE, Guild V, Grant-Kels JM, Halpern AC, Johnson TM, Sober AJ, Thompson JA, Wisco OJ, Wyatt S, Hu S, Lamina T (2019) Guidelines of care for the management of primary cutaneous melanoma. J Am Acad Dermatol 80(1):208–250

    Article  Google Scholar 

  17. Castro LG, Messina MC, Loureiro W, Macarenco RS, Duprat Neto JP, Di Giacomo TH, Bittencourt FV, Bakos RM, Serpa SS, Stolf HO, Gontijo G (2015) Guidelines of the Brazilian Dermatology Society for diagnosis, treatment and follow up of primary cutaneous melanoma--part I. An Bras Dermatol 90(6):851–861

    Article  Google Scholar 

  18. Castro LG, Bakos RM, Duprat Neto JP, Bittencourt FV, Di Giacomo TH, Serpa SS, Messina MC, Loureiro WR, Macarenco RS, Stolf HO, Gontijo G (2016) Brazilian guidelines for diagnosis, treatment and follow-up of primary cutaneous melanoma - part II. An Bras Dermatol 91(1):49–58

    Article  Google Scholar 

  19. Cancer Council Australia. Clinical practice guidelines for the diagnosis and management of melanoma. 2020. https://wiki.cancer.org.au/australiawiki/index.php?oldid=209426

  20. Jafry MA, Peacock S, Radick AC, Shucard HL, Reisch LM, Piepkorn MW, Knezevich SR, Weinstock MA, Barnhill RL, Elder DE, Kerr KF, Elmore JG (2020) Pathologists’ agreement on treatment suggestions for melanocytic skin lesions. J Am Acad Dermatol 82(6):1435–1444

    Article  Google Scholar 

  21. Piepkorn MW, Longton GM, Reisch LM, Elder DE, Pepe MS, Kerr KF, Tosteson ANA, Nelson HD, Knezevich S, Radick A, Shucard H, Onega T, Carney PA, Elmore JG, Barnhill RL (2019) Assessment of second-opinion strategies for diagnoses of cutaneous melanocytic lesions. JAMA Netw Open 2(10):e1912597

    Article  Google Scholar 

  22. Elder DE, Xu X (2004) The approach to the patient with a difficult melanocytic lesion. Pathology 36(5):428–434

    Article  Google Scholar 

  23. Zembowicz A, Carney JA, Mihm MC (2004) Pigmented epithelioid melanocytoma: a low-grade melanocytic tumor with metastatic potential indistinguishable from animal-type melanoma and epithelioid blue nevus. Am J Surg Pathol 28(1):31–40

    Article  Google Scholar 

  24. Zembowicz A, Knoepp SM, Bei T, Stergiopoulos S, Eng C, Mihm MC, Stratakis CA (2007) Loss of expression of protein kinase a regulatory subunit 1alpha in pigmented epithelioid melanocytoma but not in melanoma or other melanocytic lesions. Am J Surg Pathol 31(11):1764–1775

    Article  Google Scholar 

  25. Cohen JN, Joseph NM, North JP, Onodera C, Zembowicz A, LeBoit PE (2017) Genomic analysis of pigmented epithelioid melanocytoma reveals recurrent alterations in PRKAR1A, and PRKCA genes. Am J Surg Pathol 41(10):1333–1346

    Article  Google Scholar 

  26. Isales MC, Mohan LS, Quan VL, Garfield EM, Zhang B, Shi K, Arva N, Beaubier N, Yazdan P, White K, Taxter TJ, Gerami P (2019) Distinct genomic patterns in pigmented epithelioid melanocytoma: a molecular and histologic analysis of 16 cases. Am J Surg Pathol 43(4):480–488

    Article  Google Scholar 

  27. Raghavan SS, Peternel S, Mully TW, North JP, Pincus LB, LeBoit PE, McCalmont TH, Bastian BC, Yeh I (2020) Spitz melanoma is a distinct subset of spitzoid melanoma. Mod Pathol 33(6):1122–1134

    Article  CAS  Google Scholar 

  28. Yazdan P, Cooper C, Sholl LM, Busam K, Rademaker A, Weitner BB, Obregon R, Guitart J, Gerami P (2014) Comparative analysis of atypical spitz tumors with heterozygous versus homozygous 9p21 deletions for clinical outcomes, histomorphology, BRAF mutation, and p16 expression. Am J Surg Pathol 38(5):638–645

    Article  Google Scholar 

  29. Harms PW, Hocker TL, Zhao L, Chan MP, Andea AA, Wang M, Harms KL, Wang ML, Carskadon S, Palanisamy N, Fullen DR (2016) Loss of p16 expression and copy number changes of CDKN2A in a spectrum of spitzoid melanocytic lesions. Hum Pathol 58:152–160

    Article  CAS  Google Scholar 

  30. Takata M, Suzuki T, Ansai S, Kimura T, Shirasaki F, Hatta N, Saida T (2005) Genome profiling of melanocytic tumors using multiplex ligation-dependent probe amplification (MLPA): its usefulness as an adjunctive diagnostic tool for melanocytic tumors. J Dermatol Sci 40(1):51–57

    Article  CAS  Google Scholar 

  31. North JP, Yeh I, McCalmont TH, LeBoit PE (2012) Melanoma ex blue nevus: two cases resembling large plaque-type blue nevus with subcutaneous cellular nodules. J Cutan Pathol 39(12):1094–1099

    Article  Google Scholar 

  32. Lallas A, Kyrgidis A, Ferrara G, Kittler H, Apalla Z, Castagnetti F, Longo C, Moscarella E, Piana S, Zalaudek I, Argenziano G (2014) Atypical Spitz tumours and sentinel lymph node biopsy: a systematic review. Lancet Oncol 15(4):e178–e183

    Article  Google Scholar 

  33. Massi D, Tomasini C, Senetta R, Paglierani M, Salvianti F, Errico ME, Donofrio V, Collini P, Tragni G, Sementa AR, Rongioletti F, Boldrini R, Ferrari A, Gambini C, Montesco MC (2015) Atypical Spitz tumors in patients younger than 18 years. J Am Acad Dermatol 72(1):37–46

    Article  Google Scholar 

  34. Lee S, Barnhill RL, Dummer R, Dalton J, Wu J, Pappo A, Bahrami A (2015) TERT promoter mutations are predictive of aggressive clinical behavior in patients with spitzoid melanocytic neoplasms. Sci Rep 5:11200

    Article  CAS  Google Scholar 

  35. Newman S, Fan L, Pribnow A, Silkov A, Rice SV, Lee S, Shao Y, Shaner B, Mulder H, Nakitandwe J, Shurtleff S, Azzato EM, Wu G, Zhou X, Barnhill R, Easton J, Nichols KE, Ellison DW, Downing JR, Pappo A, Potter PM, Zhang J, Bahrami A (2019) Clinical genome sequencing uncovers potentially targetable truncations and fusions of MAP3K8 in spitzoid and other melanomas. Nat Med 25(4):597–602

    Article  CAS  Google Scholar 

  36. Houlier A, Pissaloux D, Masse I, Tirode F, Karanian M, Pincus LB, McCalmont TH, LeBoit PE, Bastian BC, Yeh I, de la Fouchardière A (2020) Melanocytic tumors with MAP3K8 fusions: report of 33 cases with morphological-genetic correlations. Mod Pathol 33(5):846–857

    Article  CAS  Google Scholar 

  37. Bastian BC, Xiong J, Frieden IJ, Williams ML, Chou P, Busam K, Pinkel D, LeBoit PE (2002) Genetic changes in neoplasms arising in congenital melanocytic nevi: differences between nodular proliferations and melanomas. Am J Pathol 161(4):1163–1169

    Article  CAS  Google Scholar 

  38. Chan MP, Andea AA, Harms PW, Durham AB, Patel RM, Wang M, Robichaud P, Fisher GJ, Johnson TM, Fullen D (2016) Genomic copy number analysis of a spectrum of blue nevi identifies recurrent aberrations of entire chromosomal arms in melanoma ex blue nevus. Mod Pathol 29(3):227–239

    Article  CAS  Google Scholar 

  39. Costa S, Byrne M, Pissaloux D, Haddad V, Paindavoine S, Thomas L, Aubin F, Lesimple T, Grange F, Bonniaud B, Mortier L, Mateus C, Dreno B, Balme B, Vergier B, de la Fouchardiere A (2016) Melanomas associated with blue nevi or mimicking cellular blue nevi: clinical, pathologic, and molecular study of 11 cases displaying a high frequency of GNA11 mutations, BAP1 expression loss, and a predilection for the scalp. Am J Surg Pathol 40(3):368–377

    Article  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Biopathology, Center Léon Bérard, Lyon, France

    Arnaud de la Fouchardiere

  2. Department of Pathology, Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Center, Utrecht, The Netherlands

    Willeke Blokx

  3. Faculty of Medical Sciences, University Medical Center Groningen, Department of Pathology & Medical Biology, University of Groningen, Groningen, The Netherlands

    Léon C. van Kempen

  4. Institute of Pathology, Medical Faculty University of Ljubljana, Ljubljana, Slovenia

    Boštjan Luzar

  5. Department of Medical Oncology, Institut Curie, 75005, Paris, France

    Sophie Piperno-Neumann

  6. EURACAN network member (rare skin and eye melanoma domain), Leiden, The Netherlands

    Sophie Piperno-Neumann

  7. Department of Dermatology, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain

    Susana Puig

  8. Institut d’Investigació Biomèdica August Pi I Sunyer (IDIBAPS), Barcelona, Spain

    Susana Puig & Llucia Alos

  9. Centro de Investigación Biomédica En Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain

    Susana Puig

  10. Department of Pathology, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain

    Llucia Alos

  11. Department of Dermatopathology, St John’s Institute of Dermatology, St Thomas’ Hospital, London, UK

    Eduardo Calonje

  12. Section of Anatomic Pathology, Department of Health Sciences, University of Florence, Florence, Italy

    Daniela Massi

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  1. Arnaud de la Fouchardiere
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  2. Willeke Blokx
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Consortia

on behalf of the ESP Dermatopathology Working Group

EORTC Melanoma Group

EURACAN

Contributions

AF and DM conceived the study. AF provided the cases for the examples and wrote the manuscript. WB, LCK, BL, SPN, SP, LA, EC, and DM edited and reviewed the manuscript.

Corresponding author

Correspondence to Eduardo Calonje.

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Virchows Archiv conforms to the ICMJE recommendation for qualification of authorship. The ICMJE recommends that authorship be based on the following 4 criteria:

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Foreword: this work is the result of a collaborative effort between the European Organisation for Research and Treatment of Cancer (EORTC) Melanoma Group, the European Society of Pathology (ESP), and the European Rare Adult Cancer Network (EURACAN). It was initiated by members of the pathology subgroup of EORTC Melanoma Group, presented and discussed at the EORTC Melanoma Group meeting October 11, 2019 in Florence, Italy. The draft was later circulated to the cited representative authors of EORTC Melanoma Group, ESP, and EURACAN until consensus was met.

Supplementary Information

Fig. 1

Schematic view of the workflow (PNG 66 kb)

High Resolution Image (TIF 1376 kb)

Example 1

BAP1-inactivated melanocytic tumors (JPG 1072 kb)

High Resolution Image (TIF 80071 kb)

Example 2

Deep penetrating nevus (DPN) type lesions (JPG 982 kb)

High Resolution Image (TIF 82323 kb)

Example 3

Pigmented epithelioid melanocytoma (JPG 1250 kb)

High Resolution Image (TIF 91539 kb)

Example 4

Spitz tumors (JPG 910 kb)

High Resolution Image (TIF 81876 kb)

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de la Fouchardiere, A., Blokx, W., van Kempen, L.C. et al. ESP, EORTC, and EURACAN Expert Opinion: practical recommendations for the pathological diagnosis and clinical management of intermediate melanocytic tumors and rare related melanoma variants. Virchows Arch 479, 3–11 (2021). https://doi.org/10.1007/s00428-020-03005-1

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