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INVESTIGATIVE REPORT A Myxoid Fibrotic Reaction Pattern is Associated with Metastatic Risk in Cutaneous Squamous Cell Carcinoma Eugenia HERNÁNDEZ-RUIZ 1,2# , Inmaculada HERNÁNDEZ-MUÑOZ 3# , Emili MASFERRER 4 , Carla FERRÁNDIZ-PULIDO 2 , Evelyn ANDRADES 3 , Javier GIMENO 5 , Xavier DURAN 6 , Vicente GARCÍA-PATOS 2 , Ramon M. PUJOL 1 and Agusti TOLL 1 Departments of 1 Dermatology and 5 Pathology, Hospital del Mar, Parc de Salut Mar, 2 Department of Dermatology, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 3 Group of Inflammatory and Neoplastic Dermatological Diseases and 6 Methodological and biostatistical advisory service, IMIM (Hospital del Mar Medical Research Institute), and 4 Department of Dermatology, Hospital Universitari Mútua de Terrassa, Barcelona, Spain # Both authors contributed equally to this work. Although desmoplasia has been associated with poor prognoses in cutaneous squamous cell carcinoma, little attention has been paid to the patterns of fibrosis. This study aimed to examine the different stromal fibrotic patterns as markers of metastatic risk. We performed a multicenter retrospective study that included 102 cu- taneous squamous cell carcinomas (52 non-metastatic and 50 metastatic carcinomas). Clinical and histopa­ thological data were registered. The fibrotic reaction pattern was classified as mature, intermediate or im- mature depending on the presence of keloid-like colla- gen and myxoid stroma. The immature pattern (areas characterized by myxoid changes with no inflamma- tion) was observed in 18 samples and its presence was significantly associated with immuno­suppression, bud- ding, desmoplasia, perineural invasion, anatomic level, tumoural depth and metastatic risk in the multivariate analysis. Our findings suggest that the presence of an immature myxoid fibrotic pattern, which can be easily identified by routine hematoxylin-eosin staining, is strongly associated with metastatic risk. Key words: metastasis; fibrosis; cutaneous squamous cell car- cinoma. Accepted Aug 31, 2018; Epub ahead of print Sep 3, 2018 89 Acta Derm Venereol 2019; 99: 89–94. Corr: Agustí Toll, Department of Dermatology, Hospital del Mar, Parc de Salut Mar, Universitat Autònoma de Barcelona, ES-08003 Barcelona, Spain. E-mail: [email protected], [email protected] M etastatic cutaneous squamous cell carcinomas (MSCCs) usually involve the regional lymph nodes, and occur in approximately 4–5% of patients (1). Active research in cutaneous SCC (cSCC) is aimed at the identification of prognostic markers of clinical value that could help identify those patients at higher metastatic risk. Prominent clinical factors linked to an aggressive clinical behaviour and metastatic risk include tumoural size, im- munosuppression and certain tumour locations such as the ears, lips and areas of chronic injury. Some histological parameters of the primary tumour, including depth, poor histological differentiation and perineural invasion have also been associated with poor prognosis (2–4). Epithelial to mesenchymal transition (EMT), a me- chanism by which epithelial cells lose adhesion and SIGNIFICANCE Cutaneous squamous cell carcinomas are the second most frequent non-melanoma skin cancers. Despite their gene- rally good prognosis, approximately 2–5% metastasize, usually to regional lymph nodes. Recent works have elu- cidated the relevance of the tumour microenvironment, consisting of a stromal reaction, a vascular and lymphatic network and the presence of specific inflammatory cell subpopulations, in the development of metastases. In this study we have characterized different types of stromal reaction patterns in cutaneous squamous cell carcinoma, including desmoplasia, and have found that the presence of a myxoid peritumoral infiltration, easily recognisable by hematoxylin eosin stains, is associated with an increased metastatic risk. acquire mesenchymal traits that allow them to invade and disseminate (5), has been shown to be involved in the metastasis of a variety of epithelial tumours. Indeed, we have previously reported that the presence of EMT markers is associated with an increased metastatic risk in cSCC (6). Tumour budding, pathologically characterized by clusters or single tumoural cells that may reflect cells undergoing EMT, has also been recently linked to nodal metastasis in cSCC (7, 8). The EMT process can be induced by the tumoural microenvironment through the release of cytokines and extracellular matrix proteins by cancer-associated fibroblasts (CAFs). In addition to their effect on epi­ thelial tumoural cells, CAFs may also generate a fibro- tic stroma. The role of the fibrotic reaction in cancer development and progression remains controversial. While some studies suggest that the host may favour a desmoplastic response to limit tumour aggressiveness (9), others have shown that the fibrotic stroma induced by CAFs might benefit the tumour by inhibiting access to immune cells (10–13). In this sense, the association between desmoplastic reaction and poor outcome has been observed in several cancers such as cholangiocar- cinoma, breast, pulmonary, pancreatic, tongue, rectal and colorectal carcinomas (11, 14–18). cSCC with a desmoplastic phenotype, characterized by strands and nests of tumour cells surrounded by a prominent fibrous stromal response, may also pose an increased risk of This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2019 Acta Dermato-Venereologica. doi: 10.2340/00015555-3025 Acta Derm Venereol 2019; 99: 89–94