Imiquimod in mixed capillary/lymphatic malformation
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2008年07月14日 11:48:53 Monday
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作者：Bongiorno M.R.,Aricò M. 作者单位：Department of Dermatology,University of Palermo,Palermo 90127,Italy
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【摘要】 Background We reported a 14-year-old white boy who came to be visited in January 2004 at our Dermatology Department.Physical examination revealed multiple translucent and hemorrhagic vesicles and skin colored nodules on the chin.The lesion had grown slowly in size over the previous 7 years.Objective To estimate the exact mechanism of action of topical imiquimod on the mixed capillary/lymphatic malformation.Results After 4 weeks of therapy the lesions were less protuberant.At the follow-up examination after a further two months of therapy,there was partial clinical regression of the capillary component with a return to normal skin colour.One month after termination of therapy the lesions had completely regressed and there was no evidence of a recurrence of the hemangioma.Conclusions Our studies suggest the efficacy of the use of topical imiquimod and this therapeutic modality may be of particular benefit in superficial type of capillary/lymphatic malformation in whom destructive intervention may be undesirable.
【关键词】 imiquimod；mixed capillary/lymphatic malformation；endothelial cells
Correspondence to Department of Dermatology，University of Palermo，Via del Vespro 131,Palermo 90127,Italy
E-mail: istderm@unipa.it
The classical Hamburg classification of arterial,venous,lymphatic,arteriovenous and combined vascular malformations can be further differentiated into truncal and extratruncal malformations.Truncal malformations are caused by a dysembryogenesis of the mature blood vessels,whereas extratruncal malformation derives from the primitive capillary network［1］,as well as from both the lymphatic system of the skin and subcutaneous tissue［2］.
In 1970,Peachey et al.divided lymphangioma circumscriptum into “classical” and “localized” forms,depending on their size and age at onset［3］.
Localized lymphatic malformation occurs at any age,and only affects small areas and needs to be differentiated from acquired lymphatic malformation.The lesion consists of fluid-filled vesicles which bulge on the skin surface.The vesicles can be either well-defined and discrete or grouped together.
In some patients,coexisting lymphatic,capillary,and venous malformations can be observed.These are characterized by ectastic venous vessels,and pseudo-vesicles,representing the superficial lesions of a lymphangioma.According to the Hamburg classification system,these are defined as an extra-truncular,mixed capillary/lymphatic malformation.Several therapies have been adopted to treat mixed capillary/lymphatic malformation.The few effective medical therapies for vascular tumours,namely corticosteroids,interferon and vincristine,require systemic administration and have been associated with potential toxicity.Surgery is
commonly resorted to［4］,but recurrent growth and side effects,such as scarring,are common.
For this reason laser treatment has been employed.The lights of both the argon laser （488~514 nm）［5］ and the dye laser （585~514 nm）［6-7］ are principally absorbed by hemoglobin,but not by lymph fluid,while CO2 laser is capable of vaporizing and sealing lymphatic and vascular lesions,independently of their hemoglobin content.While all laser treatments have proved successful to some extent,local recurrences can occur.
We reported a 14-year-old white boy,in otherwise excellent health,who came to be visited in January 2004 at our Dermatology Department.
Physical examination revealed multiple translucent and hemorrhagic vesicles and skin colored nodules on the chin（Figure 1）.The lesion had grown slowly in size over the previous 7 years.The patient complained of pain and itching but denied any preceding lesion or history of trauma to the region.
Microscopic examination （H&E stain） of a biopsy specimen obtained from a lesion shows cystically dilated lymph vessels lined by a single layer of endothelium in the uppermost portion of the dermis.The overlying epidermis shows acanthosis,papillomatosis and hyperkeratosis.
To appreciate the true anatomic extent and involvement of the lesion,high-frequency Color Doppler sonography （20 MHz） was performed.The predominant sonographic features were multiple inter-connected hypoechoic cystic lesions in the subcutaneous tissues with arterial flow （15 cm/s） and venous flow （5 cm/s）.
The patient had undergone surgical treatment for small lesions,as well as cryotherapy and CO2 laser treatment on several occasions,and each procedure was followed by a recurrence.Due to continuously occurring symptoms,such as bleeding,leakage of lymphatic fluid,discomfort and for cosmetic reasons,the young boy came to our Dermatology Clinic to be re-examined.
We decided to treat the patient with three applications per week of 5% Imiquimod Cream to be applied locally.After 4 weeks of therapy the lesions were less protuberant.At the follow-up examination after a further two months of therapy,there was partial clinical regression of the capillary component with a return to normal skin colour.One month after termination of therapy the lesions had completely regressed and there was no evidence of a recurrence of the hemangioma,however,there was still evidence of persistent lymphatic lesions（ Figure 2）.
Figure 1 Mixed capillary/lymphatic
malformation before treatment Figure 2 Mixed capillary/lymphatic malformation
on 16 weeks of topical imiquimod
Imiquimod,a heterocyclic amine,is an immune-response modifier.
The exact mechanism of action of imiquimod has yet to be elucidated,but it acts by affecting the innate and acquired immune response to challenges.Topical application of imiquimod to human skin stimulates the innate immune response through induction,syntesis,and release of cytokines,including interferon-F-）,interleukin-6 （IL-6） and tumor necrosis factors-［8~10］.Acquired immunity is enhanced through production of interleukins such as interleukin IL-1,IL-5,IL-8,IL-10 and IL-12 as well as granulocyte and macrophage stimulatory factor.
Although the pathomechanism of infantile vascular tumors is unknown,the rapid proliferation of endothelial cells［11］ suggests the importance of angiogenesis.In fact,angiogenic factors,such as vascular endothelial growth factor,basic fibroblastic growth factor［12］,and insulin-like growth factor-2［13］ are overexpressed during the proliferation of hemangiomas,whereas the anti-angiogenic factor tissue inhibitor of matrix metalloproteinase （TIMP） 1 is expressed during involution.
Involuting tumors also show a marked decrease in expression of markers of proliferation （ proliferating cell nuclear antigen and Ki-67）［14］ and an increase in cell apoptosis［15］.The inhibition of tumor growth correlated with increased epidermal expression of interleukin-12,and increased local levels of both interferon-and tumor necrosis factor-The mechanism of the imiquimod-induced inhibition of mixed capillary/lymphatic malformation involves both inhibition of proliferation and increase in tumor cell apoptosis.In fact,locally cytokines and interleukins produced by imiquimod,such as INF-and IL-12,would slow or prevent vascular growth.Furthermore,the increase in TIMP-1 expression,a inhibitor of angiogenesis and cell motility,caused by topical application of imiquimod cream has been show to attenuate vascular growth.
In our patient,the clinical effect may be result from imiquimod-mediated induction of antiangiogenic cytokines.
Our preliminary studies suggest the efficacy of the use of topical imiquimod and this therapeutic modality may be of particular benefit in superficial type of capillary/lymphatic malformation in whom destructive intervention may be undesirable.
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（Editor LEE）
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