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June 20, 2011

Failure of Extensive Extramammary Paget Disease of the Inguinal Area to Clear With Imiquimod Cream, 5%: Possible Progression to Invasive Disease During Therapy

Author Affiliations

Author Affiliations: Departments of Dermatology (Dr Green), Dermatopathology (Dr Burkemper), Mohs Surgery and Cutaneous Oncology (Dr Fosko), Pathology (Dr Burkemper), Ophthalmology (Dr Fosko), Otolaryngology–Head and Neck Surgery (Dr Fosko), and Internal Medicine (Dr Fosko), Saint Louis University School of Medicine, and Saint Louis University Cancer Center (Dr Fosko), St Louis, Missouri.

Arch Dermatol. 2011;147(6):704-708. doi:10.1001/archdermatol.2011.121

Background  Surgical approaches are the standard treatment for extramammary Paget disease (EMPD), but nonsurgical modalities may be preferred and more appropriate for some patients. Topical administration of imiquimod cream, 5%, has improved or resolved in situ EMPD (n = 21), but treatment failures (n = 6) have also been reported.

Observations  We treated an elderly patient with initial biopsy-proved in situ genital EMPD with daily topical imiquimod, 5%, for 14 weeks. Midtreatment mapping biopsy specimens demonstrated invasive disease, with minimal clinical improvement. The patient subsequently underwent surgical excision.

Conclusions  Of the 27 published cases that describe imiquimod treatment of EMPD, 6 report treatment failure (22%), but factors that may contribute to treatment failure are not well understood. In the present patient, treatment with imiquimod may have been complicated by variable lesion thickness, which inhibited uniform penetration of imiquimod, or the presence of invasive disease not detected on initial biopsy. The efficacy of imiquimod to treat extensive invasive EMPD has not been demonstrated, and surgical approaches remain the most appropriate treatment for invasive disease. Variable responses to topical imiquimod use among patients suggest that other factors may be important in determining response to therapy.

Surgical management of extramammary Paget disease (EMPD) remains a therapeutic mainstay, but alternative treatments for primary limited cutaneous EMPD in the anogenital area that avoid cosmetic and functional defects after extensive tissue removal are under investigation. Local recurrence of EMPD can be significant,1 highlighting the insidious nature of EMPD and the need to identify more effective treatments. The topical immunomodulator imiquimod, 5%, has been reported to induce clinical and histologic resolution of superficial EMPD,2-12 but several cases of imiquimod failure have also been described.13-17 Herein, we present a case of genital EMPD considered to be limited to in situ disease at the beginning of treatment with topical imiquimod that proved refractory, with demonstration of invasive disease during treatment. We also review the current literature (articles published in English and obtained through PubMed, Ovid, and GoogleScholar searches conducted between July 1, 2009, and August 31, 2010) regarding successes (n = 21) and failures (n = 6) of imiquimod therapy for EMPD and present characteristics that could portend treatment failure.

Report of a case

An 82-year-old man presented with a 1-year history of a pruritic lesion in the left inguinal area. Physical examination revealed a 9 × 5-cm velvety pink patch with a central, slightly elevated, verrucous plaque involving the suprapubic area, scrotum, and base of the penis (Figure 1A). Invasive disease was clinically suspected given the central plaque. Six 3-mm mapping punch biopsy specimens were collected peripherally and centrally and demonstrated only in situ EMPD (Figure 1B and C). Findings from lymph node and full-body skin examination, colonoscopy, and cystoscopy were unremarkable. After a urology consultation and discussion of treatment options, the patient chose a nonsurgical approach and applied imiquimod cream, 5%, to the lesion once daily for 14 weeks for a total of 98 applications. During treatment, tolerable mild lesional tenderness and erythema developed. Eleven weeks after the start of treatment, clinical improvement was limited to the periphery of the lesion (Figure 2A). Four 3-mm mapping punch biopsy specimens detected residual in situ EMPD peripherally but an invasive component at the center of the lesion. The patient then underwent excision of the lesion. Histopathologic analysis revealed invasive EMPD to a depth of 7.5 mm (Figure 2B). Peripheral margins were free of tumor; however, 1 tumor nest was identified 0.2 mm from the deep margin. The patient elected close observation.

Figure 1. 

A, Clinical appearance of the lesion before imiquimod cream, 5%, treatment. B, Histopathologic appearance of the lesion before treatment demonstrating in situ extramammary Paget disease (EMPD) (hematoxylin-eosin, original magnification ×10). C, Histopathologic appearance of the lesion before treatment demonstrating in situ EMPD (cytokeratin 7, original magnification ×10).

A, Clinical appearance of the lesion before imiquimod cream, 5%, treatment. B, Histopathologic appearance of the lesion before treatment demonstrating in situ extramammary Paget disease (EMPD) (hematoxylin-eosin, original magnification ×10). C, Histopathologic appearance of the lesion before treatment demonstrating in situ EMPD (cytokeratin 7, original magnification ×10).
Figure 2. 

A, Clinical appearance of the lesion after 11 weeks of daily imiquimod cream, 5%, application. B, Histopathologic appearance of the surgical excision demonstrating dermal invasion (hematoxylin-eosin, original magnification ×20).

A, Clinical appearance of the lesion after 11 weeks of daily imiquimod cream, 5%, application. B, Histopathologic appearance of the surgical excision demonstrating dermal invasion (hematoxylin-eosin, original magnification ×20).


Extramammary Paget disease is a relatively rare neoplasm classically involving skin-bearing apocrine glands in locations other than the nipple or areola of the breast.18,19 For unclear reasons, EMPD can be associated with underlying adnexal adenocarcinoma or other internal malignant neoplasms.18 Most commonly, EMPD involves vulvar skin in women, but it may present in the inguinal, scrotal, and penile areas in men and in the perineal and perianal regions in both sexes.18,19 Clinically, EMPD has an insidious onset, with patients reporting symptoms of itching, burning, and pain in affected areas even before visible lesions appear.19 Lesions of EMPD are described as erythematous or white, well-demarcated plaques with variable amounts of crust, ulceration, and scale.19 Histopathologic analysis reveals large round cells with abundant pale cytoplasm at all levels of the epithelium.18-20 Generally, patients with in situ EMPD have a good prognosis,20 but the presence of dermal invasion or metastasis seems to significantly increase morbidity and mortality.21 Similarly, EMPD associated with an underlying visceral malignancy carries a worse prognosis.19,22

Historically, EMPD has been treated with wide surgical excision despite high recurrence rates (31%-61%).1 More recently, EMPD has been treated with Mohs micrographic surgery, the often preferred modality given its lower recurrence rate (23%) compared with standard excision.1 Nonsurgical modalities used alone or in conjunction with surgical excision may be more appropriate for some patients. In the past, such treatment modalities have included irradiation,23-25 topical chemotherapy with fluorouracil26,27 or bleomycin,28 various systemic chemotherapeutic regimens,29-32 laser ablation,33-36 and photodynamic therapy,37-39 with varying efficacy. Recently, topical imiquimod, 5%, has emerged as a potential treatment for superficial EMPD. Treatment of EMPD of the vulva,4,6-8,12,40 groin and scrotum,3,5,9,10,40,41 perineum,2,5,11,42 thigh,43 and bilateral chest17 with topical imiquimod, 5%, has been reported in 27 patients, with treatment success documented in 21 patients (78%).

Of the 21 patients with treatment success, 13 had primary EMPD,2-5,9,11,12,40,43 7 had recurrent EMPD,5-8,10,41 and 1 had residual EMPD (Table 1).42 Imiquimod cream, 5%, was applied with a frequency ranging from twice weekly for 16 weeks7 to daily for 12 weeks.42 Recurrent and residual cases of EMPD had been treated previously with surgical excision and vulvectomy,6-8,42 Mohs micrographic surgery,10,41 electrodessication and curettage,5 or photodynamic therapy.41 Of the 21 reported cases of treatment success, 18 were characterized as in situ EMPD on pretreatment biopsy, 1 contained dermal microinvasion, and 2 were not clarified.10,40 Posttreatment biopsy specimens were negative for EMPD in 18 patients and were not obtained in 3 patients.12,40 Follow-up was a relatively brief 10.8 months for the 18 patients for whom such details were provided (Table 1). In 5 of these patients, follow-up was 6 months or less, and in 4 patients, follow-up was recorded for 4 months or less.

Table 1. 
Summary of Articles in the Literature Documenting Successful Treatment of EMPD With Imiquimod
Summary of Articles in the Literature Documenting Successful Treatment of EMPD With Imiquimod

To date, there are 6 cases (6 of 27 [22% of cases reported]) of topical imiquimod failure in the treatment of EMPD in the literature (Table 2).13-17 Among these, 3 cases of in situ EMPD were noted on pretreatment biopsy,13,15,17 but pretreatment biopsy findings were not reported for the remaining 3 cases (Table 2). One case was documented to be recurrent in situ EMPD,13 for which the patient had previously undergone surgical excision. The treatment regimen in these patients ranged from application of imiquimod cream, 1%, daily for 12 weeks15 to application of 5% cream every other day for 24 weeks and then every 3 days for 12 additional weeks.17 Posttreatment biopsy specimens revealed residual EMPD in all 5 patients for which such information was provided (Table 2). Length of follow-up was noted only for 1 case, in which recurrence was noted clinically 11 weeks after the cessation of treatment, with no posttreatment biopsies performed.17

Table 2. 
Summary of Articles in the Literature Documenting Failure of Imiquimod Treatment in EMPD
Summary of Articles in the Literature Documenting Failure of Imiquimod Treatment in EMPD

Herein, we report apparent resistance to imiquimod therapy in an elderly patient with genital EMPD with either missed invasive disease at initial presentation or progression from in situ to invasive disease during treatment. In this case, only in situ EMPD was initially detected on mapping biopsies, including biopsies of the thicker and more hyperkeratotic portion of the lesion. Given these pathology results, our impression was that the biopsy specimens of the thick central portion of the lesion represented pronounced in situ disease. Therefore, we proceeded with imiquimod therapy. Several important points should be considered. Mapping biopsy specimens are typically collected from multiple representative areas of a lesion in an attempt to predict the general histopathologic condition of the lesion as a whole, but they do not allow the pathologist to examine the entire lesion. They are merely a “sampling” of a lesion's histopathologic appearance. Therefore, in the present patient, invasive disease may have been missed from the outset by the initial mapping biopsy specimens. The efficacy of topical imiquimod use in extensive invasive EMPD has not been documented,5 and surgical excision in these cases may be more appropriate. Another point to consider is that therapeutic responses may be related to the depth of penetration of imiquimod such that thicker portions of an in situ lesion or tumor with extensive adnexal involvement or invasive disease may exhibit incomplete responses. In addition, variable responses to imiquimod in patients with presumed in situ EMPD suggests that additional, as yet unknown, factors may be important in predicting response to treatment. Furthermore, although topical imiquimod application may be effective in cases of in situ EMPD, refractory cases of presumed in situ EMPD may require further evaluation for an invasive component or other contributing factors.

Correspondence: Julie S. Green, MD, PhD, Department of Dermatology, Saint Louis University School of Medicine, 1402 S Grand Blvd, St Louis, MO 63104 (schwarj2@gmail.com).

Accepted for Publication: November 24, 2010.

Author Contributions: Drs Green and Fosko had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Green and Fosko. Acquisition of data: Green, Burkemper, and Fosko. Analysis and interpretation of data: Green, Burkemper, and Fosko. Drafting of the manuscript: Green and Fosko. Critical revision of the manuscript for important intellectual content: Burkemper and Fosko. Administrative, technical, and material support: Burkemper and Fosko. Study supervision: Burkemper and Fosko.

Financial Disclosure: None reported.

Additional Contributions: Christine Nelsen, MD, Department of Dermatopathology, Saint Louis University School of Medicine, collected the photomicrographs; Mark Doig, PA-C, Department of Mohs Surgery and Cutaneous Oncology, Saint Louis University School of Medicine, and James Cummings, MD, formerly of the Department of Surgery, Urology Division, Saint Louis University and currently with the Department of Surgery, Urologic Surgery Division, University of Missouri–Columbia, assisted with patient care; and Steven Palmer, MD, private practice, St Louis, referred the patient.

Coldiron  BMGoldsmith  BARobinson  JK Surgical treatment of extramammary Paget's disease: a report of six cases and a reexamination of Mohs micrographic surgery compared with conventional surgical excision.  Cancer 1991;67 (4) 933- 938PubMedGoogle ScholarCrossref
Mirer  EEl Sayed  FAmmoury  ALamant  LMesser  LBazex  J Treatment of mammary and extramammary Paget's skin disease with topical imiquimod.  J Dermatolog Treat 2006;17 (3) 167- 171PubMedGoogle ScholarCrossref
Cohen  PRSchulze  KETschen  JAHetherington  GWNelson  BR Treatment of extramammary Paget disease with topical imiquimod cream: case report and literature review.  South Med J 2006;99 (4) 396- 402PubMedGoogle ScholarCrossref
Sendagorta  EHerranz  PFeito  M  et al.  Successful treatment of three cases of primary extramammary Paget's disease of the vulva with Imiquimod: proposal of a therapeutic schedule.  J Eur Acad Dermatol Venereol 2010;24 (4) 490- 492PubMedGoogle ScholarCrossref
Zampogna  JCFlowers  FPRoth  WIHassenein  AM Treatment of primary limited cutaneous extramammary Paget's disease with topical imiquimod monotherapy: two case reports.  J Am Acad Dermatol 2002;47 (4) ((suppl)) S229- S235PubMedGoogle ScholarCrossref
Hatch  KDDavis  JR Complete resolution of Paget disease of the vulva with imiquimod cream.  J Low Genit Tract Dis 2008;12 (2) 90- 94PubMedGoogle ScholarCrossref
Geisler  JPManahan  KJ Imiquimod in vulvar Paget's disease: a case report.  J Reprod Med 2008;53 (10) 811- 812PubMedGoogle Scholar
Wang  LCBlanchard  AJudge  DELorincz  AAMedenica  MMBusbey  S Successful treatment of recurrent extramammary Paget's disease of the vulva with topical imiquimod 5% cream.  J Am Acad Dermatol 2003;49 (4) 769- 772PubMedGoogle ScholarCrossref
Hieken  TLasser  A Successful nonoperative treatment of extensive extramammary Paget's disease.  J Clin Oncol 2005;23 (16S) 2584Google Scholar
Berman  BSpencer  JVilla  APoochareon  VElgart  G Successful treatment of extramammary Paget's disease of the scrotum with imiquimod 5% cream.  Clin Exp Dermatol 2003;28 ((suppl 1)) 36- 38PubMedGoogle ScholarCrossref
Cecchi  RPavesi  MBartoli  LBrunetti  LRapicano  V Perineal extramammary Paget disease responsive to topical imiquimod.  J Dtsch Dermatol Ges 2010;8 (1) 38- 40PubMedGoogle ScholarCrossref
Challenor  RHughes  GFitton  AR Multidisciplinary treatment of vulval extramammary Paget's disease to maintain sexual function: an imiquimod success story.  J Obstet Gynaecol 2009;29 (3) 252- 254PubMedGoogle ScholarCrossref
Ye  JNRhew  DCYip  FEdelstein  L Extramammary Paget's disease resistant to surgery and imiquimod monotherapy but responsive to imiquimod combination topical chemotherapy with 5-fluorouracil and retinoic acid: a case report.  Cutis 2006;77 (4) 245- 250PubMedGoogle Scholar
Gass  JRytina  ESterling  JTodd  P Unsuccessful treatment of extramammary Paget's disease with topical imiquimod [abstract].  Br J Dermatol 2008;159 ((suppl 1)) 64PubMedGoogle Scholar
Bamford  JSeidelmann  S Clinical and immunologic response of extramammary Paget's disease to imiquimod [abstract].  J Invest Dermatol 2001;117 (2) 537PubMedGoogle Scholar
Urosevic  MDummer  R Role of imiquimod in skin cancer treatment.  Am J Clin Dermatol 2004;5 (6) 453- 458PubMedGoogle ScholarCrossref
Yeh  MHHu  SL Treatment of double ectopic extramammary Paget's disease of bilateral chest with imiquimod 5% cream.  J Eur Acad Dermatol Venereol 2007;21 (7) 997- 999PubMedGoogle ScholarCrossref
Shepherd  VDavidson  EJDavies-Humphreys  J Extramammary Paget's disease.  BJOG 2005;112 (3) 273- 279PubMedGoogle ScholarCrossref
Kanitakis  J Mammary and extramammary Paget's disease.  J Eur Acad Dermatol Venereol 2007;21 (5) 581- 590PubMedGoogle ScholarCrossref
Shaco-Levy  RBean  SMVollmer  RT  et al.  Paget disease of the vulva: a histologic study of 56 cases correlating pathologic features and disease course.  Int J Gynecol Pathol 2010;29 (1) 69- 78PubMedGoogle ScholarCrossref
Hatta  NYamada  MHirano  TFujimoto  AMorita  R Extramammary Paget's disease: treatment, prognostic factors and outcome in 76 patients.  Br J Dermatol 2008;158 (2) 313- 318PubMedGoogle Scholar
Chanda  JJ Extramammary Paget's disease: prognosis and relationship to internal malignancy.  J Am Acad Dermatol 1985;13 (6) 1009- 1014PubMedGoogle ScholarCrossref
Moreno-Arias  GAConill  CSola-Casas  MAMascaro-Galy  JMGrimalt  R Radiotherapy for in situ extramammary Paget disease of the vulva.  J Dermatolog Treat 2003;14 (2) 119- 123PubMedGoogle ScholarCrossref
Moreno-Arias  GAConill  CCastells-Mas  AArenas  MGrimalt  R Radiotherapy for genital extramammary Paget's disease in situ.  Dermatol Surg 2001;27 (6) 587- 590PubMedGoogle Scholar
Besa  PRich  TADelclos  LEdwards  CLOta  DMWharton  JT Extramammary Paget's disease of the perineal skin: role of radiotherapy.  Int J Radiat Oncol Biol Phys 1992;24 (1) 73- 78PubMedGoogle ScholarCrossref
Bewley  APBracka  AStaughton  RCBunker  CB Extramammary Paget's disease of the scrotum: treatment with topical 5-fluorouracil and plastic surgery.  Br J Dermatol 1994;131 (3) 445- 446PubMedGoogle ScholarCrossref
Del Castillo  LFGarcia  CSchoendorff  CGarcia  JFTorres  LMGarcia Almagro  D Spontaneous apparent clinical resolution with histologic persistence of a case of extramammary Paget's disease: response to topical 5-fluorouracil.  Cutis 2000;65 (5) 331- 333PubMedGoogle Scholar
Watring  WGRoberts  JALagasse  LD  et al.  Treatment of recurrent Paget's disease of the vulva with topical bleomycin.  Cancer 1978;41 (1) 10- 11PubMedGoogle ScholarCrossref
Thirlby  RCHammer  CJ  JrGalagan  KATravaglini  JJPicozzi  VJ  Jr Perianal Paget's disease: successful treatment with combined chemoradiotherapy: report of a case.  Dis Colon Rectum 1990;33 (2) 150- 152PubMedGoogle ScholarCrossref
Kariya  KTsuji  TSchwartz  RA Trial of low-dose 5-fluorouracil/cisplatin therapy for advanced extramammary Paget's disease.  Dermatol Surg 2004;30 (2, pt 2) 341- 344PubMedGoogle Scholar
Watanabe  YHoshiai  HUeda  HNakai  HObata  KNoda  K Low-dose mitomycin C, etoposide, and cisplatin for invasive vulvar Paget's disease.  Int J Gynecol Cancer 2002;12 (3) 304- 307PubMedGoogle ScholarCrossref
Yamazaki  NYamamoto  AWada  TIshikawa  MMoriya  YNakanishi  Y A case of metastatic extramammary Paget's disease that responded to combination chemotherapy.  J Dermatol 1999;26 (5) 311- 316PubMedGoogle Scholar
Becker-Wegerich  PMFritsch  CSchulte  KW  et al.  Carbon dioxide laser treatment of extramammary Paget's disease guided by photodynamic diagnosis.  Br J Dermatol 1998;138 (1) 169- 172PubMedGoogle ScholarCrossref
Lai  YLYang  WGTsay  PKSwei  HChuang  SSWen  CJ Penoscrotal extramammary Paget's disease: a review of 33 cases in a 20-year experience.  Plast Reconstr Surg 2003;112 (4) 1017- 1023PubMedGoogle ScholarCrossref
Louis-Sylvestre  CHaddad  BPaniel  BJ Paget's disease of the vulva: results of different conservative treatments.  Eur J Obstet Gynecol Reprod Biol 2001;99 (2) 253- 255PubMedGoogle ScholarCrossref
Valentine  BHArena  BGreen  E Laser ablation of recurrent Paget's disease of vulva and perineum.  J Gynecol Surg 1992;8 (1) 21- 24PubMedGoogle ScholarCrossref
Zollo  JDZeitouni  NC The Roswell Park Cancer Institute experience with extramammary Paget's disease.  Br J Dermatol 2000;142 (1) 59- 65PubMedGoogle ScholarCrossref
Raspagliesi  FFontanelli  RRossi  G  et al.  Photodynamic therapy using a methyl ester of 5-aminolevulinic acid in recurrent Paget's disease of the vulva: a pilot study.  Gynecol Oncol 2006;103 (2) 581- 586PubMedGoogle ScholarCrossref
Shieh  SDee  ASCheney  RTFrawley  NPZeitouni  NCOseroff  AR Photodynamic therapy for the treatment of extramammary Paget's disease.  Br J Dermatol 2002;146 (6) 1000- 1005PubMedGoogle ScholarCrossref
Ho  S-AJEAw  DC Extramammary Paget's disease treated with topical imiquimod 5% cream.  Dermatol Ther 2010;23 (4) 423- 427PubMedGoogle ScholarCrossref
Qian  ZZeitoun  NCShieh  SHelm  TOseroff  AR Successful treatment of extramammary Paget's disease with imiquimod.  J Drugs Dermatol 2003;2 (1) 73- 76PubMedGoogle Scholar
Vereecken  PAwada  AGhanem  G  et al.  A therapeutic approach to perianal extramammary Paget's disease: topical imiquimod can be useful to prevent or defer surgery.  Med Sci Monit 2007;13 (6) CS75- CS77PubMedGoogle Scholar
Badgwell  CRosen  T Treatment of limited extent extramammary Paget's disease with 5 percent imiquimod cream.  Dermatol Online J 2006;12 (1) 22PubMedGoogle Scholar