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Morphea and systemic sclerosis are associated with an increased risk for melanoma and nonmelanoma skin cancer

2018; Elsevier BV; Volume: 80; Issue: 5 Linguagem: Inglês

10.1016/j.jaad.2018.10.022

1097-6787

Emily Boozalis, Ami A. Shah, Fredrick M. Wigley, Sewon Kang, Shawn G. Kwatra,

Skin Diseases and Diabetes

To the Editor: It is well-known that systemic autoimmune diseases confer an increased risk for cancer.1Joseph C.G. Darrah E. Shah A.A. et al.Association of the autoimmune disease scleroderma with an immunologic response to cancer.Science. 2014; 343: 152-157Crossref PubMed Scopus (285) Google Scholar In recent years, studies have described an increased risk for epithelial malignancies in patients with systemic sclerosis—most commonly lung carcinoma.2Onishi A. Sugiyama D. Kumagai S. Morinobu A. Cancer incidence in systemic sclerosis: meta-analysis of population-based cohort studies.Arthritis Rheum. 2013; 65: 1913-1921Crossref PubMed Scopus (126) Google Scholar, 3Shah A.A. Rosen A. Hummers L. Wigley F. Casciola-Rosen L. Close temporal relationship between onset of cancer and scleroderma in patients with RNA polymerase I/III antibodies.Arthritis Rheum. 2010; 62: 2787-2795Crossref PubMed Scopus (161) Google Scholar, 4Shah A.A. Casciola-Rosen L. Cancer and scleroderma: a paraneoplastic disease with implications for malignancy screening.Curr Opin Rheumatol. 2015; 27: 563-570Crossref PubMed Scopus (44) Google Scholar There are no current studies in the literature evaluating the prevalence of epithelial skin cancers in patients with the localized form of scleroderma, morphea. Using the Slicer Dicer feature of the electronic medical record system EPIC, we retrospectively collected anonymous, aggregate-level data on patients ≥18 years of age seen at Johns Hopkins Hospital (JHH) over a 6-year period (March 9, 2012-March 9, 2018). The prevalences of melanoma, squamous cell carcinoma of the skin, and basal cell carcinoma were collected for patients with concomitant diagnosis of morphea or systemic sclerosis. As a control, we compared these values with those of the general JHH patient population and then calculated the odds ratios (ORs) and P values for each comparison using a 95% confidence interval (CI) (Table I). We found that, compared with the general population of patients at JHH, patients with morphea were 6.6 times more likely to have melanoma (OR 6.6, 95% CI 4.1-10.9; P < .0001), 12.8 times more likely to have squamous cell carcinoma of the skin (OR 12.8, 95% CI 8.8-18.6; P < .0001), and 13.1 times more likely to have basal cell carcinoma (OR 13.1, 95% CI 9.7-17.5; P < .0001). The prevalence of these skin cancers was also significantly elevated in patients with systemic sclerosis compared with the general population, although not to the same degree. This increased risk for skin cancer in patients with morphea and systemic sclerosis was still present after stratifying by race (Table I). In both our morphea and systemic sclerosis cohorts, most patients with concomitant skin cancer were white females (Table II).Table IPatients >18 years with morphea or systemic sclerosis and concomitant diagnosis of melanoma, squamous cell carcinoma, or basal cell carcinoma compared with the general Johns Hopkins Hospital patient population, by race, March 9, 2012-March 9, 2018RaceCancerMorphea, n (%)General population, n (%)OR (95% CI)P valueSystemic sclerosis, n (%)OR (95% CI)P valueAll Morphea, n = 1445Melanoma16 (1.1)7936 (0.2)6.6 (4.1-10.9)<.000116 (0.6)3.4 (2.1-5.5)<.0001 Systemic sclerosis, n = 2822SCC28 (1.9)7269 (0.2)12.8 (8.8-18.6)<.000131 (1.1)7.2 (5.0-10.3)<.0001 General population, n = 4,713,781BCC45 (3.1)11,546 (0.2)13.1 (9.7-17.5)<.000128 (1.0)4.1 (2.8-5.9)<.0001White Morphea, n = 1105Melanoma13 (1.2)7455 (0.3)4.1 (2.4-7.1)<.000115 (0.8)2.8 (1.7-4.6).0001 Systemic sclerosisSCC27 (2.4)6476 (0.3)9.9 (6.7-14.6)<.000129 (1.5)6.2 (4.3-9.0)<.0001 General population, n = 2,574,911BCC45 (4.1)11,255 (0.4)9.7 (7.2-13.0)<.000127 (1.4)3.3 (2.3-4.9)<.0001Black Morphea, n = 217Melanoma1 (0.5)163 (0)25.7 (3.5-184.3).0010 (0)NANA Systemic sclerosis, n = 520SCC1 (0.5)500 (0.1)8.4 (1.2-59.8).032 (0.4)7.0 (1.7-28.1).006 General population, n = 904,608BCC0 (0)67 (0)NANA0 (0)NANAIn all cases, morphea and systemic scleroderma were associated with a statistically significantly increased risk of both melanoma and non-melanoma skin cancer. Our findings suggest that a diagnosis of morphea or systemic sclerosis is associated with an additional increased risk of developing skin cancer that is unrelated to race.BCC, Basal cell carcinoma; CI, confidence interval; NA, not applicable; OR, odds ratio; SCC, squamous cell carcinoma. Open table in a new tab Table IISex and race of patients with morphea, systemic sclerosis, morphea or systemic sclerosis with concomitant skin cancer, and general population at Johns Hopkins HospitalPatient populationSexRaceFemale, n (%)Male, n (%)White, n (%)Black, n (%)Unknown/other, n (%)General population2,579,606 (54.4)2,160,855 (45.6)2,574,911 (54.2)904,608 (19.0)1,274,821 (26.8)All with morphea1294 (89.4)154 (10.6)1105 (76.3)217 (15.0)126 (8.7)Morphea and melanoma16 (100)0 (0)13 (81.3)1 (6.3)1 (6.3)Morphea and SCC25 (86.2)3 (10.7)27 (96.4)1 (3.6)0 (0)Morphea and BCC40 (88.9)5 (11.1)45 (100)0 (0)0 (0)All with systemic sclerosis2347 (83.1)479 (16.9)1877 (66.4)520 (18.4)429 (15.2)Systemic sclerosis and melanoma14 (87.5)2 (12.5)15 (93.8)0 (0)1 (6.3)Systemic sclerosis and SCC18 (58.1)13 (41.9)29 (93.5)2 (6.5)0 (0)Systemic sclerosis and BCC25 (89.3)3 (10.7)27 (96.4)0 (0)1 (3.6)The majority of patients with either morphea or systemic sclerosis and skin cancer were white females. This distribution is likely reflective of the tendency for autoimmune diseases to predominantly affect females and for skin cancer to predominantly affect white patients.Female patients with morphea were not significantly more likely to have melanoma or nonmelanoma skin cancer than male patients with morphea (OR 1.2, 95% CI 0.6-2.6; P = .6). Likewise, female patients with systemic sclerosis were not significantly more likely than male patients with systemic sclerosis to receive a melanoma or nonmelanoma skin cancer diagnosis (OR 0.6, 95% CI 0.3-1.1; P = .1). Thus, this increased risk for skin cancer appears to be unrelated to sex.In all of our cohorts, most patients were between 50-75 years of age (66.3% of morphea patients, 68.8% of systemic sclerosis patients, 68.5% of melanoma patients, 77.1% of SCC patients, 81.5% of BCC patients).BCC, Basal cell carcinoma; CI, confidence interval; OR, odds ratio; SCC, squamous cell carcinoma. Open table in a new tab In all cases, morphea and systemic scleroderma were associated with a statistically significantly increased risk of both melanoma and non-melanoma skin cancer. Our findings suggest that a diagnosis of morphea or systemic sclerosis is associated with an additional increased risk of developing skin cancer that is unrelated to race. BCC, Basal cell carcinoma; CI, confidence interval; NA, not applicable; OR, odds ratio; SCC, squamous cell carcinoma. The majority of patients with either morphea or systemic sclerosis and skin cancer were white females. This distribution is likely reflective of the tendency for autoimmune diseases to predominantly affect females and for skin cancer to predominantly affect white patients. Female patients with morphea were not significantly more likely to have melanoma or nonmelanoma skin cancer than male patients with morphea (OR 1.2, 95% CI 0.6-2.6; P = .6). Likewise, female patients with systemic sclerosis were not significantly more likely than male patients with systemic sclerosis to receive a melanoma or nonmelanoma skin cancer diagnosis (OR 0.6, 95% CI 0.3-1.1; P = .1). Thus, this increased risk for skin cancer appears to be unrelated to sex. In all of our cohorts, most patients were between 50-75 years of age (66.3% of morphea patients, 68.8% of systemic sclerosis patients, 68.5% of melanoma patients, 77.1% of SCC patients, 81.5% of BCC patients). BCC, Basal cell carcinoma; CI, confidence interval; OR, odds ratio; SCC, squamous cell carcinoma. This is the first report describing an increased risk for both melanoma and nonmelanoma skin cancer in patients with morphea. There are several explanations for this association. One is that the treatment of morphea—either with immunosuppressive agents or ultraviolet light therapy—increases the risk for epithelial malignant transformation. Chronic inflammation and elevated levels of the cytokine transforming growth factor β in patients with morphea might contribute to malignant transformation of epithelial tissue as well.5Takahashi M. Akamatsu H. Yagami A. et al.Epithelial–mesenchymal transition of the eccrine glands is involved in skin fibrosis in morphea.J Dermatol. 2013; 40: 720-725Google Scholar Another explanation is that the anticancer immune response to epithelial malignancy leads to attack of normal host tissue, resulting in autoimmunity. Patients with a genetic predisposition for autoimmune disease might also be predisposed to the development of cancer, and it is possible that the inciting exposure for both outcomes is the same. Limitations of this study include an inability to determine a temporal relationship between the diagnosis of skin cancer and morphea. Further, patients with morphea or systemic sclerosis are more likely to be seen by either a rheumatologist or dermatologist, who are skilled at diagnosing skin cancer. The characteristics of morphea or treatments associated with a greater risk for epithelial malignancy should be evaluated in future studies to determine which patients might benefit from an increased frequency of skin cancer screening.