Research within the past few decades has elucidated the immune-mediated nature of the psoriasis and the specific elevated levels of chemokines and cytokines that promote inflammation in this disease. Many different cell types are involved, including keratinocytes, natural killer T cells, dermal dendritic cells, and macrophages. Activated dermal dendritic cells secrete IL-12 and IL-23, and both of these cytokines are integral in the cellular cascade of psoriasis pathophysiology. IL-12 causes differentiation of native T cells to Th1 cells (which produce IFN-γ and TNF-α), and IL-23 is important for the proliferation of Th17 cells, which produce IL-17 and IL-22. This pathway allows for the revolutionary use of multiple highly effective biologic therapies for psoriasis that antagonize TNF-α, IL-12, IL-17, and IL-23.
Psoriasis does not only affect the skin. There is an association with inflammatory arthritis (psoriatic arthritis), depression, inflammatory bowel disease, metabolic syndrome, and cardiovascular disease. Furthermore, because of the chronic inflammatory state of psoriasis and the immunosuppression produced by some systemic medications, patients with psoriasis may have an increased risk of lymphoma and nonmelanoma skin cancer (NMSC).1,2 Pooled data from multiple clinical trials with long-term safety data for ustekinumab (an IL-12/IL-23 inhibitor) reported the risk of malignancy to be negligible. But there was a recent case report of a woman receiving ustekinumab who also developed stage IV Hodgkin lymphoma, raising concern for the oncogenic potential of ustekinumab given that there is evidence that IL-12 functions in an antitumor fashion.3 Given conflicting data and clinician/patient concern, a recent review in the Journal of International Immunology entitled “Psoriasis and skin cancer – is there a link?” sought to investigate the relation between psoriasis and cancer risk, and the various classes of drugs used to treat psoriasis to see if there is an increase in cancer risk.4
Research Connecting the Dots
A recent meta-analysis found that psoriasis patients are more likely than the general population to develop NMSC, especially squamous cell carcinoma (SCC) and basal cell carcinoma (BCC).5,6 The Psoriasis Longitudinal Assessment and Registry (PSOLAR) observational study followed over 10,000 psoriasis patients who received phototherapy or systemic therapy without a personal history of SCC or BCC for 8 years.7 The results demonstrated an elevated chance of developing BCC in the TNF-α inhibitors and the methotrexate group, but not SCC. Interestingly, the elevated risk of NMSC in psoriasis appears to be unrelated to the severity of the condition or if the patient has a concurrent diagnosis of psoriatic arthritis. Although the risk of NMSC is a concern, many of the studies relating melanoma with psoriasis have shown inconsistent results, especially when studying patients with mild and severe forms of psoriasis.8,9 Furthermore, patients who develop melanoma while on immunosuppressive psoriasis therapies do not appear to have reduced survival.8,10 Some studies have shown an increased risk of cutaneous lymphoma in psoriasis patients, but given the chance of misdiagnosis between these 2 papulosquamous diseases, a clear link has not been established.1
Treatments Linked to Skin Cancer Risk
There is also some concern that the immunosuppressive and immunomodulatory medications used to treat psoriasis can increase the risk of cancer. Similar concerns exist with narrowband ultraviolet A (NB-UVA) and narrowband ultraviolet B (NB-UVB) phototherapy given that UV radiation is a known carcinogenic agent. Research has shown that there is no increased risk of skin cancer with UVB phototherapy but patients with greater than 250 sessions of psoralen plus UVA phototherapy (PUVA) may have an increased risk of melanoma.4 Cyclosporine, which is FDA approved for psoriasis and prophylaxis of organ rejection in kidney, liver, and heart allogenic transplants, has been shown to increase the risk of NMSC. It has been debated whether methotrexate, another traditional immunosuppressive agent used in psoriasis, can increase the risk of melanoma, but an increased risk of BCC with methotrexate was seen when analyzing the PSOLAR data.4,7 A comprehensive review concluded that there is no increased risk of skin cancer using topical therapy (vitamin D and topical corticosteroids) for psoriasis.4 In terms of biologic therapy, there are data to support an increased risk of NMSC with TNF-α blockers (infliximab, certolizumab, adalimumab, etanercept) compared to the general population.3 “The title of the article discussed here is a little misleading. The authors here are not necessarily reviewing the link between psoriasis and cancer but are reviewing possible reasons for the association between psoriasis and nonmelanoma skin cancer that has been previously reported in the literature,” said Tina Bhutani, MD, MAS, an associate professor and codirector of the Psoriasis and Skin Treatment Center in the Department of Dermatology at the University of California, San Francisco, in California.
Keeping Comorbidities in Mind
In conclusion, it is well-known that patients with psoriasis have many comorbidities, which can significantly affect their quality of life and physical health. If psoriatic arthritis remains undiagnosed for many years, patients may suffer from irreversible joint damage. Therefore, it is imperative to conduct a focused review of systems for both new and follow-up psoriasis patients. While the data are mixed, some evidence shows that psoriasis patients may have an increased risk of malignancies such as lymphoma, lung cancer, and NMSC.4 This further stresses the importance of a thorough physical exam and a focused review of systems for any psoriasis patient. There exists more convincing evidence that some psoriasis therapies increase the risk of malignancies. Clinicians and patients should be aware of these associations so that more effective counseling and preventative measures can be discussed in the office, which will ultimately lead to an improvement in patient care. “Although this review article presents many hypotheses, such as psoriasis therapies [that] increase the risk of skin cancer (namely PUVA phototherapy and cyclosporine), the effects of chronic inflammation on the skin, and lifestyle factors in patients such as smoking, no particular mechanism is supported more than others. This was a good review of potential mechanisms but did not leave me with any new conclusions or present novel information that could add to our current knowledge base,” Bhutani concluded.
Nicholas Brownstone, MD, is a dermatology resident at Temple University Hospital in Philadelphia, Pennsylvania.
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