Journal of Dermatological Treatment

ISSN: 0954-6634 (Print) 1471-1753 (Online) Journal homepage: http://www.tandfonline.com/loi/ijdt20

5-aminolevulinic acid photodynamic therapy for

condyloma acuminatum of urethral meatus

Jiajia Xie, Chunping Ao, Junpeng Li, Lifen Jiang, Hui Liu & Kang Zeng

To cite this article: Jiajia Xie, Chunping Ao, Junpeng Li, Lifen Jiang, Hui Liu & Kang Zeng (2018):
5-aminolevulinic acid photodynamic therapy for condyloma acuminatum of urethral meatus, Journal
of Dermatological Treatment, DOI: 10.1080/09546634.2018.1544406

To link to this article: https://doi.org/10.1080/09546634.2018.1544406

Accepted author version posted online: 14

Nov 2018.

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5-aminolevulinic acid photodynamic therapy for condyloma acuminatum of

urethral meatus

Jiajia Xie1, Chunping Ao1, Junpeng Li, Lifen Jiang, Hui Liu, Kang Zeng*

(Department of Dermatology and Venereology, Nanfang hospital, Southern Medical

University, Guangzhou, 510515, China)

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The first author of this article

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* Corresponding author

E-mail addresses: [email protected] (J. Xie),

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[email protected] (C. AO),
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[email protected] (J. Li), [email protected] (L. Jiang), [email protected] (H. Liu),
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[email protected] (K. Zeng).

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ABSTRACT
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Condyloma acuminatum are the most common sexually transmitted diseases

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worldwide, and they are closely associated with human papillomavirus (HPV)

infections. Urethral meatus warts are uncommon. And many treatments are limited by
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a difficult approach, recurrences, and potential complications. In our study, 21

patients diagnosed with urethral condyloma acuminatum were included. After 4h

treatment of 5-aminolevulinic acid (ALA), patients received photodynamic therapy

(PDT). Each patient received HPV test before every PDT cycle. The frequency of

PDT was dependent on viral load changes. As a result, all patients achieved complete
clinical remission after the last session of ALA-PDT. There were significant

differences in HPV viral loads between pretherapy and after one or three rounds of

PDT treatment. So we concluded that ALA-PDT is a safe and effective method for

treatment of condyloma acuminatum in urethra meatus. Dynamic monitoring of HPV

viral loads can more objectively demonstrate the effectiveness and guide the treatment

of PDT.

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Keywords: urethral meatus, condyloma acuminatum, ALA-PDT, HPV

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1. Introduction

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Condyloma acuminatum are common sexually transmitted diseases caused by

human papillomavirus infection. HPV-induced lesions rarely develop in the urethral

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meatus. The urethra is afflicted in only 20% of cases, of which 80% are at the meatus
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and 20% in the proximal urethra[1]. Studies have demonstrated that a larger urethral
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meatus size is an important risk factor for the development of genital warts in the

urethral meatus; nevertheless, being married, delaying sexual debut, and avoidance
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mulyiple sexual partners seem to be associated with a decreased risk of genital warts
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especially within the urethral meatus region[2, 3].

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Urethral meatus warts are prone to unsuccessful treatment because of a difficult

approach, limitations in safe optional treatment, and fear of complications, especially

urethral stenosis[4]. The efficacy of traditional methods such as CO2 laser

vaporization, cryotherapy, electrosurgery, and YAG laser, etc. are limited because of

the specificity of the anatomical site. On the one hand, there are large amount of
bleeding during the treatment of condyloma acuminata in the area of urethral, and

prone to infection, urethral stenosis and other complications which aggravating the

patient’s suffering. On the other hand, tiny lesions of the urethra and hidden lesions

are not easy to detect, so it is difficult to completely remove the warts, resulting in

increased recurrence rate. Compared with conventional therapies,

topical ALA-PDT is a simple, effective, safe and well-tolerated treatment

for urethral condylomata acuminata that is associated with a low recurrence rate[5-7].

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2. Materials and Methods

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2.1 Patients and preparation for photodynamic therapy

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There were 21 patients diagnosed with urethral meatus condylomata acuminata
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recruited into our study. They came from the Department of Dermatology and
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Venereology, Nanfang Hospital between January 2016 and April 2018. Condylomata
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acuminata was confirmed in all patients based on medical history, human

papillomavirus detection, and clinical performance, and even pathological biopsy

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when necessary. The lesions were located at or near the urethral orifice and warts
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were pink or bright red range from millet to soybean size with shape of papillary or
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cauliflower. None of the patients received systemic corticosteroid therapy or

immunosuppressive therapy within a month. They were not accompanied by syphilis,

human immunodeficiency virus infection or autoimmune diseases either. Before

treatment, patients needed to empty the bladder. The area covered by lesions was

locally anesthetized with 2% lidocaine and radiofrequency was used to remove all
visible warts.

This research was approved by the ethics committee of the Nanfang Hospital.

2.2 Photosensitizers

A solution of 20% ALA was prepared by dissolving powdered ALA (Fudan

Zhangjiang Bio-Pharm Co. Ltd, Shanghai, China) into a sterile 0.9% NaCl solution

immediately before treatment. For male, immediately after the radiofrequency

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treatment, we slowly injected 1ml ALA solution into the urethra. Then a absorbent

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cotton soaked with ALA solution was used to cover the skin around the distal urethra

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and prevent solution from flowing out. For female patients, we just needed to place

the cotton soaked with ALA solution on the lesion sites and the adjacent normal skin
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within a 3-4cm radius. Next we put plastic film over the cotton to fix it to patients’
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skin. After 4h, the cotton and plastic film were removed. Patients were asked not to go
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to the toilet during this process.

2.3 Photodynamic therapy

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Patients lied on the treatment bed and exposed the lesions. PDT was performed at

an energy density of 100 J/ cm2 with irradiance of 100 mW/cm2, a wavelength of 635
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nm for 20-30 min emitted by a semiconductor laser (LED-IB PDT instrument, Wuhan

Yage Optic and Electronic Technique Co. Ltd., Wuhan, China). Each device was

equipped with a cylindrical optical fiber. For male, we inserted the distal of fiber into

a disposable cannula (Fudan Zhangjiang Bio-Pharm Co. Ltd., Shanghai, China) and

gently inserted it into the urethra to depth of the warts. As for female, it only required
to irradiate skin with the laser. Each patient received PDT every week. Physical

examination and HPV detection were repeated one week after the PDT treatment.

2.4 Human papillomavirus deoxyribonucleic acid detection

In the past, HPV detection was only used to determine if there was an infection. In

our study, we first combined HPV quantification with PDT dynamically. The test was

performed at the beginning and before each PDT treatment. We stopped

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photodynamic procedure until the virus loads dropped to zero. In addition, the virus

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detection was also used to monitor viral infections at follow-up. For each patient,

samples were scraped from the lesions by dry Dacron swabs and stored at 4℃ before

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test. Then DNA was extrated from the samples via the Genotyping Kit for Human
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Papillomavirus (bio Perfectus Technologies, Jiangsu, China). Each polymerase chain
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reaction (PCR) assay contained a final volume of 20 μl with 2 μl primer added. Each

PCR run contained 2μl positive and negative control. The PCR cycling condition was
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followed by an initial denaturation at 95℃ for 10 min and then 40 cycles of 95℃ for
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10 sec, 58℃ for 40 sec and 72℃ for 10 sec. The reaction was ended with a final 72℃
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for 2 min[8].
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2.5 Statistical analyses

All statistical analyses were performed by SPSS Statistics 19.0. The Wilcoxon test

and the Mann-WhitneyU (MWU) test were used to assess the difference of HPV viral

loads during the process. And p value less than 0.05 was considered to be statistically

significant.
3. Results

The clinical characteristics of the patients are presented in Table 1. Seventeen

patients were male, and only four were female. The difference may be related to the

sexual behaviors. Nineteen patients(90.48%) were primary cases who had not

undergone any previous treatment, while two patients(9.52%) had been treated with

several cycles of photodynamic therapy or laser in other hospitals and experienced

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new warts and high HPV loads.

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Multi-site infections were predominated obviously(71%). For men, the main

infection areas were urethral meatus combined with penis or perianal. For women,

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three of the four patients were infected with cervix and vaginal simultaneously, one of
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them also combined with vulva infection.
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We have detected a total of ten genotypes of HPV in all cases, two types of
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low-risk (LR) and eight types of high-risk (HR). HPV6 and HPV11 were mainly

prevalent in urethral meatus. Ten cases were infected with HPV11, and six cases were
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infected with HPV6, followed by the high-risk HPV16, HPV56, HPV51, HPV66,
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HPV58, HPV53, HPV73 and HPV82 (Figure 1). As for HPV infection forms, up to
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four types HPV infections were found at urethral meatus in the same one patient.

Single type HPV infection was 66.7% (14/21), double infection (23.7%,5/21), three

types infection (4.8%,1/21), and four types infection (4.8%,1/21)(Table 2). The single

HPV infection was prone to occur in urethral meatus.

After removing the visible warts by radiofrequency treatment under local

anesthesia, we applied ALA-PDT to each patient once a week. We detected the HPV

subtypes and viral loads one week after each round of PDT. Before treatment,

LR-HPV viral loads were found to be higher than HR-HPV viral loads (p < 0.05).

This also indicated that the urethra meatus was dominated by LR-HPV infection.

Nine(42.86%) cases’ HPV loads reduced to 0(Copies/IU) after the first session of

ALA-PDT, and six of them were infected with single HPV6. There were significant

differences in HPV viral loads between pretherapy and after one round of PDT

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treatment (p<0.001). Further, there was also significant difference in HPV viral loads

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between pretherapy and after three rounds of PDT (p=0.002). PDT cycle is terminated

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until HPV loads changed to zero. In the end, eighteen patients(85.71%) received three

to six sessions of ALA-PDT, two patients(9.53%) received seven sessions, and the
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last one(4.76%) received nine sessions. Furthermore, all patients showed complete
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clinical remission after the last session of PDT (Figure 2). Unfortunately, one patient
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appeared complications of urethral stenosis who had received laser therapy before

PDT in other hospital.

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4. Discussion
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As a sexually transmitted disease, genital warts are widely spread throughout the
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world. It can lead to the mucocutaneous intraepithelial neoplasia, which often occur in

the genital mucosa. The urethra is a hidden, warm and humid site for the HPV hiding

and replicating at the same time. So the urethral genital warts tend to relapse. Up to

now, there has been no large-scale epidemiological investigation about the incidence

rate of urethral condyloma acuminatum. A report about 123 patients with urethral
genital warts shows that the incidence is 12.5%[9]. Another research examined

HPV-DNA of 463 healthy men reports that the urine samples were the poorest to

detect with a rate of 10.1% among other genital sites[10]. However, urethral

condylomas are often combined with penile or vulva warts as well as urethritis,

gonorrhea or other sexually transmitted infections. They mostly occurs in people

between 20 to 40 years old with high risk behaviors. Patients complain of stinging,

urethrorrhagia or dysuria when voiding[9]. Some of them can find visible lesions in

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the distal urethra, such as the urethral meatus and navicular fossa places. But some

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others are not aware of suffering urethral meatus lesions[9]. However, this does not

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rule out the possibility of genital warts. One of the reasons may be latent infection, the

other lies in that the warts can present in the upper urethra.
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Studies demonstrated that HR-HPV infection is associated with carcinoma in cervix,
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oropharynx, anus, and vagina[11]. HPV in urinary tract can also cause bladder
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cancer[12, 13]. A meta-analysis included 19 cases reported that among bladder

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carcinoma patients, HPV incidence could be highly as 16.88% and mostly were

high-risk types, such as HPV 16[14]. Another meta-analysis of 20 cases also found
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HPV infection was a risk factor for bladder tumors with an odds ratio of
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2.13(95%CI,1.54%-2.95%)[15]. The studies suggested that HPV infection could

ascend from the distal urethra to the upper urethra. Therefore, we need take necessary

examination, such as urethroscopy, pathology and immunohistochemisty, on those

with recurrent urethral genital warts. On the one hand, we are committed to cure

genital warts, and on the other hand, we have to rule out the possibility of malignant
transformation earlier. Only when cancer is suspected and identified early can there be

a good chance of cure.

The studies above tell us that HPV infection plays an important role in the

development of urethral meatus condyloma acuminatum and genital cancer. In the

research group, we are the first to combine HPV quantification with photodynamic

therapy dynamically for the condyloma acuminata. Monitoring HPV loads can more

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objectively demonstrate the effectiveness of treatment but not only judged by naked

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eye. Besides, HPV quantification can identify latent infections to facilitate early

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intervention which can reduce the recurrence of genital warts and the possibility of

tumors caused by long-term infection.

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As we mentioned above, most established methods are not necessarily applicable to
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the urethra, and these methods have multiple side effects, from buring, oedema to

micturition disorders (oliguria, dysuria). More seriously, laser treatment could

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increase the risk of urethral stenotic scars[16]. A randomized clinical trial with 86
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patients showed that urethral malformations occurred in two of five patients with
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uretharal genital warts treated with laser, while ALA-PDT just caused mild burning

during irradiation[17]. In our treatment, most patients experienced mild buring,

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moderate pain, swelling or erythema at the first cycle. These side effects disappeared

within one week and had no influence on urination.

As a technique combination with photosensttizers and corresponding light, ALA-PDT

has been widely used in recent years, especially in skin and mucosa diseases[18]. It
has also been successfully used to treat HPV-related genital warts and dysplasia[19].

HPV infected cells proliferate actively and the accumulative concentration of ALA is

higher than that of normal tissue. With specific wavelength and energy irradiation, the

warts can be destroyed but little impact on the surrounding normal tissue. In addition,

the recurrence rate of PDT is low[19]. A multicenter study enrolled 531 patients

reported the clearance rate as 95.27% after three PDT cycle and six month visits[20].

In our study, all patients achieved completely clinical remission without recurrence at

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follow-up. Therefore, we conclude that ALA-PDT could be a more effective and safer

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therapy with lower recurrence to treat condyloma acuminatum, especially for urethra

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which is narrow and difflcult to expose. Furthermore, ALA-PDT can clear subclinical

and latent infections around the lesions. HPV testing can help clinicians make better
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diagnoses and treatment. And it should be applied to clinical more widely and
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flexibly.
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Acknowledgements: The photos were taken with the assistance of technicians in the
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dermatology department from the Nanfang Hospital.

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Conflicts of interest: None.

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Funding: This research did not receive any specific grant from funding agencies in

the public, commercial, or not-for-profit sectors.

Compliance with ethical standards.

Informed consent: Informed consent was obtained from all individual participants

included in the study.

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Figure legends

Figure 1 HPV distribution of different type.

Figure 2 Pre- and post-treatment images of 2 cases.

a:before treatment of patient 1; b:one week after treatment of patient 1; c:before treatment of

patient 2; d:one week after treatment of patient 2. We can see from the pictures that patients

received complete clinical remission. The mucous returned to normal color and smooth look.

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Table

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Table 1. General characteristic of 21 patients

Characteristic Value
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Age (years), mean ± SD 31.95 ±14.038
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Gender
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Male 17 81%
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Female 4 19%
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Primary cases 19 90%

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Recurrence cases 2 10%

Single site infection 6 29%

Concurrent sites infection 15 71%

 Penis/balanus 6 29%

Perianal/anal canal 6 29%

Cervix/vaginal/vulva 3 13%

SD: Standard Deviation.

Table 2. HPV infection types in urethral meatus

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HPV value(n)

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HPV genotypes detected 10

LR-HPV
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2
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HR-HPV 8
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Infection forms
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Single type infection(HPV6/11/16/51//73) 14

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2-type infection(HPV11+66/6+82/51+56/6+51/16+11) 5
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3-type infection(HPV11+56+58) 1
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4-types infection(HPV16+11+53+56) 1

LR: low risk; HR: high risk.

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