Current status and progress in the treatment of cutaneous hemangioma Hemangioma is a benign tumor in infants and children, mostly appearing at birth or within one month after birth, and is usually found in the superficial parts of the head and limbs [2], but also in mucous membranes, muscles, bones, and even in special parts of the skull. Hemangioma is a congenital dysplasia that occurs during the formation of blood vessels in the embryonic period, and is a malformation with both tumor and malformation properties. It can grow in any part of the body, with the head and neck being the most common, accounting for about 60%, followed by the limbs and trunk. The prevalence is 3% to 8% in newborns and can be as high as 10% to 12% by the age of 1 year, and can be multiple [3-5]. There are many types of hemangiomas, and according to the traditional clinical classification, hemangiomas are classified as nevus, strawberry hemangioma, cavernous hemangioma and mixed hemangioma. According to Williams et al [6], early treatment is very important because the disease can cause great psychosocial trauma to patients and their families. As the demand for quality of life increases, the treatment of proliferative hemangiomas has gradually changed from the traditional treatment model to the cosmetic model. At present, different treatment methods are often chosen according to age, type, period and size of hemangioma. The methods of treatment of hemangioma are reviewed as follows. 1.Current treatment status 1.1 Cryotherapy Cryotherapy for hemangioma is a kind of induced destructive irreversible tissue reaction, which is applicable to capillary hemangioma. Commonly used freezing agents include carbon dioxide snow (dry ice), hyperbaric oxygen freezer, chloroethane, liquid nitrogen and so on. The method is to place the freezing agent on the hemangioma for 5-10 s (liquid nitrogen freezing is appropriate for no more than 60 s), and the freezing time is reduced by half for infants and children, and freezing can be done 1 to 2 times. Generally, dry ice freezing is more effective in children within 2 weeks after birth, and can reduce scar formation. The disadvantages are: easy to cause epidermal ulceration, causing infection, and often have skin scarring and color change after treatment. When freezing, attention should be paid to the patient’s age, tumor type, size, location and depth, etc. The operation should be skilled, the freezing dose should be moderate, and postoperative attention should be paid to anti-infection and local care, and the treatment results are satisfactory [9]. However, due to the non-specific nature of cryotherapy, it is not strongly advocated, especially for hemangiomas involving deeper tissues. 1.2 Pingyangmycin Since 1977, when Yura [10] and others used bleomycin for the successful treatment of lymphangioleiomyomatosis by local injection, pingyangmycin, which is the same as A5, the main component of bleomycin, has been used for the treatment of hemangioma in China [11-13], and has achieved good results. The principle of the action of Pingyangmycin is: using Pingyangmycin can specifically bind to DNA, causing NDA breakage, interfering with tumor cell division and proliferation, Pingyangmycin can easily accumulate after entering the tumor, and the high concentration of the drug can induce atrophy and necrosis of vascular endothelial cells, and the tumor can degenerate and disappear, so as to achieve the purpose of treating hemangioma. It is mainly applied to cavernous hemangioma and mixed type hemangioma. Hao Xinhe treated 58 cases of various types of hemangioma in the maxillofacial area with Pingyangmycin, with an efficiency of 95.23% for cavernous hemangioma and 83.32% for strawberry hemangioma. The main side effects were rash, fever, and allergic reactions, etc. In this regard, Shou Boquan et al. suggested that intramuscular injection of dexamethasone before PYM injection has a certain preventive effect. PYM has no immunosuppressive effect and hardly suppresses the hematopoietic function of bone marrow, so it is suitable for the treatment of hemangioma in infants and children. This method is simple and effective in treating hemangioma, and if injected properly, the tumor will gradually shrink without necrosis, leaving no scar and satisfactory appearance, which is more in line with medical cosmetic requirements. 1.3 Hormone therapy Treatment mechanism, experimental research has found that rapidly growing capillary hemangioma contains high estradiol receptors, which can promote the formation and development of hemangioma, corticosteroids can compete with estradiol receptors in hemangioma, thus inhibiting hemangioma proliferation, in addition, steroid hormones can make the pre-capillary sphincter contract, increase the sensitivity of blood vessels to blood reactive amines, inhibit the rate and scope of new blood vessel proliferation. In addition, steroid hormones can contract the precapillary sphincter, increase vascular sensitivity to blood reactive amines, and inhibit the rate and extent of neovascularization. Yu Song et al. found that exogenous glucocorticoids (tretinoin) may inhibit vascular endothelial cell growth factor secretion through glucocorticoid receptor mediation, impede vascular endothelial cell proliferation, and promote the regression of hemangioma. Hormone therapy can be considered in the following cases: ① proliferating hemangiomas within 1 year of age; ② hemangiomas located in functional areas or with more serious complications; ③ facial hemangiomas affecting the patient’s appearance; ④ multiple, refractory and critically ill children with hemangiomas. For the dose and duration of systemic administration, Mulliken advocates that prednisone should be administered at 2-3 mg/kg/d for two consecutive weeks for the treatment of pediatric hemangioma, and if the tumor responds (slower growth, lighter tumor color, softer tumor, etc.), the hormone dosage should be gradually reduced to maintenance dosage in the following two to four weeks, and then discontinued before the child reaches one year of age. Stop the drug. According to domestic scholars, the treatment of hemangioma with prednisone can be calculated as 1mg/kg/day, taken every other morning for a total of 8 weeks, and then the dosage is reduced by half every week. Long-term use of hormone therapy for hemangioma may result in more serious complications such as infection and hypertrophic obstructive cardiomyopathy. Therefore, attention should be paid to the side effects of hormones during administration. For local injection administration, it depends on the size of the tumor. Zhao Pingping et al [19] used oral prednisone to treat infantile hemangiomas with an efficiency of 80%. O’Keefe et al [20] concluded that the treatment of hemangioma with local injections of hormones is to some extent satisfactory, but the treatment of hemangioma with glucocorticoids alone is associated with higher doses and more side effects, therefore, the combination of drugs is often used in clinical practice [21]. 1.4 Surgical treatment methods Surgical resection of hemangioma is still controversial, and most people believe that the lesions are small, relatively limited, and not in exposed parts of the body, surgical resection can be used. Surgery is essential to reduce bleeding, to avoid recurrence, and to be vigilant about the appearance of scars and cosmetic damage. The lesion should be removed as much as possible to avoid recurrence, and the excised lesion should be closed with sutures that do not cause local organ displacement and dysfunction. For large traumas on the head, face, hands and other important areas, full-thickness skin or medium-thickness skin grafting and repair are feasible. Because of its serious side effects, such as inconsistent skin color and pattern, skin necrosis, atrophy, scar formation, etc., it seriously affects the patient’s beauty, and most hemangiomas are difficult to remove cleanly and have a high recurrence rate [22], so it is less used now. 1.5 Biological factor therapy mainly includes interferon alpha-2a, which was proposed by White in 1989 and is mainly used for the treatment of severe hemangiomas, such as ①Kasabach-Merritt syndrome; ②severe hemangiomas in young children with limbs at risk of amputation and failing to respond to corticosteroid therapy; ③occupying lesions that invade major organ (iii) patients with life-threatening lesions invading major organs and channels. The main mechanisms of action include antiviral, anti-cell proliferation, inhibition of angiogenesis, and regulation of the body’s immune response. It has been used clinically to treat severe hemangiomas with good results. The exact dose of interferon alpha-2a is not yet known, and its clinical application is limited by the serious side effects, such as seizures during hyperthermia and even spastic diplegia, and retinal cotton wool exudates. 1.6 Combination therapy For complex and extensive hemangiomas, the combination of multiple therapeutic methods with positive efficacy is appropriate, which can synergistically increase the effectiveness, shorten the course of treatment or reduce the side effects of certain drugs. For example, Zhang Bo [25] and others treated 126 cases of complex hemangioma with the combination of pinyamycin and dexamethasone, and the results showed that the efficiency of injected capillary hemangioma and mixed hemangioma was 100%, that of cavernous hemangioma was 89.7%, and that of trapezius hemangioma was 25.0%. Xu Fengguang [26] and others treated 11 cases of cavernous hemangioma with Pingyangmycin iodine oil emulsion combined with dexamethasone. 3 months after treatment, 4 cases were effective, 7 cases were effective; 6 months after treatment, 5 cases were effective, 6 cases were effective, and no invalidation was seen. Huang Xintian [27] et al. treated 87 cases of diffuse cavernous hemangioma with surgery combined with Nd:YAG laser, and the follow-up ranged from 1 to 63 months. 71 cases (81.6%) were found to be effective and 16 cases (18.4%) were found to be effective after clinical and imaging evaluation, and the total effective rate was 100%. 1.7 Laser treatment Since Apfelberg used argon ion laser for the treatment of superficial cutaneous hemangioma in the proliferative stage in 1981, the application of 480-630 nm wavelength laser for the treatment of superficial vascular diseases has become more popular in recent years. Currently, the pulsed dye laser has replaced the argon laser as the treatment of choice for selective photothermal action. david et al [28] and Michel [29] both concluded that the pulsed dye laser has good results for hemangiomas complicated with ulceration and bleeding. Since the effective penetration depth of visible light in this wavelength range is less than 1.5 mm, which is insufficient to damage the whole layer of most hemangiomas, it is only suitable for superficial, small and slow-growing or partially stopped hemangiomas, provided that no scar and permanent pigmentation changes are formed. Yang et al [31] suggested that combined surgical and laser treatment could improve the efficacy of hemangioma. 1.8 Copper needle treatment A copper needle of about 5 cm in length and 1.0-2.5 mm in diameter was inserted into the tumor and fixed properly, with a distance of 1-2 cm, and the number of copper needles was determined according to the size of the tumor. The number of copper needles was determined according to the size of the tumor. The needles were kept for 7 to 9 days. The mechanism of action is that the copper needle piercing into the hemangioma body will cause the endothelium of the blood vessel to swell and break down, forming a thrombus, and a large amount of fibrous tissue outside the blood vessel will grow into the thrombus and the blood vessel wall will disappear, thus causing the tumor to fibrosis and atrophy, thus achieving the effect of hemangioma cure. However, scarring may be formed after treatment, which limits the prospect of its wide application. 1.9 Radionuclide treatment Generally, 32P dressing or 32P intra-tumor injection and 90Sr dressing are used. The mechanism of action is that the radioisotope acts on the hemangioma and causes degenerative changes such as microvascular atrophy and occlusion, thus achieving the treatment purpose. The adverse reactions are mild, but a few patients have localized darkening of skin color after the patching, and some patients have radioactive dermatitis, and very few patients have localized skin pigment loss and atrophy due to excessive dosage of the drug, and children are prone to hematopoietic system changes. Zhang Yuan et al [32] reported that 90Sr patching is a better method for the treatment of hemangioma on the body surface, and its efficacy varies greatly depending on the type of hemangioma, the size of the tumor and the individual, and the therapeutic effect depends on the reasonable choice of irradiation dose and time. For superficial and thin capillary hemangiomas on the head, face, trunk and limbs, 32P patching therapy is generally chosen. The dose of patching depends on the location and extent of the lesion. Inappropriate treatment can lead to chronic radiation dermatitis or ulceration, skin pigmentation changes and other consequences. Other scholars believe that radiation therapy is still an option for proliferating hemangiomas that affect important areas such as vision, respiration and feeding, when hormone use is expected to be ineffective in the short term. The operation should pay attention to small dose, short course of treatment, and the treatment area should not exceed the range of hemangioma. Recent experiments have shown that capillary hemangioma has obvious endothelial cell proliferation during the proliferative phase, while spongy and trapezius hemangioma do not have endothelial cell proliferation. The former is a true hemangioma, while the latter is a vascular malformation, which are essentially two different diseases, so they should be treated differently. The treatment of inhibiting endothelial cell proliferation is being widely used in the treatment of malignant tumors. Because of the pathological similarities between true hemangiomas and malignant tumors, both are accompanied by significant endothelial cell proliferation. There are three main ways to inhibit endothelial cell proliferation, one is to counteract angiogenic growth factors, the other is to increase angiogenic inhibitory factors, and the third is to apply chemical drugs that inhibit angiogenesis. 2.1 Angiogenic growth factor Vascular endothelial growth factor (VEGF) [33] VEGF was first purified by FeI-rara from bovine pituitary follicular stellate cells in vitro culture in 1989 and named vasoendothelial growth factor (VEGF). VEGF is known to act specifically on endothelial cells and is also the most potent vascular permeabilizer, causing increased vascular permeability, promoting fibrin deposition in the extracellular matrix, and promoting neovascularization. In recent years, VEGF has been recognized as a major regulator of angiogenesis in tumor tissues. Fibroblast growth factor (FGF) FGF mainly includes acidic fibroblast growth factor (aFG) and basic fibroblast growth factor (bFGF), among which bFGF is more closely related to angiogenesis. They are involved in the regulation of cell growth, differentiation, embryonic development and vascular growth under normal physiological conditions. Tumor necrosis factor-a (TNF-a) is a mononuclear macrophage-derived multifunctional factor. It acts as both an angiogenic growth factor and an angiogenic inhibitory factor. Angiogenesis is induced at low doses, but growth is inhibited at high doses. In addition, TNF-a can also regulate the expression of other angiogenic growth factors, and can increase the content of three angiogenic growth factors, IL-8, VEGF and bFGF, in stromal cells and tumor cells, thus promoting the formation of neovascularization. Transforming growth factor-β (TGF-β) [34] is produced by macrophages and activated platelets and acts as a chemotactic agent for macrophages, thus having an indirect angiogenesis-promoting effect. However, its effects are dose-dependent, i.e., stimulatory at low concentrations, inhibitory at high concentrations, and deficient in poor vascular integrity and reduced remodeling. Other interleukin-8 (IL-8) has been shown to have the ability to induce tumor angiogenesis and tumor cell motility metastasis. Cell adhesion molecules are closely associated with angiogenesis. Platelet-derived endothelial cell growth factor (PD-ECGF) is an endothelial cell divider but not a typical growth factor that promotes endothelial cell migration and differentiation. Endotoxin is involved in angiogenesis by stimulating the production of VEGF, bFGF, TGF-p, IL-1 and IL-6. 2.2 Angiogenesis inhibitory factor Angiostatin, a specific fragment of fibrinogen with a relative molecular weight of 3.8×104, is the first tumor-derived tumor angiogenesis inhibitory factor, which can inhibit angiogenesis at downstream sites far from the tumor, keep the dormant state of carcinoma in situ, and prevent the growth and vascularization of metastases. Endostatin (endostatin), the C-terminus of type XV1Q collagen with a relative molecular weight of 2.0×104, is the 2nd tumor-derived angiogenesis inhibitor identified and is a highly active endothelium-specific inhibitor that induces apoptosis of endothelial cells and significantly reduces bcl-2 and bcl-XL anti-apoptotic proteins. Platelet factor-4 (PF-4), a naturally potent angiogenesis inhibitor, inhibits endothelial cell proliferation mainly by blocking the binding of bFGF and VEGF to their receptors. Other interleukin-12 (IL-12), a cytokine, contributes to the production of endogenous angiogenesis inhibitor interferon-inducible protein I-10 (IP-10) by inducing the activity of IFN-V. Tumor necrosis factor-a (TNF-a) and transforming growth factor-p (TGF-p) act as inhibitors of angiogenesis at high concentrations. Fibronectin and prolactin have been confirmed by in vitro experiments to contain inhibitory factors that inhibit endothelial cell proliferation, and these precursor macromolecules are converted into tumor vascular suppressors by the action of various protein hydrolases. 2.3 Chemical drugs that inhibit angiogenesis Their effects are indirect, affecting only the microenvironment that regulates tumor angiogenesis, and their effects are highly variable. For example, sulforaphane inhibits the binding of bFGF to receptors, interferon (IFN-a) interferes with endothelial cell migration, NP470 (AGM-1470) reduces endothelial cell proliferation, and triamcinolone inhibits VEGF-mediated endothelial cell proliferation and migration, etc. To inhibit angiogenic growth factors, use their antibodies or block their binding to receptors; to increase angiogenic inhibitory factors, give exogenous supplementation; chemical drugs should be used with caution because of their side effects. Among them, vasopressor, endothelial inhibitor and anti-human VEGF monoclonal antibody, which have the advantages of less toxic side effects and high specificity, have wide application prospects. In conclusion, true hemangioma and vascular malformation are essentially two different diseases and should be treated differently. Some hemangiomas can be cured by one method alone, while others require the combination of several methods to achieve more satisfactory results, so we should treat patients with hemangiomas with careful diagnosis and classification, and take the best treatment method. At present, many scholars have tried to achieve the purpose of tumor treatment by selectively inhibiting the action of growth factors, inhibiting the synthesis and secretion of growth factors through various pathways, or preventing the binding of growth factors to their receptors and combining PDT therapy to inhibit the formation of hemangioma proliferation. According to Hu Qiong-Hua et al [36], the future direction of treatment should rely on the study of the molecular mechanism of angiogenesis and angiogenesis, and the treatment should target the causative genes. 3. Problems and prospects Cutaneous hemangioma is the most common congenital cutaneous vascular lesion in infants and children. Cutaneous hemangiomas are mostly found in the skin and subcutaneous tissues. The ideal treatment should be able to inhibit tumor growth in time and promote its short-term regression, while maintaining normal appearance and physiological functions without interfering with the normal physiological metabolic process of the body. There are many methods to treat the disease, each with its own advantages and disadvantages. Although there are more treatment methods for hemangioma, the purpose of treating cutaneous hemangioma is to control growth and promote regression, and this purpose is achieved with full consideration of cosmetic effects. Therefore, early treatment of hemangiomas is necessary, and some hemangiomas can be treated early with good results. It should be recognized, however, that for deep hemangiomas such as cavernous hemangiomas, a combination of treatments is necessary. To date, there is still no ideal device for the treatment of hemangioma, but relatively speaking, the use of comprehensive treatment according to the different types of hemangioma and the size of the lesion has better treatment results than in the past. The future direction of treatment should depend on the study of the molecular mechanisms of angiogenesis and angiogenesis and the treatment of the causative genes.