Successful imiquimod treatment of multiple basal cell carcinomas after radiation therapy for Hodgkin’s disease

ARTICLE

Auteur(s) :, Mirjam Beyeler¹, Mirjana Urosevic¹, Bernhard Pestalozzi², Reinhard Dummer^1,*

¹Department of Dermatology, University Hospital Zurich, Gloriastrasse 31, 8091 Zurich SwitzerlandFax. (+41) 1 255 89 88.
²Department of Oncology, University Hospital Zurich, Zurich, Switzerland

accepté le 20 Juin 2004

Case report

The diagnosis of stage IIa mediastinal Hodgkin’s disease was made in January 1980. The patient was treated with radiation therapy (mantle field, 31 × 1.5 = 46.5 Gy, photons) from March until May 1980 and, due to a relapse, from September to October 1980 (infrascapular right side, 20 × 2 = 40 Gy, electrons and inverted Y field, 27 × 1.5 = 40.5 Gy, photons). This was followed by six cycles of chemotherapy with CCNU (lomustine), vinblastine, procarbazine and prednisone leading to complete remission.

A second mediastinal relapse occurred in November 1992 and was treated with one cycle of MOPP (mechlorethamine, vincristine (Oncovin), procarbazine, prednisone) in November 1992. In April 1993 an autologous stem cell transplantation was performed, which led to the current ongoing complete remission.

During his annual follow-up in January 2003 several reddish skin lesions on the back were noticed. They showed a size of up to 15 mm and tended to grow slowly. The patient was referred to our Department in July 2003 for further examination and therapy.

We found 3 lesions on the back with the diameters of 7 × 9, 12 × 13 and 8 × 15 mm. There was an additional lesion on the left shoulder measuring 11 × 7 mm and one (7 × 10 mm) located in the subscapular region (( Figure 1 )). One lesion was biopsied. Histology showed a superficial BCC (( Figure 2 )).

To evaluate the patient’s response to topical immunotherapy, only one lesion was initially treated with imiquimod cream (Aldara^®, 3M Pharmaceuticals, St.Paul, MN) for 5 days. After the treatment, we observed erythema, mild edema, vesicles and crusting in the treated area (( Figure 3 )). Histology revealed remains of the BCC with a pseudo-lymphomatous inflammation (( Figure 4 )).

Encouraged by these results, we also treated the other BCCs with imiquimod cream three times weekly for eight weeks. We observed no significant side effects during this time. After eight weeks the lesions showed mild erythema. A punch biopsy was performed in two treated areas and we again found fading signs of inflammation with no remains of the former BCC (( Figure 5 )).

Discussion

Landthaler et al. found 12 BCC (2%) and 9 SCC (1.5%) in 612 irradiation fields (soft X-ray radiation) of 522 patients [6]. Patients were treated for malignant cutaneous tumors (95.5%), precancerous diseases (4%) and, in two cases, for benign dermatosis (0.5%). Follow-up period was a minimum of 10 years. The authors distinguished between recurrences and irradiation induced tumors. However, they did not indicate their distinction criterias. The recurrence rate in BCC patients treated with superficial radiotherapy in our center was 8.2% for nodular BCC and 27.7% for sclerosing BCC [7].

All in all, Landthaler could not prove any relationship between the total radiation dose and the frequency of tumors [6]. In our patients treated with Grenz or soft X-ray irradiation therapy for lentigo maligna (LM) or LM melanoma, no BCC was found in the irradiation fields of 150 patients with a mean follow-up period of 8 years [8].

Mice experiments performed by Mancuso show that mice lacking a gene called patched (Ptch) 1, which is a transmembrane protein, tend to develop BCC precursor lesions [9]. X-ray irradiation of Ptch-deficient mice resulted in multiple microscopically detectable, intradermal nodular BCCs as well as large infiltrative BCC-like tumors. Genetic studies on patients with basal cell nevus syndrome led to the identification of inactivating mutations in the human homologue of the Drosophila gene Ptch1 as the genetic defect underlying the syndrome.

Lear et al. found a possible relationship between basal cell carcinomas and hematological neoplasms [10]. In his case-control study, 5 out of 141 patients with BCCs suffered from hematological diseases, such as non-Hodgkin’s lymphoma and chronic myeloid leukemia, whereas none of the controls developed such diseases. These results suggest a link between BCC and hematological malignancies.

There are several case reports of patients developing multiple BCCs after radiation therapy (Table 1( Table 1 )). Wollenberg et al. describes a patient with 43 BCCs, 20 years after the treatment of immunoblastoma with 60 Co irradiation. All skin tumors were located within the irradiation fields [11]. Beswick et al. presents the case of a 53-year-old woman with seven BCCs and one malignant melanoma in situ on her back, which was irradiated for ankylosing spondylitis 30 years ago. Since the woman had no other risk factors for cutaneous malignancy, Beswick et al. postulate that all her skin cancers developed as a consequence of radiotherapy [2]. In all these cases surgery was performed as therapy for BCCs.

We found no case reports discussing an eventual association between Hodgkin’s lymphoma and BCCs. It seems that the diagnosis of Hodgkin’s lymphoma does not increase the risk of developing BCCs. BCCs are more likely to be associated with radiation treatment and therefore should be limited to the radiation areas, as in our case.

Imiquimod is a synthetic immune response modulator that has shown efficacy in the treatment of various skin conditions. Via interaction with Toll-like receptor 7 (TLR7) imiquimod exerts effects on immune cells inducing local production of interferon-α, tumor necrosis factor (TNF)-α and interleukin-12, leading to the activation of Th1-cells [12, 13]. Imiquimod improves antigen presentation by dendritic cells and enhances production of antibodies [14]. Imiquimod has been successfully used in the treatment of viral infections (human papilloma virus in anal and genital warts, herpes simplex virus, molluscum contagiosum), skin tumors (actinic keratosis, keratoacanthoma, squamous cell carcinoma, BCC, lentigo maligna, malignant melanoma and Bowen’s disease) and Mycosis fungoides [15-23]. Geisse performed randomized vehicle-controlled trials for the treatment of superficial basal cell carcinomas with imiquimod 5% cream and achieved clearance rates of 75% when imiquimod was applied five times per week for 6 weeks [24]. In the treatment of facial superficial basal cell carcinoma, imiquimod has also been successfully applied [25, 26].

Our case demonstrates that the self-application of imiquimod is another easy and effective treatment of this special clinical situation resulting in excellent cosmetic results.
Table 1 Published case reports of multiple BCCs after radiation therapy

References

2 Beswick SJ, Garrido MC, Fryer AA, Strange RC, Smith AG. Multiple basal cell carcinomas and malignant melanoma following radiotherapy for ankylosing spondylitis. Clin Exp Dermatol 2000; 25(5): 381-3.

3 Ekmekci P, Bostanci S, Anadolu R, Erdem C, Gurgey E. Multiple basal cell carcinomas developed after radiation therapy for tinea capitis: a case report. Dermatol Surg 2001; 27(7): 667-9.

4 Stante M, Salvini C, De Giorgi V, Carli P. Multiple synchronous pigmented basal cell carcinomas following radiotherapy for Hodgkin’s disease. Int J Dermatol 2002; 41(4): 208-11.

5 Lichter MD, Karagas MR, Mott LA, Spencer SK, Stukel TA, Greenberg ER. Therapeutic ionizing radiation and the incidence of basal cell carcinoma and squamous cell carcinoma. The New Hampshire Skin Cancer Study Group. Arch Dermatol 2000; 136(8): 1007-11.

6 Landthaler M, Hagspiel HJ, Braun-Falco O. Late irradiation damage to the skin caused by soft X-ray radiation therapy of cutaneous tumors. Arch Dermatol 1995; 131(2): 182-6.

7 Zagrodnik B, Kempf W, Seifert B, Muller B, Burg G, Urosevic M, et al. Superficial radiotherapy for patients with basal cell carcinoma: recurrence rates, histologic subtypes, and expression of p53 and Bcl-2. Cancer 2003; 98(12): 2708-14.

8 Farshad A, Burg G, Panizzon R, Dummer R. A retrospective study of 150 patients with lentigo maligna and lentigo maligna melanoma and the efficacy of radiotherapy using Grenz or soft X-rays. Br J Dermatol 2002; 146(6): 1042-6.

9 Mancuso M, Pazzaglia S, Tanori M, Hahn H, Merola P, Rebessi S, et al. Basal cell carcinoma and its development: insights from radiation-induced tumors in Ptch1-deficient mice. Cancer Res 2004; 64(3): 934-41.

10 Lear JT, Tan BB, Smith AG, Fryer AA, Strange RC, Jones PW. Non-Hodgkins lymphoma and solar ultraviolet radiation. Basal cell carcinoma may be linked to haematological malignancy. BMJ 1996; 313(7052): 298-9.

11 Wollenberg A, Peter RU, Przybilla B. Multiple superficial basal cell carcinomas (basalomatosis) following cobalt irradiation. Br J Dermatol 1995; 133(4): 644-6.

12 Gibson SJ, Lindh JM, Riter TR, Gleason RM, Rogers LM, Fuller AE, et al. Plasmacytoid dendritic cells produce cytokines and mature in response to the TLR7 agonists, imiquimod and resiquimod. Cell Immunol 2002; 218(1-2): 74-86.

13 Stanley MA. Imiquimod and the imidazoquinolones: mechanism of action and therapeutic potential. Clin Exp Dermatol 2002; 27(7): 571-7.

14 Hengge UR, Benninghoff B, Ruzicka T, Goos M. Topical immunomodulators--progress towards treating inflammation, infection, and cancer. Lancet Infect Dis 2001; 1(3): 189-98.

15 Tyring S, Conant M, Marini M, Van Der Meijden W, Washenik K. Imiquimod; an international update on therapeutic uses in dermatology. Int J Dermatol 2002; 41(11): 810-6.

16 Stockfleth E, Meyer T, Benninghoff B, Salasche S, Papadopoulos L, Ulrich C, et al. A randomized, double-blind, vehicle-controlled study to assess 5 0miquimod cream for the treatment of multiple actinic keratoses. Arch Dermatol 2002; 138(11): 1498-502.

17 Gupta AK, Browne M, Bluhm R. Imiquimod: a review. J Cutan Med Surg 2002; 6(6): 554-60.

18 Bong AB, Bonnekoh B, Franke I, Schon MP, Ulrich J, Gollnick H. Imiquimod, a topical immune response modifier, in the treatment of cutaneous metastases of malignant melanoma. Dermatology 2002; 205(2): 135-8.

19 Ahmed I, Berth-Jones J. Imiquimod: a novel treatment for lentigo maligna. Br J Dermatol 2000; 143(4): 843-5.

20 Dummer R, Urosevic M, Kempf W, Kazakov D, Burg G. Imiquimod induces complete clearance of a PUVA-resistant plaque in mycosis fungoides. Dermatology 2003; 207(1): 116-8.

21 Peris K, Micantonio T, Fargnoli MC. Successful treatment of keratoacanthoma and actinic keratoses with imiquimod 5ream. Eur J Dermatol 2003; 13(4): 413-4; author reply 415.

22 Dendorfer M, Oppel T, Wollenberg A, Prinz JC. Topical treatment with imiquimod may induce regression of facial keratoacanthoma. Eur J Dermatol 2003; 13(1): 80-2.

23 Stockfleth E, Ulrich C, Hauschild A, Lischner S, Meyer T, Christophers E. Successful treatment of basal cell carcinomas in a nevoid basal cell carcinoma syndrome with topical 5 0miquimod. Eur J Dermatol 2002; 12(6): 569-72.

24 Geisse J, Caro I, Lindholm J, Golitz L, Stampone P, Owens M. Imiquimod 5ream for the treatment of superficial basal cell carcinoma: Results from two phase III, randomized, vehicle-controlled studies. J Am Acad Dermatol 2004; 50(5): 722-33.

25 Mirza B, De’Ambrosis B. Treatment of facial superficial basal cell carcinomas with imiquimod 5ream. Clin Exp Dermatol 2003; 28(Suppl 1): 16-8.

26 Oster-Schmidt C, Altmeyer P, Stucker M. Successful treatment of basal cell carcinoma on the face with imiquimod 5ream. Acta Derm Venereol 2002; 82(6): 477.