Keratoacanthoma

Abstract

Imiquimod is an immune-response modifier that has the potential to be useful in many dermatological indications (Table 1). To date, the approved use is for condyloma acuminata; approval for use in treating basal cell carcinoma (BCC) has been filed with the FDA and is expected to be approved in the coming months. In the interim, the expansion of the horizons for this immunomodulator depends on the application of the science and immunology behind the drug to the appropriate disease states.

Recent investigations have presented explanations on the possible mechanisms behind the anti-tumor activity of imiquimod, more specifically for its use in treating superficial BCC. There are studies currently underway as well as anecdotal data published for its possible use in treating squamous cell carcinoma (SCC), although this is not as widely accepted for off-label use as BCC among many dermatologists. However, many patients who may not be surgical candidates that present with tumors other than BCC have been successfully treated with imiquimod. This is a case of an elderly patient who could not undergo surgery that presented with a large keratoacanthoma and was clear of her tumor after five months using imiquimod 5% cream on a daily basis.

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Case Report

This is a case of an elderly patient, not a candidate for surgery, who presented with a lesion clinically suggestive of a keratoacanthoma. She was unable to tolerate a biopsy, which prevented histological confirmation of the tumor, but was clear after five months using imiquimod 5% cream on a daily basis.

[FIGURE 1 OMITTED]

Her history was significant for actinic keratoses (AKs) and extensive unprotected solar exposure in the past. In addition, her overall general health was extremely poor due to severe end-stage CHF, oxygen-dependent COPD and asthma, and recurrent herpes zoster. She was to be placed in hospice care and was in very frail physical condition. As a result, her family did not wish her to undergo any surgical procedures or skin biopsy.

On physical exam (Figure 1), there was a 3.0 X 3.2 cm firm ulcerated nodule with prominent rolled borders and crater-like center suggestive of a keratoacanthoma (KA). There was neither purulence nor peripheral erythema. In addition, there was no evidence of cervical adenopathy. The remainder of the exam revealed an adjacent open comedone cyst, healed actinic keratoses, and dermatoheliosis.

The working differential diagnosis included keratoacanthoma, ulcerated BCC, and ulcerated SCC, although the history and morphology were most suggestive of KA. Given the patient's health and the family's wishes, an extensive discussion of the risks, benefits, and alternatives ensued. More conservative options were considered such as topical destruction, cryotherapy, and radiation therapy. The consensus option was to proceed with imiquimod 5% cream (Aldara[TM]; 3M Pharmaceuticals, Northridge, California, USA) on an alternate-day basis until tolerated, then to increase to daily use for 3 months. The patient was to follow-up monthly for assessment and excision was to be the next step if there was no evidence of regression or improvement.

After one month, the patient returned with minimal improvement in the size and induration of the nodule (Figure 2), but treatment was continued for the anticipated 3 month course.

[FIGURE 2 OMITTED]

However, the patient did not return for her 2nd and 3rd month appointment checks as she was then placed in a long-term care facility and was unable to leave. Upon an inpatient evaluation after 5 months, it was learned that she did not return because the lesion had cleared (Figures 3 and 4). Her examination revealed clinical resolution of the tumor without any residual ulceration. There was no peripheral lesion of concern, although the adjacent cyst and photodamage areas were unchanged.

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Discussion

Keratoacanthomas are common tumors in the elderly and have abrupt onset as well as the potential for larger sizes in this age group. They are more common on the extremities but presentations on the head and neck can be more striking in appearance. There is a small potential for spontaneous regression although this decreases with age and relative immunocompromise, which was likely given her overall physical health. In addition, the patient's ability to tolerate surgery was of concern to her family as well as to the clinic, which brought to light the need for other options. Although the patient's insurance did not cover the medication, the family was willing to pay out of pocket and was fully informed regarding the off-label use of this therapy.

It is unclear if the anti-tumor effects of imiquimod on keratoacanthoma are similar to those that apply against BCC compared to those at work against AKs. In BCC, the induction of apoptosis is marked by the increased expression of the ICAM-1, Fas ligand and receptor, known as "death receptors," as well as a decrease in Bcl-2, known to be over-expressed in BCC (1). These changes involve the upregulation of tumor markers as well as the inflammatory mechanisms from Th1 conversion. In AKs, the presumed mechanisms of atypia involve the activation of p53 tumor-suppressor gene as well as other mutations and pyrimidine dimer formation. This is often characterized as the "UV signature," where patterns of cytosine and thymidine (either alone or in pairs) become grouped and recognizable by assay (2). Chronic exposure to UV radiation is not only responsible for the p53 gene mutation but also results in a local immunosuppression due to altered dendritic cell function (3). In addition, as imiquimod's main purpose is to enhance the body's innate responses, it can be suggested that in an area of local immunosuppression, the production of cytokines may be compromised compared to that seen in normal skin (4). It has been demonstrated on mice models with epidermal dysplasia and chronic UV exposure treated with imiquimod that more cytokines are produced at UV-exposed than non-UV areas. More importantly, there is more activity against thymidine dimers and cells that overexpress p53 antigen. This pattern was seen in 90% of SCC and 50% BCC observed in the treated mice. Whether this means that imiquimod is target-selective is yet to be determined (4).

The markers that serve as targets for the immune response that is mounted are not the same in SCC variants because of the nature of the atypical keratinocytes. It is possible that changes seen in warts may be applied to those in SCC. For example, DNA viruses such as Human Papilloma (HPV) express both early and late genes, but the oncogenes that encode malignant degeneration, such as in cervical dysplasia or epidermoplasia verruciformis, involve the p53 antigen.

One potential mechanism in keratoacanthoma is that either the cell products affected by the pyrimidine dimers or the expression of products encoded by the p53 genes by atypical keratinocytes may serve as the targets for the inflammation initiated by Toll-like receptors. It has been demonstrated on mice models with epidermal dysplasia and chronic UV exposure treated with imiquimod that more cytokines are produced at UV-exposed than non-UV areas. More importantly, there is more activity against thymidine dimers and cells that overexpress p53 antigen. This pattern was seen in 90% of SCC and 50% BCC observed in the treated mice. Whether this means that imiquimod is target-selective is yet to be determined (4).

Finally, the possibility of spontaneous regression of the tumor based on the theory of local immunosuppression in UV damaged areas, in combination with the patient's overall poor health, is lower than considered in the average population.

It should be noted that the cyst adjacent to the tumor was unaffected by the effects of the medication. This is a common observation with satellite benign lesions such as seborrheic keratoses, lentigines, and angiomas. As these benign tumors do not reflect an atypical process and therefore do not contain an antigen for presentation and recognition, they are not involved in the process that imiquimod initiates.

Conclusion

The use of imiquimod in this patient was a conservative alternative to surgery, and the tumor involved was of low malignant potential. The location of the tumor on the cheek would give rise to the possibility of perineural or parotid gland invasion in a more aggressive SCC subtype or if present for longer duration. These possibilities need to be discussed with patients as well as the risks, benefits, and alternatives to surgery for these tumors. In addition, thorough documentation of the off-label use of this agent is essential. Nevertheless, as more information on the mechanisms of inflammation against SCC is elucidated, there may eventually be a role for this treatment either as an adjunct or alternative to surgery.

References:

1 Dummer R, et al. Mechanisms Underlying Imiquimod-Induced Regression of Basal Cell Carcinoma in vivo. Arch Dermatol 2003; 139:1325-1332.

2 Ouhtit A, Ananthaswamy HN. A model for UV-induction of skin cancer. J Biomed Biotechnol 2001; 1:5-6.

3 Vink AA, et al. The inhibition of antigen-presenting activity of dendritic cells resulting from UV irradiation of murine skin is restored by in vitro photorepair of cyclobutane pyrimidine dimmers. Proc Natl Acad Sci USA 1997; 94:5255-5260.

4 Suzuki H, et al. Imiquimod, a topical immune response modifier, induces migration of Langerhans cells. J Invest Dematol 2000; 114:135-141.

NEAL BHATIA MD

ASSISTANT CLINICAL PROFESSOR OF DERMATOLOGY

UCSD SCHOOL OF MEDICINE

SAN DIEGO, CA

ADDRESS FOR CORRESPONDENCE:

Neal Bhatia MD

Assistant Clinical Professor of Dermatology

UCSD School of Medicine

350 W. Catalina Drive

Yuma AZ 85364

Tel: 619-987-6325

E-mail: ndbhatia@juno.com

The author wishes to thank 3M Pharmaceuticals for assistance in research for the project as well as to Dr. Mitch Stashower, Dr. Mark Kaufmann, and Dr Timothy Brown for their assistance and inspiration.

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