e-ISSN 1941-5923

© Am J Case Rep, 2022; 23: e937867

DOI: 10.12659/AJCR.937867

Received:
Accepted:
2022.07.20
2022.09.13 Cantharidin-Podophyllin-Salicylic Acid
Available online:
Published:
2022.10.04
2022.11.09 Formulation as a First-Line Treatment for Plantar
Warts? A Case Report with Multiple Plantar
Warts of Human Papillomavirus Biotype 27 and
Previous Failed Treatments
Authors’ Contribution: ABCD David Navarro-Pérez University Clinic of Podiatry, Complutense University of Madrid, Health Research
Study Design A ABCEF Sara García-Oreja Institute of the Hospital Clínico San Carlos (IdISSC), Madrid, Spain
Data Collection B
Statistical Analysis C ACDEF Francisco Javier Álvaro-Afonso
Data Interpretation D DEF Mateo López-Moral
Manuscript Preparation E CDE Marta García-Madrid
Literature Search F
Funds Collection G BCDG José Luis Lázaro-Martínez

Corresponding Author: Francisco Javier Álvaro-Afonso, e-mail: alvaro@[Link]

Financial support: None declared
Conflict of interest: None declared

Patient: Female, 53-year-old

Final Diagnosis: Plantar warts of human papillomavirus biotype 27
Symptoms: Pain
Medication: —
Clinical Procedure: Treatment of plantar warts
Specialty: Podiatry

Objective: Unusual clinical course

Background: Plantar warts are benign skin tumors caused by the human papillomavirus (HPV). There are multiple treatments,
but none ensure absolute success. Successful treatment depends on several factors, such as the location, num-
ber of lesions, HPV biotype, and the patient’s health condition. This report presents a 53-year-old woman who
had multiple recalcitrant plantar warts with HPV biotype 27 that were treated using a cantharidin-podophyl-
lin-salicylic acid (CPS) formulation after 2 failed treatments.
Case Report: A 53-year-old woman was seen on October 25, 2021. She had 6 plantar warts due to HPV biotype 27, which
was confirmed by polymerase chain reaction using a sample of hyperkeratosis scales obtained from the wart
after debridement. Five cryotherapy sessions were applied, without clinical improvement. Two sessions of ni-
tric-acid–zinc complex were then applied, from which the patient reported severe pain, without clinical im-
provement. Finally, 3 sessions of CPS formulation were applied, and the HPV remitted in all warts.
Conclusions: Conservative treatments, such as cryotherapy, have not been effective in a case of multiple recalcitrant plan-
tar warts. The combined action of the 3 compounds of CPS formulation was key in the resolution of this case.
Plantar wart treatment should be easy to apply, effective, fast, and efficient. In cases of recalcitrant or numer-
ous warts, treatment should be more aggressive from the beginning if the patient’s lifestyle allows it. It would
be interesting to conduct randomized clinical trials to find out which patients could be indicated for the CPS
formulation as a first line of treatment.

Keywords: Cantharidin • Conservative Treatment • HPV L1 Protein, Human Papillomavirus • Warts

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 Navarro-Pérez D. et al:
Cantharidin-podophyllin-salicylic acid for plantar warts
© Am J Case Rep, 2022; 23: e937867

Background Table 1. Cure rates of the main treatments for plantar warts [15].

Plantar warts are benign tumors caused by the human papil- Treatment Cure rate
lomavirus (HPV), which infects the cells of the epidermis [1,2].
Salicylic acid 13.6%
HPV is an infiltrative and highly contagious virus, and due to
the pressures produced on the sole of the foot, it tends to be- Cryotherapy 45.61%
come embedded and penetrate the epidermis, surrounding it-
self with a hyperkeratotic coat [1,2]. This compresses underly- Laser 79.36%
ing tissues, including nerve endings, which causes pain [1,2]. Intralesional bleomycin 83.37%

Cantharidin-podophyllin-
There are about 230 genotypes of HPV, of which genotypes 1, 97.82%
salicylic acid formulation
2, 4, 10, 27, 57, and 63 are the most common on the soles of
the feet [3,4]. The prevalence is around 79% in all age ranges,
and it is most common in adolescents (9 to 16 years old) [5]. (liquid nitrogen), cantharidin-podophyllin-salicylic acid (CPS)
It is transmitted by direct contact, and the risk factors are the formulation, and surgical treatment [14,15].
use of showers, swimming pools, and common spaces; living
with patients who have warts; and immunosuppression or au- Chemical treatment with salicylic acid ointment has been com-
toimmune diseases [6]. The characteristic clinical signs are hy- pared to cryotherapy in a randomized controlled clinical trial
perkeratosis, hemorrhagic stippling, loss of continuity of der- conducted with 229 patients [16]. However, the study observed
matoglyphics, and pain upon pinching [7,8]. The diagnosis is low cure rates in both groups: 13.6% in the group treated with
essentially clinical, and confirmation by microbiological cul- salicylic acid and 14.3% in the group treated using cryother-
ture or polymerase chain reaction (PCR) is recommended [4]. apy with liquid nitrogen [16]. A recent systematic review [15]
showed that treatments have different cure rates (Table 1),
There are many types of treatments, which have different ef- and CPS formulation had the highest cure rate (97.82%) [15].
fects, aims, and methods of administration, but none of them
ensure absolute success [9,10]. Success depends on many fac- A narrative review by Lipke et al [17] suggests that there are
tors, such as the location, number of lesions, and health con- much higher success rates with less widely tested approach-
dition of the patient [9,10]. Another problem with HPV is that es and combination therapies. A 2011 clinical trial showed
there is no antigen presentation to the immune system, un- 100% efficacy of CPS formulation compared to cryotherapy
like with other viruses [8]. This means that there is no immune (41.7%) [18]. Case series published by Nguyen et al [19] and
response or inflammatory process, and HPV generates anti- Lopez-Lopez et al [20] showed cure rates of 62.7% and 100%,
inflammatory processes by activating suppressor T cells [8]. respectively. In addition, Nguyen et al [19] reported a higher
Therefore, even with an intact immune system, treatment is cure rate in children (86.5%).
difficult [8].
This report presents a 53-year-old woman with multiple HPV
The HPV biotype also influences the natural course and treat- biotype 27 plantar warts. All lesions were treated conservative-
ment response [11]. De Planell-Mas et al [12] observed dif- ly with cryotherapy and acids, but without success. Eventually,
ferences in the time to development of warts based on the CPS formulation was applied, and there was complete heal-
HPV genotype. In that study, warts belonging to the mu ge- ing. Therefore, the aim of this article is to generate discussion
nus were mainly detected in less than 1 year, and warts be- and promote future research on the treatment of recalcitrant
longing to the alpha genus were mainly detected over a long warts by means of clinical trials.
period of time [12].

Treatments should be inexpensive, simple, and painless, they Case Report

should have no adverse effects, and they should offer immunity
against the virus and resolution of all or most warts [9,10,13]. On September 16, 2021, a 53-year-old female patient came to
In other words, they should not affect the patient’s lifestyle, the University Podiatric Clinic of the Complutense University
which should return to normal as soon as possible [9,10,13]. of Madrid. HPV had been diagnosed on the ball of the hallux
The fastest treatments are also the most aggressive, while the of her right foot, which had developed over several years. At
slowest are usually conservative, such as cryotherapy [9,10,13]. her referral hospital, she had been treated with 10 sessions of
Usually, the initial treatments are the most conservative, and cryotherapy from late 2019 to early 2020, but total remission
based on scientific evidence, the protocol involves 70% sal- was not achieved. She reported that multiple plantar warts had
icylic acid, nitric-acid–zinc complex (Verrutop®), cryotherapy appeared on both feet since the summer of 2021 (Figure 1).

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Navarro-Pérez D. et al:
Cantharidin-podophyllin-salicylic acid for plantar warts
© Am J Case Rep, 2022; 23: e937867

A B C D

Figure 1. Plantar warts at visit 1. (A) Ball of the hallux, ball of the second toe, and first metatarsal head of the right foot. (B) Heel of
the right foot. (C) First metatarsal head of the left foot. (D) Heel of the left foot.

On October 25, we were able to confirm the diagnosis. The fi-

nal diagnosis comprised plantar warts caused by HPV biotype
27 on the ball of the hallux of the right foot with small satel-
lite lesions around it, as well as on the ball of the second toe
under the first metatarsal head and the heel of the same foot.
The left foot had warts on the first metatarsal head and 2 on
the heel. In total, the patient had 6 plantar warts.

The patient was offered the possibility of participating in a

randomized clinical trial (RCT) ([Link] Identifier:
NCT04654091) that was currently taking place in our center
to compare a nitric-acid–zinc complex and cryotherapy. The
patient decided to participate in the study, and treatment
was started with the application of liquid nitrogen cryothera-
py using CryoPen b® (HO Equipments, Ghislenghien, Belgium).
Figure 2. Sampling using the scraping method. Cryopen® is an instrument that is used for the direct applica-
tion of liquid N2O, which reaches temperatures of -89ºC. Once
The patient reported no allergies or relevant medical history. the hyperkeratotic tissue has been debrided [14], the device
She had no history of surgeries and was not taking any medi- is used to evaporate the gas, projecting it onto the area to be
cation regularly. She had no risk factors and did not smoke or treated. It should be applied at a distance of 0.5 to 4 mm from
drink alcohol. After the clinical examination, we took a sam- the wart at an angle of 45º until a whitish halo of 2 mm is ob-
ple for culture and PCR to confirm the presence of HPV and served around the wart.
to determine the biotype (Figure 2).
Two 15-s applications are done per session with an interval of
The diagnosis and biotype were confirmed using PCR from a hy- 30 s between each one, as recommended by the manufactur-
perkeratosis scale sample that was obtained from the wart after ers. The lesion is then covered with a non-adherent dressing,
debridement [4]. The sample was processed within 24 h after col- and the patient is instructed to keep it on for 24 h. The ap-
lection. The genomic DNA was extracted from the hyperkeratosis plication of liquid povidone-iodine once a day is recommend-
scales using an NZY Tissue gDNA Isolation kit (NZYTech), accord- ed until the next check-up after 1 week, when a decision is
ing to the manufacturer’s instructions, after 5 h of sample pre-ly- made about whether to reapply the product, according to the
sis at 56°C [4]. DNA concentration was quantified after extraction development of the lesion. The maximum number of sessions
at 260 nm using a Nanodrop 2000 spectrophotometer [4]. Nested of product application is 5, based on previous studies [13].
PCR was performed using previously described primers and con-
ditions. Sequences were analyzed using Sequencing Analysis soft- The treatment consisted of the application of cryotherapy on a
ware v.5.1 (Applied Biosystems), and the HPV sequence alignment weekly basis, alternating 1 foot per week. In each session, two
was determined through comparison with known sequences in 15-s applications were done on each plantar wart. During the
the GenBank database using BLASTn software [4]. 7 cryotherapy visits, there was no great improvement in signs

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 Navarro-Pérez D. et al:
Cantharidin-podophyllin-salicylic acid for plantar warts
© Am J Case Rep, 2022; 23: e937867

and symptoms on 5 occasions, and several plantar warts dis- had been treated. Therefore, we decided not to apply treat-
appeared and returned on subsequent visits. In several visits, ment for 2 weeks to allow the skin area to regenerate. After
the patient presented hematomas and burns that are charac- 2 weeks, the nitric-acid-zinc complex was applied for a third
teristic of the treatment, and during the fifth and sixth visits, time, which caused the patient much pain (10/10 visual ana-
she reported great pain (7/10 visual analogue scale). logue scale). Thus, we decided to cancel the session.

Having completed 5 cryotherapy sessions of the RCT without This was the second turning point in the treatment of the pa-
showing clear improvement, we decided to change the treat- tient’s plantar warts. Some doubts began to appear because
ment. The protocol involved 70% salicylic acid, nitric-acid–zinc we had been treating the patient for 12 weeks, 5 months had
complex (Verrutop®), cryotherapy (liquid nitrogen), CPS formu- passed since the first consultation, and we had not made much
lation, and surgical treatment [15]. The nitric-acid-zinc com- progress. Therefore, at visit 13, we decided to start with the
plex was applied on the same day to both of the first metatar- application of 1% cantharidin, 30% salicylic acid, and 5% podo-
sal heads, the ball of the hallux, and the heel of the right foot. phyllin (CPS formulation) on the first metatarsal head of the
The nitric-acid–zinc complex (Verrutop®) is an aqueous solu- left foot after debridement.
tion of organic acids (lactic, oxalic, and acetic acid), nitric acid,
zinc, and copper salts. The effect occurs through mummifica- CPS should be prescribed as a formulation that is applied by
tion of the wart tissue, leading to its detachment once healthy swabbing the entire surface of the plantar wart and covered
skin is formed, and it also reduces the amount of HPV DNA. with an impermeable occlusive dressing for the tissue to mac-
erate to increase the therapeutic effect. The treatment was
After scalpel debridement of the keratinized surface of the maintained for 72 h, followed by liquid povidone-iodine treat-
wart, the product was applied using small touches with a cap- ment until the next visit, when all affected tissue not adhering
illary containing it. The lesion was then covered with a nonad- to the remaining skin was debrided. The application can be re-
herent dressing, and the patient was instructed to clean the peated 1 or 2 more times to obtain good results (Figure 3A, 3B)
area each day with 70% alcohol to reactivate the product until [18,21]. The key to treatment using this formulation is that it
check-up in the following week. At that time, a decision was combines the action of 3 compounds. The keratolytic and caus-
made about whether to reapply the product according to the tic action of salicylic acid acts against hyperkeratosis and sur-
development of the lesion. rounding skin, the vesicant action of cantharidin acts against
the wart, and the podophyllin inhibits cell mitosis and inter-
One week later, the patient came to the clinic with severe pain rupts the process of cell division, preventing the advance and
(9/10 visual analogue scale) in the days following the applica- development of HPV [18,21].
tion. The nitric-acid–zinc complex was reapplied to all of the
plantar warts, and the patient was in great pain for that week. Owing to the pain, the blisters caused by this treatment, and
We thought that the patient’s pain was generated by the high the presence of warts in different locations on the soles of both
sensitivity of the skin due to the time over which the patient feet of the patient, we decided to treat them one by one at

A B

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Navarro-Pérez D. et al:
Cantharidin-podophyllin-salicylic acid for plantar warts
© Am J Case Rep, 2022; 23: e937867

C D

E F

Figure 3. Treatment for plantar wart with cantharidin-podophyllin-salicylic acid (CPS) formulation. (A, B) Application by swabbing the
entire surface of the plantar wart. (C) Ball of the hallux of the right foot after 2 days of application. (D) Heel of the left foot
after 2 days of application. (E) First metatarsal head of the left foot after 1 day of application. (F) Plantar wart removed.

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 Navarro-Pérez D. et al:
Cantharidin-podophyllin-salicylic acid for plantar warts
© Am J Case Rep, 2022; 23: e937867

A B

Figure 4. (A, B) End of treatment, showing no plantar warts.

Table 2. Evolution of the treatment.

Applied treatment Application time Observed adverse events

Cryotherapy 7 visits, 5 sessions Hematomas and burns characteristic of the treatment on several
visits. During the fifth and sixth visits, she reported great pain
(7/10 visual analogue scale)

Nitric-acid-zinc complex 5 visits, 3 sessions Great pain (10/10 visual analogue scale)

Cantharidin-podophyllin-salicylic acid 6 visits, 3 sessions No adverse events

formulation

Follow-up visits 4 visits No adverse events

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Navarro-Pérez D. et al:
Cantharidin-podophyllin-salicylic acid for plantar warts
© Am J Case Rep, 2022; 23: e937867

different visits to avoid affecting the patient’s walking. At the as salicylic acid or cryotherapy, have low cure rates (13.6% and
next visit, we observed the tissue, which showed the charac- 45.61%, respectively). Previous clinical trials, such as that by
teristic papillae of plantar warts, and treated them using liq- Cockayne et al [16], also found very low cure rates with sali-
uid povidone-iodine. At visit 15, we applied the treatment to cylic acid (13.6%) or cryotherapy (14.3%). Other more aggres-
the 2 plantar warts on the heel of the left foot. At visit 16, not sive treatments included in the conservative group were more
only did we see improvement in the treated plantar warts, effective, such as CPS formulation (97.82%), laser treatment
but also the warts on the right foot began to improve in both (79.36%), and intralesional bleomycin (83.37%), among others
signs and symptoms without having applied any treatment [15]. Other studies, such as that by Kaçar et al [18], showed
to them (Figure 3C-3F). At subsequent visits, only the ball of 100% efficacy of CPS formulation compared to cryotherapy
the right hallux was treated, as the remaining warts had im- (41.7%). In a case series, Nguyen et al [19] and Lopez-Lopez
proved without treatment during that period. et al [20] showed cure rates of 62.7% and 100%, respectively.

On March 29, we concluded the treatment for plantar warts, Given the high efficacy of the CPS formulation, it would be
but fearing the possibility of a recurrence, we decided to set tempting to treat all plantar warts with this formula, but this
up a series of follow-up visits. A week later, we observed that is not appropriate as it can cause great pain, blisters, and large
both feet were in good condition and recommended the appli- injuries [15]. Patients who work all day in a standing position,
cation of hydrating cream to the hyperkeratotic areas. We also athletes, and people who are very sensitive to pain would not
made another appointment a month later, at which time both be candidates for this treatment [15]. The main contraindi-
feet were in perfect condition (Figure 4). After 22 visits distrib- cations of CPS formulation are allergies to the components
uted over 8 months, we discharged the patient and scheduled of the product, elderly patients, and immunosuppressed pa-
a visit after 3 months for a check-up (Table 2). tients [22]. Due to the risk of ulceration, it is not indicated for
patients with diabetes or for those with peripheral vascular
disease [22]. Finally, it is also not indicated in lactating wom-
Discussion en and children less than 5 years of age owing to the absence
of safety data [22].
Eight sessions of conservative treatments of cryotherapy or
nitric-acid–zinc complex for 12 weeks were ineffective for a On the other hand, we must bear in mind that treatments
53-year-old woman with multiple recalcitrant HPV biotype 27 should affect the patient’s lifestyle as little as possible
plantar warts with several months of development. However, 3 [20,23,24]. For this patient, we carried out 22 consultations
applications of the CPS formulation at different sites achieved with different treatments, which was equivalent to approxi-
resolution of all plantar warts. In this clinical case, the treat- mately 8 months of discomfort from plantar warts, pain from
ment consisted of 3 phases. In the first phase, the patient was the treatments, worsening of the patient’s mood as she saw
treated with cryotherapy, which showed slow but positive de- that they were not improving, time spent going to the doctor,
velopment, bordering on stagnation, but without worsening. and a general decrease in quality of life.
This is also what happened 2 years prior when the patient was
treated with cryotherapy for 10 sessions. As for how to apply the CPS formulation, it would be interest-
ing to quantify the dose that is applied according to certain
In the second phase, the patient was treated with the nitric- criteria, as we have observed that this formulation generates
acid-zinc complex and had much pain (9/10 visual analogue larger lesions in some patients than in others. Finally, we must
scale), without any results to compensate for the pain. At this be careful with the treatment that we choose, and it is neces-
point, we had to decide how to approach the treatment, as sary to follow an action protocol, but we must also be as ef-
the next step would be to use the CPS formulation; however, ficient as possible. Thus, we may have to carry out more ag-
we were uncertain due the fact that the patient had 5 active gressive treatments from the beginning.
plantar warts. Eventually, we decided to treat 1 plantar wart
per visit so as not to cause severe injuries or impede the pa-
tient’s walking. As a result, positive development was observed Conclusions
not only in the treated lesions, but also in those that were not
treated. Based on the data, we questioned whether all plantar More conservative treatments, such as cryotherapy and nitric-
warts should be treated from the beginning with more aggres- acid-zinc complex, have not been effective in a case of multiple
sive treatments, such as the CPS formulation. recalcitrant plantar warts of several months of development.
The combined action of the 3 compounds of the CPS formula-
García-Oreja et al (2021) [15] conducted a systematic review tion was key in the resolution of this case because it was not
and observed that first-line treatments for plantar warts, such necessary to treat all the plantar warts for their resolution due

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 Navarro-Pérez D. et al:
Cantharidin-podophyllin-salicylic acid for plantar warts
© Am J Case Rep, 2022; 23: e937867

to the activation of the immune system against the papilloma- indicated for the CPS formulation as a first line of treatment.
virus. Plantar wart treatment should be easy to apply, effec- Nevertheless, it is important to maintain long-term follow-up
tive, fast, and efficient, with the aim of returning the patient to avoid recurrence.
to normal activity as soon as possible. In the case of recalci-
trant or numerous warts, we should be more aggressive from Declaration of Figures’ Authenticity
the beginning of treatment if the patient’s lifestyle allows it in
cases of multiple plantar warts, previously unsuccessful treat- All figures submitted have been created by the authors who
ment, recurrence, or a long history of disease. It would be in- confirm that the images are original with no duplication and
teresting to carry out RCTs to find out which patients could be have not been previously published in whole or in part.

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