An Alternative Treatment for Vaginal Cuff Wart: a Case Report

Human papillomavirus (HPV) has been directly related to acuminate warts and cervical cancer, the second most common neoplasia among women. Given the lack of treatment against the virus itself, many medications have been utilised, mainly aiming in modifying the host’s immunological response. We present the case of a 54 years old postmenopausal patient with a history of vaginal cuff wart and HPV persistence that we managed in our clinic for 6 months with a mix of curcumin, aloe vera, amla and other natural ingredients. As the patient was found to be intolerant to imiquimod (one of the most common conservative methods of treatment) we attempted the use of curcumin, which was applied to the area of the wart three times per week for 6 months. Both clinical and colposcopical improvement was noted in regular clinic visits with regression of the lesion. The outcome of this case encourages our view that curcumin should be considered as a significant treatment modality against HPV infection and acuminate warts.


INTRODUCTION
Cervical cancer is the 4th most common cancer among women worldwide, with an estimated 527,624 new cas es and 265,672 deaths in 2012 (1). HPV is recognized as a wellestablished causative factor, mainly through the work of Harald zur Hausen, who also later identified the two most oncogenic types of the virus, 16 and 18 (2). Now adays there is upcoming conclusive evidence with respect to carcinogenicity of HPV in other anogenital cancers (anus, vulva, vagina and penis) as well as head and neck cancers (3).
Primary HPV infection usually occurs early in life and it is asymptomatic in most cases. Genital warts are the visible manifestation of the infection, typically caused by HPV types 6 and 11, which rarely are associated with invasive squamous cell carcinoma (4). Patients with con dylomata (genital warts) can present with burning, itch ing, bleeding, and pain as well as psychological anxiety and embarrassment (5). The disease is estimated to lead to high morbidity and significant healthcare costs, since the lesions typically recur even after different ablative (elec trocautery, liquid nitrogen, and laser therapy) techniques or surgical excision. Specifically, the recurrence rate with each technique reach 20-40% for cryotherapy, 15% for im iquimod, 5-50% for laser treatment, 5-30% for podofilox and 2065% for podophyllin resin (6).
Currently many natural plant origin compounds have been identified as promising sources of drugs for treat ment and prevention against recurrence of genital warts, with podofilox and imiquimod being the most recom mended (7). Another noninvasive treatment agent is cur cumin, a topical immune response modifier, isolated from the root of Curcuma longa. Curcumin, introduced as a safe and effective treatment for HPVassociated genital warts, has not been found to achieve its optimum therapeutic outcome, mainly because of its low solubility and poor bi oavailability. Lately, it has been developed as a therapeutic drug through alterations in formulation properties and improvement of delivery systems (8).
We present a case of a vaginal cuff wart diagnosed and managed in our clinic with a mix of curcumin, aloe vera, amla and other natural ingredients. Our aim is to discuss an alternative option in the treatment of acute warts that persist or recur after other methods of therapy.

CASE REPORT
A 54yearold woman, with a HGSIL Pap smear was re ferred to our clinic. The patient has a THBO medical his tory due to uterus fibroids ten years ago. Clinical exam ination and colposcopy revealed a vaginal cuff wart and histopathology confirmed the HPV infection. The patient was treated with ALDARA 5% cream, a regimen of imi quimod produced by Meda AB in Sweden, which was ap plied three times weekly. However, her clinical situation worsened after two cycles of therapy as she presented with symptoms of intense intolerance of the medica ment, including burning and itchiness of the affected area. Administration of imiquimod was discontinued for the following two months. The patient was then reevalu ated and an alternative treatment with a mixture of cur cumin, Indian Grapefruit (AMLA), aloe vera, Docosanol, lactic acid and CMβ glucans was applied. The vaginal cream SiloffGyn, produced by Heremco Pharmaceuticals in Athens, was locally applied at the wart, daily for one week and then three times a week. Three months later the patient's clinical and colposcopy findings improved; both Pap smear result and colposcopy were negative. Two years later the patient has no clinical or laboratory suspi cion of recurrence.

DISCUSSION
HPVs belong to the family of papilloma viruses, usual ly infecting exclusively skin and mucosal surfaces of the mouth, the anal, the female genitalia, and the epithelium of the endometrium resulting in cell proliferation and proliferative, precancerous, but also cancerous lesions. To date, 189 types of papillomaviruses have been identified, 120 of which infect humans (9).
HPV infection is the most common sexually transmit ted disease in the U.S, affecting almost 1% of the sexual ly active population (10). Warts or condylomata are eti ologically associated with some HPV types, mainly low risk types 6 or 11, but not exclusively. In contrast with the cervical intraepithelial neoplasias, which are silent, warts are usually noticed by the patient herself/himself and they vary from flat papules to large, cauliflowerlike lesions. Diagnosis is clinical, but atypical lesions should be confirmed by histology. Therapy ranges between surgical (excision, electrosurgery, cryotherapy) and conservative. The latter depends on the topical application of various medicaments such as imiquimod, podofilox, podophyl lin, bichloroacetic acid, and trichloroacetic acid. The cure rates are of each method are estimated to reach 30-50%, 45-80%, 30-80% and 50-80% respectively (6).
Derived from the perennial herb Curcuma longa (tur meric) curcumin is a polyphenol of plant origin known since many years as traditional Indian medicine. Turmeric Fig. 1 Vaginal cuff wart before treatment.
was introduced into Europe in the 13th century by Marco Polo and surprisingly, since 1937, when an early study was published in The Lancet by Oppenheimer, it is in the last 15 years that it has gained increasing popularity and it has become the subject of many studies (8).
In the last decades, curcumin has been found to me diate in various cell signaling molecules and this way to downregulate inflammation mediators, cytokines, inter leukins and enzymes, gaining antiinflammatory effects and therapeutic potential against a wide range of patho logic conditions, such as many types of cancer, inflam matory bowel disease, osteoarthritis, H. Pylori infection, psoriasis, acute coronary syndrome, atherosclerosis, type 2 diabetes, renal transplantation and βThalassemia (11)(12)(13).
In the context of the aforementioned multiple prop erties, curcumin is considered cytotoxic against cervical cancer cells and has been found to downregulate the ex pression of HPV oncoproteins. Importantly, with regards to its safety, turmeric has been established to be safe and welltolerated by human trials and is Generally Recog nized As Safe (GRAS) by the US FDA (14). Interestingly, Debata et al, recently developed a curcuminbased vaginal cream that eradicates HPV positive cancer cells without affecting the healthy tissues (15).

CONCLUSIONS
As far as we know, most of the curcuminrelated studies have highlighted its potential to clear HPV infection, and consequently the intraepithelial precancerous lesions it induces. Literature review about condylomata treatment with curcumin was poor but encouraging. The patient applied vaginally curcumin 2 times a week without fur ther anti HPV treatment for 6 months and for 18 months now she has remained recurrentfree. Repeat cytology confirmed the recession of the wart. To the best of our knowledge, this is the first report in which curcumin has demonstrated an objective response in conventional treat ment of a vaginal cuff condyloma. Fig. 2 Vaginal cuff wart after treatment with imiquimode. Fig. 3 Vaginal cuff wart after treatment with SiloffGyn.