Bowen's disease

Abstract

Topical imiquimod is an immune response modifier FDA approved for the treatment of anogenital warts. Recent studies have reported its effectiveness in the treatment of some types of basal cell carcinomas. There have also been some case reports and case series reporting success treating of squamous cell carcinoma in situ with imiquimod. We report two patients with squamous cell carcinoma in situ and one with invasive squamous cell carcinoma treated with 5% imiquimod cream. Lesions were located on shin, posterior shoulder, and nasal tip. 5% imiquimod cream was applied at night for six weeks. Side effects included erythema and crusting in one patient. Biopsies taken four weeks after treatment revealed no residual squamous cell carcinoma in situ or squamous cell carcinoma. Topical 5% imiquimod cream is becoming established as a promising treatment for squamous cell carcinoma in situ. It also seems to be an alternative treatment for some cases of squamous cell carcinoma.

Introduction

There are several options for the treatment of squamous cell carcinoma, including: surgical excision, 5-fluorouracil, electro-dessication and curettage, laser vaporization, chemical peel, cryotherapy, and Mohs micrographic surgery. Some of these proposed treatments are limited by significant morbidity and high recurrence rates. Consequently, the search for treatment innovations continues.

Topical imiquimod is an immune response modifier currently FDA approved for the treatment of anogenital warts. Its antiviral and anti-tumor activities have been linked to the stimulation of local cytokine production and cell-mediated immune response.

Recent studies have reported that topical imiquimod is effective in the treatment of basal cell carcinomas (1-6). There have also been some case reports and case series on its use in the treatment of squamous cell carcinoma in situ (7-10). We report two patients with squamous cell carcinoma in situ and one with invasive squamous cell carcinoma who received treatment with topical imiquimod.

Patients and Methods

The three patients ranged in age from 73 to 79 (Table 1). There were two women and one man. Diagnoses were squamous cell carcinoma in situ (n=2) and squamous cell carcinoma (n=1). Lesion sizes ranged from 0.3 to 1 cm. Locations were lower leg (n=l), posterior shoulder (n=1), and nasal tip (n=1). Treatment options were explained to patients. The three patients refused surgical intervention, but were interested in a trial of imiquimod. Patients were advised of possible side effects such as erythema, swelling, induration, crusting, ulceration, pain, and burning. Patients were instructed to apply 5% imiquimod cream every, night over the entire lesion for six weeks. Patients were seen in clinic for follow up midway through treatment. One month after completion of the imiquimod regimen, lesions were reevaluated and biopsies taken. At each of these visits, patients were evaluated for any side effects and these were carefully noted (Figures 1A-B and 2A-D).

[FIGURE 1-2 OMITTED]

Case Report--Patient 3

A 79 year old white female was seen in clinic for evaluation of three lesions: a scaly patch on the nasal bridge, an erythematous plaque on the tip of her nose, and a pearly papule in the right nasal sulcus (Figure 2A). All lesions were biopsied. Diagnosis by pathology was actinic keratosis on the nasal bridge, invasive squamous cell carcinoma of the superficial type on right nasal tip, and basal cell carcinoma of right nasal sulcus.

Patient vehemently refused surgical intervention and other tissue destructive measures such as cryotherapy. Options were discussed with the patient and she expressed interest in a topical agent. Studies with imiquimod have shown success with the treatment of basal cell carcinoma, and host of case reports and cases series have shown imiquimod as effective in the treatment of squamous cell carcinoma in situ. Therefore, imiquimod was discussed as an option for the treatment of both lesions. Side effects of imiquimod were discussed with the patient. She was made to understand that this treatment, though valid, was not a first line treatment. Understanding these parameters, she contracted to maintain close follow-up with us. Treatment of both the basal cell carcinoma and squamous cell carcinoma was then undertaken: 5% imiquimod was to be applied to both lesions at night for six weeks.

This patient developed irritation and crusting of the treatment area midway through treatment (Figure 2B). At this time the patient was allowed to stop applying imiquimod for two weeks. She was told to restart treatment for another three weeks to complete a total of six weeks of treatment.

One month post treatment, this patient had no visible erythema and no clinically visible lesions on the nasal bridge, nasal tip, or nasal sulcus (Figures 2C and 2D). At this time, shave biopsies of the nasal tip and nasal sulcus were taken. Both biopsies showed dermal cicatrix, but no residual squamous cell carcinoma, or basal cell carcinoma.

Results

All three patients completed six full weeks of the treatment. They were evaluated midway through treatment and four weeks post treatment. In general, the protocol was well tolerated.

Significant side effects included erosions and crusting in one patient. Patient 3 experienced irritation and crusting of her nose three weeks into treatment. These side effects resolved without complication after a two week respite from treatment. The patient then continued her treatment course and completed a full six weeks of therapy (Figures 2A-2D).

Patients were followed up one month after completion of the protocol. At that time all lesions appeared clear and there was no residual erythema. Shave biopsies were performed during this office visit. All biopsy results were clear, with no evidence of residual squamous cell carcinoma in situ or squamous cell carcinoma.

Discussion

Imiquimod, an imidazoquinoline amine, came onto the market in 1997 with FDA approval for the treatment of external genital and perianal warts. Current dosing recommendations for this indication are a maximum of three applications per week for sixteen weeks (11). Interestingly, this product has not been shown to have direct anti-viral activity in-vitro (12-14). Its in-vivo anti-viral and anti-tumor activity have been linked to its actions as an immune modulator (12-14).

Imiquimod stimulates the body's innate immune response by inducing production of cytokines: IL-6, TNF-a, and IFN-a, among others (12-14). It enhances the cellular arm of acquired immunity by inhibiting production of interleukin-4 and interleukin-5, and inducing production of interferon-a, interferon-g, and interleukin-12 (12-14). This pathway downregulates the Th-2 (helper) and activates the Th-1 response (14). Murine and human studies have shown that imiquimod enhances migration and antigen presentation of Langerhans' cells (13). Dahl et al. add that imiquimod is linked to an increase of the ability of Langerhans' cells to induce T-cell proliferation by 30 to 300% above baseline (14).

As a topically applied immune enhancer, imiquimod could be a potential treatment for many cutaneous diseases. It has a marked effect on local cellular activity, while maintaining a relatively benign side effect profile. Possible complications consist of local reactions to the medication such as erythema, crusting, scabbing, ulceration, bleeding, necrosis, induration, hypopigmentation, itching, pain, and burning. Systemic absorption of topical imiquimod is minimal: radionucleotide studies have shown that less than 1% of the topically applied dose is absorbed systemically (13). Imiquimod is also safe enough to be used in pregnancy and has been classified as a category B drug.

A recent focus of interest has been the use of imiquimod for the treatment of malignancies. An oral dosing of the drug was found to have potent antitumor effects in mice transplanted with tumor cells from various cell lines, including M-26 colon carcinoma, bladder cell carcinoma, Lewis Lung sarcoma, and B16-F10 melanoma (13,15,16). A phase I trial of oral imiquimod as a chemotherapeutic agent in human cancer patients was less successful (17). No clinical response was observed, but interferona levels were increased in the blood stream.

In clinical practice there has been success with the use of topical imiquimod for the treatment of cutaneous malignancies. Basal cell carcinoma has been treated successfully with imiquimod (1-6). Beutner et al. had success treating basal cell carcinomas of both nodular and superficial types with 5% imiquimod cream. In a randomized, double-blind pilot trial with 35 patients, the investigators had a 100% cure rate with BID, QD, and tri-weekly dosing. Patients were treated up to 16 weeks. Marks et al. conducted a multicenter, randomized clinical trial using 5% imiquimod to treat superficial basal cell carcinoma in 99 patients (6). Their goal was to assess the safety and efficacy of different dosing regimens. The time frame for all treatment groups was six weeks of treatment. They achieved 100% cure rate in the group treated BID, 87.9% cure rate in the group treated QD, 73.3% cure rate in the group treated the twice daily for three days per week, and 69.7% cure rate in the group treated once daily for three days a week. They came to the conclusion that side effects were dose related, but that even the highest dosage regimens were well tolerated in their patient population.

Squamous cell carcinoma in situ has also been treated successfully with 5% imiquimod cream. Scroeder et al. reported successful use of imiquimod in a case of squamous cell carcinoma in situ of the penis (7). The patient was treated with 5% imiquimod applied each night for a total of 24 days. They were pleased with the cosmetic outcome, and clinically the patient remained free of recurrence eighteen months out. Mackenzie-Wood et al. performed a phase II open label study in 16 patients with biopsy-proven Bowen's disease (8). They used a once daily application of 5% imiquimod with a treatment goal of sixteen weeks. Ten patients completed sixteen weeks of therapy, but six had to stop between 6 and 8 weeks secondary to local skin complications. Patients returned for biopsies 6 weeks after completing treatment and 93% had no residual tumor. Six month follow-up of these patients showed no recurrence. Of the patients that had to stop treatment early. 100% were clear of residual tumor at six weeks and 6 months.

In our case series, we had success treating two cases of squamous cell carcinoma in situ and one case of invasive squamous cell carcinoma with imiquimod. There is a definite precedent for the treatment of squamous cell carcinoma in situ with imiquimod, though most of this data is anecdotal. Treatment of squamous cell carcinoma with imiquimod is undoubtedly more controversial. The highly effective and time tested treatments such as surgical excision and Mohs surgery remain the mainstay of treatment for squamous cell carcinoma, but for some patients they are not an option. Surgery may be precluded by health concerns or by patient choice, leaving the physician scrambling for treatment options.

Patient three had both a basal cell carcinoma and a squamous cell carcinoma on her right nose. Imiquimod was deemed a good option, because of its reported effectiveness in treatment of both basal cell carcinoma and squamous cell carcinoma in situ. We extended the use of imiquimod in this case to squamous cell carcinoma, as the patient was only interested in topical treatments. The patient understood that close follow-up would be necessary, as this was not a first line treatment.

During treatment, one patient experienced side effects. The patient with invasive squamous cell carcinoma experienced irritation, erythema, and crusting. It is well established that patients with genital warts who experience uncomfortable irritation may decrease the frequency of application (14). Following the lead of Schroeder et al. and Mackenzie et al., we extended this paradigm to treatment of other cutaneous tumors, and advised the patient to hold off on treatment to allow the side effects to resolve. The treatment goal was still six weeks of total treatment.

In all three cases treatment was successful. There was no evidence of residual tumor in any of the follow-up biopsies. Results were cosmetically pleasing, and there was no clinical evidence of fibrosis, scarring, discoloration, or residual erythema.

Conclusion

Consequent to its relatively benign side effect profile, topical imiquimod is well tolerated by patients, and study outcomes thus far have supported its use in patients with a variety of cutaneous malignancies. Topical 5% imiquimod is becoming established as a promising treatment for some forms of basal cell carcinoma and squamous cell carcinoma in situ. It also seems to be an alternative treatment for some cases of squamous cell carcinoma. The results of this case series and other recent studies support these assertions, but more extensive trials with long term follow up will be essential to verify and expand these results.

References

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(2.) Kagy MK, Amonette R. The use of imiquimod 5% cream for the treatment of superficial basal cell carcinomas is a basal cell nevus syndrome patient. Dermatologic Surgery 2000; 26:578-579.

(3.) Marks R, Gebauer K, Schumack S. Imiquimod 5% cream in the treatment of superficial basal cell carcinoma: results of a multi-center 6-week dose response trial. Journal of the American Academy of Dermatology 2001; 44:807-811.

(4.) Sterry WK, Ruzicka T, Herrera E, Takwale A, et al. Imiquimod 5% cream for the treatment of superficial and nodular basal cell carcinoma: randomized studies comparing low-frequency dosing with and without occlusion. British Journal of Dermatology 2002; 147(6):1227-36.

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(7.) Schroeder T, Sengelmann R. Squamous cell carcinoma in situ of the penis successfully treated with imiquimod 5% cream. Journal of the American Academy of Dermatology 2002; 46:545-8.

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KEYVAN NOURI MD (1), CHRISTOPHER O'CONNELL (2), MARIA PATRICIA RIVAS MD (3)

(1) ASSOCIATE PROFESSOR OF THE DEPARTMENT OF DERMATOLOGY AND OTOLARYNGOLOGY, UNIVERSITY OF MIAMI SCHOOL OF MEDICINE. DIRECTOR OF MOHS, DERMATOLOGIC AND LASER SURGERY AND DIRECTOR OF SURGICAL TRAINING FOR THE DEPARTMENT OF DERMATOLOGY AND CUTANEOUS SURGERY AT UNIVERSITY OF MIAMI SCHOOL OF MEDICINE

(2) MEDICAL STUDENT AT THE UNIVERSITY OF MIAMI SCHOOL OF MEDICINE

(3) RESEARCH FELLOW OF THE DEPARTMENT OF DERMATOLOGY AND CUTANEOUS SURGERY. UNIVERSITY OF MIAMI SCHOOL OF MEDICINE MIAMI, FLORIDA

ADDRESS FOR CORRESPONDENCE:

Keyvan Nouri MD

1475 NW 12th Avenue

Miami, FL 33136

Phone: (305) 243-9443

Fax: (305) 243-4184

E-mail: KNouri@med.miami.edu

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