Background: Cutaneous warts are common viral skin infections caused by human papillomavirus (HPV) and often present therapeutic challenges due to recurrence and resistance to conventional treatments. Intralesional therapies, including 5-fluorouracil (5-FU), have emerged as promising alternatives, demonstrating targeted cytotoxic effects on infected keratinocytes. Previous randomized and comparative studies have reported favorable clearance rates and acceptable safety profiles for intralesional 5-FU in treating different wart types.

Objective: to evaluate the efficacy and safety of intralesional 5-FU in the treatment of cutaneous warts and to assess treatment response, side effects, and recurrence rates.

Methods: A multi-centric prospective cohort study was conducted on patients with clinically diagnosed warts at a dermatology outpatient clinic. This multicenter study was conducted across three dermatology centers in Cairo, Egypt. Patients received intralesional 5-FU (50 mg/mL) injections every two weeks for up to six sessions. Clinical evaluation included wart type, number, and response to treatment, categorized as complete, partial, or no response. 

Results: Sixty patients were included, with a mean age of 29.5 ± 8.8 years. The majority had plantar warts (56.7%). Complete response was achieved in 83.3% of patients, while 16.7% showed partial response. No recurrence was observed among completely cured patients. Pain was reported in all patients (100%), while mild erythema occurred in 13.3%. A significant association was found between treatment response and number of sessions (p = 0.006).

Conclusions: Intralesional 5-FU is an effective and safe treatment modality for cutaneous warts, with high clearance rates and minimal recurrence. Despite mild local side effects, it represents a valuable therapeutic option, particularly for resistant cases.

Cutaneous warts are benign proliferative lesions of the skin caused by infection with human papillomavirus (HPV), affecting a significant proportion of the population worldwide. Despite their self-limiting nature in some cases, many warts persist, spread, or recur, leading to both physical discomfort and psychosocial burden [1]. Various therapeutic modalities have been employed, including topical keratolytics, cryotherapy, laser therapy, and immunotherapy; however, no single treatment has demonstrated universal efficacy. Recurrence, prolonged treatment duration, pain, and variable response rates continue to make wart management a clinical challenge [2].

Intralesional therapies have gained increasing attention as they deliver medication directly into the lesion, enhancing local drug concentration while minimizing systemic effects. Among these, 5-fluorouracil (5-FU), an antimetabolite that inhibits DNA synthesis in rapidly dividing cells, has shown promising results in treating HPV-infected keratinocytes [3].

Despite growing evidence supporting intralesional 5-FU, the available literature remains limited by small sample sizes, heterogeneity in treatment protocols, and lack of standardized randomized controlled trials. Additionally, comparative data on response rates, recurrence, and predictors of treatment success are still insufficient. Some systematic reviews highlight variability in outcomes and emphasize the need for well-designed clinical trials to establish its efficacy and safety more conclusively [4-6].

Given the ongoing challenges in wart treatment and the promising yet inconclusive evidence regarding intralesional 5-FU, this study was conducted to provide more robust clinical data on its therapeutic value. Therefore, the aim of this study was to evaluate the efficacy and safety of intralesional 5-fluorouracil in the treatment of cutaneous warts and to assess treatment outcomes, adverse effects, and recurrence rates.

This multi-centric prospective cohort study was conducted and performed on a total of 60 patients with clinically diagnosed cutaneous warts. This multicenter study was conducted across three dermatology centers in Cairo, Egypt at the Department of Dermatology of El-Aml Specialized Hospital, the El-Mataria Teaching Hospital, and Al-Haud Al-Marsoud Hospital, from June 2022 to May 2023. These centers provided a diverse patient population and enhanced the generalizability of the study findings. All procedures were performed in accordance with ethical standards for human research.

In our study, participants were selected based on clearly defined inclusion criteria to ensure appropriate patient representation. Eligible patients were those aged between 18 and 60 years, including both males and females. All participants had clinically diagnosed cutaneous warts and presented with one or more lesions. Additionally, only patients who were willing to provide informed consent were included. Participants were required to demonstrate the ability to comply with scheduled follow-up visits throughout the study period. Furthermore, all included patients agreed to clinical photography for documentation and assessment of treatment response.

Patients were excluded from our study if they had conditions that could interfere with treatment safety or outcome assessment. This included pregnant or lactating women, as well as immunocompromised individuals or those receiving chemotherapy. Patients with major systemic illnesses were also excluded. Certain wart types and conditions were not considered, including facial warts and condyloma acuminata. Individuals with Raynaud’s phenomenon or peripheral vascular disease, known hypersensitivity to 5-fluorouracil, or hematological disorders were excluded due to potential risks. Additional exclusion criteria included a history of keloid formation, active infection, inflammation, or unhealed wounds at the injection site, and receipt of any wart treatment within the previous month. Patients with needle phobia were also excluded to ensure compliance and procedural feasibility.

1. Pre-Procedure Preparations

Before initiation of treatment, all patients underwent thorough evaluation and preparation. Written informed consent was obtained after explaining the study objectives, procedure steps, expected outcomes, and possible adverse effects. A detailed history was taken, including personal, present, past, and family history, with special emphasis on wart characteristics (onset, duration, number, size, and prior treatments).

A complete dermatological examination was performed to document the type, number, and location of warts. Baseline clinical photographs were obtained for future comparison. The treatment area was assessed to exclude any signs of infection, inflammation, or contraindications. Patients were instructed about the procedure, expected pain during injection, and the need for multiple sessions.

2. Procedure

Intralesional injection of 5-fluorouracil (5-FU) (50 mg/mL) was performed under aseptic conditions. Initially, superficial paring of each wart was carried out using a sterile surgical blade to remove hyperkeratotic layers and enhance drug penetration. The area was then cleansed with alcohol.

Using a 1 mL insulin syringe with a 30-gauge needle, 5-FU was injected directly into the base of each wart at a dose of 0.1–0.2 mL per lesion, depending on its size. The endpoint of injection was blanching of the lesion, indicating adequate intralesional distribution.

The procedure was repeated at two-week intervals. A maximum of six sessions was allowed, or treatment was discontinued earlier if complete clearance of the wart was achieved.

3. Post-Procedure Care

After each session, patients were provided with detailed post-procedure instructions. They were advised to keep the treated area clean and dry for 12–24 hours, followed by gentle cleansing with mild soap and water. Application of any topical medications was avoided unless prescribed.

Patients were informed that mild pain, redness, or swelling at the injection site was expected and usually transient. Cold compresses were recommended during the first 24 hours to alleviate discomfort. Normal daily activities could be resumed immediately; however, patients were advised to avoid excessive pressure, friction, or trauma to the treated area, particularly in plantar warts.

Patients were instructed to monitor for adverse effects such as excessive pain, ulceration, blistering, discharge, or signs of infection. In such cases, they were advised to seek medical attention promptly. General advice included avoiding scratching or picking the lesion and maintaining good hygiene.

4. Follow-Up

Patients were followed up at two-week intervals during the treatment period. At each visit, clinical assessment included evaluation of wart size, number, and response to treatment, categorized as complete, partial, or no response. Side effects were recorded systematically. Serial clinical photographs were taken at baseline and during follow-up visits.

After completion of treatment, patients were followed up one month after the final session to assess recurrence or any increase in lesion size. This follow-up period allowed evaluation of both treatment efficacy and durability of response.

Sample Size: The sample size of 60 patients was determined based on feasibility and previous studies reporting high efficacy of intralesional 5-FU. This number was considered sufficient to assess treatment outcomes and safety while allowing basic statistical analysis. Additional patients were initially screened to account for exclusions and dropouts.

Our study was conducted in accordance with the ethical principles of human research. All participants were fully informed about the study objectives, procedures, potential benefits, and possible adverse effects before enrollment. Written informed consent was obtained from all patients prior to participation. Patient safety and well-being were prioritized throughout the study, and all procedures were performed under appropriate aseptic conditions. The study protocol adhered to institutional and international ethical standards.

Statistical analysis: Data were analyzed using the Statistical Program for Social Science (SPSS) version 24. Qualitative variables were presented as frequencies and percentages, while quantitative variables were expressed as mean ± standard deviation (SD). The mean represents the average value, calculated by dividing the sum of observations by their total number. The standard deviation was used to measure the dispersion of data around the mean, where a low SD indicates values clustered closely around the mean, and a high SD reflects greater variability.

For inferential analysis, appropriate statistical tests were applied according to the type of data. The independent sample t-test was used to compare the means between two groups for quantitative variables. The chi-square (χ²) test was applied to assess associations between categorical variables across the studied groups.

The level of statistical significance was determined using the p-value. A p-value less than 0.05 was considered statistically significant, while a p-value less than 0.001 was considered highly significant. A p-value greater than 0.05 was regarded as statistically insignificant.

Illustrative Case Presentation:

To further demonstrate the clinical effectiveness of intralesional 5-fluorouracil (5-FU), we present a representative case from our cohort.

Figure 1: Clinical images demonstrate the lesion prior to treatment and after complete resolution, highlighting the effectiveness of intralesional 5-FU in achieving clearance of plantar warts.

A 50-year-old male patient presented with a solitary lesion on the plantar surface of the right foot, persisting for approximately 3 months. The lesion was initially small and asymptomatic but progressively increased in size and became painful, particularly during walking and weight-bearing activities. The patient denied any prior treatment before presentation.

On clinical examination, a well-defined hyperkeratotic papule was observed on the plantar aspect of the foot, characterized by a rough surface and the presence of thrombosed capillaries (black dots), consistent with a diagnosis of plantar wart. The lesion was tender upon lateral pressure, further supporting the diagnosis.

The patient underwent intralesional injection of 5-fluorouracil (50 mg/mL) following standard protocol. Superficial paring of the lesion was 

performed prior to injection to enhance drug penetration. A total of 0.1–0.2 mL of 5-FU was administered directly into the base of the lesion. The procedure was repeated at two-week intervals.

After a total of five treatment sessions, the patient demonstrated marked clinical improvement, with complete resolution of the lesion and restoration of normal skin lines. Pain during ambulation resolved completely. No significant adverse effects were observed apart from mild transient pain during injection.

Follow-up evaluation one month after the final session revealed no evidence of recurrence.

The results of the present study are demonstrated in the following tables.

Table 1: Demographic Characteristics of Studied Patients.

Out of 60 patients, males constituted 53.3% (n=32) and females 46.7% (n=28). The mean age was 29.5 ± 8.8 years, with a range of 18–52 years.

Table 2: Clinical Characteristics of Studied Patients.

Plantar warts were present in 56.7% (n=34), common warts in 40% (n=24), and mosaic warts in 3.3% (n=2). The sole was affected in 43.3% (n=26), fingers in 33.3% (n=20), toes in 16.7% (n=10), and lateral foot in 6.7% (n=4). Single warts were observed in 93.3% (n=56), while 2 and 5 warts were each present in 3.3% (n=2). Regarding sessions, 33.3% (n=20) required 3 sessions, 20% (n=12) required 4 sessions, and 20% (n=12) required 6 sessions.

Table 3: Side Effects Among Studied Patients.

Pain was reported in 100% (n=60) of patients, while erythema occurred in 13.3% (n=8).

Table 4: Treatment Response

Complete response was achieved in 83.3% (n=50), while partial response occurred in 16.7% (n=10). No recurrence was observed among complete responders.

Table 5: Correlation Between Response and Variables

Mean age was 34.6 ± 8.3 years in complete responders and 39.8 ± 10.9 years in partial responders (p=0.239). All partial responders were males (100%, n=10), while females constituted 56% (n=28) of complete responders (p=0.022).

For wart site, complete response occurred in 48% (n=24) of sole cases versus 20% (n=2) partial (p=0.480). Plantar warts showed 60% (n=30) complete response versus 40% (n=4) partial (p=0.579).

Single warts showed 96% (n=48) complete response versus 80% (n=8) partial (p=0.07).

Regarding sessions, 60% (n=30) of complete responders required 2–3 sessions, while 80% (n=8) of partial responders required 6 sessions (p=0.006).

X2: Chi-square test. S: p-value < 0.05 is considered significant. T: independent sample T test. NS: p-value> 0.05 is considered non-significant.

Cutaneous warts are common viral infections caused by human papillomavirus (HPV) and remain a frequent challenge in dermatological practice due to their tendency for persistence, recurrence, and variable response to treatment. Although multiple therapeutic modalities are available, including cryotherapy, surgical methods, and topical agents, none provide consistently satisfactory outcomes for all patients. Recurrence and resistance to therapy are still major concerns, particularly in plantar and recalcitrant warts. In recent years, intralesional therapies, including 5-fluorouracil (5-FU), have gained attention due to their targeted action and promising efficacy. However, existing studies show variability in response rates, limited follow-up for recurrence, and insufficient evaluation of factors influencing treatment outcomes [7].

Despite growing evidence supporting intralesional 5-FU, there remains a clear gap in the literature regarding its effectiveness across diverse patient populations and clinical settings. Many previous studies are limited by small sample sizes, single-center designs, or lack of comprehensive analysis of demographic and clinical predictors of response. Furthermore, the relationship between treatment sessions and clinical outcomes, as well as long-term recurrence patterns, is not fully established [8].

Consequently, our study was conducted to evaluate the efficacy and safety of intralesional 5-FU in the treatment of cutaneous warts in a multicenter setting. In addition, it aimed to analyze the association between patient-related and lesion-related factors and treatment response, with particular emphasis on identifying predictors of therapeutic success and assessing recurrence outcomes.

Our study included 60 patients with a slight male predominance, where males represented 53.3% (n=32) and females 46.7% (n=28). The mean age was 29.5 ± 8.8 years, ranging from 18 to 52 years. This indicates that cutaneous warts predominantly affected young adults in our cohort, which is consistent with increased exposure to environmental risk factors and HPV transmission in this age group. 

Regarding clinical features, plantar warts were the most common type, observed in 56.7% (n=34) of patients, followed by common warts in 40% (n=24), while mosaic warts were rare (3.3%, n=2). The most frequently affected site was the sole (43.3%, n=26), followed by fingers (33.3%, n=20), toes (16.7%, n=10), and lateral foot (6.7%, n=4). Most patients (93.3%, n=56) presented with a single wart, while only 6.6% had multiple lesions. Regarding treatment sessions, 33.3% (n=20) required 3 sessions, 20% (n=12) required 4 sessions, and 20% (n=12) required 6 sessions, reflecting variability in treatment response. The predominance of plantar lesions aligns with previous reports emphasizing their recalcitrant nature, which is largely attributed to their depth and continuous pressure during ambulation [9]. The sole was the most frequently affected site (43.3%), followed by fingers, toes, and the lateral aspect of the foot. Most patients (93.3%) presented with a single lesion, a factor generally associated with a more favorable prognosis compared to multiple warts.

Regarding treatment response, our study demonstrated a high efficacy of intralesional 5-FU, with complete response achieved in 83.3% of patients (n=50), while partial response was observed in 16.7% (n=10). Importantly, no recurrence was reported among patients who achieved complete clearance, indicating sustained therapeutic effect. These findings are encouraging and are largely consistent with previously published data evaluating intralesional 5-fluorouracil (5-FU) in wart management.

Comparable results were also reported by Zoheir et al. [10], who observed complete resolution in 80% of patients with plantar warts, partial response in 15%, and no response in 5%. Sepaskhah et al. [11], in a comparative study between intralesional 5-FU combined with lidocaine and epinephrine and cryotherapy, found that 64.3% of patients in the 5-FU group achieved complete clearance after six weekly sessions.

However, response rates have varied across studies. Sunny and Doshi [12] reported a lower complete clearance rate of 38.89%, with 61.11% of patients showing residual lesions. This discrepancy may be explained by differences in lesion characteristics, particularly the inclusion of endophytic palmoplantar warts, which often have higher viral loads and thickened stratum corneum that may hinder adequate drug penetration. Variability in HPV subtypes and host immune responses may also contribute to differences in treatment outcomes.

Other investigations further support the efficacy of intralesional 5-FU. Bdaiwi and Abdul-Saheb [13] documented an 80% complete response rate in patients with cutaneous warts. Srivastava et al. [14] reported an even higher clearance rate of 95.38%, highlighting both the effectiveness and safety of this modality in palmoplantar lesions. Ghonemy et al. [3] observed complete resolution in 76.7% of patients treated with intralesional 5-FU, while Kannambal et al. (15) reported a 60% clearance rate in recalcitrant warts. Likewise, Kamal et al. [9] demonstrated excellent outcomes in 75% of patients, and Yazdanfar et al. [16] reported a 64.7% response rate. Earlier work by Iscimen et al. [16] also showed a 70% complete clearance rate in plantar warts.

Regarding safety, all patients (100%, n=60) experienced pain during injection, making it the most common adverse effect. Mild erythema was observed in 13.3% (n=8) of patients. No serious complications such as ulceration, necrosis, or scarring were reported, suggesting that intralesional 5-FU is generally safe and well tolerated. These findings indicate that intralesional 5-fluorouracil (5-FU) is a relatively safe therapeutic option. Our observations are in agreement with Sepaskhah et al. [11], who reported that intralesional 5-FU was associated with minimal adverse effects compared with more aggressive modalities such as cryotherapy or surgical removal.

Similarly, Kamal et al. [9] identified localized pain and irritation as the most frequent side effects following intralesional 5-FU administration. Iscimen et al. [16] documented erythema and edema in a limited number of patients treated for plantar warts, without any cases of necrosis or permanent scarring.

Furthermore, Sunny and Doshi [12] similarly reported that injection-related pain was the principal adverse event in their 5-FU group, with occasional hyperpigmentation around treated lesions. Collectively, these findings reinforce that intralesional 5-FU is generally well tolerated, with side effects that are typically mild and self-limiting.

As regards Correlation Between Response and Patient Variables, the statistical analysis in our study revealed several meaningful relationships between patient characteristics and treatment outcomes. A significant association was identified between sex and therapeutic response (P = 0.022), with females showing better outcomes. Specifically, females constituted 56% of complete responders, while males represented 44%, and all cases with partial response were males (100%). This pattern may suggest a role of biological or immunological differences in influencing the effectiveness of intralesional 5-fluorouracil (5-FU), although further research is needed to confirm this.

A highly significant correlation was also observed between the number of treatment sessions and clinical response (P = 0.006). Most patients who achieved complete clearance required fewer sessions, with 60% responding within 2–3 sessions, whereas 80% of partial responders required 6 sessions. This indicates that early improvement is a strong indicator of successful treatment, while persistence after multiple sessions may reflect resistance and the need for alternative therapeutic approaches. Similarly, Zoheir et al. (10) demonstrated variability in session requirements, with a proportion of patients achieving complete resolution after three or four sessions, while others required up to six sessions.

On the other hand, no statistically significant relationships were found between treatment response and age (P = 0.239), wart location (P = 0.480), wart type (P = 0.579), or number of lesions (P = 0.07). Although Bristow (17) suggested that certain anatomical sites, particularly plantar lesions, may exhibit greater resistance to therapy, our findings did not support a significant association between site and outcome. The mean age was 34.6 ± 8.3 years among complete responders and 39.8 ± 10.9 years among partial responders, indicating that age had no substantial impact on treatment outcome. Likewise, response rates were similar across different wart sites and types. Although a higher complete response rate was observed in patients with a single wart (96%) compared to those with multiple lesions (80%), this difference did not reach statistical significance.

The effectiveness of intralesional 5-FU can be explained by its multiple mechanisms of action. As a pyrimidine analog, it disrupts DNA and RNA synthesis in rapidly proliferating cells, including those infected with HPV. Additionally, its intralesional administration may stimulate local immune responses, enhancing viral clearance. This targeted delivery allows for high drug concentration at the lesion site while reducing systemic exposure and associated side effects.

Clinically, intralesional 5-FU offers several advantages over traditional treatment options. It provides a localized, effective therapy with a high clearance rate and a favorable safety profile safety (18). Notably, our study also demonstrated no recurrence among patients who achieved complete response, suggesting durable treatment effects and potential long-term viral eradication or immune-mediated control.

The results of our study demonstrate that intralesional 5-fluorouracil (5-FU) is an effective and clinically applicable treatment for cutaneous warts, achieving a high complete response rate with no recurrence among completely treated patients. The multicenter nature of our study enhances the clinical relevance of these findings by reflecting outcomes across different clinical settings and patient populations, thereby improving external validity. The significant association between fewer treatment sessions and better outcomes highlights the importance of early response as an indicator of therapeutic success. 

From a practical perspective, intralesional 5-FU offers a localized, minimally invasive treatment option with acceptable tolerability. Future perspectives should focus on expanding multicenter trials with larger sample sizes and longer follow-up durations to confirm sustained efficacy, assess long-term recurrence, and explore combination or alternative therapies for resistant cases.

Our study possesses several strengths that support the validity of its findings. It included a well-defined cohort of patients (N = 60) with clearly documented demographic and clinical characteristics. Additionally, the study comprehensively evaluated multiple factors affecting treatment response, including age, sex, wart type, site, number, and number of sessions. Another important strength is the clear documentation of treatment outcomes, including both complete and partial responses, as well as the absence of recurrence in completely treated cases, which adds clinical significance to the results.

Despite its strengths, our study has certain limitations that should be considered when interpreting the results. The predominance of patients with a single wart may have influenced the analysis of the relationship between wart number and treatment response. In addition, the study lacked a control or comparison group, which makes it difficult to directly compare intralesional 5-FU with other treatment modalities. The follow-up duration was also limited, which restricts the ability to assess long-term recurrence beyond the study period.

In conclusion, our study demonstrates that intralesional 5-FU is a highly effective and safe treatment for cutaneous warts, with a complete clearance rate of 83.3% and no observed recurrence among responders. The number of treatment sessions was identified as a significant predictor of response, while other demographic and clinical variables showed no significant influence. The multicenter design further strengthens the applicability of these findings in real-world clinical practice.

Based on the findings of our study, intralesional 5-FU can be recommended as an effective therapeutic option for the management of cutaneous warts, particularly in cases requiring a localized approach. Early evaluation of treatment response is important, as patients with delayed improvement may require alternative or adjunctive therapies. Future research should focus on larger multicenter studies with extended follow-up to validate these results and assess long-term outcomes.

Acknowledgment: none

All authors contributed significantly to our study. Ahmed Adel Ali Ali contributed to study design, data collection, analysis, and manuscript drafting and was responsible for the main supervision and performed the intervention procedures. Aliaa Atef participated in patient recruitment, clinical assessment, and data interpretation. Fatema Saber contributed to data collection, follow-up, and revision of the manuscript. All authors reviewed and approved the final version of the manuscript.

The authors declare that there are no conflicts of interest regarding the publication of our study.