Multiple Bowen's disease due to long‐term narrow‐band ultraviolet B phototherapy: A case report and literature review

By presenting a case study on multiple instances of Bowen's disease and the consistent use of narrow‐band ultraviolet B (NB‐UVB) phototherapy over a three‐year period, our aim is to enhance the comprehension of domestic clinicians regarding the disease. Additionally, we seek to review existing literature, encouraging dermatologists to consider clinical secondary primary lesion diagnoses.


| INTRODUC TI ON
Bowen's disease, also known as squamous cell carcinoma in situ, is a common malignant skin tumor that usually manifests as solitary plaques on the head, neck, and lower extremities, 1 with multiple rashes in a few cases. 2 Risk factors for Bowen's disease include ultraviolet radiation, human papillomavirus (HPV) infection, 3 arsenic exposure, 4 human immunodeficiency virus (HIV) infection, 5 and other forms of immunosuppression. 6The rash sites caused by different factors are different. 3is paper reports a case of multiple Bowen's disease caused by long-term narrow-band ultraviolet B (NB-UVB) phototherapy.The patient was diagnosed by histopathological examination and cured by liquid nitrogen cryotherapy.Long-term, continuous use of NB-UVB phototherapy has the risk of inducing skin malignancies.It is hoped that this case will arouse the vigilance of dermatologists.

| C A S E REP ORT
The patient was a 63-year-old man of East Asian descent with a Fitzpatrick skin phototype III.He has a 30-year history of psoriasis vulgaris.Repeated red papules and plaques with silvery white scales appeared on his trunk and extremities.Three years ago, the patient purchased a home NB-UVB therapy device for treating psoriasis.
The maximum frequency of NB-UVB phototherapy is 6 min once a day for 6 months.After the psoriatic skin lesions subsided, the patient continued to use NB-UVB phototherapy to prevent recurrence, with an average frequency of 8 min every 3 days for 2 years.One year ago, red plaques appeared on the face, trunk, lower extremities, and scrotum, which did not subside on their own.The topical application of calcipotriol betamethasone ointment (trade name: Daivobet) was ineffective, and the lesions gradually increased in size.The patient continued to receive NB-UVB phototherapy for 1 year thereafter.Throughout the 3 years of treatment, the patient did not seek medical attention at the hospital.The patient denied a history of arsenic exposure, the use of immunosuppressive agents, the use of topical tacrolimus ointment, and a family history of Bowen's disease.
The patient used to be a civil servant, with no excessive exposure to ultraviolet radiation in their work and living environment.The patient's systemic examination showed no obvious abnormality.Dermatological examination showed multiple red patches of varying sizes on the left forehead with clear boundaries and scaly, rough surfaces.Multiple red patches approximately 1 cm in diameter were seen on the chest, back, and left thigh with clear boundaries, with a small amount of scales on them.There were multiple red patches on the scrotum with crusting on the surface (Figure 1).
No typical psoriatic skin lesions on the whole body, no swelling or tenderness of the joints, and no obvious abnormalities in the nails were observed.Reflectance confocal microscopy (RCM) showed that keratinocytes in the epidermis of the forehead, trunk, left thigh, and scrotum were disorderly, varied in size, and irregular in were not abnormal.Cyclosporine and tacrolimus were not detected in the blood, and the HIV antibody test was negative.Based on clinical manifestations, imaging, and pathological examinations, multiple Bowen's disease was diagnosed.The patient's skin lesions disappeared after onetime cryotherapy with liquid nitrogen, and no recurrence was found during the 3-month follow-up.The follow-up is ongoing.The patient underwent cryotherapy with liquid nitrogen.
On the day of treatment, blisters appeared on the surface of the skin lesions.7 days later, the blisters dried up and formed scabs, which peeled off after 3 weeks.After 1 month of treatment, a follow-up visit revealed that Bowen's skin lesions had subsided.The patient has been re-evaluated every 3 months, and there has been no recurrence in the past year.

| DISCUSS ION
Bowen's disease is a squamous cell carcinoma that occurs in the skin and mucous membranes.Early lesions are limited to the epidermis.If not treated in time, 3%-5% of cases will develop into invasive squamous cell carcinoma. 7UV radiation from sunlight is an important environmental factor affecting human skin health. 8A small number of UV-damaged keratinocytes can be cleared by apoptosis induced by the tumor suppressor gene p53, 9 thereby protecting epidermal cells.
Chronic UV irradiation can induce a decrease in Fas-L expression and an increase in p53 mutations, destroying apoptotic homeostasis.Long-term accumulation of antiapoptotic mutations eventually leads to skin cancer. 10After 24-72 h of irradiation of mouse skin with ultraviolet rays (290-400 nm) of 2.5 kJ/cm 2 , the expression level of the pro-apoptotic gene Bax was increased, and the expression of the anti-apoptotic gene Bcl-2 was decreased at the same time. 11Bcl-2/ Bax is abnormally expressed in Bowen's disease, 12 so it is speculated that long-term repeated UV exposure may be involved in Bowen's disease development through this pathway.
This report is on a case of Bowen's disease that occurred in multiple parts of the body, which is relatively rare.The patient has received NB-UVB phototherapy for up to 3 years and denied the use of immunosuppressive agents such as cyclosporine and methotrexate, as well as of arsenic agents and a history of arsenic poisoning.
Excessive UV radiation was likely the cause of this case.
The NB-UVB is an important therapeutic method in clinical treatment for psoriasis, vitiligo, pityriasis rubra pilaris, and atopic dermatitis.Due to its narrow wavelength range and precise treatment dosage, it typically does not lead to severe adverse reactions.
However, for patients who need long-term treatment and patients who have used immunosuppressants, there are still risks of developing skin tumors, cataracts, reproductive toxicity, and other complications.Therefore, in clinical treatment, doctors and patients should consider the balance of NB-UVB treatment.
Multiple Bowen disease needs to be differentiated from psoriasis vulgaris, solar keratosis, and seborrheic keratosis.Clinically, Bowen's disease mostly manifests as red patches or plaques with clear borders, scales and crusts may appear on the surface, and verrucous hyperplasia may appear in some cases. 13Psoriasis vulgaris often presents as multiple red patches or plaques, covered with silvery white scales; the wax drop phenomenon, film phenomenon, and Auspitz sign may appear.Solar keratosis occurs in sun-exposed areas, manifested as red macules or patches covered with sticky white scales, which are not easy to remove.Seborrheic keratosis is also common in sun-exposed areas such as the head, face, and extremities and can have a variety of presentations, including well-defined brown patches, exophytic raised papules, and plaques.
Reflectance confocal microscopy has certain value in the diagnosis and differential diagnosis of Bowen's disease.Bowen disease skin lesions under RCM exhibit an atypical honeycomb pattern, atypical keratinocytes of different sizes and shapes, and "buttonhole signs" consistent with tortuous blood vessels. 14Typical RCM features of psoriasis vulgaris are roundish congested papillae in the upper portion of the epidermis, homogeneously distributed, roundish, dilated dermal papillae with vessel ectasia at the dermalepidermal junction, and enlargement and merging of the dermal papillae in the deepest portion of the dermal-epidermal junction. 15There are atypical honeycombs in the spinous layer of solar F I G U R E 2 Imaging and pathological examination.Skin RCM appearance of multiple Bowen's disease: keratinocytes are disordered, the degree of keratinization varies, and the size of the cells varies (A).Histopathological appearance of thoracic skin lesions: the keratinocytes throughout the thickness of the epidermis were disordered, the cells had obvious atypia and an abnormal division phase, and no invasive growth was seen (B: H&E staining, ×100, C: H&E staining, ×400).
keratosis lesions, but there are typical honeycombs in the granular layer. 16Seborrheic keratosis can be seen under RCM with epidermal projections and keratin-filled invaginations at the lesion surface, corneal pseudocysts at epidermal layers, melanophages, and dilated round and linear blood vessels in the papillary dermis. 17The gold standard for diagnosing Bowen's disease is histopathological examination. 18In cases with atypical clinical manifestations, if imaging examinations suggest the disease or if invasiveness is suspected, a diagnostic biopsy should be performed, while in cases with typical clinical manifestations combined with imaging findings, treatment can be carried out on the basis of the clinical diagnosis. 19In this case, histopathological examination of the skin lesions on the chest was performed, and the diagnosis was Bowen's disease; the skin lesions on the face, lower extremities, back, and scrotum were examined by in vivo RCM, all of which were consistent with the manifestations of Bowen's disease, so multiple Bowen's disease was finally diagnosed.
Approximately 3%-5% of typical Bowen's disease progresses to invasive squamous cell carcinoma, 20 for which active treatment is generally recommended.There are many treatments for Bowen's disease, including surgical resection, curettage, cryotherapy, CO 2 laser irradiation, photodynamic therapy, topical 5-fluorouracil, and imiquimod.Factors such as the efficacy, tolerability, feasibility, and cost-effectiveness of treatment options and patient preference should be comprehensively considered to select an appropriate treatment regimen.Among the above treatment methods, cryotherapy, photodynamic therapy, topical 5-fluorouracil, and imiquimod are currently the treatment methods with higher evidence levels for Bowen's disease, 20 being more effective against multiple Bowen's disease than traditional surgery.Photodynamic therapy is currently considered the first-line treatment for Bowen's disease, 21 but it is expensive for patients with multiple skin lesions, which is unacceptable for some patients.All skin lesions in this case were treated with liquid nitrogen cryotherapy, and there was no recurrence after 3 months of follow-up.Multiple Bowen's disease is relatively rare in clinical practice.UV radiation, arsenic poisoning, HPV infection, immunosuppressive diseases such as HIV infection, and the application of immunosuppressive agents are important triggers.Although NB-UVB phototherapy is the first-line method and is safe for the treatment of psoriasis vulgaris, long-term and excessive exposure may lead to Bowen's disease.Clinicians need to be alert to this adverse effect when using phototherapy for dermatological conditions, and patients need to be closely observed during the follow-up.

CO N FLI C T O F I NTER E S T S TATEM ENT
The authors declare no competing financial interests.
figures, disordered cell arrangement, lost polarity, and an intact epidermal basement membrane band.The superficial dermal blood vessels were dilated and hyperemic, and a few inflammatory cells had infiltrated the area around the blood vessels (Figure2B,C).The patient's peripheral blood arsenic and urine arsenic concentrations AUTH O R CO NTR I B UTI O N S Yunyan Pang and Weiyuan Ma designed the study, Dong Zhang was responsible for management of the patients and drafting the manuscript, Huiping Fan, Xuankai Liu, Shuai Wang participated in management of the patients, and Xiaoqiao Lang analyzed and processed the images.The manuscript has been read and approved by all named authors.FU N D I N G I N FO R M ATI O N This study was supported by the Traditional Chinese Medicine Science and Technology Project of Shandong Province (No. 2021Q093) and the Doctoral Startup Fund of the Affiliated Hospital of Weifang Medical University (No. 2021BKQ02).