β-Catenin nuclear expression discriminates deep penetrating nevi from other cutaneous melanocytic tumors

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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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.

Funding

This work was funded by LYric grant INCa-DGOS-4664.

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Correspondence to Arnaud de la Fouchardière.

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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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Keywords

  • Deep penetrating nevi
  • Beta catenin
  • Immunohistochemistry
  • Melanocytic tumors
  • Differential diagnosis