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Β-Catenin Nuclear Expression Discriminates Deep Penetrating Nevi from Other Cutaneous Melanocytic Tumors

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Β-Catenin Nuclear Expression Discriminates Deep Penetrating Nevi from Other Cutaneous Melanocytic Tumors Virchows Archiv (2019) 474:539–550 https://doi.org/10.1007/s00428-019-02533-9 ORIGINAL ARTICLE β-Catenin nuclear expression discriminates deep penetrating nevi from other cutaneous melanocytic tumors Arnaud de la Fouchardière1,2 & Claire Caillot1 & Julien Jacquemus1 & Emeline Durieux3 & Aurélie Houlier1,2 & Véronique Haddad1 & Daniel Pissaloux1,2 Received: 15 November 2018 /Revised: 21 January 2019 /Accepted: 25 January 2019 /Published online: 12 February 2019 # Springer-Verlag GmbH Germany, part of Springer Nature 2019 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: Bblue^ 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. Keywords Deep penetrating nevi . Beta catenin . Immunohistochemistry . Melanocytic tumors . Differential diagnosis Virchows Archiv conforms to the ICMJE recommendation for Introduction qualification of authorship. The ICMJE recommends that authorship be based on the following four criteria: • Substantial contributions to the conception or design of the work; or the Cutaneous melanocytic tumors are known for important var- acquisition, analysis, or interpretation of data for the work; AND iations of their morphologic appearance. In early lesions, dis- • Drafting the work or revising it critically for important intellectual tinction between several subtypes of nevi can be challenging. content; AND • Final approval of the version to be published; AND Atypical cases are often difficult to classify within any specific • Agreement to be accountable for all aspects of the work in ensuring that category. While genetic studies have enhanced the modern questions related to the accuracy or integrity of any part of the work are morpho-genetic classification, widely available techniques appropriately investigated and resolved. such as immunohistochemistry (IHC) can be a convenient first-line molecular tool in many pathology laboratories. * Arnaud de la Fouchardière Deep penetrating nevus (DPN) is a rare subtype of cutaneous [email protected] melanocytic tumors that is often not recognized clinically [1]. DPN appears as small, dome-shaped, pigmented nodule(s) 1 Departement de Biopathologie, Centre Léon Bérard, 28, rue mainly located in the upper body region. It occurs in young Laennec, 69008 Lyon, France adults with a slight female predominance. Histologically, its 2 Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, architecture can vary greatly [2]. The junctional component is Centre Léon Bérard, Cancer Research Center of Lyon, Equipe Labellisée Ligue contre le Cancer, Université de Lyon, Lyon, France inconstant and limited to scarce nests or lentiginous melano- cytes without any pagetoid spread. The tumor is predominant- 3 Department of Pathology, Centre Hospitalier Lyon-Sud, 69310 Lyon, France ly located in the dermis, forming a wedge-shaped silhouette at 540 Virchows Arch (2019) 474:539–550 scanning magnification [3]. Large spindled or epithelioid me- checked for notable morphological and IHC features. The lanocytes with a wide cytoplasm often harboring thin melanin histological features in each selected sample were typical for pigment are arranged in small nests or ill-defined fascicles. each subtype of tumor. DPN were classified as either pure or The nucleus is often large, oval, with prominent nucleoli. combined when a common compound nevus component was This peculiar cytology is found throughout the lesion without associated. Cases were classified as atypical DPN according any maturation. The BDPN^ denomination is related to verti- to the WHO classification when they had Batypical features cally oriented expansions, usually following skin appendages, such as large size, asymmetry, aberrant architecture (e.g. nerves, or blood vessels. Areas of spitzoid cytology with an sheet-like arrangements of melanocytes), increased mitotic eosinophilic cytoplasm can be identified. Mild lymphocytic rates, and severe cytological atypia^ [8]. Malignant variants infiltrates and intermingled melanophages are common fea- of DPN, that would include the combination of all criteria, tures. Dermal fibrosis is limited, with patches of normal der- were excluded. BBlue^ melanocytic tumors encompassed ei- mis often found in between nests. Superficial plexiform spin- ther common, or cellular, or sclerosing cellular blue nevus, or dle cell nevus described by Barnhill et al. is the subject of an malignant blue melanoma ex-blue nevus. Spitz tumors were ongoing debate regarding its relationship with DPN [4, 5]. classified as either Spitz nevus or atypical Spitz tumor. Combined DPN is a frequent variant of DPN in which a com- Malignant Spitz tumors were excluded. PEM were of pure pound nevus with common cytology is associated with vari- type. Melanomas were classified as either superficial spread- ous amounts of pigmented nests with DPN cytology. When ing, or nodular, or nevoid melanoma according to the current the disposition of the pigmented component is asymmetric, WHO classification [8]. Neither acral lentiginous nor lentigo these combined DPN are often clinically worrisome and sent maligna melanoma was included. BTumors with an ambigu- for referral as putative melanoma. Scolyer et al. have thor- ous morphological diagnosis of DPN^ were selected when oughly discussed the pathogeny of combined nevi and favor nests of dermal pigmented epithelioid melanocytes suggested the divergent terminal differentiation hypothesis based on the a potential diagnosis of DPN without all the usual morpholog- frequency of overlapping cytological features in merging ical features including atypia or potential malignancy. Clinical areas [6]. DPN is frequently regarded as a difficult diagnosis information regarding gender, age at diagnosis, and topogra- as there are many similarities with plexiform and pigmented phy of each lesion was obtained from the referring pathologist Spitz tumors, blue nevi, and pigmented epithelioid or the clinician. All cases were discussed in a multihead ses- melanocytomas (PEM). In a recent study, we have shown that sion including at least two senior dermatopathologists. The DPN are genetically defined by activation of both MAP ki- study was conducted according to the Declaration of nase and β-catenin pathways [7]. This can occur through sev- Helsinki and has been approved by the Centre Léon eral combinations of events, the most frequent being com- Bérard’s research ethics committee (Ref: L15-152). Sixty- bined BRAF V600E and exon 3 CTNNB1 mutations. In that eight DPN cases had been previously published [7]. setting, strong nuclear β-catenin expression was present in the dermal DPN nests even when deeply located. DPN often arise from a pre-existing common acquired nevus resulting in a Immunohistochemistry biphenotypic tumor where CTNNB1 mutation is limited to the DPN component whereas the MAP kinase activating al- Immunohistochemical staining was performed on 4 μmsec- teration is found in both components. tions cut from formalin-fixed, paraffin-embedded (FFPE) tis- In this study, we compared β-catenin IHC expression pro- sue using a Ventana BenchMark Ultra automated stainer files in an expanded panel of DPN and melanocytic lesions (Ventana, Tucson, USA) and revealed with the Enhanced that are usual differential diagnoses of DPN: Spitz tumors, Alkaline Phosphatase Red Detection Kit (Ventana #800- Bblue^ type tumors, PEM, and melanomas. A group of tumors 031). The following antibodies were used: β-catenin (clone with ambiguous morphological diagnosis was subsequently beta catenin-1, 1:200, Dako), CCND1 (clone SP4, 1:1, assessed. In a large subset of all these cases, cyclin D1 IHC Thermo Scientific), ALK (clone 5A4, 1:50, Novocastra), expression and specific genetic drivers were also assessed. ROS1 (clone D4D6, 1:50, Cell Signaling), NTRK1 (clone EP1058Y, 1:200, Abcam), BRAF (clone VE1, 1:200, Spring Biosciences), BAP1 (clone C4, 1:50, Santa Cruz Material and methods Biotechnology),
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