Risk of Skin Cancer with Phototherapy in Moderate-to-Severe Psoriasis: An Updated Systematic Review

J Clin Aesthet Dermatol. 2022;15(6):68-75.

by Akshitha Thatiparthi, BS; Amylee Martin, BS; Jeffrey Liu, BS; and Jashin J. Wu, MD

Ms. Thatiparthi is with Western University of Health Sciences in Pomona, California. Ms. Martin is with the School of Medicine at University of California in Riverside, California. Mr. Liu is with the Keck School of Medicine at the University of Southern California in Los Angeles, California. Dr. Wu is with the Dermatology Research and Education Foundation in Irvine, California.

FUNDING: No funding was provided for this study.

DISCLOSURES: The author reports no conflicts of interest relevant to the content of this article.

ABSTRACT: Phototherapy is a standard treatment for moderate-to-severe psoriasis. However, concern remains regarding the associated cutaneous carcinogenic risk. Our objective is to conduct a systematic review of skin cancer risk for psoriasis patients treated with phototherapy. To achieve our goal, we searched Cochrane, PubMed, and Embase databases. We aimed to evaluate existing literature (from July 1, 2010, to December 31, 2020) on phototherapy for all Fitzpatrick skin phototypes (FSP) which includes 71 articles, and eight articles being categorized in this review. Five studies did not report an increased skin cancer risk with narrowband-ultraviolet blue (UVB) and unspecified UVB for FSP II through VI, with one study not reporting FSP. Three studies did report an increased risk of skin cancer with narrowband-UVB and broadband-UVB for FSP I-VI, with one study also not specifying skin phototypes or UVB phototherapy type. Additionally, a study with psoralen and ultraviolet A with and without narrowband-UVB demonstrated an increased risk of skin cancer in phototypes III and IV. The most commonly reported secondary outcomes with phototherapy were actinic keratosis (123) and solar lentigines (10). Numerous patients were also on additional therapies including methotrexate, acitretin, and biologics. Study limitations include publication bias due to limited number of studies published on this topic in the last ten years along with heterogeneity in reporting. The relationship between phototherapy, psoriasis, and cutaneous oncogenic risk remains contradictory. While phototherapy for psoriasis is an efficacious therapy, further studies are needed to understand the cutaneous oncogenic risk based on FSP to help clinicals tailor treatment recommendations based on skin phototypes.

Keywords: Cancer, phototherapy, psoriasis, PUVA, UVB, melanoma, narrowband UVB, broadband UVB

Since phototherapy was discovered to be an effective psoriasis treatment in the twentieth century, it has been a mainstay therapeutic option for moderate-to-severe psoriasis. 1,2 Skin conditions commonly treated with phototherapy include psoriasis, atopic dermatitis, vitiligo, mycosis fungoides, and morphea.3 The broad therapeutic options for phototherapy can be attributed to its mechanism of action. As ultraviolet light enters the dermis and epidermis, DNA damage and photoproducts are produced. The byproducts and resulting damage induce apoptosis in keratinocytes, fibroblasts, inflammatory cells, and endothelial cells allowing suppression of the inflammatory cascade.3 Further, the local immunosuppression inhibits DNA cell turnover and induces apoptosis of T lymphocytes. As psoriasis results from dysregulation of T cells and dendritic cells causing an inflammatory cascade leading to keratinocyte hyperproliferation, phototherapy is able to induce remission and improve clinical outcomes.4 Two main types of phototherapy are used in the treatment of psoriasis, ultraviolet A (UVA) and ultraviolet B (UVB). 

Ultraviolet A phototherapy emits wavelength between 320 and 400 nanometers (nm).3,5 Psoralen is an organic compound, which can be derived from plants or synthetically created. When psoralen is combined with UVA, they generate a greater phototoxic effect. This combination of UVA and psoralen is known as PUVA.3,6 PUVA is able to penetrate deep into the dermis.3 However, utilization of PUVA has declined over the years due to a dose-dependent risk of carcinogenesis and additional adverse effects.7-12 

Initial treatments for psoriasis involving UVB included combining the treatment with tar and anthralin paste or oral/topical psoralen in conjunction with UVA irradiation.2 Broadband UVB (BB-UVB), which emits wavelengths between 290 to 320 nm, became an increasingly popular option.2,3 In the 1980s, researchers discovered wavelengths of 311 to 313 nm had superior efficacy compared to BB-UVB.2 Narrowband UVB (NB-UVB) was able to induce greater clinical and histopathological clearance with greater remission rate compared to BB-UVB.13-15 Due to superiority of NB-UVB, the phototherapy type became a standard of care.5

The prescribed dosage of UVB administered depends on either Fitzpatrick skin phototype (FSP) or minimal erythema dose (MED) testing16-18 Fitzpatrick skin phototype is more commonly utilized to determine initial dose and subsequent increase than MED.18 Fitzpatrick skin phototype is a skin classification system used to rank skin phototypes (from I to VI) based on human skin pigmentation and reaction to UV light.16, 19 This ranking system is relevant to our review as a relationship has been established in literature reporting higher FSP are able to better tolerate higher doses of ultraviolet radiation (UVR) compared to lower skin phototypes. Further, erythema resulting from UVR has been correlated with increased cancer risk due to greater DNA damage in lower FSP compared to higher skin phototypes.17, 18, 20-22

As UV light has phototoxic and cariogenic properties, the carcinogenic risk of this treatment modality in psoriasis needs to be evaluated. Recent comprehensive reviews were published in 2010 and 2015 summarizing literature up to 2015 on skin cancer risk with phototherapy.5, 23 However, both studies broadly examined carcinogenic risk of phototherapy in psoriasis patients on Caucasians vs non-Caucasians. Our review’s objective is to conduct a comprehensive review of multiple databases with further examination of cutaneous carcinogenic risk by FSP. Additionally, we hope to categorize recent additional research published on this topic. Overall, we aim to systematically categorize literature on skin cancer risk with PUVA, UVB, NBUVB, and BBUVB, based on skin phototypes, where available. We hope our comprehensive review will help guide physicians in selecting an appropriate therapeutic regime for patients with psoriasis based on specific skin phototypes. 

Methods

Our systematic review was conducted according to the Preferred Reporting items for Systematic Reviews and Meta-Analyses. Pubmed, Embase and Cochrane databases were queried on December 21, 2020 using the following search terms: “Psoriasis” AND “UVB therapy” AND “skin” AND “cancer” OR “neoplasm” OR “melanoma”. We also utilized the following search terms: “Psoriasis” AND “UVA therapy” AND “skin” AND “cancer” OR “neoplasm” OR “melanoma”. Articles written in English published in the last 10 years were included. Systemic reviews with or without meta-analyses, narrative reviews, and articles with irretrievable records were excluded. After reviewing abstracts and full-text review, only articles pertaining to phototherapy in cancer, and psoriasis were extracted and analyzed. Relevant studies identified through the references of articles during full-text review were added if missed during database searching (Figure 1). Study design, treatment types, patient skin cancer outcomes, and overall results were summarized from each article (Table 1).

Results

Study selection. A total of 71 results were identified from all three databases from July 1, 2010 to December 31, 2020. After removal of duplicates, the search yielded 21 results. Initial screening of text was performed by reviewing article titles and abstracts. Sixteen articles were included for full-text review; thirteen articles were excluded after full-text review. During examination of the bibliography sections, nine additional records were added. A total of eight studies were categorized in this review. These included two cross-sectional studies and six retrospective studies. The selection process of the articles and ranking of the studies by the Oxford Centre for Evidence based medicine are summarized in Figure 1 and Table 1.

Skin cancer risk in specified skin type with NB-UVB. A national cohort study of 22,891 Taiwanese patients with psoriasis with skin phototypes III and IV treated with NB-UVB found one case of melanoma, 13 cases of non-melanoma skin cancer (NMSC), and 14 cases of Bowen’s disease.24 Between the two cohorts, the study did not report a difference in the risk (p=0.691) of skin cancer between long term (≥ 90) and short-term (<90) phototherapy.24 Jo et al25 performed a retrospective cohort study of 445 (358 psoriasis) patients treated with NB-UVB for skin types III-IV (52 skin type III, 92 skin type IV, 40 skin type V, 261 unknown skin type). The study noted no increased risk of NMSC compared to a national skin registry (standardized incidence ratio 17; 95% confidence interval (CI) 0.4-94.8). Also, zero cases of melanoma were reported. The study noted they did not find an increased risk of skin cancer but stated over 25,000 patients need to be examined to achieve statistical significance for results reporting.25

A Turkish study evaluated NB-UVB phototherapy of 100 patients to 100 control patients with skin phototypes with five (5%) phototype II, 92 (92%) phototype III, and three (3%) phototype IV.26 The treatment cohort did not develop a significant risk of skin cancer compared to the control group. Further, the study reported a longer follow-up period and greater number of patients are needed to better elucidate the relationship between NB-UVB and skin cancer.26

Similarly, a study in Italy investigated the effects of NB-UVB used to treat various dermatologic conditions, including vitiligo and psoriasis.27 The skin types of patients include 131 (34.9%) skin phototype II, 202 (53.9%) skin phototype III, 30 (8.0%) skin phototype IV, and 12 (3.2%) skin phototypes I, V, VI.[27] Overall, the study reported an increased risk of NMSC (p=0.02), without an increased risk of melanoma. Raone et al27 found patients who received a lower number of treatment sessions developed NMSC (BCC <299 treatments, SCC <99 treatments). The overall risk of NMSC (2.1%) in the study population was increased compared to general European population NMSC prevalence (1.4%).

Skin cancer risk in specified skin type with BB-UVB and/or NB-UVB. A cross-sectional study by Osmancevic et al28 studied 162 Caucasian patients of 9 (5.6%) skin type I, 26 (16.0%) skin type II, 107 (66.0%) skin type III, 13 (8.0%) skin type IV, and 7 (4.3% ) unknown, treated with BB-UVB, NB-UVB, or both. The study reported an increased risk (4.9%, 0.95 CI 2.2-9.5%) of histopathologically verified skin cancer that was dependent on age and treatment number.28

Skin cancer risk in specified skin type with PUVA and/or NB-UVB. In 2016, Maiorino et al29 retrospectively studied outcomes for 92 patients previously treated with PUVA or NB-U VB. Most of the Italian patients were either skin type III or IV.29 For PUVA therapy, patients treated with less than or equal to 250 sessions had one case of melanoma, while patients with greater than 250 sessions had seven cases of BCC and one case of SCC. With NB-UVB, one case of melanoma was reported with less than or equal to 200 sessions and for greater than 200 sessions, one case of melanoma, nine cases of BCC, and eight cases of SCC were found.29 This study advised against high number of phototherapy sessions in darker III and IV skin phototypes as there was a risk of skin cancer with these skin types.29

Skin cancer risk in unspecified skin type and unspecified phototherapy. Paradisi et 30, 31 al. completed two large retrospective cohort studies in Italy. The first study compared 72,739 patients with psoriasis to a referent cohort of 25,956 non-dermatologic vascular surgery patients for risk of melanoma.30 Out of the 1,372 treated with phototherapy for psoriasis, four (2.9%) patients developed melanoma. However, the study reported a non-significant increased risk for melanoma (adjusted odds ratio (aOR) 1.50, 95% CI 0.56-4.15, p=0.402).30 The second study similarly examined 1,372 patients for the risk of NMSC.31 A total of 300 patients were treated with phototherapy, with four patients developing NMSC. Paradisi et al31 reported a significant increased risk of NMSC compared to the control group (aOR 2.67, 95% CI 1.89-3.75, p<0.001). Neither of the studies specified phototherapy type nor skin phototype.30, 31  

Prior treatments. Additionally, four of the studies reported concomitant medications (3,974) for patients.24, 26-28 In descending order, the most common medications were: 2,470 methotrexate, 1,013 acitretin, 274 cyclosporine, 83 biologics, 70 none or topical therapies (i.e. topical steroids), 17 cyclosporine and methotrexate, 15 azathioprine, 13 immunosuppressive therapies (i.e. methotrexate, cyclosporine), 12 leflunomide, 6 biologics and immunosuppressive therapies, and 1 chemotherapy. 

Comorbid skin conditions and secondary outcomes. Dermatologic conditions other than psoriasis were reported 273 times. Vitiligo (182) was the most common condition and pityriasis lichenoides chronica (6) was least commonly observed skin condition. Twenty-one cases of non-skin cancer were observed in patient histories. Moreover, as a result of the phototherapy, 123 cases of actinic keratosis and 10 cases of solar lentigines were reported. 

Discussion

As the cutaneous oncogenic risk based on skin phototype remains poorly reported in literature, our study conducted a systematic review of this topic. We evaluated 71 articles and categorized eight articles published from December 2010 to December 2020. Majority (5/8) of the studies evaluated in our study did not report an increased risk of skin cancer in FSP phototypes II-VI. However, three studies did report an increased risk of skin cancer in skin types I-VI. Additionally, in patients with psoriasis and darker skin phototypes, a dose dependent increased cancer risk with PUVA and/or NB-UVB was noted in one report. Overall, due to contradictory evidence and limited reporting of FSP in studies evaluated, strong conclusions cannot be drawn about the oncogenic risk in psoriasis patients based on skin phototypes. Clinicians should make continue to make recommendations for patients on a case-by-case basis with respect to preference and medical history. 

Several previous studies demonstrated an significantly increased risk of SCC with PUVA with a non-significant increased risk for BCC in exposed and un-exposed areas for psoriasis patients.5, 10, 32-38 However, Chen et al7, 39, 40 did not report a significant increase in cancer risk (adjusted hazard ratio (HR) 1.1, 95% CI 0.58-2.28) with PUVA, which is consistent with two additional European studies reporting no increased risk of melanoma with PUVA. As cutaneous oncogenic risk based on skin phototype with PUVA remains contraindicatory, NB-UVB is a good alternative option.23, 41-46 Chen et al39 also noted that UVB reduced the risk (adjusted HR 0.52, 95% CI 0.29-0.95, p=0.03) of cancer in patients with psoriasis compared to control. Similarly, a meta-analysis did not report a significant carcinogenic risk, including melanoma, in patients with psoriasis treated with phototherapy or systemic treatments (HR=1.09, 95% CI 0.74–1.63).47 A population-based epidemiology study by Fuxench et al48 reported risk of NMSC was highest for patients who received phototherapy or systematic treatments for psoriasis. Overall, high exposure to UV light from increased phototherapy treatment sessions may increase cutaneous oncogenic risk for all skin phototypes.29, 49 Caution is advised with greater than 250 sessions of PUVA and 300 sessions of UVB, as UVB and PUVA may have an synergistic effect in increasing skin cancer.8, 25, 29

Skin phototype should be considered when interpreting results regarding phototherapy related cutaneous cancer risk due to variances in reactions to factors, such as UV exposure.50 Numerous studies have been conducted on Caucasian patients for risk of skin cancer with phototherapy.44, 51, 52 Thus, lighter skin phototypes (I/II) are well-studied for these factors.2, 53, 54 However, darker phototypes have increased morbidity and mortality for skin cancer due to atypical lesions or advanced stage at presentation. A potential reason for the worse outcomes in skin of color are increase socioeconomic barriers to accessing care.54, 55 Increased education for patients of all phototypes and screening could help mitigate adverse outcomes.  

Numerous patients in the studies included in this review were previously treated with additional medications. Studies have reported an increase in skin cancer with systemic biologics and immunosuppressants.12, 56-58 The medications could be a confounding factor for skin cancer risk with phototherapy. Similarly, patients may have a diagnosis of additional skin conditions or cancers increasing cutaneous oncogenic risk.59, 60 Long term trials and pharmacovigilance studies, with reporting of additional concomitant treatment modalities and comorbid conditions, will provide further insights into the risk of cutaneous malignancy by FSP in psoriasis patients.58 

Strengths for studies include extensive review of three databases. Our study also uniquely reported on cutaneous carcinogenic risk based on skin phototype, which has limited reports in literature. Moreover, only a few studies investigating the relationship between phototherapy and cancer risk in psoriasis patients were published in the last ten years. Specifically, studies with PUVA in patients with psoriasis were limited. Owing to the eight limited studies published, the risk of skin cancer in patients with psoriasis may be underreported compared to the general population. Many articles did not specifically report melanoma and NMSC risk by FSP, which limited categorization of study results. Moreover, the extent of phototherapy exposure was seldom reported affecting the strength of conclusions drawn by the studies. 

Further long-term studies and clinical trials regarding the phototherapy and patients with psoriasis by phototype are needed to draw stronger conclusions, especially for darker FSP. While phototherapy is an efficacious treatment option with a mild side effect profile, a decreasing trend has been found for the prescription of the treatment modality in psoriasis. Recent advancements have increased availability treatment options including biologics, biosimilars, non-biologic systemic immunosuppressants, with numerous clinical trials supporting the safety and efficacy of additional treatment options might be the cause for the decreasing trend.61 Clinicians should consider phototherapy a viable treatment option for psoriasis even during COVID-19, where home phototherapy is an option for patients who do not have pre-pandemic access to office-based phototherapy practices or infusion treatments.62 Additionally, risks versus benefits of phototherapy should be considered on a case-by-case basis while prescribing the treatment modality.

Conclusion

As a fundamental treatment option for moderate-to-severe psoriasis, phototherapy has demonstrated efficacy, safety, and safety profiles for affected patients. However, concern for cutaneous oncogenic risk remains. The results of this systematic review should be interpreted with caution as current evidence is heterogenous in nature, impeding the ability to draw strong conclusions. Most studies examined in our systematic review did not demonstrate an increased cutaneous oncogenic risk for phototherapy, however data exists supporting skin cancer risk. Future studies on this topic should increase categorization of patients based on FSP in phototherapy for psoriasis, with comparison of skin cancer risk between individuals with lighter and darker phototypes when possible. 

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