br INTRODUCTION br Discoid lupus erythematosus DLE is the most
Discoid lupus erythematosus (DLE) is the most common type of cutaneous lupus and is characterized by scarring lesions with pigmentary changes on the sun-exposed skin (Walling and Sontheimer, 2009). Squamous cell carcinoma (SCC) has been reported in 2.3%e3.3% of DLE patients, with substantially higher rates of recurrence and Midostaurin compared with sporadic SCC (Tao et al., 2012). A 4-fold increase in the risk of SCC has been reported in patients with DLE (Gro¨nhagen et al., 2012), which is associated with a 20-fold increase in mortality compared with sporadic SCC (Tao et al., 2012). The poor prognosis of SCC in DLE patients
1Center for Cancer Immunology and Cutaneous Biology Research Center, Department of Dermatology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; 2Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA;
3Division of Dermatology, Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA; and 4Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri, USA
5These authors contributed equally to this work.
Correspondence: Shadmehr Demehri, Department of Dermatology and MGH Cancer Center, Building 149 13th Street, 3rd Floor, Charlestown, Massachusetts 02129, USA. E-mail: [email protected]
Abbreviations: DLE, discoid lupus erythematosus; DMBA, 7,12-dimethylbenz(a)anthracene; SCC, squamous cell carcinoma; Th, T helper; TPA, 12-O-tetradecanoylphorbol-13-acetate; Treg, regulatory T cell
highlights the need to better understand the etiology of skin cancer development in this disease.
Several factors may predispose DLE patients to skin cancer. UVR is an established risk factor for SCC; UV exposure triggers lupus flares, and DLE lesions occur preferentially on UV-exposed areas of the body (Chen et al., 2013; Fernandez and Kirou, 2016). Immunosuppressive medications used to treat cutaneous lupus, like mycophenolate mofetil, tacroli-mus, and azathioprine, may promote SCC development by suppressing the antitumor immune response in the skin (Walling and Sontheimer, 2009). However, a similar preva-lence of SCC is reported among DLE patients who never received systemic immunosuppressive medications (Tao et al., 2012). Inflammation and scarring are other potential risk factors for skin cancer. Inflammation in DLE lesions is characterized as predominantly T helper (Th) type 1 mediated (Jabbari et al., 2014). Therefore, cancer development within such a tumor-suppressive immune environment, albeit in a small subset of DLE patients, raises the need to determine the nature of inflammation specifically in DLE lesions susceptible to SCC development.
Although there are several potential tumor-inducing factors affecting DLE, the pathophysiology underlying the development of DLE-associated SCC has not been defined. Long-term follow-up of SCC-prone DLE lesions in African American patients suggested the role of inflammation as the promoter of SCC in DLE. We showed that DLE inflammation in the absence of scarring and systemic immunosuppression significantly enhanced skin cancer development in mice ho-mozygous for the lymphoproliferation spontaneous mutation
62 Journal of Investigative Dermatology (2019), Volume 139ª 2018 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology.
A Zaalberg et al. DLE-Associated Inflammation Promotes Skin Cancer
Figure 1. Skin cancer development is associated with areas of active skin inflammation in DLE. (a) Clinical and pathological images of three independent skin cancers, (1) SCCIS, (2) SCC, and (3) SCCIS, that were diagnosed concurrently at the margins of a depigmented DLE plaque on a patient’s sun-exposed skin are shown. (b) The review of clinical images and pathology reports shows the locations of neoplastic skin lesions (SCC, SCCIS, and AK) and active LE inflammation that were biopsied to rule out skin cancer during the 8-year follow-up period on the stable DLE plaque. Each lesion is mapped onto a topographic outline of the DLE plaque with the opposite gradients of scarring and inflammation in DLE highlighted in the background. (c) The extent of dermal scarring (Masson’s trichrome stain) and inflammation (CD45 stain) are shown in the patient’s skin cancer compared with aged-matched normal facial skin. The insert shows a positive control for Masson’s trichrome staining in a skin sample with scarring. Cytoplasm and muscle fibers stain red, whereas collagen displays blue coloration. Scale bars ¼ 100 mm. AK, actinic keratosis; LE, lupus erythematosus; SCC, squamous cell carcinoma; SCCIS, squamous cell carcinoma in situ. Photograph published with patient’s consent.