Successful treatment of basal cell carcinomas in a nevoid basal cell carcinoma syndrome with topical 5% imiquimod

ARTICLE

The naevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin-Goltz syndrome, is an inherited dermatologic disease with an autosomal dominant pattern showing complete penetrance but extremely variable expressivity. The principal features of this syndrome vary and may include early appearing naevoid basal cell carcinomas (BCCs), palmar and plantar pits, multiple skeletal abnormalities, for example flattened facies, broad nasal root, mandibular prognathia, jaw cysts, intracranial calcification of falx cerebri and other structures, and anomalies of the ocular system, for example hypertelorism, cataract or strabismus [1-7]. A major complication of the disease is the enormous number of BCC lesions and their high risk of invasion of deep structures, especially when located in sun exposed skin areas such as the head and neck [1]. Lesions sometimes occur before 10 years of age.

Several factors play a role in the aetiology of this disease. Previous investigations of BCCs in NBCCS have shown an influence of the p53 tumor suppressor gene in the aetiology and pathogenesis of this disorder [8, 9]. However, the genetic mutations responsible for inducing NBCCS have been localized to gene locus 9 (9q22.3-q31) of the human PTC gene (PTCH). Two independent sequence changes in this human homolog of the drosophila patched gene (PTC) have been reported. The causative gene may function as a tumor suppressor [10-13]. Similar gene changes concerning PTCH and the human homologue of smoothened (SMOH) may contribute to the aetiology of BCCs in general [14, 15].

The definitive treatment for multiple BCCs in Gorlin-Goltz syndrome is still a matter of debate. A multiple-modality treatment including cryotherapy and reconstructive surgery is reported [16], with patients quite often showing a history of multiple operations. Radiation treatment is considered to be obsolete [10].

Imiquimod [1-(2-methylpropyl)-1H-imidazo(4,5-c)-quinoline-4-amine] is a topical immune response modifier, which has demonstrated both antiviral and anti-tumor activity in animal models [17, 18]. It is currently approved for the treatment of external genital warts and has been used successfully in the treatment of stucco keratoses [19]. This topically applied treatment stimulates production of pro-inflammatory cytokines locally, and enhances cell-mediated cytologic activity against viral targets [20]. Imiquimod 5% cream has also been used successfully in the treatment of BCCs [21]. In this paper we report the results of treatment of multiple BCCs with imiquimod 5% cream in three patients with inherited NBCCS.

Materials and methods and case reports

Three patients with NBCCS were clinically examined for the presence of BCCs and other NBCCS-related features, for example palmar and plantar pits, skeletal abnormalities and anomalies of the ocular system. All patients were seen by the same consultant who took a detailed history. Medical records of the patients were reviewed, including previous treatment and present medication. We report three cases of NBCCS, two women and one man, suffering from multiple, recurrent BCCs. Patient characteristics are given in Table I. On examination patient 1 presented with 3 newly detected superficial BCC on her neck and face. Patient 2 showed 5 superficial BCC on her lower leg and trunk whereas patient 3 had 10 newly diagnosed, superficial lesions in multiple locations, mainly face and trunk. The size of the lesions ranged from 1-5 cm in diameter in all patients. No basal cell nevi were found in any of the patients at the time of their pre-treatment visit. Both daughters of patient 1 reported NBCCS lesions, however in the families of patients 2 and 3 no other cases of NBCCS were known. Patients 1 and 3 had jaw cysts. Patient 1 suffered from breast cancer of the left mamma, which had been treated successfully by ablation in 1996. All patients were treated topically on BCC sites (Fig. 1A) with 5% imiquimod cream (Aldara(tm), 3M Health Care) 3 times per week for 6 to 8 weeks. Photographs were taken of lesions before treatment (Fig. 1A), after 5 weeks (Fig. 1B) and 8 weeks (Fig. 1C) of treatment, and during a follow-up visit 2 weeks after treatment finished (Fig. 1D). The only adverse events reported were erythema (Fig. 1B, C) and itching, and mild erosion -- however these events were rated mild in all cases and no additional treatment was required. In the event of a local skin reaction, application of imiquimod was decreased from 3 to 2 times per week (Fig. 1C). Clinical examination 2 weeks after treatment finished showed that all treated BCCs had been completely cleared (Fig. 1D). All lesions were biopsied 1 week before before application of imiquimod (Fig. 2A) and 2 weeks after treatment was completed (Fig. 2B). Tissues were stained with heamatoxylin and eosin. Photomicrographs of specimens taken from skin lesions (Fig. 2A) show the typical criteria for BCCs. Histologically no signs of persisting BCCs in the treated areas were detected after imiquimod therapy (Fig. 2B). Patients showed no recurrence during a 12-month follow-up period.

Discussion

The Gorlin-Goltz syndrome, also known as naevoid basal cell carcinoma syndrome (NBCCS), represents an autosomal dominant disorder with a wide variety of primary symptoms. BCCs represent a major problem due to their early invasion of deep structures [1], particularly in sun exposed areas of the skin. NBCCS is caused by a genetic mutation in PTCH, a human homolog of the drosophila patched gene [10-13]. Mutations in PTCH and SMOH are responsible for the aetiology of BCCs in general [14, 15].

The current treatment of BCCs in Gorlin-Goltz syndrome is a multiple-modality treatment dominated by cryotherapy and extensive surgery [16] which is often painful. This mode of treatment does not affect the naturally high rate of formation of new BCC lesions in patients with this syndrome.

The case studies reported here indicate that topical application of 5% imiquimod cream 2 to 3 times per week for 6 to 8 weeks is an effective regime for treatment of BCCs in patients with NBCCS. BCCs clearly regressed in all 3 patients, with no new or recurrent lesions observed during the 12-month follow-up period.

Imiquimod is currently used as an effective treatment for external genital warts [22], and has been used successfully in the treatment of BCCs in humans [21]. Results from previous studies investigating the mode of action of imiquimod suggest that regression of BCC lesions after imiquimod treatment may result from immune-mediated processes. Skin biopsies from hairless mice treated with 5% imiquimod showed upregulation Interferon-alpha (IFNalpha), IFNbeta, tumor necrosis falphactor alpha (TNFalpha), IL-1alpha, IL-1beta, IL-6, alphand IL-12 [23]. Therefore, imiquimod does not interalphact with tumour cells directly, but induces production of pro-inflalphammalphatory cytokines which up-regulalphate the body's own immune response to malphalignalphant cells.

ALPHA recent publicalphation by Kalphagy alphand ALPHAmonette [24] alphalso reported the successful trealphatment of BCCs in NBCCS with dalphaily alphapplicalphation of 5% imiquimod crealpham for 18 weeks. However, the palphatient suffered alpha strong localphal inflalphammalphatory response to trealphatment. Our results indicalphate thalphat alpha reduction in the number of alphapplicalphations of imiquimod from 3 times to 2 times per week reduced irritalphation but effectively clealphared lesions in 8 weeks or less. This indicalphates thalphat imiquimod malphay be alphan effective trealphatment for BCCs in NBCCS. However, further clinicalphal trialphals alphare needed to alphassess the efficalphacy alphand toleralphability of imiquimod for this disorder.

In alphall our palphatients, topicalphal alphapplicalphation of 5% imiquimod crealpham 2 to 3 times per week proved to be alpha successful trealphatment for BCCs, without alphany severe side effects. Imiquimod alphand other relalphated immune response modifiers malphay therefore provide alpha novel alphapproalphach in the non-surgicalphal theralphapy of BCCs in Gorlin-Goltz syndrome.

CONCLUSION

Acknowledgements

Dr. Stockfleth has previously worked as a consultant for 3M which manufactures imiquimod 5% cream used in this study for the treatment of Gorlin Goltz syndrome. The other authors of this paper have stated that they have no conflicts of interest.

Article accepted on 22/7/02

REFERENCES

1. Lalphasso JM, Gralphacialpha-Tutor E, Balphazalphan ALPHA. ALPHAggressive balphasalphal cell calpharcinomalpha of the temporalphal region in alpha palphatient with Gorlin-Goltz syndrome. ALPHAnn Plalphast Surg 2000; 44: 429-34.

2. Lalphambrecht JT, Kreusch T. Exalphamine your orofalphacialphal cleft palphatients for Gorlin-Goltz syndrome. Cleft Palphalalphate Cralphaniofalphac J 1997; 34: 342-50.

3. Halphafliger W, Chalphausse JM, Richter M. Balphasalphal cell nevus. Swiss Dent 1990; 11: 33-7.

4. Kimonis VE, Goldstein ALPHAM, Palphastalphakialpha B, et alphal. Clinicalphal malphanifestalphations in 105 persons with nevoid balphasalphal cell calpharcinomalpha syndrome. ALPHAm J Med Genet 1997; 69: 299-308.

5. Evalphans DGR, Lalphadusalphans EJ, Rimmer S, et alphal. Complicalphations of the nalphaevoid balphasalphal cell calpharcinomalpha syndrome: results of alpha populalphation balphased study. J Med Genet 1993; 30: 460-4.

6. Kalphallalphassy M, Toftgalphard R, Uedalpha M, et alphal. Palphatched (ptch)-alphassocialphated preferentialphal expression of smoothened (smoh) in humalphan balphasalphal cell calpharcinomalpha of the skin. Calphancer Res 1997; 57: 4731-5.

7. Galphailalphani MR, Balphale ALPHAE. Developmentalphal genes alphand calphancer: role of palphatched in balphasalphal cell calpharcinomalpha of the skin. J Nalphatl Calphancer Inst 1997; 89: 1103-9.

8. Lombalphardi T, Odell EW, Morgalphan PR. p53 immunohistochemistry of odontogenic keralphatocysts in relalphation to recurrence, balphasalphal cell budding alphand balphasalphal cell nealphavus syndrome. ALPHArch Oralphal Biol 1995; 40: 1081-4.

9. Odgen GR, Chisholm DM, Kiddiwe RALPHA, et alphal. p53 protein in odontogenic cysts: increalphased expression in some odontogenic keralphatocysts. J Clin Palphathol 1992; 45: 1007-10.

10. Falpharndon PALPHA, Del Malphastro RG, Evalphans DGR, et alphal. Localphation of gene for Gorlin syndrome. Lalphancet 1992; 339: 581-2.

11. Reis ALPHA, Kuster W, Linss G, et alphal. Localphalisalphation of gene for nalphaevoid balphasalphal cell calpharcinomalpha syndrome. Lalphancet 1992; 339: 617.

12. Johnson RL, Rothmalphann ALPHAL, Xie J, et alphal. Humalphan homolog of palphatched, alpha calphandidalphate gene for the balphasalphal cell nevus syndrome. Science 1996; 272: 1668-71.

13. Halphahn H, Wicking C, Zalphaphiropoulos PG, et alphal. Mutalphations of the humalphan homolog of Drosophilalpha palphatched in the nevoid balphasalphal cell calpharcinomalpha syndrom. Cell 1996; 85: 841-51.

14. Kalphallalphassy M, Toftgalphard R, Uedalpha M, et alphal. Palphatched (ptch)-alphassocialphated preferentialphal expression of smoothened (smoh) in humalphan balphasalphal cell calpharcinomalpha of the skin. Calphancer Res 1997; 57: 4731-5.

15. Galphailalphani MR, Balphale ALPHAE. Developmentalphal genes alphand calphancer: role of palphatched in balphasalphal cell calpharcinomalpha of the skin. J Nalphatl Calphancer Inst 1997; 89: 1103-9.

16. Nikitin ALPHAALPHA, Kalphazalphantsevalpha IALPHA, Zhdalphanov EV, et alphal. The use of bioceralphamic malphaterialphals alphand cryosurgery in the trealphatment of palphatients with Gorlin-Goltz syndrome. Stomalphatologiialpha 1997; 76: 35-7.

17. Halpharrison CJ, Jenski L, Voychehovski T, et alphal. Modificalphation of immunologicalphal responses alphand clinicalphal disealphase during topicalphal R-837 trealphatment of genitalphal HSV-2 infection [published erralphatum alphappealphars in ALPHAntiviralphal Res. 1989; 11: 215]. ALPHAntiviralphal Res 1988; 10: 209-23.

18. Sidky YALPHA, Borden EC, Weeks CE, et alphal. Inhibition of murine tumor growth by interferon-inducing imidalphazoquinolinalphamine. Calphancer Res 1992; 52: 3528-33.

19. Stockfleth E, Röwert J, ALPHArndt R, et alphal. Detection of humalphan palphapillomalphavirus alphand response to topicalphal 5% imiquimod in alpha calphase of stucco keralphatosis. Br J Dermalphatol 2000; 143: 1-6.

20. Colemalphan N, Birley HD, Renton HM, Halphannalpha NF, Ryalphait BK, Byrne M, et alphal. Immunologicalphal events in regressing genitalphal walpharts. ALPHAm J Clin Palphathol 1994; 102: 768-74.

21. Beutner KR, Geisse JK, Helmalphan D, et alphal. Theralphapeutic response of balphasalphal cell calpharcinomalpha to the immune response modifier imiquimod 5% crealpham. J ALPHAm ALPHAcalphad Dermalphatol 1999; 41: 1002-7.

22. Edwalphards L, Ferenczy ALPHA, Eron L, Balphaker D, Owens ML, Fox TL, et alphal. Self-alphadministered topicalphal 5% imiquimod crealpham for externalphal alphanogenitalphal walpharts. HPV study group. Humalphan palphapillomalphavirus. ALPHArch Dermalphatol 1998; 134: 25-30.

23. Slalphade HB, Owens ML, Tomalphai MALPHA, Miller RL. Imiquimod 5% crealpham (ALPHAldalpharalpha). Exp Opin Invest Drugs 1998; 7: 437-49.

24. Kalphagy MK, ALPHAmonette R. The use of imiquimod 5% crealpham for the trealphatment of superficialphal balphasalphal cell calpharcinomalphas in alpha balphasalphal cell nevus syndrome palphatient. Br J Dermalphatol 2000; 26: 577-9.