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The Cutting Edge |

Topical Imiquimod to Treat Intraepidermal Carcinoma FREE

Ulrich R. Hengge, MD; Roxana Stark, MD
[+] Author Affiliations

Section Editor: George J. Hruza, MD
Assistant Section Editor: Dee Anna Glaser, MD
Assistant Section Editor: Elaine Siegfried, MD

More Author Information
Arch Dermatol. 2001;137(6):709-711. doi:10-1001/pubs.Arch Dermatol.-ISSN-0003-987x-137-6-dce10001.
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Published online

CASE 1

An 82-year-old man with severe cardiac arrhythmia and recurrent heart failure presented with a 3-year history of erythematous plaques on the left orbita and on the chest. The lesion on his left eye was a hypertrophic actinic keratosis (2 × 1.5 cm), a scaly erythematous plaque on the saddle of the nose extending to the opening of the left lacrimal duct. The chest lesion consisted of a 5 × 2.5-cm plaque with a hemorrhagic crust that caused recurrent itching. On histologic examination, the epidermal cells in the lower epidermis were atypical and showed large, hyperchromatic nuclei and abnormal mitoses (Figure 1A). The biopsy specimen tested positive for human papillomavirus (HPV) type 33 using consensus primers and polymerase chain reaction.1

Place holder to copy figure label and caption
Figure 1.

A, Histological examination of patient 1 revealed epidermal keratinocytes with large hyperchromatic nuclei and atypical mitoses in several layers of the epidermis. B, After 8 months, a control biopsy specimen showed an atrophic epidermis, dilated blood vessels, and a mild lymphohistiocytic infiltrate consistent with vascularized scar tissue (hematoxylin-eosin, original magnification ×100).

Graphic Jump Location
CASE 2

A 52-year-old woman who previously underwent cryotherapy for a 4-mm shiny papule on the right side of the osseous part of the nose presented with a recurrence (Figure 2). On histologic examination, the lesion showed irregular keratinocytes with some dyskeratosis, increased mitoses, focal horn pearls, and a lymphohistiocytic infiltrate.

Place holder to copy figure label and caption
Figure 2.

A, Four-millimeter shiny papule on the right side of the nose of patient 2. During therapy, the patient experienced erythema and erosions at week 9 (B) prior to complete resolution at week 12 (C).

Graphic Jump Location

Given the high prevalence of actinic keratoses and Bowen disease and the potential for malignant transformation,25 there remains a need for convenient treatments. Currently used therapies, such as cryotherapy, laser vaporization, excision, Mohs surgery, chemical peel, trichloroacetic acid, photodynamic therapy, or fluorouracil, are associated with substantial patient discomfort and significant tissue destruction.

We evaluated the novel topical immune response modifier imiquimod (1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-4-amine; 3M, St Paul, Minn) as a therapeutic alternative in 2 difficult-to-treat patients with intraepidermal carcinoma. Imiquimod was applied as 5% cream 3 times per week in an amount that could be rubbed in. In patient 1, treatment was continued for 17 weeks, when both lesions resolved. The patient did not experience any adverse effects such as erythema or discomfort while receiving treatment. A control biopsy specimen of the chest, taken 8 months after the initial presentation, showed a scar with an increased number of blood vessels without evidence of carcinoma (Figure 1B). At the time of this report (15 months after treatment), there had been no recurrence.

Patient 2 experienced an erythema and small erosions in the treated area at week 9 (Figure 2). Treatment was stopped, and 3 weeks later, the lesion had healed without sequelae (Figure 2). During 12 months of follow-up, there was no recurrence.

Since actinic keratoses have a rate of progression to invasive squamous cell carcinoma of about 0.085% per lesion per year, with an even higher risk for Bowen disease,2,3 adequate treatment is necessary.

Imiquimod belongs to the new class of topical immune response modifiers. It has been successfully used for the treatment of viral infections, such as condyloma, warts, mollusca, and genital herpes, and, most recently, for basal cell carcinoma.610 Its mechanism of action in humans is not completely understood, but several studies suggest that it involves stimulation of the cellular immune system, including the induction of cytokines, such as interferon alfa, tumor necrosis factor α, and interleukin 12 (IL-12), from monocytes and macrophages.11 Through the induction of interferon alfa, imiquimod could enhance antigen presentation by increasing the expression of major histocompatibility complex class I and thus, together with IL-12, augment the development of a TH1-type immune response. Other cytokines that are induced by imiquimod from the epidermis, such as IL-1 and IL-6, may contribute to lesion regression by maturation and migration of Langerhans cells, increasing T-cell trafficking to the epidermis, enhancing natural killer cell cytotoxic effects, and stimulating B-cell proliferation.12,13 The local skin reactions noted with imiquimod are most likely a consequence of cytokine-induced inflammation,11 which is also observed with ablative therapies, such as trichloroacetic acid or fluorouracil.

The relatively long time to clinical efficacy suggests a cell-mediated immune response either against the HPV type associated with the cancerous lesion or directly against the malignant cells. This mode of action distinguishes the new class of immune response modifiers from conventional ablative techniques. Whether early forms of cutaneous neoplasia, such as actinic (solar) keratoses and Bowen disease, are associated with HPV infection is currently under debate.1416

Patient-applied imiquimod, the first topical immune response modifier, represents a new drug with potential for treating initial squamous cell cancers of the epidermis in selected patients. While treatment is convenient, it may be associated with erythema and erosions and infrequent scarring. Our initial observations suggest the need for larger trials to confirm this potential novel indication.

Accepted for publication February 7, 2001.

We thank Eggert Stockfleth, MD, for his analysis of the HPV genotype and Werner Schlake, PhD, for the findings of the initial histologic examination of patient 1.

Corresponding author: Ulrich R. Hengge, MD, Department of Dermatology, Venereology and Allergology, University of Essen, Hufelandstrasse 55, 45122 Essen, Germany (e-mail: ulrich.hengge@uni-essen.de).

Meyer  TArndt  RChristophers  E  et al.  Association of rare human papillomavirus types with genital premalignant and malignant lesions. J Infect Dis. 1998;178252- 255
Link to Article
Dodson  JMDeSpain  JHewett  JEClark  DP Malignant potential of actinic keratoses and the controversy over treatment: a patient-oriented perspective. Arch Dermatol. 1991;1271029- 1031
Link to Article
Marks  RRennie  GSelwood  TS Malignant transformation of solar keratoses to squamous cell carcinoma. Lancet. 1988;1795- 797
Link to Article
Cockerell  CJ Histopathology of incipient intraepidermal squamous cell carcinoma ("actinic keratosis") [review]. J Am Acad Dermatol. 2000;4211- 17
Link to Article
Guenthner  STHurwitz  RMBuckel  LJGray  HR Cutaneous squamous cell carcinomas consistently show histologic evidence of in situ changes: a clinicopathologic correlation. J Am Acad Dermatol. 1999;41443- 448
Link to Article
Beutner  KRSpruance  SLHougham  AJFox  TLOwens  MLDouglas  JM Treatment of genital warts with an immune-response modifier (imiquimod). J Am Acad Dermatol. 1998;38230- 239
Link to Article
Hengge  UREsser  SSchultewolter  T  et al.  Self-administered topical 5% imiquimod for the treatment of common warts and molluscum contagiosum. Br J Dermatol. 2000;1431026- 1031
Link to Article
Christensen  BHengge  UR Recurrent urogenital herpes simplex—successful treatment with imiquimod? Sex Transm Infect. 1999;75132- 133
Kagy  MKAmonette  R The use of imiquimod 5% cream for the treatment of superficial basal cell carcinomas in a basal cell nevus syndrome patient. Dermatol Surg. 2000;26577- 578discussion 570-579
Link to Article
Miller  RLImbertson  LMReiter  MJGerster  JF Treatment of primary herpes simplex virus infection in guinea pigs by imiquimod. Antiviral Res. 1999;4431- 42
Link to Article
Slade  HBOwens  MLTomai  MAMiller  RL Imiquimod 5% cream (Aldara). Exp Opin Invest Drugs. 1998;7437- 449
Link to Article
Suzuki  HWang  BShivji  GM  et al.  Imiquimod, a topical immune response modifier, induces migration of Langerhans cells. J Invest Dermatol. 2000;114135- 141
Link to Article
McKenzie  RCSauder  DN Keratinocyte cytokines and growth factors: functions in skin immunity and homeostasis [review]. Dermatol Clin. 1990;8649- 654
Lampert  APauwels  CDuboucher  CMorel  GPoveda  JDPerie  G Detection of human papillomavirus in cutaneous extragenital Bowen's disease in immunocompetent patients [in French]. Ann Dermatol Venereol. 2000;12740- 45
Bouwes Bavinck  JNStark  SPetridis  AK  et al.  The presence of antibodies against virus-like particles of epidermodysplasia verruciformis–associated humanpapillomavirus type 8 in patients with actinic keratoses. Br J Dermatol. 2000;142103- 109
Link to Article
Lu  STiekso  JHietanen  SSyrjanen  KHavu  VKSyrjanen  S Expression of cell-cycle proteins p53, p21 (WAF-1), PCNA and Ki-67 in benign, premalignant and malignant skin lesions with implicated HPV involvement. Acta Derm Venereol. 1999;79268- 273
Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

A, Histological examination of patient 1 revealed epidermal keratinocytes with large hyperchromatic nuclei and atypical mitoses in several layers of the epidermis. B, After 8 months, a control biopsy specimen showed an atrophic epidermis, dilated blood vessels, and a mild lymphohistiocytic infiltrate consistent with vascularized scar tissue (hematoxylin-eosin, original magnification ×100).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

A, Four-millimeter shiny papule on the right side of the nose of patient 2. During therapy, the patient experienced erythema and erosions at week 9 (B) prior to complete resolution at week 12 (C).

Graphic Jump Location

Tables

References

Meyer  TArndt  RChristophers  E  et al.  Association of rare human papillomavirus types with genital premalignant and malignant lesions. J Infect Dis. 1998;178252- 255
Link to Article
Dodson  JMDeSpain  JHewett  JEClark  DP Malignant potential of actinic keratoses and the controversy over treatment: a patient-oriented perspective. Arch Dermatol. 1991;1271029- 1031
Link to Article
Marks  RRennie  GSelwood  TS Malignant transformation of solar keratoses to squamous cell carcinoma. Lancet. 1988;1795- 797
Link to Article
Cockerell  CJ Histopathology of incipient intraepidermal squamous cell carcinoma ("actinic keratosis") [review]. J Am Acad Dermatol. 2000;4211- 17
Link to Article
Guenthner  STHurwitz  RMBuckel  LJGray  HR Cutaneous squamous cell carcinomas consistently show histologic evidence of in situ changes: a clinicopathologic correlation. J Am Acad Dermatol. 1999;41443- 448
Link to Article
Beutner  KRSpruance  SLHougham  AJFox  TLOwens  MLDouglas  JM Treatment of genital warts with an immune-response modifier (imiquimod). J Am Acad Dermatol. 1998;38230- 239
Link to Article
Hengge  UREsser  SSchultewolter  T  et al.  Self-administered topical 5% imiquimod for the treatment of common warts and molluscum contagiosum. Br J Dermatol. 2000;1431026- 1031
Link to Article
Christensen  BHengge  UR Recurrent urogenital herpes simplex—successful treatment with imiquimod? Sex Transm Infect. 1999;75132- 133
Kagy  MKAmonette  R The use of imiquimod 5% cream for the treatment of superficial basal cell carcinomas in a basal cell nevus syndrome patient. Dermatol Surg. 2000;26577- 578discussion 570-579
Link to Article
Miller  RLImbertson  LMReiter  MJGerster  JF Treatment of primary herpes simplex virus infection in guinea pigs by imiquimod. Antiviral Res. 1999;4431- 42
Link to Article
Slade  HBOwens  MLTomai  MAMiller  RL Imiquimod 5% cream (Aldara). Exp Opin Invest Drugs. 1998;7437- 449
Link to Article
Suzuki  HWang  BShivji  GM  et al.  Imiquimod, a topical immune response modifier, induces migration of Langerhans cells. J Invest Dermatol. 2000;114135- 141
Link to Article
McKenzie  RCSauder  DN Keratinocyte cytokines and growth factors: functions in skin immunity and homeostasis [review]. Dermatol Clin. 1990;8649- 654
Lampert  APauwels  CDuboucher  CMorel  GPoveda  JDPerie  G Detection of human papillomavirus in cutaneous extragenital Bowen's disease in immunocompetent patients [in French]. Ann Dermatol Venereol. 2000;12740- 45
Bouwes Bavinck  JNStark  SPetridis  AK  et al.  The presence of antibodies against virus-like particles of epidermodysplasia verruciformis–associated humanpapillomavirus type 8 in patients with actinic keratoses. Br J Dermatol. 2000;142103- 109
Link to Article
Lu  STiekso  JHietanen  SSyrjanen  KHavu  VKSyrjanen  S Expression of cell-cycle proteins p53, p21 (WAF-1), PCNA and Ki-67 in benign, premalignant and malignant skin lesions with implicated HPV involvement. Acta Derm Venereol. 1999;79268- 273
Link to Article

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