Clinical features of cutaneous infantile hemangioma combined with asymptomatic infantile hepatic hemangioma and efficacy of propranolol treatment

Infantile hepatic hemangioma (IHH) is a common liver tumor in infants and shares the same characteristics as cutaneous infantile hemangioma (IH). Propranolol is effective for symptomatic IHH. The clinical features between cutaneous IH and IHH, and treatment efficacy of IHH (smaller than 4 cm) is unclear. To evaluate the correlation of clinical features between cutaneous IH and IHH, as well as efficacy of systemic propranolol in the treatment of cutaneous IH combined with IHH.

younger than 6 months with five or more skin IH lesions be screened with abdominal sonography to determine if IHH is present. 5,6H is usually asymptomatic, although life-threatening complications, such as anemia, thrombocytopenia, jaundice, hypothyroidism, or even abdominal compartment syndrome, high output heart failure, and liver failure, can develop. 7Symptomatic IHH requires medication (propranolol), intervention or surgery. 8,9Propranolol is routinely used for children with asymptomatic IHH over 4 cm. 10 Propranolol is a first-line treatment for complicated IH and represents one of the options for IHH; additionally, it is expected to be a first-line treatment for IHH. 10,11However, the effect of propranolol to IHH smaller than 4 cm is unclear.The aim of this study was to evaluate the correlation of clinical features between cutaneous IH and IHH, as well as their response to propranolol.

| Subject
The clinical data of 45 cases of cutaneous complicated IH with asymptomatic IHH treated with oral propranolol from January 2011 to October 2020 at our hospital were retrospectively analyzed.The informed consent was obtained from the guardian of patients before propranolol treatment.The study was approved by Medical Ethics Committee of Beijing Children's Hospital, Capital Medical University.

| Pretreatment examination
Pretreatment examinations included determination of the complete blood count (CBC), electrolyte levels, liver function, renal function, cardiac enzyme levels, blood glucose level, and thyroid function, electrocardiography (ECG), ultrasound echocardiography (UCG), measurement of weight and vital signs (temperature, heart rate, respiratory rate, blood pressure), hemangioma ultrasound, and abdominal ultrasound.

| Methods
The initial dose of propranolol was 0.75 ~ 1 mg/(kg d) once every 12 h.Heart rate and blood pressure were monitored at 1 and 2 h after administration, and blood glucose was monitored at 1 h after administration.If these indexes were within the normal reference ranges, the dose was increased to 1.5 ~ 2 mg/(kg d) and administered twice after the initial dose.
There was one case (2.2%) with more than a 2-fold increase in the normal aspartate transaminase (AST) value and eight cases (17.8%) with more than a 2-fold increase in the normal γ-glutamyl transpeptidase value, as shown in Table 1.

| Efficacy and adverse reactions
Ten cases (22.2%) were lost to follow-up before the IHH receded, and two cases had PR.Five cases (11.11%) were followed up (18-58 months), two cases had PR, one case was stable, and two cases During the follow-up period, one child had hepatolithiasis, one child had central calcification of intrahepatic hemangioma.

| DISCUSS ION
At present, the classification of IHH in children is not standard.
Based on the model of liver involvement, Christison Lagay et al. 3 classified IHH into three types: focal, multifocal and diffuse hemangioma, which may arise from multifocal hemangioma.
There are still controversy about how many cutaneous hemangiomas should be suggested to do routine visceral ultrasound to screen for hemangioma. 12As reported, IHH was associated with five or more skin lesions in 16% of the patients. 13In this study, the number of cutaneous hemangiomas was five or less, thus accounting for 71.1% of patients with complicated cutaneous IH combined with IHH.Although the high rate of IHH in patients with five or less cutaneous IH in our study, the majority IHH were asymptomatic.
Single cutaneous IH is more likely to be combined with focal IHH, cutaneous IH greater than five, more likely to be combined with multiple IHH.
The mean age of IHH naturally remission was unclear.In this study, the median age of IHH (focal and multiple IHH smaller than 4 cm) remission with propranolol treatment was 11.07 months.
Among the 30 complete regressed patients, 76.7% had complete regression within 1 year of age.The median duration of propranolol therapy for symptomatic IHH was 24.0 months (range 4.0-30.0). 11Mild symptom IHH of fifty-six patients with propranolol monotherapy without a description of efficacy. 14Meanwhile, in a single center-based 30-year study, 39% to 47% of asymptomatic patients received expectant treatment but did not describe the age of tumor reduction or regression. 15Even IHH with coagulopathy shows an excellent response and tolerance to propranolol. 16wever, there is also IHH that aggregated with a poor response to propranolol. 17IHH with underlying symptoms (>4 cm) 10  F I G U R E 4 Efficacy of propranolol in cutaneous hemangioma.A 1-month-old boy had two cutaneous hemangiomas in perioral (A) and parotid (B) with two hepatic hemangiomas.After 2 years of systemic propranolol therapy, the cutaneous hemangioma nearly disappeared (C and D).

Follow
-up visits were arranged at intervals of 1-3 months.The curative effect of cutaneous IH and IHH treatment was evaluated by clinical measurement, ultrasound examination and subjective evaluation by clinicians.The evaluation of the curative effect of IHH treatment can be divided into four grades: complete remission (CR): complete tumor regression under ultrasound; partial remission (PR): decrease in tumor volume of more than 20% under ultrasound or improvement in clinical symptoms under ultrasound; tumor progression: increase in tumor volume by more than 20% or appearance of new lesions; and tumor stability: except in all three cases.2.5 | Statistical methods SPSS 21.0 was used for the statistical analysis.Measurement data with a normal distribution are described by the mean ± standard deviation, and measurement data with a nonnormal distribution are described by the median.Pearson correlation was used for the correlation analysis.The difference in the mean value of measurement data was analyzed by a nonparametric test of two correlated samples (Wilcoxon test) and a nonparametric test of two independent samples (Mann-Whitney U test).The chi-square test was used to compare composition ratios.
(92.3%) had multiple IHH.A correlation was observed between the number of cutaneous and hepatic hemangiomas (Pearson = 0.546, p < 0.01), as shown in Figure2.

9 ) 1 F I G U R E 2 F I G U R E 3
were progressive.Thirty patients (66.7%) with IHH achieved CR.The mean course of remission was 8.43 ± 11.80 months (1 ~ 56 months).The mean age of IHH remission was 11.07 ± 11.90 months (2 ~ 59 months).The mean course of focal and multiple IHH remission was 9.13 ± 14.18 months and 7.73 ± 9.28 months, respectively, and there was no difference in the course of CR (p = 0.838).The mean age of focal and multiple IHH regression was 11.93 ± 14.42 months and 10.20 ± 9.15 months, respectively, and there was no difference in the course of CR (p = 0.838), as shown in Figure 3.At 1 year old, 23 patients (76.7%) with IHH achieved CR, 7 patients (23.3%) achieved PR in 30 patients with CR in our center.As shown in Table 2, the following factors did not affect the time of IHH regression: treatment age, low birth weight, sex, twins, preterm birth, cesarean section, cutaneous hemangioma number, type of IHH and treatment dose.The efficacy of propranolol in treating cutaneous IH was not followed up to be more than 75% ~ 100% regression in six patients (13.3%).Four (8.9%) of them achieved 75% ~ 100% regression at ≤6 months of age, 21 patients (46.7%) achieved 75% ~ 100% regression at >6 ~ ≤12 months of age, 12 patients (26.7%) achieved TA B L E 1 Demographic and baseline clinical characteristics of the study patients.-weight infants (<2.5 kg), no.(%) 14 (31.1)Very-low-birth-weight infants (<1.5 kg), no.(%) 4 (8.Extremely low-birth-weight infants (<1.0 kg), no.Ultrasound of focal infantile hepatic hemangioma.The correlation between cutaneous hemangioma and infantile hepatic hemangioma type.The difference of course and age between focal and multiple hepatic hemangioma remission.(A) The difference of course between focal and multiple hepatic hemangioma remission; (B) the difference of age between focal and multiple hepatic hemangioma remission.75% ~ 100% regression at >12 ~ ≤24 months of age, two patients (4.4%) achieved 75% ~ 100% regression at >24 months of age.The regression of the cutaneous hemangioma is shown in the Figure 4.In four cases (8.9%), the initial dose was not doubled within the first 3 days due to bradycardia, although the dose was increased to 1.5 ~ 2 mg/(kg d) after 1 month.One child stopped taking propranolol at 20 months of age (after a course of 8 months) due to a prolonged PR interval, and one child stopped taking the propranolol at 19 months (after a course of 17 months) due to degree II atrioventricular block.No other severe adverse reactions, such as airway hyperresponsiveness, lethargy or irritability, were observed during the follow-up period.

Subsided within 1 year of age χ 2 p Yes No
Influencing factors of regression time of infantile hepatic hemangioma.
or symptomatic IHH are recommended to receive treatment, including medication, intervention or surgery.Although we cannot claim that the reduction in size or regression of hemangioma was an effect of propranolol or the IHH's clinical course alone, our study provides an overview of IHH (smaller than 4 cm in diameter regression) based on our single-center observations of propranolol there were no severe complications requiring surgical intervention, and no severe side effects in the rest of the patients.For focal symptomatic IHH, propranolol treatment is an option when no pathological examination confirmed the expression of GLUT-1, as the minor risk of side effects of propranolol is outweighed by its possible benefits. 18TA B L E 2