Infantile Haemangiomas with Minimal or Arrested Growth.

Infantile hemangioma. Part 1: Epidemiology, pathogenesis, clinical presentation and assessment

Infantile hemangioma (IH) is a common benign tumor, which mostly resolves spontaneously; however, children with high-risk IH need treatment. To compare the efficacy of single drug pharmacotherapy and combined drugs pharmacotherapy for a spectrum of Infantile Cutaneous Hemangiomas ranging from smaller and simpler lesions to large and complicated lesions selectively chosen. It is a Retrospective and Prospective study done for 2yrs. All children less than 2 years of age, with Infantile Cutaneous Hemangiomas. Infantile Cutaneous Hemangiomas not amenable for complete primary excision because of size and site of lesion are included in the study. Children with Infantile Cutaneous Hemangiomas presenting after 2 years of age and Hemangiomas associated with Visceral Hemangiomas. Infantile hemangiomas (IHs) are the most-common soft-tissue tumors of infancy, occurring in 4% to 10% of children under 1 year of age, with a clear female to male predominance of 2.5 – 4:1­. 27(64.2%) presented with lesion in the head and neck region. Three (3) out of the 42 presented (7.1%) on the chest. Four (4) out of the 42 (9.5%) presented on the Anterior abdominal wall.

Infantile and congenital hemangiomas are difficult to distinguish in infants. The aim of this study was to compare the conventional ultrasonographic (US) and elastographic features of infantile and congenital hemangiomas. The US findings in 118 patients with congenital hemangioma (58 non-involuting, 36 rapidly involuting, 24 partially involuting) and 111 with 120 infantile hemangioma were retrospectively evaluated. On US imaging, 31.7% of infantile hemangiomas were hyperechoic, 31.7% hypoechoic and 36.6% mixed-echoic with hyperechoic and hypoechoic areas; 57.6% of congenital hemangiomas were mixed-echoic with a hypoechoic area and many vessels visible, 39.0% hypoechoic and 3.4% were mixed-echoic with hyperechoic and hypoechoic area. Calcifications were present in 6.8% and visible vessels involving muscle in 24.6% of congenital hemangiomas. All infantile hemangiomas and 82.2% of congenital hemangiomas were well-defined. All congenital hemangiomas were subcutaneous whereas 17.5% of the infantile hemangiomas were superficial. The maximum diameter and vascular density were greater in congenital hemangiomas. Elastography demonstrated that the congenital hemangiomas were softer than the infantile hemangiomas. The maximum diameter (including of visible vessels), thickness, vascular density, venous blood flow velocity and elasticity scores were greater for rapidly and partially involuting congenital hemangiomas than for non-involuting ones. The density of visible vessels in congenital hemangiomas decreased in the order of non-involuting, partially involuting and rapidly involuting. In conclusion, congenital hemangiomas have distinctive US imaging characteristics, including a greater maximum diameter, vascular density, number of visible vessels, visible vessels involving muscle, calcifications and elasticity score.

Infantile hemangioma (IH) is the most common vascular tumor of infancy. We evaluated the incidence of and the environmental risk factors for IH using data from the Japan Environment and Children's Study, a large-scale nationwide epidemiological study. The materials and methods are described in detail in the Supplementary Materials and Methods. The 85,244 mother–infant pairs selected for the analysis had an average ± SD gestational age of 39.2 ± 1.6 weeks and an average ± SD birth weight of 3,010 ± 428 g (Table 1). In the infant population, 51.3% of the infants were male, 42.4% were first children, and 98.2% were single birth. Among the mothers, 72.9% were aged <35 years, 73.6% had a prepregnancy body mass index between 18.5 and 25, and 92.1% achieved pregnancy by spontaneous conception.Table 1Characteristics of Participants (N = 85,244)CharacteristicsTotal NumberCaseIncidenceCharacteristicsTotal NumberCaseIncidencen(%)N%n(%)n%Infantile hemangiomaSmoking status Total85,244(100.0)6130.72 Never49,671(58.3)3600.72Maternal age (years) Ex31,047(36.4)2330.75 <3562,119(72.9)4330.70 Current3,273(3.8)150.46 ≥3522,505(26.4)1790.80 Missing1,253(1.5)50.40 Missing620(0.7)10.16Physical activity (METs・hours/day)Annual household income (JPY) Low (<0.472)28,727(33.7)2010.70 <4 million30,913(36.3)1980.64 Medium (0.472–<2.349)24,417(28.6)1940.79 4–<6 million26,319(30.9)1960.74 High (≥2.349)27,470(32.2)1980.72 ≥6 million21,591(25.3)1740.81 Missing4,630(5.4)200.43 Missing6,421(7.5)450.70Apgar score, mean ± SD8.6± 0.98.5±1.2Highest educational level Present83,201(97.6)6010.72 ≤12 years29,261(34.3)1790.61 Missing2,043(2.4)120.59 >12–<16 years35,925(42.1)2630.73Gestational age (weeks), mean ± SD39.2± 1.638.9±1.8 ≥16 years19,008(22.3)1670.88 Present85,244(100.0)6130.72 Missing1,050(1.2)40.38Birth weight, (g), mean ± SD3,010± 4282,939±483Employed Present85,193(99.9)6130.72 No38,432(45.1)2700.70 Missing, n (%)51(0.1)00.00 Yes45,478(53.4)3390.75Sex of the child Missing1,334(1.6)40.30 Male43,770(51.3)2080.48Body mass index before pregnancy Female41,474(48.7)4050.98 <18.513,801(16.2)1010.73Previous deliveries 18.5‒<2562,719(73.6)4470.71 Nullipara36,148(42.4)2890.80 ≥258,663(10.2)650.75 Multipara46,974(55.1)3070.65 Missing61(0.1)00.00 Missing2,122(2.5)170.80AsthmaMultiple conceptions No75,627(88.7)5550.73 No83,676(98.2)5970.71 Yes9,084(10.7)540.59 Yes1,568(1.8)161.02 Missing533(0.6)40.75Infant congenital anomalyPollinosis No83,243(97.7)6050.73 No53,907(63.2)3460.64 Yes2,001(2.3)80.40 Yes30,804(36.1)2630.85Pregnancy complications Missing533(0.6)40.75 No72,261(84.8)5090.70Atopy Yes12,983(15.2)1040.80 No71,257(83.6)5010.70Labor complications Yes13,454(15.8)1080.80 No45,674(53.6)3010.66 Missing533(0.6)40.75 Yes39,570(46.4)3120.79Allergic conjunctivitisFertilization method No76,184(89.4)5260.69 Spontaneous conception78,532(92.1)5380.69 Yes8,527(10.0)830.97 Missing533(0.6)40.75 Intrauterine ovulation induction/3,467(4.1)300.87Food allergy Artificial insemination with No80,685(94.7)5680.70 husband's semen Yes4,026(4.7)411.02 Missing533(0.6)40.75 In vitro fertilization/2,770(3.2)401.44Alcohol intake Intracytoplasmic sperm injection/ Never28,217(33.1)2000.71 Fresh embryo transfer/ Ex53,498(62.8)3930.73 Frozen embryo transfer Current2,264(2.7)150.66 Missing1,265(1.5)50.40 Blastocyst transfer88(0.1)11.14 Missing387(0.5)41.03Abbreviations: JPY, Japanese Yen; MET, metabolic equivalent. Open table in a new tab Abbreviations: JPY, Japanese Yen; MET, metabolic equivalent. The incidence of IH at age 1 year was 0.72%. IH was associated with the maternal lifetime incidence of pollinosis (adjusted OR: 1.27, 95% confidence interval [CI]: 1.07–1.51), male child (adjusted OR: 0.48, 95% CI: 0.40–0.56), gestational age (adjusted OR: 0.92, 95% CI: 0.87–0.97), and the use of reproductive medicine (adjusted OR: 1.78, 95% CI: 1.26–2.50). IH was marginally associated with allergic conjunctivitis (adjusted OR: 1.27, 95% CI: 1.00–1.63) (Table 2).Table 2Factors Involved in IH at Age of 1 Year (N = 85,244)FactorsCrude ModelAdjusted ModelFactorsCrude ModelAdjusted ModelOR(95% CI)OR(95% CI)OR(95% CI)OR(95% CI)Infantile hemangiomaPhysical activity (Mets・hours/day) Total—— Low (<0.472)——Maternal age (years) Medium (0.472–<2.349)1.15(0.95–1.39)1.15(0.95–1.40) <35—— High (≥2.349)1.00(0.81–1.22)1.03(0.84–1.27) ≥351.14(0.96–1.36)1.04(0.86–1.25)Annual household income (JPY)Apgar score0.89(0.83–0.96)0.94(0.87–1.02) <4 million—— 4–<6 million1.15(0.94–1.42)1.08(0.88–1.34)Gestational age (weeks)0.92(0.88–0.95)0.92(0.87–0.97) ≥6 million1.26(1.02–1.56)1.09(0.86–1.38)Highest educational levelBirth weight (g)0.69(0.58–0.82)0.99(0.77–1.26) ≤12 years—— >12–<16 years1.19(0.98–1.44)1.12(0.92–1.37) ≥16 years1.43(1.16–1.76)1.31(1.04–1.65)Sex of the childEmployed Male0.48(0.41–0.57)0.48(0.40–0.56) No—— Female—— Yes1.06(0.90–1.25)1.03(0.87–1.22)Previous deliveriesBody mass index before pregnancy Nullipara—— <18.51.03(0.83–1.28)1.04(0.83–1.29) Multipara0.82(0.70–0.96)0.85(0.71–1.01) 18.5‒<25——Multiple conceptions ≥251.05(0.81–1.37)1.09(0.83–1.42) No1.44(0.87–2.36)1.11(0.65–1.88)Asthma Yes—— No——Infant congenital anomaly Yes0.82(0.61–1.08)0.71(0.53–0.95) No——Pollinosis Yes0.55(0.27–1.10)0.47(0.23–0.96) No——Pregnancy complications Yes1.34(1.14–1.57)1.27(1.07–1.51) No——Atopy Yes1.14(0.92–1.41)1.05(0.84–1.30) No——Labor complications Yes1.15(0.93–1.41)1.07(0.86–1.33) No——Allergic conjunctivitis Yes1.20(1.02–1.40)1.08(0.92–1.28) No——Fertilization method Yes1.41(1.12–1.78)1.27(1.00–1.63) Spontaneous conception——Food allergy No—— Intrauterine ovulation induction /1.26(0.87–1.82)1.10(0.75–1.60) Yes1.45(1.06–2.00)1.33(0.96–1.85) Artificial insemination withAlcohol intake husband's semen Never—— Ex1.03(0.87–1.23)1.01(0.85–1.20) In vitro fertilization /2.11(1.53–2.92)1.78(1.26–2.50) Current0.92(0.54–1.56)1.00(0.59–1.71) Intracytoplasmic sperm injection /Smoking status Fresh embryo transfer / Never—— Frozen embryo transfer Ex1.04(0.88–1.23)1.12(0.94–1.33) Current0.62(0.37–1.04)0.76(0.44–1.28) Blastocyst transfer1.66(0.23–11.92)1.43(0.20–10.37)Abbreviations: CI, confidence interval; IH, infantile hemangioma; JPY, Japanese Yen; MET, metabolic equivalent.— represents reference.Bold indicates significance (P < 0.05). Open table in a new tab Abbreviations: CI, confidence interval; IH, infantile hemangioma; JPY, Japanese Yen; MET, metabolic equivalent. — represents reference. Bold indicates significance (P < 0.05). Furthermore, IH was associated with having >16 years of education (adjusted OR: 1.31, 95% CI: 1.04–1.65). Meanwhile, asthma and congenital anomaly were associated with IH in the adjusted analysis; however, their significance disappeared in the sensitivity analysis (Supplementary Table S1). The incidence of IH in mature neonates was reported to be approximately 4.5% (Smith et al., 2017Smith C.J.F. Friedlander S.F. Guma M. Kavanaugh A. Chambers C.D. Infantile hemangiomas: an updated review on risk factors, pathogenesis, and treatment.Birth Defects Res. 2017; 109: 809-815Crossref PubMed Scopus (46) Google Scholar). The incidence of IH in this study was 0.72%, which was lower than previous reports. IH was reported to be routinely seen in Caucasians but relatively uncommon in African or Asian children (Hoornweg et al., 2012Hoornweg M.J. Smeulders M.J. Ubbink D.T. van der Horst C.M. The prevalence and risk factors of infantile haemangiomas: a case-control study in the Dutch population.Paediatr Perinat Epidemiol. 2012; 26: 156-162Crossref PubMed Scopus (50) Google Scholar). The incidence of IH in Japan is reported to be 0.78% (Hidano and Nakajima, 1972Hidano A. Nakajima S. Earliest features of the strawberry mark in the newborn.Br J Dermatol. 1972; 87: 138-144Crossref PubMed Scopus (80) Google Scholar). In Japan, IH is diagnosed by primary care providers, and large or potentially problematic lesions are typically confirmed by a specialist. IHs are sometimes misdiagnosed because they can mimic other vascular anomalies; however, it was interesting that our incidence was similar to that reported by Hidano and Nakajima, 1972Hidano A. Nakajima S. Earliest features of the strawberry mark in the newborn.Br J Dermatol. 1972; 87: 138-144Crossref PubMed Scopus (80) Google Scholar. The known risk factors for IH include Caucasian race, multiple gestations, female sex, low birth weight, advanced maternal age, family history of IH, use of certain prenatal medications, invasive antepartum procedures, placental abnormalities, and the use of in vitro fertilization (Smith et al., 2017Smith C.J.F. Friedlander S.F. Guma M. Kavanaugh A. Chambers C.D. Infantile hemangiomas: an updated review on risk factors, pathogenesis, and treatment.Birth Defects Res. 2017; 109: 809-815Crossref PubMed Scopus (46) Google Scholar). In our study, female sex and the use of reproductive medicine were also significantly associated with IH. Low birth weight was not significantly associated with IH; however, the risk of IH decreased by 9% for every 1 week of gestational age. The risk of IH did not differ to a statistically significant extent among preterm, post-term, and full-term births (data not shown). A previous report showed a 40% increase in the risk of IH for every 500 mg decrease in birth weight (Drolet et al., 2008Drolet B.A. Swanson E.A. Frieden I.J. Hemangioma Investigator GroupInfantile hemangiomas: an emerging health issue linked to an increased rate of low birth weight infants.J Pediatr. 2008; 153: 712-715.e1Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar). IH incidence increases with low birth weight and decreasing gestational age and is as high as 23% in premature babies with a birth weight <1,000 g (Goelz and Poets, 2015Goelz R. Poets C.F. Incidence and treatment of infantile haemangioma in preterm infants.Arch Dis Child Fetal Neonatal Ed. 2015; 100: F85-F91Crossref PubMed Scopus (36) Google Scholar). Hypoxia is considered the trigger of angiogenesis that leads to the formation of IH (Smith et al., 2017Smith C.J.F. Friedlander S.F. Guma M. Kavanaugh A. Chambers C.D. Infantile hemangiomas: an updated review on risk factors, pathogenesis, and treatment.Birth Defects Res. 2017; 109: 809-815Crossref PubMed Scopus (46) Google Scholar). Various conditions that predispose an infant to the development of IH (i.e., preterm birth, low birth weight) are associated with hypoxia. Furthermore, it has recently been suggested that the renin-angiotensin system may play a role in endothelial cell proliferation in IH (Smith et al., 2017Smith C.J.F. Friedlander S.F. Guma M. Kavanaugh A. Chambers C.D. Infantile hemangiomas: an updated review on risk factors, pathogenesis, and treatment.Birth Defects Res. 2017; 109: 809-815Crossref PubMed Scopus (46) Google Scholar). Higher renin levels have been detected in females, Caucasians, and premature births; all of which are risk factors for IH (Smith et al., 2017Smith C.J.F. Friedlander S.F. Guma M. Kavanaugh A. Chambers C.D. Infantile hemangiomas: an updated review on risk factors, pathogenesis, and treatment.Birth Defects Res. 2017; 109: 809-815Crossref PubMed Scopus (46) Google Scholar). Interestingly, the maternal lifetime incidence of pollinosis and allergic conjunctivitis, which cannot be explained by hypoxia, was identified as a significant risk factor for IH. We did not investigate the severity of pollinosis and allergic conjunctivitis or the drugs used for these diseases. Topical drugs (antihistamines or corticosteroids) or systemic antihistamines are the treatment of choice during pregnancy. The use of these drugs is reported to be unassociated with adverse neonatal outcomes, such as congenital anomalies, preterm birth, and low birth weight. (Etwel et al., 2017Etwel F. Faught L.H. Rieder M.J. Koren G. The risk of adverse pregnancy outcome after first trimester exposure to H1 antihistamines: a systematic review and meta-analysis.Drug Saf. 2017; 40: 121-132Crossref PubMed Scopus (19) Google Scholar; Hashimoto et al., 2020Hashimoto Y. Michihata N. Yamana H. Shigemi D. Morita K. Matsui H. et al.Ophthalmic corticosteroids in pregnant women with allergic conjunctivitis and adverse neonatal outcomes: propensity score analyses.Am J Ophthalmol. 2020; 220: 91-101Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar). The potential link between IH and the maternal lifetime incidence of pollinosis and allergic conjunctivitis warrants further investigation. The strength of this study is that it is the largest study to date to investigate the incidence of IH and the association between environmental factors and the risk of IH. Because the study was conducted in 15 regional centers in the country, its participants can be considered to be representative of children in Japan. However, this study was associated with some limitations. First, this was an observational study, and unmeasured residual factors might have confounded the results. Second, owing to the limitation of using self-reported survey responses to identify IHs, we excluded subjects who were simply diagnosed with hemangioma (0.3%). We performed a sensitivity analysis where hemangioma was classified as an IH for logistic regression to evaluate the validity of the risk factors. However, the actual incidence of IH might have been underestimated, and a selection bias might have been introduced. Third, we did not capture data on the number or size of IHs. Further research is required to determine whether the risk factors identified are the same across the full spectrum of IHs. Fourth, the highest educational level (≥16 years) was significantly associated with IH in this study. Highly educated parents may be highly health conscious (Wardle and Steptoe, 2003Wardle J. Steptoe A. Socioeconomic differences in attitudes and beliefs about healthy lifestyles.J Epidemiol Community Health. 2003; 57: 440-443Crossref PubMed Scopus (412) Google Scholar). Furthermore, the exclusion of patients who did not submit questionnaires may have resulted in a selection and recall bias by excluding patients without the ability to read and answer questionnaires. In conclusion, the incidence of IH in Japan was found to be 0.72%. Five factors appear relevant to the development of IH. Maternal lifetime incidence of pollinosis and allergic conjunctivitis were newly identified as significant risk factors for IH. Further investigations are required to confirm our findings. Approval for the study protocol was granted by the Japanese Ministry of the Environment's Institutional Review Board on Epidemiological Studies and the ethics committees of all the participating institutions. All participants provided their written informed consent. Data are unsuitable for public deposition due to ethical restrictions and legal framework of Japan. It is prohibited by the Act on the Protection of Personal Information (Act No.57 of 30 May 2003, amendment on 9 September 2015) to publicly deposit the data containing personal information. Ethical Guidelines for Epidemiological Research enforced by the Japan Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labour and Welfare also restricts the open sharing of the epidemiologic data. All inquiries about access to data should be sent to: [email protected] . The person responsible for handling enquiries sent to this e-mail address is Dr Shoji F. Nakayama, JECS Programme Office, National Institute for Environmental Studies. Megumi Mizawa: https://orcid.org/0000-0003-3348-3240 Kenta Matsumura: https://orcid.org/0000-0002-4271-1543 Kei Hamazaki: https://orcid.org/0000-0003-0456-6805 Fumina Furukawa: https://orcid.org/0000-0002-4387-3579 Teruhiko Makino: https://orcid.org/0000-0002-0536-1679 Tadamichi Shimizu: https://orcid.org/0000-0002-3231-0279 Hidekuni Inadera: https://orcid.org/0000-0002-3548-221X The authors state no conflict of interest. We are grateful to all of the Japan Environment and Children's Study participants and all individuals involved in data collection. We are also grateful to Haruka Kasamatsu and Kumiko Ishikawa for their technical assistance. The Japan Environment and Children's Study was funded by the Ministry of the Environment , Japan. Members of the Japan Environment and Children's Study group as of 2021 are listed as follows: Michihiro Kamijima (principal investigator, Nagoya City University, Japan), Shin Yamazaki (National Institute for Environmental Studies, Tsukuba, Japan), Yukihiro Ohya (National Center for Child Health and Development, Tokyo, Japan), Reiko Kishi (Hokkaido University, Sapporo, Japan), Nobuo Yaegashi (Tohoku University, Sendai, Japan), Koichi Hashimoto (Fukushima Medical University, Japan), Chisato Mori (Chiba University, Japan), Shuichi Ito (Yokohama City University, Japan), Zentaro Yamagata (University of Yamanashi, Chuo, Japan), Hidekuni Inadera (University of Toyama, Japan), Takeo Nakayama (Kyoto University, Japan), Hiroyasu Iso (Osaka University, Suita, Japan), Masayuki Shima (Hyogo College of Medicine, Nishinomiya, Japan), Youichi Kurozawa (Tottori University, Yonago, Japan), Narufumi Suganuma (Kochi University, Nankoku, Japan), Koichi Kusuhara (University of Occupational and Environmental Health, Kitakyushu, Japan), and Takahiko Katoh (Kumamoto University, Japan). Conceptualization: MM, KM, KH; Data Curation: KM, KH; Formal Analysis: KM; Investigation: MM, KM, KH, FF, TM, TS, HI, the JECS Study group; Supervision: TS, HI; Writing - Original Draft Preparation: MM, KM, KH; Writing - Review and Editing: MM, KM, KH, FF, TM, TS, HI, the JECS Study group The findings and conclusions of this article are solely the responsibility of the authors and do not represent the official views of the Ministry of the Environment, Japan. The Japan Environment and Children's Study protocol has been described elsewhere (Kawamoto et al., 2014Kawamoto T. Nitta H. Murata K. Toda E. Tsukamoto N. Hasegawa M. et al.Rationale and study design of the Japan environment and children's study (JECS).BMC Public Health. 2014; 14: 25Crossref PubMed Scopus (317) Google Scholar, Michikawa et al., 2018Michikawa T. Nitta H. Nakayama S.F. Yamazaki S. Isobe T. Tamura K. et al.Baseline profile of participants in the Japan environment and children's study (JECS).J Epidemiol. 2018; 28: 99-104Crossref PubMed Scopus (188) Google Scholar). Briefly, the aim of the Japan Environment and Children's Study, a nationwide government-funded birth cohort study, is to evaluate the impact of certain environmental factors on child health and development. Pregnant participants in the Japan Environment and Children's Study were enrolled from 15 Japanese regions from January 2011 to March 2014 (Kawamoto et al., 2014Kawamoto T. Nitta H. Murata K. Toda E. Tsukamoto N. Hasegawa M. et al.Rationale and study design of the Japan environment and children's study (JECS).BMC Public Health. 2014; 14: 25Crossref PubMed Scopus (317) Google Scholar, Michikawa et al., 2018Michikawa T. Nitta H. Nakayama S.F. Yamazaki S. Isobe T. Tamura K. et al.Baseline profile of participants in the Japan environment and children's study (JECS).J Epidemiol. 2018; 28: 99-104Crossref PubMed Scopus (188) Google Scholar). The eligibility criteria for participants (expectant mothers) were as follows (Kawamoto et al., 2014Kawamoto T. Nitta H. Murata K. Toda E. Tsukamoto N. Hasegawa M. et al.Rationale and study design of the Japan environment and children's study (JECS).BMC Public Health. 2014; 14: 25Crossref PubMed Scopus (317) Google Scholar): (i) residing in the study areas at the time of recruitment and expecting to reside in Japan continuously for the foreseeable future, (ii) having an expected delivery date between August 1, 2011 and the middle of 2014, and (iii) the ability to participate in the study without difficulty (i.e., ability to understand the Japanese language and complete a self-administered questionnaire). Those residing outside the study areas were excluded from the study, even if they visited cooperating healthcare providers working within the study areas. This study was based on the Japan Environment and Children's Study-an-20180131 dataset, which was released in March 2018. The full dataset includes 104,065 records; however, cases were excluded because of miscarriage/stillbirth (n = 3,921), because of multiple registrations (n = 5,547), or if there was no response to a questionnaire at the age of 1 year (n = 9,353). A total of 85,244 mother–infant pairs were selected for the analysis. Approval for the study protocol was granted by the Japanese Ministry of the Environment's Institutional Review Board on Epidemiological Studies and the ethics committees of all the participating institutions. All participants provided their written informed consent. Data on the diagnosis of infantile hemangioma (IH) were collected 1 year after delivery. Parents of the subjects responded to the question "From birth, has your child ever been diagnosed by a physician?" for 12 congenital disease sections, including skin diseases. If they marked a check in the checkbox, they were asked to write the diagnosis of the skin disease. We defined the subject as having IH if they were diagnosed with IH or something related to strawberry angioma or strawberry mark. Hemangioma alone, which was observed in 275 individuals, was excluded from the definition of IH. There were 1,792 individuals with skin disease in the uncategorized comment sections. We evaluated the respective comments and categorized them as IH if they were related to strawberry hemangioma or IH. We included potential confounding factors and covariates in the statistical analysis if previous studies found them to be associated (or if they were theoretically inferred to be associated) with the outcome. The covariates considered in this study were as follows: gestational age; birth weight; Apgar score; annual household income (<4 million, 4–<6 million, or ≥6 million Japanese Yen), highest maternal educational level (≤12 years, >12–<16 years, or ≥16 years); employment status during mid-late pregnancy (yes or no); maternal age (<35 or ≥35); prepregnancy body mass index (<18.5, 18.5–<25, or ≥25 kg/m2); maternal lifetime prevalence of asthma (yes or no), pollinosis (yes or no), atopic dermatitis (yes or no), and allergic conjunctivitis (yes or no); food allergy (yes or no); alcohol intake during pregnancy (1, never; 2, ex; or 3, status during pregnancy (1, never; 2, ex; or 3, activity during mid-late pregnancy as by the et al., M. et activity and 2003; PubMed Scopus Google Scholar, et al., N. T. S. T. and of Japanese of Health sex of the child or previous deliveries or the of a congenital anomaly et al., H. A. K. K. T. M. et of congenital in the Japan environment and children's Epidemiol. PubMed Scopus Google (yes or no); pregnancy complications (yes or no); complications (yes or no); multiple birth (yes or no); and fertilization method et al., H. A. F. N. A. N. et risk of sex and increased after data from the Japan environment and children's PubMed Scopus Google (1, spontaneous 2, reproductive ovulation induction or insemination with husband's 3, embryo transfer vitro sperm embryo or embryo Data were as the mean ± SD or the association between environmental factors and the risk of IH, we performed a logistic regression analysis to the and the 95% confidence adjusted for all of the covariates in the of We performed multiple for the of covariates using S. of and data by Res. PubMed Scopus Google to We performed a sensitivity analysis where hemangioma (n = was classified as an IH for logistic regression (Supplementary Table S1). < were considered to statistical All statistical were performed using the Abbreviations: CI, confidence interval; IH, infantile hemangioma; JPY, Japanese Yen; MET, metabolic equivalent. — represents reference. Bold indicates significance < 0.05).

Pulsed-dye laser (PDL), as an effective and frequently-used treatment modality for infantile hemangiomas (IH), could render patients at risk of developing long-term alopecia. Data on alopecia caused by PDL treatment remain scant and the contributing factors are not clear. Our objective was to identify the risk factors associated with long-term alopecia resulting from PDL treatment for scalp IH. We conducted a retrospective study incorporating patients with IH diagnosis and PDL intervention via thoroughly reviewing the clinical database of the dermatology department. Scalp IH patients were further screened and their medical records were collected. Long-term alopecia was defined as no signs of terminal hair regrowth for at least 2years in this study. Of the 1293 IH patients, 47 (14 boys and 33 girls) with a mean age of 4.5months (standard deviation, 3.2) were diagnosed as scalp IH and had subsequently undergone PDL treatments. Hair growth in the treatment area of 18 patients (38.3%) nearly returned to normal, 22 patients (46.8%) had varying degrees of hair loss, and seven patients (14.9%) had no hair regrowth (long-term alopecia). Compared with the older patients receiving treatment, IH patients younger than 3months who started PDL treatment had a higher risk of developing long-term alopecia (odds ratio, 30.833; 95% confidence interval, 4.079-232.025; p=0.01). The total number of PDL sessions, post-treatment blisters, and location of IH were not shown to be significantly associated with the development of long-term alopecia. Collectively, our study provides an important insight into curating treatments for IH in infants younger than 3months. PDL treatments for scalp IH may perhaps be avoided or delayed to prevent the development of treatment-associated long-term alopecia.

Capillary hemangioma (capillary lobular hemangioma) and cavernous hemangioma (venous malformation) are relatively common oral tumors/malformations and are characterized by increased numbers of normal and abnormal blood vessels. However, the causes of these lesions are not well understood. CD105 (endoglin) is predominantly expressed in proliferating blood endothelial cells (ECs). We analyzed expressions of CD105, CD34, von Willebrand factor, Ki-67, cyclooxygenase-2 (COX-2), and vascular endothelial growth factor (VEGF)-A in 31 capillary hemangiomas and 34 cavernous hemangiomas. Staining scores were calculated as the product of the proportion score and intensity score. Morphologically normal oral mucosa specimens (n = 10) were simultaneously evaluated as normal controls. As compared with cavernous hemangiomas and normal controls, capillary hemangiomas had higher staining scores for CD105, VEGF-A, and COX-2. The Ki-67 labeling index was significantly higher in capillary hemangiomas than in cavernous hemangiomas and normal controls (P < 0.01). These findings suggest that the biological characteristics of capillary and cavernous hemangiomas are quite different. The ECs of capillary hemangiomas actively proliferated and were generally regulated by VEGF-A. In contrast, the ECs of cavernous hemangiomas lacked proliferative activity. These results suggest that angiogenesis and vasodilatation of pre-existing blood vessels are important in the development of capillary hemangioma and cavernous hemangioma, respectively.

The authors analyzed the clinical characteristics and treatment results of capillary and cavernous hemangiomas in the nasal cavity. A total of 14 patients who underwent surgical treatment for sinonasal hemangiomas between January 2010 and May 2020 were analyzed. The study population was subdivided into capillary and cavernous hemangiomas groups. The 14 patients with sinonasal hemangiomas involved 8 (57.1%) capillary hemangiomas and 6 (42.9%) cases of cavernous hemangioma. Clinical features, such as age, gender, medical condition, symptom, duration of symptom, size and site of sinonasal hemangiomas, surgery, anesthesia method, treatment outcomes, and recurrence of capillary and cavernous hemangiomas of nasal cavity showed no statistically significant difference (P > 0.05). A case of relapse involving a patient with cavernous hemangioma of vestibule was observed without recurrence after reoperation. The comparison of clinical features of capillary and cavernous hemangiomas of nasal cavity showed no statistical significance. Transnasal endoscopic tumor removal including the surrounding structure is a safe and effective procedure for sinonasal hemangiomas.

Infantile hemangioma is the most common benign tumor in infants. Many studies have confirmed that basic fibroblast growth factor (bFGF) and its key receptor FGFR1 are highly expressed in hemangioma. Moreover, several miRNAs can regulate angiogenesis. In this regard, miR-424 often plays a role as tumor suppressor gene. This study was designed to investigate the mechanism of miR-424 in infantile skin hemangioma. Our results showed low expression of miR-424 in infantile skin hemangioma tissues, and that miR-424 overexpression downregulated FGFR1 expression in hemangioma-derived endothelial cells, while miR-424 inhibition upregulated FGFR1 expression. Luciferase reporter analysis confirmed that FGFR1 was a target gene of miR-424. CCK-8, flow cytometry, transwell migration and tube formation assays demonstrated that miR-424 overexpression inhibited cell proliferation, migration and tube formation, at least in part by blocking the bFGF/FGFR1 pathway. In contrast, miR-424 inhibition significantly enhanced these functions. Furthermore, miR-424 overexpression significantly inhibited ERK1/2 phosphorylation, whereas miR-424 inhibition enhanced ERK1/2 phosphorylation. In conclusion, miR-424 could suppress the bFGF/FGFR1 pathway, thereby inhibit ERK1/2 phosphorylation, and thus inhibit cell proliferation, migration and tube formation capabilities and the development of infantile skin hemangioma.

A successful first-line treatment with propranolol of multifocal infantile hepatic hemangioma with high-flow cardiac overload is described

Periorbital Mass in a 2-month-old Girl.

Cardiac capillary hemangioma originating from the mitral valve.

To investigate the development, distribution and GLUT-1 expression of infantile hemangioma and to discuss the early surgical intervention for better results and avoiding severe complication. The lesion site of each case was recorded and analyzed by SPSS V13.0 to study the distribution. The operation was guided by the principle of plastic surgery to remove the hemangioma. The GLUT-1 expression was detected by immunohistochemical technique in all the resected samples. All the results were satisfactory. The GLUT-1 expression was positive in all the cases. The incidences in different sites were significantly different (P < 0.05). 71.7% of the hemangiomas were located at upper and lower lip, periorbital region and facial midline. It indicates that hemangioma is not randomly distributed. Most of them were located at the fusion of facial prominences during embryological development. Infantile facial hemangioma maybe originated from endothelial progenitor cells of placenta which migrate and implant on the fusion of facial prominences. Early surgical intervention is one of the best choice for infantile facial hemangioma.

This chapter describes and richly illustrates imaging features of infantile and congenital hemangiomas as well as less common pediatric vascular tumors. Malformative associations with infantile hemangioma are included: PHACE and LUMBAR (spinal dysraphism and other ventral-caudal anomalies). Details are given for the wide variety of intracranial and cardiovascular anomalies associated with facial hemangioma, including cerebrovascular occlusions leading to moyamoya phenomenon and cerebral infarction, dural AVM, and intracranial hemangioma with dural sinus occlusion. There are examples of hemangiomas of the neuraxis as well as a possible association between infantile hemangioma and AVM. Infantile and congenital hepatic hemangiomas are presented in detail, with multiple figures demonstrating their variations in angioarchitecture as well as imaging features during regression. Other pediatric vascular tumors are included: kaposiform hemangioendothelioma and kaposiform lymphangiomatosis, intramuscular hemangioma (“capillary type”), PTEN hamartoma, epithelioid hemangioendothelioma, hepatic adenoma, angiosarcoma, infantile fibrosarcoma and myoblastoma. Most of the 48 figures have multiple components depicting a variety of imaging modalities, including color Doppler ultrasonography, MRI, MRA, CTA and digital subtraction angiography.The chapter also includes a section on antenatal detection of vascular tumors, including chorangioma, with beautiful antenatal sonograms and magnetic resonance images.

To review and evaluate the medical literature on new treatments for periocular infantile (capillary) hemangioma. Recent studies have shown a promising new therapy for infantile hemangioma using nonselective β-blockers, including oral propranolol and topical timolol. Conventional treatments for infantile hemangioma include the use of corticosteroids, laser, surgery, and immunomodulator therapy. Recently, systemic and topical β-blockers have been used to successfully treat infantile hemangioma. The drugs' mechanism of action remains uncertain, but plausible theories include vasoconstriction, modulation of pro-survival signal transduction pathways, and endothelial cell apoptosis. Whereas no life-threatening adverse events from β-blocker treatment have been described, there have been reports of bradycardia, hypotension, bronchospasm, hypoglycemia, and electrolyte disturbances resulting from systemic use of propranolol to treat infantile hemangioma. Sleep and gastrointestinal disturbances have also been frequently reported. Topical timolol application for localized, superficial tumors may confer similar efficacy as oral propranolol while reducing systemic effects. Despite the recent explosion of interest surrounding this novel treatment, current treatment and protocol-monitoring recommendations are based largely on the experience of individual centers. Several randomized controlled studies are currently underway, the results of which will guide future standard-of-care treatment for infantile hemangioma.

Capillary and cavernous hemangiomas are often grouped together as if they were modulations of the same entity. To clarify this nosologic question, three capillary hemangiomas in children and four cavernous hemangiomas in adults were studied by transmission electron microscopy. The capillary hemangiomas consisted of two variably admixed zones, solid cellular zones and zones with open vascular lumens. However, both zones had similar organization. Each vascular unit was composed of endothelial cells and pericytes, which persisted in a tumor three years after its clinical appearance. Macrophages and degenerating cells were found in the interstitium and may be related to the clinical feature of partial spontaneous regression. The cavernous hemangiomas had much larger lumens, and wider and more heavily collagenized trabeculae. The vascular walls were created by multilaminar smooth muscle cells. Therefore, capillary hemangioma is completely different from cavernous hemangioma, which resembles a venous tumor.