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

Extramammary Paget's disease (EMPD) is an uncommon skin neoplasm that usually affects the elderly population and occurs in the genital, anorectal, or axillary areas. The recommended treatment of EMPD involves surgical excision, including Mohs micrographic surgery; however, surgery is associated with a high rate of recurrence. There have been reports of successful treatment of recurrence with monochemotherapy involving topical imiquimod 5% cream. We report a case of EMPD recurrence after surgery that was resistant to imiquimod monotherapy but that completely resolved after imiquimod was combined with topical 5-fluorouracil (5-FU) and retinoic acid. To our knowledge, this is the first reported case of imiquimod combination therapy with 5-FU and retinoic acid for the treatment of recurrent EMPD.     

Imiquimod 5% cream as a therapeutic option for extramammary Paget's disease

A wide local excision is the standard treatment for extramammary Paget's disease (EMPD), though this treatment often leads to permanent anogenital mutilation and functional impairment. The purpose of our study is to evaluate the efficacy and safety of the topical application of imiquimod 5% cream for non‐invasive EMPD. We examined nine patients with EMPD. Eight of the nine patients were treated with imiquimod 5% cream three times per week for 16 weeks; one case was treated for 6 weeks. The response rate was 100% including five complete remissions. Local irritation was observed in three patients, which was controlled by a provisional withdrawal of the treatment. These results suggest that imiquimod 5% cream may be considered an alternative therapeutic option for the treatment of non‐invasive EMPD.     

Extramammary Paget's disease treated with topical imiquimod 5% cream

Extramammary Paget's disease (EMPD) is a rare cutaneous, intraepithelial adenocarcinoma usually found in the apocrine gland bearing areas. It is traditionally treated with surgery but has a high rate of recurrence. Of late, topical imiquimod 5% cream has come into use as another treatment option. We present two cases of EMPD in Asian skin treated successfully with topical imiquimod 5% cream.     

Extramammary Paget disease successfully treated with topical imiquimod 5% and tazarotene

Extramammary Paget disease (EMPD) is an intraepithelial adenocarcinoma usually localized in areas rich in apocrine sweat glands. Surgery remains the treatment of choice for EMPD. However, several nonsurgical treatments have been also described. Around 40 cases of EMPD treated with imiquimod 5% have been published; of these, only six correspond to nonresponses. We describe a recurrent vulvar EMPD with failure to respond to topical imiquimod 5% in monotherapy but a favorable response to its association with tazarotene.     

Treatment of limited extent extramammary Paget's disease with 5 percent imiquimod cream

Extramammary Paget's disease (EMPD) is a rare neoplastic condition of apocrine gland-bearing skin, which may be associated with internal malignancy. Although surgical excision is the generally accepted standard of care for EMPD, treatment with topical imiquimod 5 percent cream has reportedly been efficacious in clearing lesions. We report the case of a 78-year-old woman with biopsy-proven EMPD of the thigh treated successfully with imiquimod application thrice weekly for 16 weeks.     

Extramammary Paget disease

We report the case of a 60-year-old man with penile-scrotal extramammary Paget disease (EMPD). The patient initially underwent Mohs micrographic surgery, but the margins remained positive after several sections; multiple scouting punch biopsies used to define the extent of the tumor were also positive. Because of concerns about functional impairment and cosmesis associated with wide local excision, the patient instead chose treatment with topical 5 percent imiquimod cream as a cytoreductive and margin-defining treatment. Owing to the association between EMPD and underlying malignant conditions, a thorough metastatic evaluation is necessary, particularly to rule out genitourinary cancer in the setting of penile-scrotal EMPD. Management of EMPD is complicated by the multifocal, non-contiguous nature of the disease and the presence of clinically occult extensions. As a result, recurrence rates after surgery are high. Several non-surgical modalities have been used to treat EMPD, which include radiotherapy, topical imiquimod, topical 5-fluorouracil, topical bleomycin, photodynamic therapy, CO2 laser ablation, and topical retinoids. Systemic chemotherapy also has been used to treat advanced EMPD. However, because EMPD is so uncommon, clinical trials comparing the various methods of treatment are lacking. Regardless of the mode of treatment, long-term follow up is essential, given the high rate of recurrence.     

Extramammary Paget Disease: Minimal Surgical Therapy

Background

Extramammary Paget disease (EMPD) is an uncommon malignant neoplasm affecting apocrine gland-bearing skin which usually occurs in the anogenital area of patients older than 50 years. Although Mohs micrographic surgery (MMS) is recommended for the treatment of EMPD, wide local excision has also been performed by many other surgeons including dermatosurgeons. However, the extent of an adequate resection margin is still under debate.

Objective

The efficacy of minimal surgical therapy consisting of a wide excision combined with preoperative multiple scouting biopsies and postoperative topical imiquimod was investigated for the treatment of EMPD in Korean patients.

Methods

Between 2006 and 2012, 10 patients with primary EMPD were treated with wide surgical excision, with a surgical margin of less than 2.5 cm. Multiple preoperative scouting biopsies and postoperative topical imiquimod were also performed to delineate the lesional boundaries and to reduce the recurrence rate.

Results

During the 6-year follow-up period, complications and recurrences were not observed.

Conclusion

Minimal surgical therapy may be an effective alternative when MMS is unavailable.     

Efficacy of imiquimod 5% cream in the treatment of recalcitrant warts in children

Long-lasting cutaneous warts are a therapeutic challenge, especially widespread or symptomatic recalcitrant warts in children. It can be speculated that natural immunity to these human papillomavirus (HPV)- induced lesions is extremely poor. Therefore ideally treatment should focus on increasing local immune response. Recently imiquimod, a topical immune modifier, has been successfully used in the treatment of external genital warts. Our purpose is to report on our experiences with imiquimod 5% cream applied to therapy-resistant, long-lasting (duration 2-7 years) common warts in children. In 18 children, imiquimod cream was self-applied by the patients or by their parents to the warts twice a day. Assessment for response and occurrence of adverse effects was performed every 4 weeks until clinical cure. Follow-ups could be arranged in 14 of the 18 patients 1-2 years after total clearance. Sixteen of 18 patients experienced total clearance of their warts; 2 showed partial improvement but were lost to follow-up. The mean duration of treatment was 5.8 months. Two of the 14 patients in whom a follow-up was performed showed a small number of new warts after a period of at least 1 year without recurrence. Our data demonstrate that the topical application of imiquimod 5% cream is an effective treatment for long-lasting cutaneous warts in children.     

Spontaneous apparent clinical resolution with histologic persistence of a case of extramammary Paget's disease: response to topical 5-fluorouracil

An 86-year-old woman presented with a 3-year history of an erythematous axillary lesion, which was histologically confirmed to be extramammary Paget's disease (EMPD) confined to the epidermis and adnexa. Surprisingly, spontaneous clinical regression occurred in the lesion, but Paget's cells persisted within the epidermis and adnexa on histologic examination. One year of intermittent topical chemotherapy with 5-fluorouracil resulted in ulcers that were interpreted as EMPD and completely excised. Histologic examination showed a complete absence of Paget's cells. To our knowledge, only one previous report investigated apparent spontaneous clinical resolution with histologic persistence of EMPD. We emphasize that topical 5-fluorouracil cannot be considered a safe treatment modality for EMPD, but it may be useful in certain cases in which the extent of the lesions, or the general condition of the patient, advise against surgery or radiotherapy.     

Characterization of the cellular infiltrate during successful topical treatment of lentigo maligna with imiquimod

Lentigo maligna (LM) is an in situ melanoma which usually occurs in sun-damaged skin on the head and neck of elderly patients. Depending on the anatomical site and its size treatment of LM can be problematic and usually includes surgical excision or radiotherapy. Recent reports indicate that topical imiquimod may be an effective treatment. However, no data on the underlying immune response in the skin during treatment of LM with topical imiquimod are available so far. We report a 62-year-old caucasian woman with a histologically verified LM which was successfully treated with topical imiquimod 5% cream. Skin biopsy specimens were obtained before, during (at week 10) and 4 weeks after cessation of topical treatment with imiquimod 5% cream. Histological and immunohistochemical examination was performed in order to detect residual atypical melanocytes and to characterize the inflammatory infiltrate. A complete clinical and histological clearance of the skin lesion was achieved, with no recurrence up to 9 months after the end of treatment. During topical application of imiquimod 5% cream a depletion of epidermal and dermal CD1a+ dendritic cells was observed. The inflammatory infiltrate consisted of CD68+ macrophages and mainly of CD3+ T cells with a slight predominance of CD8+ T cells. An enhanced expression of granzyme B and TIA-1 was also noted particularly in the epidermis and near the dermoepidermal junction. In conclusion, our data indicate that imiquimod 5% cream induces a cytotoxic T-cell-mediated immune response in situ which may account for the complete destruction of the malignant melanocytes in LM. Further clinical trials and longer follow-up periods on the use of imiquimod for LM are warranted.     

Topical Imiquimod for the Treatment of Childhood Cutaneous Langerhans Cell Histiocytosis

Although topical steroids are considered first‐line treatment for cutaneous Langerhans cell histiocytosis (LCH), the appropriate therapy for refractory cases remains controversial. We report a 16‐month‐old girl with isolated cutaneous LCH refractory to treatment with topical corticosteroids and topical tacrolimus. Treatment was initiated with 5% topical imiquimod cream and the rash completely resolved after 5 months of therapy. There was no disease recurrence after more than 2 years of follow‐up. We present this case to highlight imiquimod as a novel therapeutic agent for the management of isolated cutaneous LCH in children.     

The use of topical imiquimod for the treatment of actinic keratosis: a status report

Topical imiquimod 5% cream is approved for the treatment of actinic keratosis (AK), superficial basal cell carcinoma, and external genital warts. The drug's mechanism of action is via stimulation of innate and acquired immune responses, which ultimately leads to inflammatory cell infiltration within the field of drug application followed by apoptosis of diseased tissue. This article reviews available data on the use of topical imiquimod for AK. Topical imiquimod is an effective and safe treatment option for AK that produces complete eradication or marked reduction in the number of lesions in most patients. Subclinical lesions also emerge during treatment of the affected skin region ("field treatment"). In addition, there is evidence that topical imiquimod at least partially reverses some of the cellular, molecular, and genetic photocarcinogenic changes that develop in skin damaged by UV light. Recent evidence suggests that many patients who effectively are cleared of AK lesions after topical imiquimod use remain free of lesions for several months to 2 years or develop a minimal number of new AK lesions.     

Possible mechanisms in the induction of vitiligo-like hypopigmentation by topical imiquimod

The pathogenesis of vitiligo was examined for clues to the pigmentary changes that may occur after treatment with topical imiquimod. The literature varies on the pigmentary changes induced by topical use of imiquimod. The US Food and Drugs Administration lists 68 reports of pigmentary changes out of a total of 1257 reports related to imiquimod lodged from 1997 to 2003. Some studies describe vitiligo-like hypopigmentation associated with imiquimod treatment of genital warts (as with the patient described in this report), molluscum contagiosum, basal cell carcinoma, extramammary Paget's disease and murine melanoma. Other studies report hyperpigmentation associated with imiquimod. The possible mechanisms of hypopigmentation associated with imiquimod treatment are discussed, including antibodies found in sera of patients with vitiligo to nonpigment cell antigens, cytoplasmic pigment cell antigens and pigment cell-surface antigens; stimulation by imiquimod of both the innate immune response and cell-mediated adaptive immunity; and increased sensitivity of melanocytes to oxidative stress. The vitiligo-like hypopigmentation following topical imiquimod treatment is in line with the mode of action of this drug.     

Imiquimod and lentigo maligna: a search for prognostic features in a clinicopathological study with long-term follow-up

Background  Melanoma in situ /lentigo maligna (LM) is a potential precursor of LM melanoma. It occurs most commonly in elderly individuals on sun-exposed skin of the head and neck. Although surgical excision is the treatment of choice, this may not be desirable or feasible for large lesions at functionally or cosmetically important sites. Imiquimod is a topical immunomodulator which can generate a local cytotoxic response with potentially antiviral and antitumour effects.
Objectives  To present our experience of LM treated with imiquimod.
Methods  A retrospective review was performed of all patients with facial LM treated in our unit with topical imiquimod between January 2001 and December 2006. Pretreatment diagnostic biopsies were also reviewed and histologically graded.
Results  Forty-eight patients were treated with imiquimod. There were 37 responders and 11 treatment failures (of whom two were 'partial responders'). Of the 37 responders, 31 showed a clinical inflammatory response to imiquimod. One patient in whom treatment failed subsequently developed invasive disease. The mean follow-up duration was 49 months. We could not identify histological features of prognostic significance. However, the ability to develop an inflammatory reaction to imiquimod was a strong predictor of therapeutic benefit.
Conclusions  We consider imiquimod to have a role in the treatment of LM in patients in whom surgery may be contraindicated or for those in whom the cosmetic or functional consequences may be considerable. Until better characterized, its use should probably be confined to centres with experience in the detection and treatment of LM and melanoma.     

Perineal extramammary Paget disease responsive to topical imiquimod

Extramammary Paget disease (EMPD) is a rare neoplasm that arises in skin rich in apocrine glands, such as the axillae and anogenital region and usually affects the elderly. In most cases, EMPD is an apocrine carcinoma in situ, but it can be associated with internal malignancy spreading to overlying skin. Surgical excision with margin control is the generally accepted standard of care. A 74‐year‐old woman presented with a 1 year history of a pruritic eczematous eruption in perineum which on biopsy was diagnosed as EMPD. Because of the location and extent of the tumor, any surgical approach would have been problematic. Imiquimod 5% cream applied three times weekly for 16 weeks induced complete resolution. Topical imiquimod appears to be a promising treatment option for EMPD, especially when surgery is a challenge, but only a few cases have been reported.     

Porokeratosis of Mibelli: successful treatment with topical 5% imiquimod cream

A 77-year-old woman with a large porokeratosis of Mibelli on the left shin was successfully treated with topical 5% imiquimod cream applied to the entire lesion once daily without occlusion three times a week. A strong inflammatory reaction was achieved in 6 weeks of treatment. The lesion had been present for approximately 6 years and prior treatments included curettage and electrocautery, cryotherapy and topical 5-fluorouracil under occlusion. At the end of treatment with topical 5% imiquimod cream, punch biopsy was negative for porokeratosis. The lesion healed without scarring. At 24-month follow up there had been no sign of clinical recurrence.     

Increased number of mast cells in the dermis in actinic keratosis lesions effectively treated with imiquimod

Actinic keratosis (AK) is a cutaneous cancer in situ which develops as a result of excessive exposure to ultraviolet (UV). Toll‐like receptor (TLR)7 agonist imiquimod is a topical immune response modifier and is effective for the treatment of non‐melanoma skin cancers. Recently, the diagnostic role of the dermatoscope has been reported in the course of treatment of AK. In addition, mast cells are now considered to contribute to both the innate and adaptive immune systems in topical imiquimod therapy. We assessed the effect of imiquimod treatment by dermatoscopic and immunohistochemical findings in 14 patients with a total of 21 AK lesions. With the dermatoscope, though the mean erythema score was not significantly different between the cured lesions and the unresponsive lesions, the erythema/red pseudo‐network (“strawberry”) pattern was decreased significantly in the cured lesions. By immunohistochemistry, the number of Ki‐67‐positive proliferative cells in the epidermis was decreased and that of CD117‐positive mast cells in the dermis was increased in the responding lesions. To the best of our knowledge, this is the first study demonstrating that the number of mast cells in the dermis was increased in AK lesions effectively treated with imiquimod. Our present result suggests that mast cells may contribute an antitumor effect in human skin treated with topical imiquimod.     

Acantholytic pityriasis rubra pilaris associated with topical use of imiquimod 5%: case report and literature review

Topical use of immune response modifiers, such as imiquimod, has increased in dermatology. Although its topical use is well tolerated, it may be associated with exacerbations of generalized cutaneous inflammatory diseases, possibly through the systemic circulation of pro-inflammatory cytokines. This report describes a case of development of pityriasis rubra pilaris, a rare erythematous-papulosquamous dermatosis, in a woman aged 60 years during treatment with imiquimod 5% cream for actinic keratosis. It evolved with erythrodermic conditions and palmoplantar keratoderma, presenting progressive clinical resolution after the introduction of methotrexate. The authors emphasize the importance of recognizing possible systemic reactions associated with the topical use of imiquimod.     

Successful treatment of actinic keratosis with imiquimod cream 5%: a report of six cases

BACKGROUND: Actinic keratoses (AK) are premalignant lesions, which are routinely treated by destructive procedures such as cryotherapy, electrodessication or topical 5-fluorouracil. OBJECTIVES: The aim of this study is to report six cases of AK treated with a potential new topical therapy, imiquimod. METHODS: Subjects included in this study had suffered with recurrent AK for between 5 and 16 years. All six men were treated with imiquimod 5% cream three times a week for 6-8 weeks. In the event of a local skin reaction treatment was modified to two times per week. RESULTS: All the AK lesions were successfully cleared after treatment with imiquimod cream 5% for 6-8 weeks. Histologically, no apparent signs of persisting AK could be detected, and no recurrences were reported during follow up. CONCLUSIONS: This study suggests that imiquimod may be useful as a new therapy for the treatment of actinic keratoses.     

Photodynamic therapy for the treatment of extramammary Paget's disease

BACKGROUND: Surgical and ablative treatment modalities for extramammary Paget's disease (EMPD) have high recurrence rates and can be associated with significant morbidity. OBJECTIVES: To evaluate photodynamic therapy (PDT) for the treatment of EMPD. METHODS: We conducted a retrospective review of notes and histology of five men with anogenital, groin and axillary EMPD treated with PDT at Roswell Park Cancer Institute between 20 April 1995 and 1 February 2001. RESULTS: Sixteen EMPD lesions were treated with topical aminolaevulinic acid (ALA)-PDT. Eleven of these lesions had failed previous Mohs micrographic surgery, excision or laser ablation. When evaluated 6 months after one treatment with ALA-PDT, eight of 16 (50%) sites achieved a complete clinical response (CR); six of eight CRs were in lesions that had failed prior conventional therapies. Three of the eight CRs (37.5%) recurred at 9, 10 and 10 months. One patient who was partially responsive to topical ALA-PDT subsequently received systemic Photofrin(R)-PDT, with a complete clinical and histological response at 1 year. Functional and cosmetic outcome was excellent in all patients. CONCLUSIONS: PDT is an effective treatment for EMPD. Recurrence rates are high with topical ALA-PDT, but comparable with standard therapies. Topical ALA-PDT causes little scarring and is preferred for superficial disease and mucosal surfaces. Systemic Photofrin(R)-PDT may be better suited for bulky disease. While further studies are indicated, PDT is well tolerated and appears to be a useful therapy for EMPD.