Abstract
Recent advances in genomics have improved the molecular classification of cutaneous melanocytic tumors. Among them, deep penetrating nevi (DPN) and plexiform nevi have been linked to joint activation of the MAP kinase and dysregulation of the β-catenin pathways. Immunohistochemical studies have confirmed cytoplasmic and nuclear expression of β-catenin and its downstream effector cyclin D1 in these tumors. We assessed nuclear β-catenin immunohistochemical expression in a large group of DPN as well as in the four most frequent differential diagnoses of DPN: “blue” melanocytic tumors, Spitz tumors, nevoid and SSM melanomas, and pigmented epithelioid melanocytomas (PEM). Nuclear β-catenin expression was positive in 98/100 DPN and 2/16 of melanomas (one SSM and one nevoid melanoma with a plexiform clone) and was negative in all 30 Spitz, 26 blue, and 6 PEM lesions. In 41% DPN, β-catenin expression was positive in more than 30% nuclei. No differences were observed in cytoplasmic and nuclear cyclin D1 expression between these tumor groups, suggesting alternate, β-catenin-independent, activation pathways. We have subsequently studied nuclear β-catenin expression in a set of 13 tumors with an ambiguous diagnosis, for which DPN was part of the differential diagnosis. The three out of four patients showing canonical DPN mutation profiles were the only β-catenin-positive cases. We conclude that nuclear β-catenin expression, independently from CCND1 expression, in a dermal melanocytic tumor is an argument for its classification as DPN. In ambiguous cases and in early combined DPN lesions, this antibody can be helpful as a screening tool. β-Catenin is also potentially expressed in a subset of malignant melanomas with CTNNB1 mutations.
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References
Seab JA, Graham JH, Helwig EB (1989) Deep penetrating nevus. Am J Surg Pathol 13:39–44
Strazzula L, Senna MM, Yasuda M, Belazarian L (2014) The deep penetrating nevus. J Am Acad Dermatol 71:1234–1240. https://doi.org/10.1016/j.jaad.2014.07.026
Mehregan DA, Mehregan AH (1993) Deep penetrating nevus. Arch Dermatol 129:328–331
Barnhill RL, Mihm MC, Magro CM (1991) Plexiform spindle cell naevus: a distinctive variant of plexiform melanocytic naevus. Histopathology 18:243–247
Hung T, Yang A, Mihm MC, Barnhill RL (2014) The plexiform spindle cell nevus nevi and atypical variants: report of 128 cases. Hum Pathol 45:2369–2378. https://doi.org/10.1016/j.humpath.2014.08.009
Scolyer RA, Zhuang L, Palmer AA et al (2004) Combined naevus: a benign lesion frequently misdiagnosed both clinically and pathologically as melanoma. Pathology (Phila) 36:419–427. https://doi.org/10.1080/00313020412331283879
Yeh I, Lang UE, Durieux E, Tee MK, Jorapur A, Shain AH, Haddad V, Pissaloux D, Chen X, Cerroni L, Judson RL, LeBoit PE, McCalmont TH, Bastian BC, de la Fouchardière A (2017) Combined activation of MAP kinase pathway and β-catenin signaling cause deep penetrating nevi. Nat Commun 8:644. https://doi.org/10.1038/s41467-017-00758-3
Elder DE, Massi D, Scolyer R, Willemze R (eds) (2018) WHO classification of skin tumours. 4th ed. IARC Press, Lyon
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 40:368–377. https://doi.org/10.1097/PAS.0000000000000568
Bender RP, McGinniss MJ, Esmay P et al (2013) Identification of HRAS mutations and absence of GNAQ or GNA11 mutations in deep penetrating nevi. Mod Pathol 26:1320–1328. https://doi.org/10.1038/modpathol.2013.77
LeBoit PE, Burg G, Weedon D, Sarasin A (eds) (2006) Pathology and genetics of skin tumours. IARC Press, Lyon
Griewank KG, Müller H, Jackett LA et al (2017) SF3B1 and BAP1 mutations in blue nevus-like melanoma. Mod Pathol 30:928–939. https://doi.org/10.1038/modpathol.2017.23
Bastian BC, LeBoit PE, Pinkel D (2000) Mutations and copy number increase of HRAS in Spitz nevi with distinctive histopathological features. Am J Pathol 157:967–972. https://doi.org/10.1016/S0002-9440(10)64609-3
Wiesner T, He J, Yelensky R, Esteve-Puig R, Botton T, Yeh I, Lipson D, Otto G, Brennan K, Murali R, Garrido M, Miller VA, Ross JS, Berger MF, Sparatta A, Palmedo G, Cerroni L, Busam KJ, Kutzner H, Cronin MT, Stephens PJ, Bastian BC (2014) Kinase fusions are frequent in Spitz tumours and spitzoid melanomas. Nat Commun 5:. https://doi.org/10.1038/ncomms4116
Yeh I, Botton T, Talevich E, Shain AH, Sparatta AJ, de la Fouchardiere A, Mully TW, North JP, Garrido MC, Gagnon A, Vemula SS, McCalmont TH, LeBoit PE, Bastian BC (2015) Activating MET kinase rearrangements in melanoma and Spitz tumours. Nat Commun 6:7174. https://doi.org/10.1038/ncomms8174
Yeh I, Tee MK, Botton T, Shain AH, Sparatta AJ, Gagnon A, Vemula SS, Garrido MC, Nakamaru K, Isoyama T, McCalmont TH, LeBoit PE, Bastian BC (2016) NTRK3 kinase fusions in Spitz tumours. J Pathol 240:282–290. https://doi.org/10.1002/path.4775
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 28:31–40
Mandal RV, Murali R, Lundquist KF, Ragsdale BD, Heenan P, McCarthy SW, Mihm MC, Scolyer RA, Zembowicz A (2009) Pigmented epithelioid melanocytoma: favorable outcome after 5-year follow-up. Am J Surg Pathol 33:1778–1782. https://doi.org/10.1097/PAS.0b013e3181b94f3c
Cohen JN, Joseph NM, North JP, Onodera C, Zembowicz A, LeBoit PE (2017) Genomic analysis of pigmented epithelioid melanocytomas reveals recurrent alterations in PRKAR1A and PRKCA genes. Am J Surg Pathol 41:1333–1346. https://doi.org/10.1097/PAS.0000000000000902
Sauter ER, Yeo U-C, von Stemm A, Zhu W, Litwin S, Tichansky DS, Pistritto G, Nesbit M, Pinkel D, Herlyn M, Bastian BC (2002) Cyclin D1 is a candidate oncogene in cutaneous melanoma. Cancer Res 62:3200–3206
Georgieva J, Sinha P, Schadendorf D (2001) Expression of cyclins and cyclin dependent kinases in human benign and malignant melanocytic lesions. J Clin Pathol 54:229–235
Ramirez JA, Guitart J, Rao MS, Diaz LK (2005) Cyclin D1 expression in melanocytic lesions of the skin. Ann Diagn Pathol 9:185–188. https://doi.org/10.1016/j.anndiagpath.2005.04.018
Alekseenko A, Wojas-Pelc A, Lis GJ, Furgał-Borzych A, Surówka G, Litwin JA (2010) Cyclin D1 and D3 expression in melanocytic skin lesions. Arch Dermatol Res 302:545–550. https://doi.org/10.1007/s00403-010-1054-3
Acknowledgments
The authors thank the pathologists and dermatologist who contributed case material and clinical data as well as the patients for their participation in this study. The authors thank Elodie Legrand, Amandine Bernard, Cyrille Py, Sandrine Paindavoine, Florine Dreux, and Elise Malandain for their technical help as well as Iwei Yeh, Keisuke Goto, and Dr. Olivier Ramuz for their input on the manuscript. We thank Dr. Christiane Bailly and Dr. Christine Castillo for their participation in the diagnostic multihead sessions during the case selection process.
Contributions
Arnaud de la Fouchardiere conceived and designed the study, and wrote, edited, and reviewed the manuscript. Julien Jacquemus, Emeline Durieux, and Aurélie Houlier researched and analyzed data. Claire Caillot, Véronique Haddad, and Daniel Pissaloux researched and analyzed data, and wrote, edited, and reviewed the manuscript. All authors gave final approval for publication. Author Arnaud de la Fouchardiere takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript.
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This work was funded by LYric grant INCa-DGOS-4664.
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The study was conducted according to the Declaration of Helsinki and has been approved by the Centre Léon Bérard’s research ethics committee (Ref: L15-152).
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de la Fouchardière, A., Caillot, C., Jacquemus, J. et al. β-Catenin nuclear expression discriminates deep penetrating nevi from other cutaneous melanocytic tumors. Virchows Arch 474, 539–550 (2019). https://doi.org/10.1007/s00428-019-02533-9
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DOI: https://doi.org/10.1007/s00428-019-02533-9