Clinical Characteristics and Prognostic Factors in Pediatric Vascular Tumors

doi:10.21203/rs.3.rs-70113/v1

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Clinical Characteristics and Prognostic Factors in Pediatric Vascular Tumors

https://doi.org/10.21203/rs.3.rs-70113/v1

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published 31 Jan, 2021

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Background: Vascular tumor is a specific entity of vascular anomalies with variable clinical manifestations and outcomes. Although surgical intervention is the gold standard to establish diagnosis and treatment, the procedure also carries certain risk especially in cases with large and inoperable tumors. Determinant factors to predict clinical outcomes among those patients were not well studied. The study aimed to explore clinical characteristics including investigational and treatment approaches as well as associated prognostic factors of vascular tumors specifically in pediatric populations.

Methods: Pediatric patients with confirmed diagnosis of vascular tumors between January 1, 2005 and December 31, 2017 were enrolled in this study. Clinical data including initial clinical manifestations with associated complications, diagnostic studies used to establish diagnosis, treatment modalities provided and final outcomes were retrospectively reviewed and analyzed.

Results: In all, 50 patients with confirmed diagnosis of vascular tumors were enrolled. The median age at diagnosis was 11.5 years with equal gender distribution. The most common type of vascular tumors was hemangioma (n=41, 82%), followed by pyogenic granuloma (n=4, 8%), kapasiform hemangioendothelioma with Kasabach-Merritt phenomenon (n=2, 4%), infantile hepatic hemangioma (n=2, 4%) and juvenile nasal angiofibroma (n=1, 2%). The median age at diagnosis among patients with cutaneous vascular tumors (12.4 years) was significantly older than the age of those with visceral vascular tumors (1.3 years) with p-value of 0.009. The mean size among patients with visceral tumors (7.46±4.84 cms) was significantly greater than the size among patients with cutaneous tumors (3.21±3.7 cms) with p-value of 0.023. Size of the tumor was the only independent risk factor associated with clinical outcomes.

Conclusion: Clinical characteristics of vascular tumors are heterogenous. Diagnosis can be made using clinical manifestations combined with radiological and histopathological examination. Treatment approaches consist of close observation, medications and surgery. Clinical outcomes are favorable among most patients and size of the tumor is an independent risk factor associated with outcomes.

This study was registered at www.clinicaltrials.in.th under the title, “Vascular tumors in pediatric hematology-oncology settings” with registration number: TCTR20190917001.

Pediatrics

pediatric

vascular tumor

prognostic factor

clinical manifestation and outcome

Vascular anomalies include a heterogeneous group of common and rare disorders of blood vessel development leading to identifiable vascular lesions and their associated deformities. According to the International Society for the Study of Vascular Anomalies (ISSVA)¹^,², vascular anomalies are classified in vascular tumors and vascular malformations³. A comprehensive medical history combined with thorough physical examination are essentially required not only to distinguish vascular tumors from vascular malformations, but also to possibly identify the specific type of vascular tumors⁴.

Among various types of vascular tumors including hemangioma⁵, tufted angioma, pyogenic granuloma, kapasiform hemangioendothelioma (KHE) and infantile hepatic hemangioma, the most common type of vascular tumors reported among children is infantile hemangioma with an incidence of 3 to 10% among infants⁶. Infantile hemangioma is typically found during infancy, and the tumor mostly continues to grow during the first 6 to 12 months of life, followed by an involution phase, in which 50% shrinkage has been noted at 6 years of age⁷. Clinical manifestations of infantile hemangioma depend on the depth of tumor as well as its location. Superficial hemangioma or intradermal hemangioma usually presents as a bright red mass described as “strawberry hemangioma”. On the other hand, hemangioma located in dermis or subcutaneous fat presents as an ill-defined border, not well circumscribed and colorless or purplish mass described as “cavernous hemangioma”⁸^,⁹ or “deep hemangioma”. Internal organ hemangioma or hemangioma with visceral involvement usually occurs less commonly¹⁰ among patients with multiple hemangiomas¹¹. Visceral hemangioma is generally associated with various complications including high output cardiac failure, compartment syndrome, hemorrhage, gut obstruction and perforation as well as coagulopathy¹⁰. Kasabach-Merritt phenomenon (KMP), a crucial complication consisting of thrombocytopenia and consumptive coagulopathy is associated with specific vascular tumors such as tufted angioma and kapasiform hemangioendothelioma¹². The incidence of KMP among children was 0.07 per 100,000 cases yearly¹³, in which the phenomenon carries a high mortality rate¹².

Even though thorough history taking and physical examination are a fundamental approach to diagnose and specify the types of vascular tumors, additional investigations including a radiological study or tissue pathology might be needed in certain circumstances of equivocal cases. Three main noninvasive imaging modalities include ultrasonography (US), magnetic resonance imaging (MRI) and computed tomography (CT)¹⁴^,¹⁵. Immunohistochemical staining is widely used to distinguish vascular tumors from vascular malformations. One example is glucose transporter protein 1 (GLUT1), which is a positive marker in infantile hemangiomas, nevertheless negative in vascular malformations^16-18. Management approaches of vascular tumors are varied including solely observation⁴, use of medication or local therapy and surgical excision of the tumor. Surgical approach is indicated among those patients who experience severe symptoms related to the tumor or those whose malignant etiology could not entirely be ruled out¹⁹. Medical approaches of vascular tumors including intralesional or systemic corticosteroid²⁰, interferon-α, vincristine²¹ or a combination of vincristine and prednisolone²⁰, oral propranolol^22-24, sirolimus²⁵ and laser therapy²⁶ have also been reported and used among those patients who have unresectable tumors with complications.

Outcomes of vascular tumors are heterogenous ranging from spontaneous regression without residual skin lesions in involuted infantile hemangioma to less than 30% of five-year overall survival rate in vascular tumors with malignant pattern of angiosarcoma²⁷. Prognostic factors associated with outcomes in vascular tumors are not well addressed in most related literature. Resectability and successful wound closure with or without skin graft²⁸ were reported and could potentially serve as a predictor to achieve disease remission.

Herein, this study primarily aimed to explore clinical characteristics including investigational and treatment approaches as well as associated prognostic factors of vascular tumors specifically in a pediatric population.

Patient selection

Fifty-five pediatric patients who were primarily clinically suspected of vascular tumors and followed at the Division of Hematology and Oncology, Department of Pediatrics, Phramongkutklao Hospital from January 1, 2005 to December 31, 2017 were retrospectively reviewed. Written informed consent and assent forms to take part in the study were obtained from all participants including the children themselves as well as their parents or legal guardians before collecting patient’s clinical data. This retrospective study was approved by the Institutional Review Board, Royal Thai Army Medical Department according to the ethics principles of the Declaration of Helsinki (1975) and its revision (reference number: IRBRTA 959/2562). The study was also registered and approved by the Thai Clinical Trials Registry (TCTR20190917001). The study’s inclusion criteria included patients from birth to 21 years old for whom the diagnosis of vascular tumors was confirmed by histopathological or radiological findings and were treated at the Division of Hematology and Oncology, Department of Pediatrics, Phramongkutklao Hospital. Patients with uncertain diagnosis, incomplete medical records or not being treated primarily at Phramongkutklao Hospital were excluded from the study.

Institutional diagnostic guidelines of vascular tumors

The institutional diagnostic guidelines for each specific type of vascular tumors were described as follows: hemangioma was diagnosed using either histopathological findings or radiological imaging of doppler or MRI-T2 weighted images; while cutaneous vascular tumor was confirmed by visible evidence of a vascular mass or histopathological confirmation in a case of any other vascular lesions located in superficial or within deep dermis or subcutis layer of skin. Visceral vascular tumor was defined by evidence of a vascular mass or lesion located at internal or visceral organs such as the liver, brain, orbit, gastrointestinal tract or retroperitoneal space; while pyogenic granuloma was confirmed by histopathological examination. KHE and liver hemangioendothelioma or infantile hepatic hemangioma were diagnosed using radiological imaging preferably MRI-T2 weighted images; while KMP was defined as hemangioma of cutaneous or internal organs with evidence of thrombocytopenia (platelet count less than 50,000/mm³) and consumptive coagulopathy, in which other causes for the abnormalities were excluded such as immune thrombocytopenia (ITP) etc. Lastly, juvenile nasal angiofibroma (JNA) was diagnosed by histopathological examination.

Treatment response criteria

Complete remission (CR) is defined as resolution of all signs and symptoms, all laboratory parameters returning to normal level for age and unrequired blood transfusion. Partial remission (PR) is defined as regression of signs or symptoms, no new lesions, improved laboratory parameters but without completely returning to normal level for age and/or requiring fewer transfusions. Persistent or stable disease is defined as the persistence of signs or symptoms, no new lesions, all laboratory parameters remaining abnormal level for age and/or still requiring blood transfusion. Progressive disease (PD) is defined as progression of signs or symptoms and/or appearance of new lesions and/or worsening in laboratory parameters and/or requiring more transfusions.

Statistical analysis

Baseline values of selected variables such as demographic data, clinical manifestations, diagnostic studies, treatment strategies, complications and outcomes from all participating patients were analyzed using descriptive statistics and presented as mean with standard deviation (SD) or as median (range) for continuous variables and were calculated using frequency and percentage for categorical variables. Categorical and continuous variables were compared using Chi-square or Fisher's exact tests and independent sample t-test, respectively. Univariate and multivariate binary logistic regression analyses were performed to analyze the impact of possible factors on defined outcomes. Statistical analysis was performed using IBM SPSS Statistics for Windows, Version 23.0. (Armonk, NY, USA: IBM Corp.) and a p-value <0.05 was considered statistically significant.

Patient characteristics

Among fifty-five patients, who were clinically suspicious for vascular tumors, five patients were excluded due to final diagnosis confirmed nonvascular tumors, incomplete data sets and lose follow up. Therefore, 50 patients with confirmed diagnosis of vascular tumors were subsequently enrolled in this study as shown in Figure 1. Medical records of all participating patients were retrospectively reviewed with complete information described in Supplementary Table 1. Patients’ characteristics including age, sex, diagnosis, diagnostic modalities including histopathological examination and imaging studies, size and location of the tumor, treatment strategies and its complications and clinical outcomes are summarized in Table 1.

Among 50 patients with vascular tumors enrolled in this study, most presented at older age with a median age at diagnosis of 11.5 years. Sex was equally distributed with a male to female ratio of 1:1. Hemangioma was the most common diagnosis followed by pyogenic granuloma, KHE with KMP, infantile hepatic hemangioma or liver hemangioendothelioma without KMP and juvenile nasal angiofibroma (JNA), in rank. Histopathological examination was the key diagnostic modality to establish diagnosis with radiological studies required in small numbers of patients whose tumors were inoperable. The reasons for inability to resect the tumors were large hemangiomas at the face and lower extremity for two patients, tumor with KMP-related complications for two patients and multiple infantile hepatic hemangiomas in 1 patient.

The average tumor size was 3.6 cm in the longest diameter located most commonly at the head and neck regions including the scalp, eyelids, face and lips. Most patients presented cutaneous vascular tumors, in which only 10% were noted to have visceral tumors located at the liver, brain, orbit and retroperitoneal regions. Hemorrhagic complication was commonly seen at initial diagnosis followed by poor weight gain, proptosis, feeding intolerance and seizures, in rank.

Radiological studies

Among 50 patients with vascular tumors enrolled in this study, radiological studies were essentially required to assist in establishing diagnosis and management plans in almost one half of the patients. The most common radiological modality used in this study was MRI followed by ultrasonography and CT scan, respectively as shown in Table 1. However, 6 in 21 patients required a combination of radiological imaging including CT scan, ultrasonography, Tc 99m-bone scan and MRI. In addition, all vascular tumors with visceral organ involvement (Figure 2), KHE with KMP, JNA and infantile hepatic hemangioma were imaged.

Treatment strategies

Over 90% of patients enrolled in this study received treatment intervention as shown in Table 1, and most underwent surgical resection of the tumors with no postoperative complications reported. However, three patients who underwent surgery had disease recurrence after partial resection of the tumors, and the remaining patients undergoing surgery remained in complete remission until their last follow-up visits. Medical treatment was administered among three patients (6%). Intravenous vincristine combined with oral prednisolone was delivered to two patients with KHE complicated by KMP resulting in complete resolution of the tumors. One patient received oral prednisolone monotherapy with partial response to treatment. The decision was made to closely observe and monitor clinical status among three patients (6%) whose tumors were inoperable including the scalp hemangioma, large intramuscular hemangioma of the right leg and multiple infantile hepatic hemangiomas. Spontaneous regression until complete resolution of the tumor was noted in one patient; however, another two experienced spontaneous regression with partial resolution of the tumor on their last follow-up visit.

Treatment Outcomes

All patients with vascular tumors enrolled in this study did not experience tumor-related mortality. Only one patient, presenting hemangioma at the extremity which was completely excised, died from liver cirrhosis and congestive heart failure due to the underlying biliary atresia status post Kasai operation. In summary, 43 patients (86%) survived without evidence of disease. Six (12%) patients survived with disease including three patients who had disease recurrence after partial resection of the tumors, one who was treated with oral prednisolone with partial response, one with intramuscular hemangioma of the right leg and one with multiple infantile hepatic hemangioma. The last two patients were closely observed clinically as shown in supplementary Table 1.

Kapasiform hemangioendothelioma (KHE) with Kasabach-Merritt phenomenon (KMP)

KMP is a life-threatening condition requiring immediate recognition and management. Two patients of KHE with KMP enrolled in this study received a diagnosis from clinical and laboratory findings combined with radiological studies as described in Table 2. Both cases required multiple platelet and cryoprecipitate transfusions to maintain platelet count as well as fibrinogen level in normal range. In addition, intravenous vincristine and oral prednisolone were administered resulting in complete resolution of the tumors. The first patient was treated with prednisolone 2 mg/kg/day for two weeks and then tapering off at six weeks and vincristine 0.625 mg/kg/day weekly for four weeks then monthly for five months (totaling six months therapy), and the patient could achieve complete remission within eight months after treatment (Figure 3). The second patient was also treated with combined vincristine and prednisolone regimen and could achieve complete resolution within six months after treatment. In addition, both patients survived without evidence of disease recurrence.

Cutaneous versus visceral vascular tumors

The majority of patients enrolled in this study presented cutaneous vascular tumors (90%) while 10% of those experienced visceral involvement. Patient characteristics including age, sex, location of the tumor, size, diagnosis, diagnostic modalities including histopathological examination and imaging studies, treatment strategies and clinical outcomes are summarized in Table 3. However, no significant difference was found regarding sex, treatment modalities and outcomes between the two groups of patients. Interestingly, the median age at diagnosis of patients with cutaneous vascular tumors was significantly older than the age of those with visceral vascular tumors (p-value 0.009). In addition, the mean size of visceral vascular tumors among patients was significantly greater than the size of those with cutaneous vascular tumors (p-value 0.023). Types of cutaneous and visceral vascular tumors also significantly differed, in which hemangioma, pyogenic granulomas and JNA were found mostly among patients with cutaneous vascular tumors with p-value <0.001. Moreover, histopathological examination was mostly performed and served as the main diagnostic modality among patients with cutaneous vascular tumors compared with those with visceral vascular tumors (p-value 0.018).

Influential factors associated with clinical outcomes

Among 50 patients with vascular tumors enrolled in this study, 49 patients survived. Only one patient, in complete remission, died from the complications of underlying biliary atresia. Age at diagnosis, sex, location of the tumor, existing visceral involvement and types of treatment were analyzed and were found not significantly associated with outcomes. However, univariate analysis was performed revealing significant differences of average tumor size between patients who survived with residual disease (8.8±4.64 cm.) and those who survived without disease (2.96±3.37 cm.) with p-value 0.008. In addition, multivariate analysis was subsequently performed affirming that the size of vascular tumor remained an independent risk factor to identify outcome of disease with p-value 0.008 as shown in Table 4 (adjusted odds ratio [OR], 1.359; 95% confidence interval [CI], 1.083-1.707).

Moreover, among 44 particular patients with cutaneous vascular tumors, age at diagnosis, sex and types of treatment were not significant predicting factors for the outcome. However, univariate analysis was performed revealing statistically significant differences of average tumor size between patients who survived with residual disease (9.00±5.15 cm.) and those who survived without disease (2.46±2.73 cm.) with p-value <0.001. In addition, multivariate analysis was subsequently performed affirming that the size of vascular tumor remained an independent risk factor to identify outcome of disease particularly among patients with cutaneous vascular tumors with p-value 0.027 as shown in Table 5 (adjusted OR, 1.487; 95% CI, 1.046-2.116).

Vascular anomalies are a specific entity of disease consisting of vascular tumors and malformations. Clinical characteristics, laboratory findings and imaging studies are the key elements to assess and distinguish vascular tumors from vascular malformations. Clinical characteristics of vascular tumors are heterogenous and vary depending on location of the tumor as well as signs and symptoms of pressure effects from the mass. The most common type of vascular tumors is hemangioma²⁹ defined by tumor locations such as cavernous hemangioma in deep dermis and strawberry hemangioma in superficial dermis. Other common vascular tumors include congenital hemangioma²⁹, infantile hemangioma³⁰, pyogenic granuloma or lobular capillary hemangioma, infantile hepatic hemangioma, angiofibroma and KHE which is a giant hemangioma that can cause KMP. Although approximately 90% of hemangiomas spontaneously resolve without complications, location of the tumors and depth of the lesion or visceral involvement are determinant factors associated with complications including ulceration, visual compromise, airway obstruction, bleeding, infection, high output congestive heart failure and other cosmetic issues³¹^,³². In our study, hemorrhagic issue was the most common complication associated with vascular tumors in the pediatric population, followed by poor weight gain, feeding intolerance in KHE with KMP, proptosis and seizure in a case of intracranial hemangioma.

Although the gold standard in establishing diagnosis of vascular tumors is histopathological examination, surgical procedure may carry unanticipated risks of developing morbidity from intra- or postoperative complications in some cases such as tumor bleeding, ulceration and infection etc. Therefore, radiological studies have been used to substitute surgical intervention especially among those high-risk patients or patients with inoperable visceral vascular tumors. A combination of MRI and magnetic resonance angiography (MRA) is a useful approach in distinguishing between high- and low-flow lesions. However, CT scan is still sufficient to diagnose certain types of vascular tumors such as infantile hepatic hemangioma³³ as shown in Figure 2. Hence, radiologic studies especially combined MRI and MRA images are currently beneficial as an optional diagnostic modality for vascular tumors³⁴. In this study, radiological studies were essentially required in establishing diagnosis and management plans in almost one half of the patients, in which MRI was the most common radiological modality used.

One of the key elements for treating vascular tumors is surgical resection of the lesions especially in the case of resectable or small sized tumors. In this study, almost 90% of patients underwent complete surgical resection of the tumors. However, the decision to select types of treatment modality for hemangioma was precautionary, based on the risk of distinct permanent cosmetic disfigurement or presence or likelihood of complications³¹^,³⁵. Because of morbidities and complications associated with surgical intervention and the benign nature of the disease, in which one half of hemangiomas tend to have complete involution by the age of 6 years³⁶, close observation with serial follow-up and imaging surveillance might be preferable especially in noncomplicated cases or in difficult cases with inoperable tumors. In this study, the decision was made to closely observe and monitor clinical status among three patients whose tumors were inoperable, and spontaneous regression until complete resolution of the tumor was observed in one patient. However, another two patients experienced spontaneous regression with partial resolution of the tumor. Oral propranolol²³^,²⁴^,³⁷, intravenous vincristine²¹^,³⁸ with or without oral corticosteroid³⁷^,³⁸, laser, sclerotherapy, embolization³⁹ and cryotherapy³⁸ have been implemented as alternative treatments in complicated unresectable hemangiomas. In this study, medical treatment was administered to three patients. A combination of intravenous vincristine and oral prednisolone could successfully induce KHE complicated by KMP to complete remission for two patients, and another patient who received oral prednisolone monotherapy had partial response to treatment.

Visceral vascular tumor is a unique entity of vascular tumors, in which the nature of the disease varies from indolent clinical course in small sized tumors at an invisible location to catastrophic features in large tumors along with serious complications from visceral involvement. Most visceral vascular tumors require additional diagnostic modalities to establish diagnosis. Chang, J.C, et al.¹¹ reported multiple hemangiomas more than five lesions were associated with increased risk of visceral involvement. Age at diagnosis in visceral vascular tumors was significantly younger than age at diagnosis in cutaneous vascular tumors. This might be from small and asymptomatic lesions in the majority of patients with cutaneous vascular tumors and aggressive nature of visceral vascular tumors as well as complications associated with visceral involvement especially in a large sized visceral tumors as reported in this study, in which the average size of visceral tumors was significantly larger than the size of cutaneous vascular tumors.

KMP was reported in 71% of patients with KHE¹³ compared with 50% in this study. KHE without cutaneous involvement presented with retroperitoneal mass is likely to involve KMP and complicated with congestive heart failure, bleeding and abdominal complications¹³^,⁴⁰. Treatment options for KMP are varied consisting of vincristine monotherapy⁴⁰^,⁴¹, prednisolone, methylprednisolone²⁰, propranolol⁴², interferon-α, sirolimus²⁵^,⁴³ and combined vincristine with oral corticosteroid²⁰. In this study, patients with KHE, complicated by KMP, were successfully treated with intravenous vincristine combined with oral prednisolone. Both of the patients were in complete remission and survived without disease recurrence.

Almost all patients with vascular tumors enrolled in this study survived with or without evidence of disease. One significant influential factor associated with outcomes was the size of the lesion at diagnosis, in which the tumor size among patients who survived with residual disease was significantly greater than the size of those who survived without disease. This result affirmed the finding reported by Akcay, A. et al.⁴⁴ that the size of hemangioma was a significant factor to predict disease complications. Haggstrom et al.³² also reported similar findings regardless of visceral involvement or types of treatment.

The limitations of this study included the study design of a retrospective chart review from a single institution. However, the uncommonness of the tumors operated in a specific pediatric population constituted our major restriction to conduct the prospective study. In addition, some patients, who were followed at dermatology or surgery clinics and had never been evaluated in pediatric department, might have been missed and this could explain the lack of data of laser or topical medicines in this study. A future large multicenter study enrolling patients in all departments involved in patient’s care including pediatric, dermatology and surgery departments would be beneficial to improve the quality of data and truly represent pediatric vascular tumors in Thailand.

This study affirmed that hemangioma was the most common vascular tumor among children. Age at diagnosis in cutaneous vascular tumors was significantly older than visceral vascular tumor which could be secondary to the significantly larger size of vascular tumors at initial presentation. Bleeding was the most common complication manifested at diagnosis. Although treatment modalities varied from close observation, medications and surgery intervention, the outcomes were satisfactory with no treatment-associated mortality. In addition, the size of the tumor was the most influential factor to predict treatment outcomes among those patients.

CI Confidence interval

CR Complete remission

CT Computed tomography

GLUT1 Glucose transporter protein 1

ISSVA International Society for the Study of Vascular Anomalies

ITP Immune thrombocytopenia

JNA Juvenile nasal angiofibroma

KHE Kapasiform hemangioendothelioma

KMP Kasabach-Merritt phenomenon

MRA Magnetic resonance angiography

MRI Magnetic resonance imaging

OR Odds ratio

PD Progressive disease

PR Partial remission

SD Standard deviation

US Ultrasonography

Ethics approval and consent to participate: Written informed consent and assent forms to participate in the study were obtained from all participating subjects including children, their parents or legal guardians before initiation of patient’s clinical data collection. This clinical study was approved by the Institutional Review Board, Royal Thai Army Medical Department (IRBRTA 959/2562) according to the ethical principles of the Declaration of Helsinki (1975) including its revision.

Consent for publication: Written informed consent and assent forms for publication were obtained from the patient and parents before initiation of patient’s clinical data collection.

Availability of data and material: The datasets generated and/or analyzed during the current study are not publicly available since these datasets are being used in a different ongoing study; however, some datasets are provided as a supplementary table and data are available from the corresponding author on reasonable request.

Competing interests: The authors declare that they have no competing interests.

Funding: The funding from the Phramongkutklao College of Medicine and Hospital, Royal Thai Army was used to conduct the study, analyze and interpret the study results and submit the study for publication.

Authors' contributions: PR contributed to editing, revising critically for important intellectual content the manuscript, writing and final approval of the manuscript version to be published (35%); CT contributed to the conception of the work, editing, revising critically for important intellectual content the manuscript and final approval of the manuscript version to be published (10%); NS contributed to interpretation of data, drafting, editing, and final approval of the manuscript version to be published (5%); KS contributed to interpretation of data, writing, editing, and final approval of the manuscript version to be published (3%); AP contributed to writing and final approval of the manuscript version to be published (2%); CM contributed to the conception and design of the work, overall management of the program, acquisition, analysis, and interpretation of data, drafting, editing, revising critically for important intellectual content the manuscript, and final approval of the manuscript version to be published (45%).

Acknowledgements: The authors gratefully acknowledged Mrs. Supak Cae-Ngow, Office of Research and Development, Phramongkutklao Hospital and Phramongkutklao College of Medicine for statistical analysis.

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Table 1: Patients’ demographic data (n=50)

Demographic data		N (%)
Age at diagnosis (years)	Median (range)	11.5 (0-18.58)
Age at diagnosis (years)	Mean±SD	10.36±5.36
Gender	Male	25(50)
	Female	25(50)
Diagnosis	Hemangioma Pyogenic Granuloma Kapasiform hemangioendothelioma with KMP Infantile hepatic hemangioma* Juvenile nasal angiofibroma	41(82) 4(8) 2(4) 2(4) 1(2)
Diagnostic modality	Tissue diagnosis Radiological diagnosis	45(90) 5(10)
Size (cm)	Median (range)	1.5 (0.3-16)
	Mean±SD	3.66±4.00
Location	Head and neck	24(48)
	Extremities	19(38)
	Trunk	3(6)
	Liver	2(4)
	Intracranial	1(2)
	Retroperitoneum	1(2)
Complication	None Bleeding Poor weight gain Bleeding and feeding intolerance Proptosis Seizure	39(78) 7(14) 1(2) 1(2) 1(2) 1(2)
Imaging	Not done	29(58)
	Done	21(42)
	MRI	8(16)
	Multi-Modalities	6(12)
	Ultrasound	6(12)
	CT scan	1(2)
Treatment	Surgery	44(88)
	Medication	3(6)
	Observation	3(6)
Outcome	Alive, no evidence of disease	43(86)
	Alive with disease	6(12)
	Deceased, no evidence of disease	1(2)

Notes: Data are presented as mean±SD and range (median) for continuous variables and number (%) for

categorical variables

Abbreviations: KMP, Kasabach-Meritt Phenomenon; MRI, magnetic resonance imaging; CT, computed tomography

*Infantile hepatic hemangioma or liver hemangioendothelioma

Table 2: Characteristics of two cases of kapasiform hemangioendothelioma (KHE) with Kasabach-Meritt phenomenon (KMP)

Age at diagnosis (months)	Size (cm)	Location	Initial platelet count (cell/mm³)	Lowest platelet count (cell/mm³)	Time to platelet recovery >150,000/mm³ (days)	Initial fibrinogen (mg/dl)	Lowest fibrinogen (mg/dl)	Time to fibrinogen >200 mg/dl (days)	Time to complete remission (months)	Status
Birth	6.5	Leg	18,000	5,000	112	72.5	<50	240	8	Alive, no evidence of disease
3	15	Retroperito- neum	22,000	7,000	119	0	0	70	6	Alive, no evidence of disease

Table 3: Characteristics and outcomes of cutaneous versus visceral vascular tumors (n=50)

Type of vascular tumor Demographic data		Cutaneous	Visceral	Total	P-value
Type of vascular tumor Demographic data		(n=45) N (%)	(n=5) N (%)	(n=50) N (%)
Age at diagnosis	Mean±SD	11.01±4.9	4.52±6.37	10.36±5.36	0.009
(years)	Median (min-max)	12.42 (0-18.58)	1.25 (0.25-15.33)	11.5 (0-18.58)
Gender	Male	23(92)	2(8)	25(50)	0.637
	Female	22(88)	3(12)	25(50)
Location	Head and neck Extremities Trunk Liver Brain Retroperitoneum	23(95.8) 19(100) 3(100) 0(0) 0(0) 0(0)	1(4.2) 0(0) 0(0) 2(100) 1(100) 1(100)	24(48) 19(38) 3(6) 2(4) 1(2) 1(2)	< 0.001
Size (cm)	Mean±SD Median (min-max)	3.21±3.7 1.45 (0.30-16.00)	7.46±4.84 7.80 (2.50-15.00)	3.66±4.00 1.50 (0.30-16.00)	0.023
Diagnosis	Hemangioma	39(95.1)	2(4.9)	41(82)	< 0.001
	Pyogenic granuloma	4(100)	0(0)	4(8)
	KHE with KMP Infantile hepatic hemangioma* Juvenile nasal angiofibroma	1(50) 0(0) 1(100)	1(50) 2(100) 0(0)	2(4) 2(4) 1(2)
Diagnostic modality	Tissue diagnosis Radiological diagnosis	42(93.3) 3(60)	3(6.7) 2(40)	45(90) 5(10)	0.018
Treatment	Surgery	41(93.2)	3(6.8)	44(88)	0.127
	Medication	2(66.7)	1(33.3)	3(6)
	Observation	2(66.7)	1(33.3)	3(6)
Outcome	Alive, no evidence of disease	39(90.7)	4(9.3)	43(86)	0.806
	Alive with disease	5(83.3)	1(16.7)	6(12)
	Deceased, from others, no evidence of disease	1(100)	0(0)	1(2)

Notes: Data are presented as mean±SD and range (median) for continuous variables and number (%) for categorical variables. Comparison between two independent data sets were analyzed using Fisher's exact test, Chi-square test or Independent Sample t-test (age at diagnosis and size). p-value <0.05 is considered as statistical significance.

Abbreviations: KHE, Kapasiform hemangioendothelioma; KMP, Kasabach-Meritt Phenomenon

*Infantile hepatic hemangioma or liver hemangioendothelioma

Table 4: Influential factors affecting clinical outcomes in patients with vascular tumors (n=49)

	Alive, no evidence of disease (n=43) N (%)	Alive, with disease (n=6) N (%)	P-value	Crude Odds ratio	95%CI	P-value	Adjusted Odds ratio	95%CI
Age at diagnosis (year)
Mean±SD	11.07±4.81	10.28±6.53	0.736	0.969	0.807-1.163	0.791	1.024	0.857-1.224
Gender
Male	21(84)	4(16)	0.420	2.095	0.346-12.671
Female	22(91.7)	2(8.3)		1
Location
Head and neck	22(91.7)	2(8.3)		1
Extremities	15(83.3)	3(16.7)	0.417	2.200	0.327-14.794
Trunk	3(100)	0(0.0)	NA	NA	NA
Liver	1(50)	1(50.0)	0.133	11.000	0.482-250.865
Intracranial	1(100.0)	0(0.0)	NA	NA	NA
Retroperitoneum	1(100.0)	0(0.0)	NA	NA	NA
Types of vascular tumor
Cutaneous	39(88.6)	5(11.4)		1
Visceral	4(80.0)	1(20.0)	0.582	1.950	0.180-21.088
Size (cm)	2.96±3.37	8.8±4.64	0.008*	1.361	1.085-1.707	0.008*	1.359	1.083-1.707
Treatment
Observation	1(33.3)	2(66.7)	0.423	4.000	0.134-119.23
Surgery	40(93.0)	3(7.0)	0.164	0.150	0.010-2.170
Medication	2(66.7)	1(33.3)		1

Notes: Univariate analysis and multivariate analysis were calculated using logistic regression. p-value <0.05 is considered as statistical significance.

Abbreviations: NA, not available

Table 5: Influential factors affecting clinical outcomes in patients with cutaneous vascular tumors (n=44)

	Alive, no evidence of disease (n=39) N (%)	Alive, with disease (n=5) N (%)	P-value	Crude Odds ratio	95%CI	P-value	Adjusted Odds ratio	95%CI
Age at diagnosis (year)
Mean±SD	11.07±4.81	10.28±6.53	0.736	0.969	0.807-1.163	0.299	1.247	0.823-1.889
Gender
Male	19(82.6)	4(17.4)	0.216	4.211	0.431-41.144
Female	20(95.2)	1(4.8)		1
Size (cm)	2.46±2.73	9.00±5.15	< 0.001*	1.513	1.114-2.055	0.027*	1.487	1.046-2.116
Treatment
Observation	1(50)	1(50)		1
Surgery	37(92.5)	3(7.5)	0.102	0.081	0.004-1.647
Medication	1(50)	1(50)	1.000	1.000	0.020-50.397

Notes: Univariate analysis and multivariate analysis were calculated using logistic regression. p-value <0.05 is considered as statistical significance.

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