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Avoiding Rash Decision Making: Skin Cancer Screening of Patients With Inflammatory Bowel Disease

Published:October 31, 2013DOI:https://doi.org/10.1016/j.cgh.2013.10.018
      To understand the full scope and impact of a chronic medical condition, researchers will investigate whether the condition under study harbors any malignant potential in both the affected organ and seemingly unaffected organs. Inflammatory bowel disease (IBD) is no different in this respect. Researchers have investigated and reported on the intestinal and extraintestinal malignant potential of ulcerative colitis (UC) and Crohn's disease (CD) for more than 50 years.
      • Lyons A.S.
      • Garlock J.H.
      The relationship of chronic ulcerative colitis to carcinoma.
      Intestinal malignancies associated with IBD include colorectal adenocarcinoma in UC and Crohn's of the colon, as well as small-bowel adenocarcinoma in Crohn's of the small intestine.
      • Ekbom A.
      • Helmick C.
      • Zack M.
      • et al.
      Ulcerative colitis and colorectal cancer. A population-based study.
      • Ekbom A.
      • Helmick C.
      • Zack M.
      • et al.
      Increased risk of large-bowel cancer in Crohn's disease with colonic involvement.
      This excess risk presumably is caused by chronic inflammation and cellular damage in the affected bowel segment. Extraintestinal malignancies associated with IBD include biliary cancer, lymphoma, and, more recently, nonmelanoma and melanoma skin cancer.
      • Ekbom A.
      • Helmick C.
      • Zack M.
      • et al.
      Extracolonic malignancies in inflammatory bowel disease.
      • Bernstein C.N.
      • Blanchard J.F.
      • Kliewer E.
      • et al.
      Cancer risk in patients with inflammatory bowel disease: a population-based study.
      • Long M.D.
      • Herfarth H.H.
      • Pipkin C.A.
      • et al.
      Increased risk for non-melanoma skin cancer in patients with inflammatory bowel disease.
      • Long M.D.
      • Martin C.F.
      • Pipkin C.A.
      • et al.
      Risk of melanoma and nonmelanoma skin cancer among patients with inflammatory bowel disease.
      The excess risk of biliary cancer is restricted to patients with primary sclerosing cholangitis, a chronic inflammatory condition of the biliary tree. The excess risk of lymphoma and skin cancer likely is mediated through therapies used to suppress inflammation and treat IBD, primarily thiopurines and tumor necrosis factor antagonists.
      The current issue of Clinical Gastroenterology and Hepatology is notable for 2 studies that evaluated how the risk of malignancy in IBD has changed over time. Such studies are useful for hypothesizing whether therapies may promote or inhibit cancer, as well as whether screening practices are effective or need to be enhanced in some way. The studies by Kappelman et al
      • Kappelman M.D.
      • Farkas D.K.
      • Long M.D.
      • et al.
      Risk of cancer in patients with inflammatory bowel diseases: a nationwide population-based cohort study with 30 years of follow-up evaluation.
      and Singh et al
      • Singh S.
      • Nagpal S.J.S.
      • Murad M.H.
      • et al.
      Inflammatory bowel disease is associated with an increased risk of melanoma: a systematic review and meta-analysis.
      differ in their approach and in the scope of cancers studied, but share in information regarding melanoma risk in IBD.
      Kappelman et al
      • Kappelman M.D.
      • Farkas D.K.
      • Long M.D.
      • et al.
      Risk of cancer in patients with inflammatory bowel diseases: a nationwide population-based cohort study with 30 years of follow-up evaluation.
      performed a historical cohort study using national Danish health care databases, spanning 32 years and comprising 13,756 patients with IBD. They found that patients with CD and UC had a 30% (standardized incidence ratio [SIR], 1.3; 95% confidence interval [CI], 1.2–1.4) and 10% (SIR, 1.1; 95% CI, 1.0–1.2) increased risk of developing any invasive cancer over the long term compared with the general population. They found that there was no increased risk of colorectal cancer associated with either CD or UC when compared with the general population (SIR for CD, 0.9; 95% CI, 0.7–1.1; SIR for UC, 1.0; 95% CI, 0.9–1.1). Patients with UC and concurrent primary sclerosing cholangitis had significantly increased risks of colorectal cancer, liver cancer, and gallbladder cancer (SIR: 8.6, 80.0, and 129.1, respectively). Patients with CD, but not UC, had an increased risk of small intestine cancer (SIR, 8.4; 95% CI, 4.3–14.7), hematologic malignancies (SIR, 1.9; 95% CI, 1.5–2.3), and smoking-related cancers (SIR, 1.5; 95% CI, 1.3–1.8). Both CD and UC were associated with an increased risk of nonmelanoma skin cancer (SIR, 2.1; 95% CI, 1.8–2.3; SIR, 1.8; 95% CI, 1.7–2.0, respectively). Melanoma risk was increased in CD (SIR, 1.4; 95% CI, 1.0–1.9), but not in UC (SIR, 1.1; 95% CI, 0.9–1.3). They reported that the relative risk of gastrointestinal cancers among IBD patients has decreased over the past decade whereas the relative risk of extraintestinal malignancies has remained unchanged. The investigators concluded that these data suggest that the benefits of current management outweigh the cancer-related risks and preventative measures, including smoking cessation and skin cancer screening, that could mitigate some excess cancer risk among IBD patients, particularly those with CD.
      Singh et al
      • Singh S.
      • Nagpal S.J.S.
      • Murad M.H.
      • et al.
      Inflammatory bowel disease is associated with an increased risk of melanoma: a systematic review and meta-analysis.
      performed a meta-analysis/systematic review, but instead focused only on the risk of melanoma in IBD. They included 12 cohort studies spanning 67 years of data and comprising 172,837 IBD patients. They found that the risk of developing melanoma with IBD was 37% higher than expected when compared with age- and sex-matched controls (relative risk [RR], 1.37; 95% CI, 1.10–1.70). When the analysis was restricted to studies that evaluated melanoma risk in the pre-biologic era (pre-1998), IBD itself was shown to confer a 52% higher risk of melanoma (RR, 1.52; 95% CI, 1.02–2.25). Although limited, the 2 studies that estimated melanoma risk after the introduction of biologic agents did not show an increased risk (RR, 1.08; 95% CI, 0.59–1.96), and there was no increased melanoma risk with thiopurine therapy (RR, 1.1; 95% CI, 0.73–1.66). The investigators concluded that routine screening should be encouraged in patients with IBD, and sun-protective measures should be advised in all patients, regardless of thiopurine and/or tumor necrosis factor use.
      The studies were well done and the conclusions are valid. The issue of course with any research is where do the data lead us? Are they the next step in a longer process of research and discovery or are they sufficient to recommend changes in practice? Should the data be applied immediately for counseling patients regarding risks and harms of therapies, or even to create a quality metric to ensure physicians are adhering to a specific practice pattern, or do we use any negative studies or conflicting data to raise doubt on the strength of the findings and await the often-discussed, long-term prospective study before commenting and acting clinically?
      With regard to melanoma risk, the study by Kappelman et al
      • Kappelman M.D.
      • Farkas D.K.
      • Long M.D.
      • et al.
      Risk of cancer in patients with inflammatory bowel diseases: a nationwide population-based cohort study with 30 years of follow-up evaluation.
      found a clinically relevant increased risk only in patients with CD (SIR, 1.4; 95% CI, 1.0–1.9), with no increased risk in UC (SIR, 1.1; 95% CI, 0.9–1.3). The study by Singh et al
      • Singh S.
      • Nagpal S.J.S.
      • Murad M.H.
      • et al.
      Inflammatory bowel disease is associated with an increased risk of melanoma: a systematic review and meta-analysis.
      found a similar magnitude risk of melanoma in all IBD patients (RR, 1.37; 95% CI, 1.10–1.70). The risk was higher in CD (RR, 1.80; 95% CI, 1.17–2.25) and lower in UC (RR, 1.23; 95% CI, 1.01–1.50), with pre-1998 studies showing an increased risk of melanoma (RR, 1.52; 95% CI, 1.02–2.25) and the 2 post-1998 studies showing no increased risk (RR, 1.08; 95% CI, 0.59–1.96). Thus, the investigators found varying degrees of risk depending on the population, with SIRs or RRs that were clinically relevant in many cases, but with 95% CIs in all but 2 analyses that, depending on rounding, either included or could include 1, indicating no increased risk.
      Skin cancer risk (nonmelanoma and melanoma) recently was reported as a concern in IBD patients. Even acknowledging potentially conflicting data, the risk appears increased in IBD. Counseling and screening would be the next natural steps for mitigating the risk. Ignoring costs, several questions become relevant in explicit or implicit calls for practicing skin cancer screening in IBD patients: (1) what would such a program look like (who to screen, does it differ from the general population, when to start, at what intervals), (2) what would be the expected impact, and (3) should gastroenterologists alone be the ones to devise such a screening program, or, unilaterally begin referring all IBD patients to dermatologists for screening, creating a de facto screening program? The European transplant organization, for example, has published explicit skin cancer prevention guidelines. Although intense, they are actionable and recommend monthly patient self-skin examinations with every 6 months to yearly whole-body examinations by an expert physician or dermatologist.
      European Best Practice Guidelines for Renal Transplantation
      Section IV: long-term management of the transplant recipient.
      They also have more general statements including encouragement to minimize sun exposure and to use UV-light–blocking agents.
      European Best Practice Guidelines for Renal Transplantation
      Section IV: long-term management of the transplant recipient.
      It is reasonable to inform IBD patients about potential increased skin cancer risk and general strategies to reduce risk (sun protection clothing and sunscreen with an SPF of at least 30 or greater). Even so, issues of counseling and screening regarding skin cancer may be more nuanced and complex. For example, the US Preventive Task Force recently concluded that the current data support counseling of children, adolescents, and adults younger than 24 years of age with fair skin about minimizing exposure to UV radiation to reduce the risk of skin cancer, but the data were insufficient to asses benefit in those older than age 24.
      • Moyer V.A.
      Behavioral counseling to prevent skin cancer: U.S. Preventive Services Task Force recommendation statement.
      A different systematic review from the US Preventive Task Force concluded that the data were insufficient regarding the efficacy of skin cancer screening by primary care physicians or patient self-examination.
      Screening for skin cancer: U.S. Preventive Services Task Force recommendation statement.
      The review did not address the potential benefit of screening by a trained dermatologist. Petrarca et al
      • Petrarca S.
      • Follmann M.
      • Breitbart E.W.
      • et al.
      Critical appraisal of clinical practice guidelines for adaptation in the evidence-based guideline “prevention of skin cancer.”.
      recently performed a critical appraisal on the process used to create evidence-based guidelines for the primary and secondary prevention of skin cancer in several countries and concluded that many lacked methodologic quality, particularly rigor, applied during the development process.
      The studies by Kappelman et al
      • Kappelman M.D.
      • Farkas D.K.
      • Long M.D.
      • et al.
      Risk of cancer in patients with inflammatory bowel diseases: a nationwide population-based cohort study with 30 years of follow-up evaluation.
      and Singh et al
      • Singh S.
      • Nagpal S.J.S.
      • Murad M.H.
      • et al.
      Inflammatory bowel disease is associated with an increased risk of melanoma: a systematic review and meta-analysis.
      published in the current issue of Clinical Gastroenterology and Hepatology are important studies that add to the mounting momentum that has put the issue of skin cancer and skin cancer screening of IBD patients into the collective consciousness of gastroenterologists. There are sufficient data and biologic plausibility to suggest an increased skin cancer risk in IBD patients. There is insufficient information, however, to tell clinicians how to use the data clinically. There are no IBD-specific recommendations that are actionable regarding if and how skin cancer counseling and screening should occur, who should be screened, and whether or not it should differ in IBD patients compared with the general population. If the epidemiologic and biologic data lead us to have concern for skin cancer in IBD patients, we suggest that the next prudent step is not to advocate widespread, nonspecific screening or to create a checkbox quality metric of yes/no for such screening, but rather to create an explicit, actionable, and evidence-based recommendation as to what screening and primary prevention/counseling entails and who should be counseled/screened and how. The rigor and strength/certainty of the data for skin cancer risk in IBD and the efficacy/impact of strategies for preventing skin cancer (screening, and primary and secondary prevention) should be critically scrutinized. We suggest this process should include dermatologists with expertise in this area in addition to gastroenterologists. The final product should include detailed actionable recommendations, supported by evidence.

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