Correspondence

Treatment of High-Grade Vaginal Intraepithelial Neoplasia with Imiquimod Cream

N Engl J Med 2002; 347:374August 1, 2002

Article

To the Editor:

Primary invasive carcinoma of the vagina is rare, accounting for less than 3 percent of malignant tumors of the female genital tract. Vaginal intraepithelial neoplasia, a precursor of invasive vaginal carcinoma, is even less common.1 Cytologic screening for vaginal tumors is not useful, unless there is a history of neoplasia of the lower genital tract.2,3 We treated three women with high-grade vaginal intraepithelial neoplasia by applying 5 percent imiquimod cream vaginally. Imiquimod induces the secretion of interferon-α, interleukin-12, and tumor necrosis factor α from mononuclear cells.

All three women were positive for the high-risk type of human papillomavirus before treatment. The treatment consisted of vaginal application of 5 percent imiquimod cream under colposcopic guidance three times a week for eight weeks. The first patient was a 38-year-old woman who had grade 3 vaginal intraepithelial neoplasia after undergoing a hysterectomy for cervical intraepithelial neoplasia, grade 3. Biopsy specimens obtained after treatment with imiquimod showed grade 1 vaginal intraepithelial neoplasia. The second patient was a 61-year-old woman who had multifocal lesions of grade 2 vaginal intraepithelial neoplasia after undergoing a hysterectomy for leiomyomas. Histologic studies performed after therapy revealed human papillomavirus infection without any indication of vaginal intraepithelial neoplasia. The third patient was a 58-year-old woman who had grade 3 vaginal intraepithelial neoplasia after undergoing a hysterectomy for microinvasive carcinoma of the cervix. Follow-up histologic studies showed regression to grade 1 vaginal intraepithelial neoplasia. There were no adverse events related to the use of the cream. Before the application of imiquimod, the p53 protein was overexpressed in biopsy specimens from the first and third patients, but not in specimens from the second. After treatment, histologic studies showed no p53-positive nuclei in the first and second patients, whereas the third continued to have overexpression of the protein.

Imiquimod is a locally active immune-response modifier that stimulates natural-killer-cell activity, enhances functional maturation of Langerhans' cells, and augments the effectiveness of T cells.4 Davis et al. recently reported that imiquimod therapy produced good results in four women who had high-grade vulvar intraepithelial lesions (vulvar intraepithelial neoplasia, grade 3).5 In our patients, application of the cream under colposcopic guidance ensured the spread of the drug into the folds, rugae, and angular funnels of the vagina. Histologic studies performed after treatment revealed regression of the disease by at least two grades. Our findings suggest the imiquimod is an alternative conservative therapy for vaginal intraepithelial neoplasia.

Emmanuel Diakomanolis, M.D., Ph.D.
Dimitrios Haidopoulos, M.D.
Konstantinos Stefanidis, M.D.
University of Athens, 11528 Athens, Greece
dhaidopoulos@hotmail.com

5 References

1. 1

   Aho M, Vesterinen E, Meyer B, Purola E, Paavonen J. Natural history of vaginal intraepithelial neoplasia. Cancer 1991;68:195-197
   CrossRef | Web of Science | Medline

2. 2

   Noller KL. Screening for vaginal cancer. N Engl J Med 1996;335:1599-1600
   Full Text | Web of Science | Medline

3. 3

   Pearce KF, Haefner HK, Sarwar SF, Nolan TE. Cytopathological findings on vaginal Papanicolaou smears after hysterectomy for benign gynecologic disease. N Engl J Med 1996;335:1559-1562
   Full Text | Web of Science | Medline

4. 4

   Miller RL, Gerster JF, Owens ML, Slade HB, Tomai MA. Imiquimod applied topically: a novel immune response modifier and new class of drug. Int J Immunopharmacol 1999;21:1-14
   CrossRef | Web of Science | Medline

5. 5

   Davis G, Wentworth J, Richard J. Self-administered topical imiquimod treatment of vulvar intraepithelial neoplasia: a report of four cases. J Reprod Med 2000;45:619-623
   Web of Science | Medline

Citing Articles (10)

Citing Articles

1. 1

   José das Neves, Maria Helena Amaral, Maria Fernanda Bahia. 2010. Vaginal Drug Delivery. .
   CrossRef

2. 2

   Christos Iavazzo, Eleni Pitsouni, Stavros Athanasiou, Matthew E. Falagas. (2008) Imiquimod for treatment of vulvar and vaginal intraepithelial neoplasia. International Journal of Gynecology & Obstetrics 101:1, 3-10
   CrossRef

3. 3

   Phillip R. Fleshner, Sridhar Chalasani, George J. Chang, David H. Levien, Neil H. Hyman, W. Donald Buie. (2008) Practice Parameters for Anal Squamous Neoplasms. Diseases of the Colon & Rectum 51:1, 2-9
   CrossRef

4. 4

   Asoka Herat, Margot Whitfeld, Richard Hillman. (2007) Anal intraepithelial neoplasia and anal cancer in dermatological practice. Australasian Journal of Dermatology 48:3, 143-155
   CrossRef

5. 5

   Padma K. EEDARAPALLI, Smita JAIN, Douglas M. MCKENNA. (2006) An unusual presentation of basaloid vaginal intraepithelial neoplasia in a young infertile woman. The Australian and New Zealand Journal of Obstetrics and Gynaecology 46:1, 61-63
   CrossRef

6. 6

   Eddie F. C. Murta, Milton A. Neves Junior, Luciano R. F. Sempionato, Marcos C. Costa, Paulo J. Maluf. (2005) Vaginal intraepithelial neoplasia: clinical-therapeutic analysis of 33 cases. Archives of Gynecology and Obstetrics 272:4, 261-264
   CrossRef

7. 7

   D. HAIDOPOULOS, E. DIAKOMANOLIS, A. RODOLAKIS, Z. VOULGARIS, G. VLACHOS, A. INTSAKLIS. (2005) Can local application of imiquimod cream be an alternative mode of therapy for patients with high-grade intraepithelial lesions of the vagina?. International Journal of Gynecological Cancer 15:5, 898-902
   CrossRef

8. 8

   Dimitrios Haidopoulos, Emmanuel Diakomanolis, Alexandros Rodolakis, George Vlachos, Alexandros Elsheikh, Stylianos Michalas. (2004) Safety and efficacy of locally applied imiquimod cream 5% for the treatment of condylomata acuminata of the vulva. Archives of Gynecology and Obstetrics 270:4, 240-243
   CrossRef

9. 9

   Hue Tran, Gilberto Moreno, Stephen Shumack. (2004) Imiquimod as a dermatological therapy. Expert Opinion on Pharmacotherapy 5:2, 427-438
   CrossRef

10. 10

    Suzanne M. Garland. (2003) Imiquimod. Current Opinion in Infectious Diseases 16:2, 85-89
    CrossRef