Porphyrias are a group of disorders caused by disruptions in heme biosynthesis, each leading to accumulation of distinct porphyrin intermediates.(Phillips et al, Mol Genet Metab. 2019) Porphyria cutanea tarda (PCT) is a disease that involves disruption to the enzyme uroporphyrinogen decarboxylase in the liver, and accumulation of uroporphyrins that absorb UV light. This results in photosensitivity of the skin and development of blisters, bullae, and hyperpigmentation. (Baravelli et al, Orphanet J Rare Dis. 2019) It is the most prevalent form of porphyria, and has risk factors including hepatitis B and C infection, alcohol, smoking, and HIV. (Aarsand et al, Clin Chem. 2009)There has been prior limited investigation into malignancy risk in PCT patients, with evidence of increased risk of hepatocellular carcinoma (HCC) and gallbladder and biliary tract cancers.This condition involves oxidative damage with its skin changes, and thus warrants further investigation into the possible association of PCT with non-melanoma skin cancer (NMSC). In patients with hereditary erythropoietic protoporphyria, there has been recent evidence suggesting a potential higher risk of NMSC, particularly squamous cell carcinoma (SCC), possibly due to the underlying chronic photodamage that occurs with the condition, and raising the question of similar mechanisms in PCT. (Kanwar et al, JAAD 2025) The cutaneous oncologic risks associated with PCT remain understudied, limiting provider awareness of potential long-term cutaneous complications beyond blistering and scarring. Hence, we sought to investigate the association of PCT and NMSC using a retrospective cohort study.

To accomplish this, we utilized the U.S. Collaborative Network on TriNetX, a global research platform that aggregates de-identified data from the electronic medical records of 67 healthcare organizations (HCOs) worldwide. The exposed group was defined using the International Classification of Diseases, 10th Revision (ICD-10) code for individuals diagnosed with PCT, E80.1, in at least two separate instances. The unexposed cohort had patients who had at least two encounters for a general medical exam (Z00.0), separated by at least six months, and no documented history of PCT. We performed adjusted analyses with 1:1 propensity score matching of age at index, sex, ethnicity, race, and the use of immunosuppressants.

Of 124 million individuals in the US network, 1,920 met PCT diagnosis criteria. In the analysis comparing PCT and controls, 1,819 were included after matching. Individuals with PCT were significantly likelier to have a diagnosis of HCC than those without PCT (HR [95% CI]: 9.77 [3.49–27.36]). There was an elevated risk of SCC in those with a PCT diagnosis compared to those without PCT (HR [95% CI]: 2.31 [1.46–3.63]), but no increase in risk of basal cell carcinoma (BCC) (HR [95% CI]: 1.12 [0.77–1.63]). When comparing PCT patients to those with a history of organ transplantation, PCT patients had an elevated risk of HCC (HR [95% CI]: 2.36 [1.28–4.35]) but no difference in risk of SCC (HR [95% CI]: 0.73 [0.57–1.11]) or BCC (HR [95% CI]: 0.72 [0.51–1.03]).

Our study suggests that patients with PCT may have increased likelihood of NMSC compared to patients without PCT, with 131% elevated risk of developing SCC. We also show that this increase in risk may be similar to patients with a history of organ transplantation, a population that is well known to have increased risk of NMSC.(Granata et al, Front Med 2023) This may be related to chronic oxidative skin damage, caused by the accumulation of porphyrins in the skin that absorb UV light and induce injury. Oxidative stress and chronic inflammation induced by porphyrin-mediated phototoxicity may contribute to altered cellular proliferation. We share the results of our study to encourage future investigation into this risk, and encourage providers to consider skin cancer possibility when treating such patients.

Limitations of this study include its retrospective nature, and the use of ICD-10 coding that may lead to misclassification. Additionally, while we did control for age, race, ethnicity, and immunosuppression, there are multiple risk factors for NMSCs that are unable to be controlled for in a real-world dataset study such as this. We encourage studies looking at this association and the various susceptibilities and factors that may contribute to such neoplasm risk in subpopulations of PCT patients.

This content is only available as a PDF.
2025
Sign in via your Institution