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Could cathepsin-k be a driver of the myofibroblastic differentiation observed in dermatofibroma, atypical fibroxanthoma and pleomorphic dermal sarcoma?

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Abstract

Dermatofibroma (BFH), atypical fibroxanthoma (AFX) and dermal pleomorphic sarcoma (DPS) are skin-based soft-tissue neoplasms of uncertain lineage. They are classified as “fibrohistiocytic” neoplasms, even if the World Health Organization stated that this term connotes a polymorphic group of lesions that histologically resemble fibroblasts and histiocytes. It is well-known that this group of lesions shows a “fibro-histiocytic-dendritic” and/or a “myofibroblastic” phenotype, even within the same lesion. We studied the expression of cathepsin-k in 34 cases (25 BFH, 5 AFX, 4 DPS) with a broad panel of antibodies. 20 cases (5 dermatofibrosarcoma protuberans, 5 melanomas, 5 basal cell carcinomas, 5 squamous cell carcinomas) were chosen as controls. Although our results need to be validated, they support a myofibroblastic and/or partial myofibroblastic (“proto-myofibroblastic”) phenotype and the lineage-plasticity of these neoplasms, highlighting the potential role of cathepsin-k in myofibroblastic trans-differentiation. Cathepsin-k proved to be an additional immunoistochemical marker potentially useful in the diagnostic algorithm.

Introduction

Dermatofibroma/benign fibrous histiocytoma (BFH), atypical fibroxanthoma (AFX) and dermal pleomorphic sarcoma (DPS) are soft-tissue neoplasms commonly encountered by dermatopathologists (Fig. 1) (Elder et al., 2018). Numerous studies have focused on the lineage of differentiation and/or cell of origin of these neoplasms, but this topic continues to be a matter of debate (Longacre et al., 1993; Harding-Jackson et al., 2015; Prieto et al., 1995; Sakamoto et al., 2002). Although they are commonly classified as “fibrohistiocytic” neoplasms, various electron microscopic and immunohistochemical studies pointed out how the cell of origin could be an undifferentiated mesenchymal cell able to trans-differentiate toward a histiocytic, dendritic, fibroblastic and myofibroblastic lineage (Elder et al., 2018; Longacre et al., 1993; Harding-Jackson et al., 2015; Prieto et al., 1995; Sakamoto et al., 2002). By contrast, other authors argue that these neoplasms are made up of neoplastic cells (fibroblasts and/or histiocytes) admixed with a great number of accompanying cells, which justifies the confusing and sometimes controversial results (Prieto et al., 1995; Sakamoto et al., 2002; Goldblum et al., 2014). In recent years, starting from an attempt to clarify the remodelling process after myocardial infarction, several authors analyzed the complex metabolic processes that regulate the genesis of the myofibroblasts during the tissue repair, highlighting the central role of the proteases of the “cathepsin family” (Hinz, 2007; Shephard et al., 2004; Chen et al., 2013; Tomasek et al., 2002). For this reason, we evaluated whether the expression of cathepsin-k supports the myofibroblastic differentiation of these neoplasms and its role in myofibroblastic trans-differentiation, also in a neoplastic background.

Section snippets

Materials and methods

We retrospectively analyzed 53 cases (25 BFH, 5 AFX, 4 DPS, 5 dermatofibrosarcoma protuberans-DFSP, 5 malignant melanoma-MM, 5 basal cell carcinomas-BCC and 5 squamous cell carcinomas-SCC) diagnosed from May 2018 to February 2019 at the Service of Pathology Unit and Dermatology Unit, University of Bologna. All the cases were evaluated with a large panel of antibodies including cathepsin-K, smooth-muscle-actin (α-SMA), desmin, S-100, cytokeratin AE1/AE3, CD68, CD34 and CD10. Clinical,

Results and discussion

Catepsin-K showed moderate and diffuse positivity in all cases of BFH (16: 3+; 9: 2+), AFX (3: 3+; 2: 2+) and DPS (2: 3+; 2: 2+), whereas it was completely negative (0) in all the other tumours (Fig. 2). Cathepsin-k stained all the different cellular compartments, regardless of their morphology (fibroblastic, myofibroblastic and histiocytic) and other immunohistochemical results. 18 tumors (53 %) showed a peculiar pattern of immunostaining for cathepsin-k, with a crescendo-pattern moving from

CRediT authorship contribution statement

Costantino Ricci: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing. Antonio De Leo: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing. Emi Dika: Writing - review & editing. Martina Lambertini: Writing - review & editing. Giulia Veronesi: Writing - review

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