Oral florid papillomatosis: Topical treatment with 5% imiquimod in orabase

Abstract Background Florid oral papillomatosis is characterized by its tendency to local recurrence that requires multiple treatments, leading to important functional sequelae. Methods We present 74‐year‐old woman with oral florid papillomatosis (OFP) who refused a new surgical treatment, and was treated with imiquimod 5% in orabase on alternate days for 16 weeks. Treatment was complemented with application of hyaluronic acid gel. Results There were no side effects to the treatment, nor signs of local recurrence, in the treated area at 2 years of follow‐up. Conclusions After reviewing the literature and according to our knowledge, this is the first published case of oral florid papillomatosis treated topically with imiquimod 5% successfully. Topical treatment with imiquimod 5% in orabase may be a valid alternative for patients with recurrent OFP located in the anterior area of the oral cavity who refuse surgical treatment, although we must closely monitor the patient for the possibility of recurrence or malignant degeneration.


| MATERIALS AND METHODS
A 74-year-old nonsmoking woman with multiple sclerosis was diagnosed in 2008 with OFP. Since then she has presented multiple recurrent lesions in the oral mucosa. The histological results of the lesions were keratosis with mild dysplasia on four occasions, papillary hyperplasia with mild atypia, proliferative verrucous leukoplakia, and verrucous carcinoma. The treatments performed were surgical excision or CO 2 laser vaporization in dysplasias and surgical resection with oncological resection margins in the case of verrucous carcinoma.
Histology of the last specimen removed showed papillary projections with fibrovascular cores, acanthosis, and hyperparakeratosis ( Figure 1).
The typing of the most common HPV species through a direct flow chip test that analyzes more frequent low-risk and high-risk viruses was negative. The patient was immunocompetent, did not perform immunosuppressive treatment for multiple sclerosis and her HIV serology was negative. In February 2017, the patient presented a new recurrence that affected the mucous edge of the lower lip, anterior oral vestibule, and tongue tip ( Figure 2) whose biopsy was keratotic papilloma with mild atypia. The patient refused a new surgical treatment, which prompted us to seek another therapeutic alternative, so we proposed the compassionate use of 5% topical imiquimod, with the approval of the ethics committee of our hospital and the detailed informed consent signed by the patient.
A formulation with 5% imiquimod was made in orabase. Our treatment regimen resembles the recommended guideline according to the leaflet for the treatment of anogenital verrucous lesions, the cream is administered three times per week (Monday-Wednesday-Friday) before going to sleep, with an applicator on the lesions to be treated. We recommend maintaining good oral hygiene, rinsing the mouth in the morning and applying gel with hyaluronic acid on the nontreatment days to minimize side effects on the mucosa adjacent to the lesions. A weekly check was carried out and good tolerance was observed (Figure 3), the F I G U R E 1 Histology of the last specimen removed shows papillary projections with fibrovascular cores, acanthosis, and hyperparakeratosis. Inset: Hyperplasia without epithelial dysplasia (hematoxylin-eosin, ×20 and ×40) F I G U R E 2 Lip and oral cavity with oral florid papillomatosis before treatment with imiquimod RUIZ-HUERTAS ET AL. | 859 treatment was maintained for 16 weeks (maximum period of use of treatment according to leaflet), confirming the complete disappearance of the lesions in this period of time. During the treatment, the patient had no side effects or complications. In subsequent reviews and after 2 years of treatment, the patient showed no signs of local recurrence of the disease in the treated area ( Figure 4), she uses her dental prosthesis without discomfort and she can eat acid food, which used to cause severe irritation of her oral mucosa.

| RESULTS
Topical treatment with imiquimod 5% in orabase may be a valid alternative for patients with recurrent OFP located in the anterior area of the oral cavity who refuse surgical treatment, although we must closely monitor the patient for the possibility of recurrence or malignant degeneration.

| DISCUSSION
Imiquimod is an immunomodulator that lacks direct antiviral or antineoplastic effects. Its main mechanism of action is the promotion of the innate and adaptive immune response, by stimulating monocytes and macrophages to produce the release of a group of cytosines, such as interferon alfa, tumor necrosis factor, and interleukins 1, 6, and 8, and also gamma interferon and interleukin 12. All of the above leads to an increase in the immune response measured by Th-1 lymphocytes, similar to delayed-type hypersensitivity and induces proliferation and differentiation of B lymphocytes (Cianfriglia et al., 2006;Luo et al., 2007;Ostwald et al., 2003).
This drug in our country has been approved for the topical treatment of genital and external perianal warts, small superficial basal cell carcinomas and clinically typical actinic, nonhyperkeratotic, and nonhypertrophic keratoses of the face and scalp in immunocompetent adult patients. Before its use in oral mucosa, we conducted a literature review in Pubmed with the following keywords: "Oral florid papillomatosis"; "Imiquimod" and "Oral cancer"; "Imiquimod" and "Oral papillomatosis"; "Imiquimod" and "Leucoplakia"; "Imiquimod" and "Oral mucosa"; "Imiquimod" and "Lichen planus." We found 11 articles that presented 17 patients with oral lesions treated with imiquimod.  (Mullins et al., 2016), dysplastic oral leukoplakia in one patient (Allam et al., 2008), oral lichen planus in one patient (Gencoglan et al., 2011), and for papillomatous lesions and lichenoid cheilitis in a patient with a history of squamous cell carcinoma of the floor of the mouth (Wenzel et al., 2003). All these lesions that are sometimes not easy to differentiate histologically, have in common an instability or disease of the oral mucosa, which over time can develop squamous cell carcinomas. Imiquimod 5% has also been used for the treatment of the affected surgical margins of oral melanoma (Spieth et al., 2006) and bowenoid papulosis (Rinaggio et al., 2006).
In five patients, positivity was detected for the HPV (Allam et al., 2008;Gemigniani et al., 2015;Martinez-Lopez et al., 2017;Rinaggio et al., 2006), in one patient the detection of the virus was negative In all the cases reviewed, topical imiquimod 5% cream without excipient was used. The most frequently used application is on alternate days and overnight; three times a week (Martinez-Lopez et al., 2017;Spieth et al., 2006;Yasar et al., 2019), but also two nights a week in combination with 0.1% retinoic acid (Gemigniani et al., 2015), daily use (Mullins et al., 2016), two times a day (Gencoglan et al., 2011) or increasing exposure from 20 min to 2 h every 2 days has also been described (Allam et al., 2008).
In 13 of the 17 published cases, the lesion disappeared without signs of local recurrence. A patient with lichen planus relapsed at 6 months (Gencoglan et al., 2011). Another patient with bowenoid papillomatosis discontinued the treatment at his own discretion to undergo cryotherapy (Rinaggio et al., 2006). A patient with a history of squamous cell carcinoma of the floor of mouth who was treated 4 years before with surgery, with papillomatous lesions and liquenoid cheilitis on the lip, suffered a degeneration to squamous cell carcinoma after 3 weeks of treatment, but the authors declare that the case was difficult to understand and could be related to the decrease in dermal dendritic cells (Wenzel et al., 2003).
In our case, and to increase the local action of the active substance and reduce possible adverse side effects in the adjacent oral mucosa observed in other studies, we reduced the concentration of imiquimod by 5% thanks to the excipient (orabase). This administration system is comfortable, it can improve the availability of the medication during the entire treatment process, prevent the loss of drug by mouth and protect the film from saliva and bioerosion produced by the tongue and teeth.
We supplement the treatment with hyaluronic acid gel on the nontreatment days to help regenerate the perilesional mucosa that may be affected by the use of the drug. All these measures have prevented the appearance of side effects and the need for a new surgical intervention while preserving the patient's quality of life. To our knowledge, this is the first case of OFP successfully treated with topical imiquimod 5%, with a 24-month follow-up period that is higher than that published by other authors whose range ranges from 3 to 18 months (Allam et al., 2008;Gemigniani et al., 2015;Gencoglan et al., 2011;Martinez-Lopez et al., 2017;Maschke et al., 2004;Méndez-Flores et al., 2019;Mullins et al., 2016;Rinaggio et al., 2006;Spieth et al., 2006;Wenzel et al., 2003;Yasar et al., 2019).

ACKNOWLEDGMENTS
This study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

CONFLICTS OF INTEREST
The authors declare no conflicts of interest.

DATA AVAILABILITY STATEMENT
The clinical relevance is based on the fact there are very few cases reported on oral pathology treated with imiquimod and this is the only case of oral florid papilomatosis treated successfully with a higher follow-up than published cases.