Review ArticlesMetastatic Basal Cell Carcinoma of the Skin: A Comprehensive Literature Review, Including Advances in Molecular TherapeuticsBisceglia, Michele MD*; Panniello, Gaetano MD†; Galliani, Carlos A. MD‡; Centola, Michele MD§; D’Errico, Maria M. MD∥; Minenna, Elena MD∥; Tucci, Francesco A. MD¶; Ben-Dor, David J. MD#Author Information *Anatomic Pathology, School of Biomedical Sciences ¶School of Biomedical Sciences, Etromapmax Pole, Lesina (FG) †Unit of Clinical Dermatology, Department of Internal Medicine, Polyclinic of Foggia ∥Department of Medical and Surgical Sciences, University of Foggia, Foggia §School of Medicine, University of Perugia, Perugia, Italy ‡Department of Pathology, Children’s and Women’s Hospital, University of South Alabama, Mobile, AL #Department of Pathology, The Barzilai Medical Center, Ashkelon, Israel The authors have no conflicts of interest to disclose. All figures can be viewed online in color at www.anatomicpathology.com. Reprints: Michele Bisceglia, MD, Via Santa Chiara, 9, Manfredonia (FG) 71043, Italy (e-mail: email@example.com). Advances In Anatomic Pathology: September 2020 - Volume 27 - Issue 5 - p 331-353 doi: 10.1097/PAP.0000000000000267 Buy Metrics Abstract Basal cell carcinoma (BCC) of the skin is the most common type of malignant human tumor. In Europe, the incidence of BCC ranges from 44.6 to 128 cases per 100,000 inhabitants annually, whereas in the United States, the yearly incidence rate ranges between 500 and 1500. The global incidence has been calculated to be as high as 10 million cases of BCC per year. There are 2 main clinical patterns of BCC—the familial BCC in basal cell nevus syndrome and sporadic BCC. The etiology of cutaneous BCC is usually the result of the interaction between solar ultraviolet radiation and genetic factors. Somatic or germline mutations in the effector components of the hedgehog signaling pathway (ie, PTCH1, PTCH2, SMO or SUFU genes) are responsible for ∼90% of the cases of both sporadic and familial BCC, all causing a constitutive activation of the hedgehog pathway. Cutaneous BCC very rarely metastasizes, and diagnosis in metastatic sites can be very difficult. Metastatic BCC has weakly effective therapeutic options with a poor prognosis until few years ago. In 2012, small-molecule therapies, involving inactivation of the hedgehog signaling pathway, and capable of reducing tumor growth and progression have been introduced into clinical practice for advanced (locally advanced or metastatic) BCC. We performed a comprehensive literature review on metastatic BCC and found at least 915 cases reported to date. In addition, we extensively discussed the differential diagnosis of metastatic BCC, and outlined the advances in clinical therapeutics involving these small molecules. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.