Treatment of Bowenoid and Basaloid Vulvar Intraepithelial Neoplasia 2/3 with Imiquimod 5% Cream DO NOT DUPLICATE

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1 The Journal of Reproductive Medicine Treatment of Bowenoid and Basaloid Vulvar Intraepithelial Neoplasia 2/3 with Imiquimod 5% Cream Claudia Marchitelli, M.D., Graciela Secco, M.D., Myriam Perrotta, M.D., Leonor Lugones, M.D., Romina Pesce, M.D., and Roberto Testa, M.D. OBJECTIVE: To evaluate the effectiveness and safety of imiquimod 5% for the treatment of bowenoid and basaloid vulvar intraepithelial neoplasia (VIN) and to evaluate recurrences following treatment. STUDY DESIGN: Eight patients < 55 years old (range, 32 51; mean, 39.7), with bowenoid or basaloid VIN 2/3 diagnosed by biopsy were treated with imiquimod 5%. Women with other types of intraepithelial neoplasia of the lower genital tract, immunosuppressed women, pregnant women and women with other types of vulvar pathology were excluded. Two patients previously treated for VIN 3 (surgical resection, resection by loop electrosurgical excision procedure) had recurrences. Patients applied imiquimod cream 3 times a week until total clearance of the lesions or up to a maximum of 16 weeks. Responses were categorized as total when there was no colposcopic evidence of a lesion, partial when the lesion area diminished > 50% and progressive when there was an increase in the lesion area. A biopsy was performed at the end of treatment. Follow-up was carried out monthly (10 30 months). RESULTS: Total clearance of lesions was observed in 6 In this study imiquimod proved to be effective for the treatment of viral VIN 2/3. patients after weeks. Two patients had a partial response (1 with 75% and the other with 50% reduction of the lesions). Posttreatment histopathology showed the absence of precancerous lesions in 7 patients (87.5%). Biopsy was positive for VIN 3 (12.5%) only in the patient showing a clinical response of 50%. Of the 7 patients with biopsies negative for VIN, 2 (25%) were positive for viral infection; 1 gave a negative reading after 2 months after treatment, and the other 1 remained positive for human papillomavirus. The patient with persistent VIN received surgical treatment. The side effects were as follows: erythema in 8 patients (100%), erosions in 1 patient (12.5%) and edema in 1 patient (12.5%). No relapses occurred after treatment during months of follow-up. CONCLUSION: In this initial series, imiquimod proved to be effective for the treatment of bowenoid and basaloid VIN 2/3 in a group of young women and was less aggressive treatment than surgical ones. The treatment was well tolerated, causing local reactions that enabled the therapy to be completed. (J Reprod Med 2004;49: ) From the Vulvar Pathology Section, Gynecology Department, Hospital Italiano, Buenos Aires, Argentina. Presented at the XVIIth World Congress of the International Society for the Study of Vulvovaginal Disease, Salvador, Brazil, October 12 16, Address reprint requests to: Claudia Marchitelli, M.D., Vulvar Pathology Section, Gynecology Department, Hospital Italiano, Pavón 4239, 1253 Buenos Aires, Argentina (claudia.marchitelli@hospitalitaliano.org.ar). Financial Disclosure: The authors have no connection to any companies or products mentioned in this article /04/ /$15.00/0 Journal of Reproductive Medicine, Inc. The Journal of Reproductive Medicine

2 Volume 49, Number 11/November Table I Patients Characteristics Characteristic Finding Age Mean 39.7, range Smokers 5 (55.5%) Parity 1.5 (0 3) Previous treatments 25% Time elapsed between diagnosis and start of treatment 3.87 months (range, 1 12) Keywords: vulvar neoplasms, vulvar intraepithelial neoplasia, imiquimod. Over the last 3 decades the incidence of vulvar intraepithelial neoplasia (VIN) increased significantly. 1-3 This increase is observed mainly in young women, < 40 years, and in smokers. 1 A clear association between VIN and HPV infections has been demonstrated, although a significant proportion of VIN cases tested negative for HPV. It is clear that there are 2 distinct types of VIN and that they are different in etiology, pathogenesis and clinical outcome. Undifferentiated, or classic, VIN (bowenoid and basaloid), associated with HPV infection, occurs mainly in young women and tends to be multifocal and pigmented. It is related to other neoplasms of the lower genital tract (generally cervical intraepithelial neoplasia 3) in > 30% of patients. Differentiated VIN, not associated with HPV, is related to nonneoplastic vulvar epithelial disorders (lichen sclerosus and squamous hyperplasia). It occurs Table III Clinical Cases Table II Reason for Consultation Reason No. Itching 5 (62.5%) Visualization of lesions 4 (50%) Gynecologist diagnosis 2 (25%) mostly in postmenopausal women and tends to be unifocal and leukoplastic. It is not connected with other types of epithelial neoplasia of the lower genital tract (LGT). 4,5 Although the evolution of VIN cannot be predicted, in young women it is stable for a long period and in some cases regresses spontaneously. 6 In elderly women these lesions have greater malignant potential. 7 Current therapies for VIN are suboptimal in terms of poor response rates, high relapse rates, and associated physical and psychosexual morbidity. Imiquimod is an immune response modifier. In view of the fact that its mechanism of action is effective for the treatment of external genital warts 8,9 it has been suggested for bowenoid and basaloid VIN 2/3. Since the lesions appearing in younger women are thought to have less malignant potential and longer transit time, we were able to offer this group of patients more conservative therapy to preserve the normal anatomy and function of the vulva. We evaluated the effectiveness and safety of imiquimod 5% cream for the treatment of bowenoid Case Age no. (yr) SM Ass. les P. VIN Lesion No VIN 3 LEEP Hyperpigmented and leukoplastic lesion in fourchette, right labium minus Cervical HPV No Hyperpigmented, raised lesions in vulvar fourchette, perineum and perianal region Cervical HPV No Raised leukoplastic lesion in vulvar fourchette 2 yr earlier 4 51 Cervical HPV VIN 3, Surg. Hyperpigmented, flat lesion in fourchette, perineum, perianal region 1 yr earlier Resec. (Figure 6) 5 35 No No Hyperkeratotic, leukoplastic lesions on internal side of both labia minora (Figure 2) Treated vulvar No Multifocal, warty VIN in both labia minora and majora, fourchette, condyloma perineum (Figure 4) No No Hyperpigmented papules in fourchette, perineum 8 47 Treated for vulvar No Extensive, warty lesions in both labia minora and majora, clitoris, condyloma perineum (Figure 8) Ass. les = associated lesion, F/U = follow-up, Mod. = moderate, P. VIN = previous VIN, PR = partial response, Rs = Response, SM = smoker, Surg. Resec. = surgical resection, TR = total response, Wks Tr. = weeks of treatment.

3 878 The Journal of Reproductive Medicine and basaloid VIN 2/3 as well as the recurrence rates after treatment. Materials and Methods Approval of the ethics committee of the Hospital Italiano, Buenos Aires, was obtained to conduct this observational and prospective study. Eight patients < 55 years of age (range, 32 51; mean, 39.7), with bowenoid and basaloid VIN 2/3 diagnosed by biopsy were included. All were > 18 years and signed informed consent forms. Vulvoscopies were performed and photographs of the lesions taken to assess the response to treatment (Table I). Biopsies were performed with a 6- mm dermatologic punch. In multifocal lesions various biopsies of the different lesions and sites were conducted. In patients with perianal lesions, anoscopy was done to rule out an anal canal lesion. Patients with other types of intraepithelial neoplasia of the LGT, immunodepressed women, pregnant women and women with other types of vulvar pathology (including differentiated VIN) were excluded from the study. Two (25%) of the 8 patients had been previously treated for VIN. In 1 patient the lesion had been resected by LEEP, with a relapse 5 months after treatment. The other patient had a local surgical resection, relapsing 4 months after treatment. Patients were instructed to apply the topical preparation at night, 3 times a week and on alternate days, washing the area in the morning. Treatment lasted until the lesions cleared completely or up to a maximum of 16 weeks. Response was categorized as total when there was no vulvoscopic evidence of the lesion, partial when the lesion area diminished > 50% and progressive when there was enlargement of the lesion site. Patients were scheduled for monthly visits to assess response to treatment and evaluate possible side effects. Mean follow-up was 22 months (10 30). Results The main reason for consulting a physician was itching (62.5%) (Table II). Seventy-five percent of patients had lesions at > 1 site (Table III). Anoscopy was negative in the 2 patients with perianal lesions. Of the total 8 patients, 2 had a history of vulvar warts treated topically, and 3 had no associated lesions. The last 3 patients had associated cervical lesions (flat condyloma); 2 were cured by cryosurgery Wks Post-Tr. F/U Biopsy Tr. Rs Side effects biopsy (mo) VIN 3, bowenoid 16 TR Mild/Mod. burning VIN 30 VIN 3, bowenoid 16 PR (> 75%) Mild/Mod. burning, erosions VIN, +HPV 29, HPV VIN 3, basaloid 12 TR NO VIN, +HPV 10, +HPV VIN 3, bowenoid 10 TR NO VIN, HPV 22 (Figure 7) VIN 3, basaloid 14 TR Mild burning VIN, HPV 20 (Figure 3) VIN 3, bowenoid 12 TR Itching, mild burning VIN, HPV 18 (Figure 5) VIN3 16 TR Mild/Mod. burning, edema VIN, HPV 16 VIN 3, bowenoid/ 16 PR (> 50%) Mild burning +VIN (Figure 9) Surg. Resec. of basaloid residual lesions, 30 % Figure Months Side effects. Burning Itching Dyspareunia Erosion Edema

4 Volume 49, Number 11/November Figure 2 Case 5. Before treatment. White, hyperkeratotic lesions on the inner aspect of both labia minora. 1 and 2 years earlier, and in the last, no treatment was applied but watchful waiting initiated. Total clearance of lesions was observed in 6 patients after weeks of treatment. Two patients had a partial response, 1 with 75% (case 2) and the other with 50% reduction of the lesions (case 8) (Figure 9). Posttreatment histopathology showed absence of VIN in 7 patients (87.5%) (Figures 3, 5 and 7). Biopsy was positive for VIN 3 in the patient showing a lesion reduction of 50% (case 8). Of the 7 patients with biopsies negative for VIN, 2 tested positive for viral infection. One of the patients had a 25% residual lesion (case 2) and gave a negative reading 2 after treatment. The other patient evidenced no posttreatment lesion on vulvoscopy (case 3). The patient with persistent VIN received surgical treatment of the residual lesion. Side effects were well-tolerated local reactions. Given that ours was a small group of patients, the women were asked about the presence of such symptoms as burning, itching, pain and dyspareunia. These symptoms were evaluated monthly and are summarized in Figure 1. Although dyspareunia was not described as an important symptom, when patients were asked about their sexuality, 87.5% Figure 3 Case 5. Complete response after treatment. Figure 4 Case 6. Before treatment. Confluent gray and white hyperkeratotic lesions on both labia majora and minora and on the perineum.

5 880 The Journal of Reproductive Medicine Figure 5 Case 6. Complete response after treatment. mentioned a decrease in sexual desire and frequency of intercourse. These symptoms disappeared a month after the end of treatment. Therapy had to be interrupted for a week in 2 patients. One patient experienced vulvar erosions and the other, vulvar edema. Treatment was resumed up to week 16 and 15, respectively. Erythema occurred in 100% of patients (Figure 1). No recurrences occurred after treatment during months of follow-up (mean, 22). Figure 7 Case 4. Complete response after treatment. Discussion There are no large reported series of patients with VIN 2/3 treated with imiquimod. Davis et al reported 4 cases. All 4 patients experienced clearance of the lesions, but 2 relapsed. 10 There were no comments on side effects. Todd reported one of the largest series of VIN 3 patients treated with imiquimod. Fifteen patients were treated, and 4 had a clinical improvement, with 3 cases of biopsy-proven to be negative for VIN. Due to important side effects, only 2 patients completed the treatment regimen of 3 times a week. This may have been the cause of the low response to treatment. 11 Figure 6 Case 4. Before treatment. Brown, pigmented VIN on the fourchette, perineum and perianal area. Figure 8 Case 8. Before treatment. Extensive, warty VIN on both labia majora and minora and on the clitoris and perineum.

6 Volume 49, Number 11/November Figure 9 VIN. Case 8. Partial response, with 2 persistent areas of Christopher retrospectively reviewed the charts of 13 patients with VIN 2/3 treated with imiquimod. Eight had a total regression of VIN, 4 showed 75% regression, and 2 had an invasive carcinoma in the area of residual disease. 12 Van Seters studied the clinical response of 15 patients with VIN 2/3. Four had a total response and 9 a partial response. Two patients did not tolerate treatment. 13 Although our study was not randomized, the sample was small, and lesions were of different sizes and at different sites, it took into account the VIN histologic type, excluding patients with differentiated, or mixed, VIN. It is possible that the good response to treatment in this series was due to the fact that all cases were viral, that most of them (75%) had not been treated previously and that once the diagnosis was made, therapy was applied rapidly. Only 1 of the patients asked for medical advice after a year; she had a posttreatment biopsy positive for VIN. Important side effects, such as those in other studies, were not observed. Patients were instructed on how to use the cream and on how and where to apply it. This may have been 1 reason for fewer side effects. That patients had good tolerance to local reactions. Two patients had to suspend treatment after clinical examination diagnosed edema and erosion. Although these symptoms were well tolerated, the study protocol did not allow continuation of treatment under these circumstances. Vulvar erythema was observed in 100% of patients and was intense in some cases. Since the mechanism of action of imiquimod is to release cytokines, erythema appears due to a local inflammatory reaction. The symptoms reported by patients did not always correlate with the intensity of the erythema. All the patients were young women with multifocal disease. If a surgical treatment had been indicated, resections would have been extensive, with significant damage to vulvar anatomy. This would have been accompanied by psychological and sexual impairment. A patient with a biopsy positive for VIN had > 50% reduction of the affected area; that enabled a smaller resection to be preferred with acceptable cosmetic results. One patient had spontaneous clearance of a residual viral lesion after treatment. In this study imiquimod proved to be effective for the treatment of viral VIN 2/3. Before starting treatment it is important to assess the histologic type to obtain greater therapeutic success and to treat lesions with a lower risk of progression. Posttreatment biopsies evidenced no persistence of VIN 2/3 in this study. Imiquimod is an alternative for the treatment of VIN in young women with multifocal lesions. It is effective, well tolerated and less aggressive than surgical treatment. References 1. Sturgeon SR, Brinton LA,Devesa SS, et al: In situ and invasive vulvar cancer incidence trends. Am J Obstet Gynecol 1992;166: Jones RW, Rowan DM: Vulvar intraepithelial neoplasia III: A clinical study of the outcome in 113 cases with relation to the later development of invasive vulvar carcinoma. Obstet Gynecol 1994;84: Iversen T, Tretli S: Intraepithelial and invasive squamous cell neoplasia of the vulva: Trends in incidence, recurrence and survival rate in Norway. Obstet Gynecol 1998;91: Haefner H, Tate J, McLachlin CM, et al: Vulvar intraepithelial neoplasia: Age, morphological phenotype, papilloma virus DNA, and coexisting invasive carcinoma. Hum Pathol 1995;26: Crum CP, McLachlin CM, Tate JE, et al: Pathology of squamous neoplasia. Curr Opin Obstet Gynecol 1997;9: Jones RW, Rowan DM: Spontaneous regression of vulvar intraepithelial neoplasia 2-3. Obstet Gynecol 2000;96:

7 882 The Journal of Reproductive Medicine 7. Hart WR, Norris HJ, Helwig EB: Relation of lichen sclerosus et atrophicus of the vulva to development of carcinoma. Obstet Gynecol 1975;45: Imiquimod for genital warts. Med Lett 1997;39: Tyring SK, Arany I, Stanley MA: A randomized, controlled molecular study of condyloma accuminata clearance during treatment with Imiquimod. J Infect Dis 1998;178: Davis G, Wentworth J, Richard J: Self administrated topical imiquimod treatment of vulvar intraepithelial neoplasia. J Reprod Med 2000;45: Todd RW, Etherington IJ, Luesley DM: The effects of 5% imiquimod cream on high-grade vulvar intraepithelial neoplasia. Gynecol Oncol 2002;85: Jayne Christopher J, Kaufman RH: Treatment of vulvar intraepithelial neoplasia 2/3 with imiquimod. J Reprod Med 2002;47: Van Seters M, Fons G, van Beurden M: Imiquimod in the treatment of multifocal vulvar intraepithelial neoplasia 2/3: Results of a pilot study. J Reprod Med 2002;47: