Treatment of extramammary Paget disease with topical imiquimod cream: case report and literature review.

Abstract: Extramammary Paget disease is an uncommon cutaneous neoplasm that presents as erythematous plaques most frequently located in the anogenital region. Management of patients with extramammary Paget disease involves evaluation of the individual for: (1) a disease-associated, unsuspected, visceral malignancy and (2) secondary adenocarcinoma in the underlying dermis or regional lymph nodes. Several modalities, each with variable effectiveness, are available to treat the cutaneous component of the disease: electrodesiccation and curettage, laser surgery, aminolevulinic acid photodynamic therapy, radiotherapy, topical chemotherapy, and wide surgical excision. However, surgical excision using the Mohs micrographic technique is currently the modality of choice for treating the cutaneous lesions of extra-mammary Paget disease. Recently, a topical imidazoquinoline immunomodulator that induces cytokine production and stimulates the innate and cellular immune responses--imiquimod cream--has been used for the management of primary or relapsing extramammary Paget disease. Complete healing, without recurrence, of extramammary Paget disease in patients whose cutaneous lesions were treated topically with imiquimod 5% cream was observed. We describe a man with suprapubic extramammary Paget disease whose condition was primary and limited to his skin. Biopsy-confirmed complete resolution of his disease was observed after the topical application of imiquimod 5% cream 3 times per week (on alternate days) for 16 weeks. After reviewing the published reports of other patients with extramammary Paget disease whose disease was successfully treated with imiquimod cream, we suggest that topical imiquimod 5% cream--at least 3 times per week (with 1-2 d of nontreatment in between) for a minimum of 8 to 16 weeks--be considered as an initial treatment for primary cutaneous extramammary Paget disease. Surgical excision or an alternative therapeutic modality is recommended for patients whose extramammary Paget disease persists or recurs after treatment with topical imiquimod.

Key Words: acid, aminolevulinic, buttock, cream, curettage, disease, electrodesiccation, excision, extramammary, groin, imiquimod, inguinal, mammary, meatus, micrographic, Mohs, Paget, penile, penis, perineal, perineum, photodynamic, pubic, scrotum, shaft, suprapubic, surgery, thigh, topical, therapy, treatment, urethra, urethral, vulva, wide

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Extramammary Paget disease is an uncommon cutaneous neoplasm. It usually affects the anogenital skin of older individuals and typically presents as erythematous to gray-white, often asymptomatic, sharply demarcated plaques. The cutaneous lesions may be crusted, eczematous, papillomatous, scaling, or ulcerated. (1,2)

Imiquimod is a topically applied imidazoquinoline immunomodulator that induces cytokine production and stimulates the innate and cellular immune responses. The Food and Drug Administration initially approved imiquimod for the treatment of genital warts in 1997. Subsequently, imiquimod has been approved for the treatment of actinic keratoses and superficial basal cell carcinomas. (3-7)

We report the case of a man with suprapubic extramammary Paget disease, limited to his skin, who underwent successful treatment with topical imiquimod 5% cream. We also review reports of other patients with extramammary Paget disease who were treated with this therapy. (8-17)

Case Report

A 75-year-old white male presented with an asymptomatic lesion of nearly one year duration on the skin of his groin area. Cutaneous examination showed a 2.0 X 1.5 cm erythematous plaque in the right suprapubic region (Fig. 1). Microscopic evaluation of a lesional skin biopsy showed a proliferation of atypical epithelial cells along the basal layer with prominent epidermal permeation (Fig. 2). The cytoplasm of the atypical cells was stained with periodic acid-Schiff stain, confirming the diagnosis of extramammary Paget disease.

An investigation for an underlying visceral malignancy or nodal involvement was negative. Inguinal lymphadenopathy was absent. Colonoscopy detected a sessile polyp in the sigmoid colon; it was removed and was histologically benign. Atypical cells were not observed on urine cytology; cystoscopy was negative for tumor. Ultrasound of the kidneys and testes showed bilateral renal cysts, renal cortical loss (compatible with age), varicoceles in the left testis, and bilateral small hydroceles.

Surgical and medical treatment options for the patient's primary and limited cutaneous extramammary Paget disease were considered. Prompted by the resolution of extramammary Paget disease in patients whose cutaneous lesions had been treated topically with imiquimod cream, (8-17) treatment with this agent was initiated. The 5% cream was applied 3 times each week on alternate evenings. Within 2 weeks after starting therapy, the lesional area became erythematous; from the third to eighth week of treatment, erythema of the right suprapubic area was prominent. Treatment site erythema markedly improved after 9 weeks of therapy. Topical treatment was continued for a total of 16 weeks.

After completion of topical treatment with imiquimod 5% cream, a 1.5 X 1.2 cm firm violaceous plaque with surrounding macular hyperpigmentation was present at the previous extramammary Paget disease site (Fig. 3). To determine if residual extramammary Paget disease was present, a shave biopsy was performed that completely sampled this area. Microscopic evaluation showed normal-appearing epidermis and dermis (Fig. 4); scar was noted in the center of the specimen where the initial biopsy had been performed (Fig. 5). The periodic acid-Schiff stain did not demonstrate cytoplasmic staining of the cells in the epidermis.

There has been no recurrence of the patient's cutaneous extramammary Paget disease on the follow-up examinations during the subsequent 9 months after treatment was discontinued.

Discussion

Extramammary Paget disease may occur in four clinical settings: (1) as a primary--isolated and limited--cutaneous form with only intraepidermal involvement, (2) as a primary intraepidermal disease with secondary adenocarcinoma present in the underlying dermis or regional lymph nodes, (3) as a secondary skin disease arising from an underlying adnexal carcinoma, and (4) as a cutaneous (epidermal or combined epidermal and dermal) disease associated with internal malignancy. (1,8) Therefore, workup of extramammary Paget disease patients should include a full skin examination, palpation of all lymph nodes, rectal examination, sigmoidoscopy or colonoscopy, and cystoscopy; a pelvic examination with a Papanicolaou test, breast examination, and colposcopy should also be performed in women. (2) Our patient's extramammary Paget disease was localized to a small area above his pubic region and was not associated with either a contiguous invasive cancer or a disease-related systemic malignancy.

The diagnosis of extramammary Paget disease may not initially be suspected. Not only the morphology, but also the location of the lesion can mimic other conditions such as chronic candidal intertrigo, dermatitis (contact, irritant, or seborrheic), dermatophyte-related tinea cruris, psoriasis vulgaris (inverse), and squamous cell carcinoma in situ (Bowen disease). (2,8-12,15,16) However, extramammary Paget disease lesions do not improve after topical or systemic antifungal medications or corticosteroids.

Microscopic evaluation, to confirm the diagnosis, shows varying degrees of hyperkeratosis, acanthosis, and parakeratosis accompanied by a diffuse infiltration of large vacuolated pale staining cells, often with a bluish cytoplasm predominantly found in the lower layers of the epidermis; they can also be present in the epithelium of the underlying adnexal structures. The cells are referred to as "Paget cells" and their abundant cytoplasm contains sialomucin, a nonsulfated acid monopolysaccharide which stains positive with aldehydefuschin at pH 1.7, Alcian blue at pH 2.5, colloidal iron, mucicarmine, periodic acid-Schiff (PAS), and zirconyl hematoxylin. In addition, immunohistochemistry studies reveal that Paget cells typically demonstrate positive staining for CAM 5.2, carcinoembryonic antigen, cytokeratin 7, epithelial membrane antigen, and gross cystic disease fluid protein. (18,19)

The treatment of choice for extramammary Paget disease is surgical excision--optimally incorporating the Mohs micrographic technique. (8,9,14,17,20,21) However, single reports and case studies describe variable results when extramammary Paget disease has been treated with alternative therapeutic modalities including electrodesiccation and curettage, (8) laser surgery, (8,9,14,16) photodynamic therapy with aminolevulinic acid, (8,14) radiotherapy, (8,14) and topical chemotherapy with either bleomycin or 5-fluorouracil. (8,14,22) Recently, immunotherapy with topical imiquimod 5% cream has been successfully used to treat extramammary Paget disease.

The immunoregulatory effects of imiquimod result from its ability to bind to the Toll-like receptor 7 on the cell surface of dendritic cells, macrophages, and monocytes. After these cells have been activated, they release proinflammatory chemokines (interleukins 1, 6, 8, and 10) and cytokines (interferon-alpha, interleukin 12, and tumor necrosis factor-alpha). Subsequently, there is stimulation of T-helper cell Type 1 cytokines (including interferon-gamma), activation of other cell-mediated immune responses, and inhibition of T-helper cell Type 2 cytokines (including interleukins 4 and 5). (3-7,23,24)

Imiquimod may also have direct antineoplastic activity. Recent studies have demonstrated that imiquimod promotes induction of apoptosis in basal cell carcinoma cells. (7) However, the specific mechanism of action whereby imiquimod promotes tumor eradication in extramammary Paget disease remains to be determined.

Successful management of previously untreated (8,13,15,16) (also current report) or recurrent (8-12,14,17) extramammary Paget disease after topical treatment with imiquimod 5% cream, including our patient, has been reported in 9 individuals, 8 men and 1 woman (Table) (8-17). They ranged in age from 57 years to 84 years (mean = 72 yr, median = 73 yr).

Extramammary Paget disease was primary and limited to the epidermis in 7 of the patients, (8,13,14-17) (also current report). Two men had primary cutaneous extramammary Paget disease with secondary adenocarcinoma in the underlying dermis, regional lymph nodes or both. "Dermal microinvasion with rare, atypical, CAM 5.2-positive cells" without nodal involvement was detected microscopically in one patient (9-12) and infiltrative apocrine adenocarcinoma was discovered not only in the disease-related nodular mass but also in the sentinel lymph node in another patient. (15) None of the patients had an associated underlying visceral malignancy.

[FIGURE 1 OMITTED]

The lesions of extramammary Paget disease were located in the suprapubic region, pubic area, groin, buttocks, thighs and perineum--including the penile shaft and urethral meatus, the scrotum, and the vulva. They ranged in size from 2.0 X 1.5 cm to 14 X 23 cm. Similar to our patient, the lesions of extramammary Paget disease can be asymptomatic. However, some of the patient's lesions were pruritic, (8,13,17) painful (16) or burning. (8,17)

Lesions of extramammary Paget disease usually appeared as patches of macular erythema, (14,16) an "erythematous eruption", (13) or erythematous papules and plaques, (8,15,16) current report. Scaling was occasionally present. (8,14,15) One patient developed a disease-related central, raised, nodular mass which was surrounded by erythematous scaling plaques of cutaneous extramammary Paget disease. (15) It was not uncommon for the lesion morphology to mimic other dermatoses such as Candidiasis, (15,16) contact dermatitis, (16) or an "eczematous eruption." (9-12) In addition, in one patient, a coexisting condition was present in the same cutaneous lesion: a biopsy-confirmed concurrent dermatophyte infection. (8)

[FIGURE 2 OMITTED]

Topical therapy with imiquimod cream was applied from 3 to 7 times each week. Frequently, the patients experienced a localized inflammatory response which occurred one (8,17) to five, (9-12,13) (also current report) weeks after starting therapy; this occurred more frequently when the cream was applied once daily and resolved after withdrawal of the therapy, with a short rest period before restarting treatment at less frequent intervals, such as 2 or 3 times per week with 1 or 2 days between therapy. (8,17) Improvement was usually noted between 6 to 9 weeks after initiating treatment (8-15,17) (also current report). Treatment duration ranged from 4 to 17 weeks.

[FIGURE 3 OMITTED]

Complete healing, without recurrence, of the cutaneous extramammary Paget disease was noted in seven patients whose disease was treated with topical imiquimod 5% cream: three patients with previously untreated extramammary Paget disease (6,13) (also current report) and four patients whose disease was recurrent following various initial treatments such as aminolevulinic acid photodynamic therapy, (14) electrodes-iccation and curettage, (8) surgical excision using the Mohs micrographic technique, (9-12) and wide surgical excision. (17) Post-treatment skin biopsies of the clinically resolved area of prior extramammary Paget disease were performed in 6 of these patients and provided histologic confirmation of disease resolution (8,13,14,17) (also current report). The disease-free follow-up ranged from 2 to 14 months (mean = 8.5 months, median = 9 months).

[FIGURE 4 OMITTED]

A partial response to imiquimod after topical treatment of extramammary Paget disease was observed in two patients. (15,16) One of the individuals, whose extramammary Paget disease included not only primary cutaneous disease but also contiguous adenocarcinoma in the dermis and sentinel lymph node, "had cleared almost completely" after 8 weeks of therapy; his treatment was discontinued because "there was some irritation to the area" and subsequent follow-up was not reported. (15) The second patient had several areas of extramammary Paget disease involving his buttocks, thighs, penis, scrotum, and pubic area; although some of these areas had biopsy-confirmed remission of Paget disease, "the response did not include all areas." (16)

Surgical excision is considered to be the principle treatment for extramammary Paget disease--with or without prior sequential topical application of 5-fluorouracil to enhance the subclinical delineation of the disease. (20-22) Recently, the efficacy of incorporating the Mohs micrographic surgical technique with microscopic examination of all excision margins, as compared with wide excision, has been reviewed. (20,21) However, the current availability of the topical immunomodulator imiquimod presents the option for an alternative approach to the management of extramammary Paget disease.

Based on our review of the currently published reports of extramammary Paget disease patients whose disease has been successfully treated with imiquimod cream, we suggest that topical application of imiquimod may be considered as an initial treatment of primary cutaneous extramammary Paget disease. We recommend topical therapy with imiquimod 5% cream at least 3 times each week (on alternate days) for a minimum of 8 weeks, and as long as 16 weeks, of treatment. At the conclusion of topical imiquimod treatment, clinical examination and possible microscopic evaluation of the treated lesional area should be performed. Periodic follow-up to assess the patient for recurrence is recommended in disease-free individuals. If complete resolution of cutaneous disease has not been achieved, either surgical excision or an alternative therapeutic modality should be initiated.

[FIGURE 5 OMITTED]

Conclusion

Extramammary Paget disease has successfully been treated with topical imiquimod. Yet, this observation requires conservative optimism since imiquimod treatment of extramammary Paget disease has only been described in a small number of case reports. It would be useful to further validate these promising observations through a properly conducted clinical trail which not only evaluates the efficacy of imiquimod treatment, but also the frequency and duration of therapy. Long-term periodic follow up evaluating these patients for recurrent cutaneous disease, coinciding underlying invasive carcinoma, or potentially associated visceral malignancy is essential. However, the dramatic improvement after topical imiquimod therapy in these individuals prompts consideration for the initial use of this modality--either as monotherapy or as an adjunctive treatment before subsequent surgical intervention or other modalities for persistent disease.

References

1. Chaudhuri SP, Smoller BR. Extramammary Paget's disease: diagnosis and disease pattern. Cutis 1992;50:195-196.

2. Heymann WR. Extramammary Paget's disease. Clin Dermatol 1993;11:83-87.

3. Sauder DN, Mofid MZ. Topical immunotherapy: what's new. Dermatol Clin 2005;23:245-258.

4. Hengge UR, Ruzicka T. Topical immunomodulation in dermatology: potential of toll-like receptor agonists. Dermatol Surg 2004;30:1101-1112.

5. Dahl MV. Imiquimod: a cytokine inducer. J Am Acad Dermatol 2002;47:S205-S208.

6. Miller R. Imiquimod stimulates innate and cell mediated immunity which controls virus infections and tumors. Int J Dermatol 2002;41(Suppl 1):3-6.

7. Navi D, Huntley A. Imiquimod 5 percent cream and the treatment of cutaneous malignancy. Dermatol Online J 2004;10(1):4.

8. Zampogna JC, Flowers FP, Roth WI, Hassenein AM. Treatment of primary limited cutaneous extramammary Paget's disease with topical imiquimod monotherapy: two case reports. J Am Acad Dermatol 2002;47(Suppl 4):S229-S235.

9. Berman B, Spencer J, Villa A, et al. Successful treatment of extramammary Paget's disease of the scrotum with imiquimod 5% cream. Clin Exp Dermatol 2003;28(Suppl 1):36-38.

10. Berman B, Poochareon VN, Villa AM. Novel dermatologic uses of the immune response modifier imiquimod 5% cream. Skin Therapy Lett 2002;7(9):1-6.

11. Berman B, Spencer J, Villa A, Poochareon V, Elgart G. Successful Treatment of Extramammary Paget's Disease of the Scrotum With Imiquimod 5% Cream. European Academy of Dermatology Meeting, October 2002, Prague, Czech Republic.

12. Spencer J, Berman B. Successful Treatment of Recurrent Extramammary Paget's Disease. Abstracts for the 3rd Combined Annual Meeting of the American Society of Dermatologic Surgery and American College of Mohs Micrographic Surgery and Cutaneous Oncology, October 30, 2002, p 190, Chicago, IL.

13. Hieken TJ, Lasser A. Successful nonoperative treatment of extensive extramammary Paget's disease: 2005 ASCO Annual Meeting Proceedings. J Clin Oncol 2005;23(16S):2584.

14. Qian Z, Zeitoun NC, Shieh S, et al. Successful treatment of extramammary Paget's disease with imiquimod. J Drugs Dermatol 2003;2:73-76.

15. Wasserman J. Presentation at the Annual Meeting of the Florida Society of Dermatologic Surgeons, 2004, Florida. Cited in McNamara D: Case of the month. Skin & Allergy News 2005;36(1):1,51.

16. Bamford J, Seidelmann S. Clinical and immunologic response of extramammary Paget's disease to imiquimod. [Abstract 888] J Invest Dermatol 2001;117:537.

17. Wang LC, Blanchard A, Judge DE, et al. Successful treatment of recurrent extramammary Paget's disease of the vulva with topical imiquimod 5% cream. J Am Acad Dermatol 2003;49:769-772.

18. Guarner J, Cohen C, De Rose PB.. Histogenesis of extramammary and mammary Paget cells: an immunohistochemical study. Am J Dermatopathol 1989;11:313-318.

19. Smith AA, Silver TM. Zirconyl hematoxylin vs alcian blue staining in a case of extramammary Paget's disease. J Cutan Pathol 2003;30:401-404.

20. Hendi A, Brodland DG, Zitelli JA. Extramammary Paget's disease: surgical treatment with Mohs micrographic surgery. J Am Acad Dermatol 2004;51:767-773.

21. O'Connor, WJ, Lim KK, Zalla MJ, et al. Comparison of Mohs micrographic surgery and wide excision for extramammary Paget's disease. Dermatol Surg 2003;29:723-727.

22. Eliezri YD, Silvers DN, Horan DB. Role of preoperative topical 5-fluorouracil in preparation for Mohs micrographic surgery of extramammary Paget's disease. J Am Acad Dermatol 1987;17:497-505.

23. Chang YC, Madkan V, Cook-Norris R, et al. Current and potential uses of imiquimod. South Med J 2005;98:914-920.

24. Wooten JM. Imiquimod [Editorial]. South Med J 2005;98:852.

Discontent is the first necessity of progress.
--Thomas Edison

Philip R. Cohen, MD, Keith E. Schulze, MD, Jaime A. Tschen, MD, George W. Hetherington, MD, and Bruce R. Nelson, MD

From the Dermatologic Surgery Center of Houston, Houston, TX; the Department of Dermatology, University of Texas, Houston Medical School, Houston, TX; St. Joseph Dermpath, Bellaire, TX; the Department of Dermatology, Baylor College of Medicine, Houston, TX; and Private Practice, Houston, TX.

Reprint requests to Bruce R. Nelson, MD, 6655 Travis, Suite 840, Houston, TX 77030.

Presented, in part, at the Zola Cooper Clinical and Dermatopathologic Seminar at the 99th Annual Scientific Assembly of the Southern Medical Association from November 10-13, 2005 in San Antonio, TX.

Accepted January 5, 2006.

RELATED ARTICLE: Key Points

* Extramammary Paget disease is an uncommon cutaneous neoplasm that presents as erythematous plaques most frequently located in the anogenital region.

* Imiquimod is a topically applied imidazoquinoline immunomodulator that induces cytokine production and stimulates the innate and cellular immune responses.

* Cutaneous lesions of extramammary Paget disease can mimic other conditions such as chronic candidal intertrigo, dermatitis (contact, irritant, or seborrheic), dermatophyte-related tinea cruris, psoriasis vulgaris (inverse), and squamous cell carcinoma in situ (Bowen disease).

* The treatment of choice for extramammary Paget disease is surgical excision--optimally incorporating the Mohs micrographic technique; however, immunotherapy with topical imiquimod 5% cream has recently been successfully used to treat extramammary Paget disease.

* Topical application of imiquimod 5% cream may be considered as an initial treatment of primary cutaneous extramammary Paget disease: at least three times each week (on alternate days) for a minimum of eight weeks, and as long as 16 weeks.

* Surgical excision, or an alternative therapeutic modality, is recommended for patients whose extramammary Paget disease persists or recurs after treatment with topical imiquimod.

Table. Characteristics of patients whose extramammary Paget disease was
treated with imiquimod cream

      Age                                       Size
Case  (yr)  Sex  Race  Location                 (cm)     Form (a)

1     57    M    W     Scrotum                  3 X 5    PLC
2     68    M    W     Scrotum                  NS       PC/SDL (e)
3     69    M    W     Groin, perineum          NS       PLC
4     72    M    W     Inguinal area, perineum  NS       PLC
5     73    M    W     Penile shaft             NS       PLC
6     75    M    W     Suprapubic region        2 X 1.5  PLC
7     77    M    W     Groin                    (g)      PC/SDL (h)
8     84    M    NS    Buttock, penile shaft,   14 X 23  PLC
                         pubic area, scrotum,
                         thigh, urethral
                         meatus
9     75    F    W     Vulva                    NS       PLC

                                                  Disease
                                                  free post
      Onset     Imiquimod                         treatment
Case  (yr) (b)  treatment (c)        Response     (mos)      Reference

1      4        17 wks (d)           CR Bx--      12         8, Case 1
2      4        Qd X 6 wks           CR            6         9-12
3      0.50     10 wks (f)           CR Bx--       8         13
4     10        Qod X 7.5 wks        CR Bx--       2         8, Case 2
5      7.25     3 X per wk X 6 wks   CR Bx--      14         14
6      1        3 X per wk X 16 wks  CR Bx--       9         Current
                                                             Report
7      0.17     3 X per wk X 8 wks   PR (i)        0         15
8      9        12 wks (j)           PR (k) Bx--   0         16
9      1        6 wks (l)            CR Bx--      NS         17

(a) The form of EMPD that the patient had. None of the patients had an
EMPD-associated visceral malignancy.
(b) The number of years that EMPD was present prior to the initiation of
treatment with imiquimod cream.
(c) One patient (case 7) was treated with imiquimod 1% cream; all of the
other patients were treated with imiquimod 5% cream.
(d) The 17 weeks of treatment initially included treatment every evening
X 6 evenings; after stopping treatment for 4 days, treatment was
restarted every other evening X 16 weeks.
(e) In addition to cutaneous EMPD that was localized to the epidermis,
dermal microinvasion with rare, atypical CAM 5.2 positive staining cells
was also noted.
(f) "The patient completed a 10 week course of therapy, with one mid-
course break for 10 days secondary to erythema, irritation and
discomfort of the adjacent scrotum. He had no systemic symptoms or
hematologic from treatment."
(g) There was a 10 [cm.sup.2] area of erythema surrounding a 1 X 1 cm
nodule.
(h) The nodule and sentinel node pathology both showed an infiltrative
apocrine adenocarcinoma.
(i) After 8 weeks of treatment, "there was some irritation to the area"
and "the patient was instructed to discontinue imiquimod for 6 wks; the
rash had cleared almost completely except for a small area in the left
lateral edge." No additional details or follow up were reported.
(j) The frequency of imiquimod cream was not reported.
(k) After treatment, "clinically there was the appearance of a
postinflammatory erythema and microscopically a complete histologic
remission of Paget's disease." "The response did not include all areas.
Unresolved smaller plaques of Paget's disease (about 2 X 3 [cm.sup.2])
were treated with C[O.sub.2] laser ablation."
(l) Treatment occurred during 8 weeks; initially every evening X 6
evenings. After stopping treatment for 4 days, treatment was restarted
every other evening X 2 treatments. After a "short rest period,"
treatment restarted at 2 times per week and eventually 3 times per week
for the final 5 weeks of treatment.
Bx--, biopsy negative for EMPD post treatment; CR, complete response;
EMPD, extramammary Paget disease; F, female; M, male; NS, not stated;
PC/SDL, primary cutaneous EMPD and secondary adenocarcinoma in the
underlying dermis or regional lymph nodes; PLC, primary and limited
cutaneous EMPD; PR, partial response; Qd, every day; Qod, every other
day; W, white.