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The diagnosis of vascular anomalies remains challenging due to significant clinical heterogeneity and uncertain etiology. Evaluation using biopsy and/or genetic testing for somatic variants is invasive, expensive, and prone to sampling error. There is great need for noninvasive and easily measured blood laboratory biomarkers that can aid not only in diagnosis, but also management of treatments for vascular anomalies. Angiopoietin-2, a circulating blood angiogenic factor, is highly elevated in patients with kaposiform hemangioendothelioma with Kasabach-Merritt phenomenon and kaposiform lymphangiomatosis. Here, we describe our clinical experience using serum angiopoietin-2 as a biomarker for diagnosis and monitoring response to treatment., (© 2024 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Introduction and Objectives: Infantile hepatic hemangioendothelioma (IHHE) is a benign liver tumor, associated with hypothyroidism and vascular malformations along the skin, brain, digestive tract and other organs. Here, we determined a single-center patient cohort by evaluating the effectiveness and safety of propranolol and sirolimus for the treatment of IHHE., Patients and Methods: We performed a monocentric and observational study, based on clinical data obtained from 20 cases of IHHE treated with oral propranolol and sirolimus at the Shanghai Children's Medical Center (SCMC), between December 2017 and April 2019. All cases were confirmed by abdominal enhanced CT examination (18/20, 90%) and sustained decrease of alpha fetoprotein (AFP) (2/20, 10%). Propranolol treatment was standardized as once a day at 1.0mg/kg for patients younger than 2 months, and twice a day at 1.0mg/kg (per dose) for patients older than 2 months. Sirolimus was used to treat refractory IHHE patients after 6 months of propranolol treatment, and initial dosing was at 0.8mg/m 2 body surface per dose, administered every 12h. Upon treatment, abdominal ultrasound scanning was regularly performed to evaluate any therapeutic effects. All children were followed up for 6-22 months (mean value of 12.75 months). The clinical manifestations and therapeutic effects, including complications during drug management, were reviewed after periodic follow-up., Results: The effective rate of propranolol for the treatment of children with IHHE was 85% (17/20). In most cases, the AFP levels gradually decreased into the normal range. A complete response (CR) was achieved in 3 cases, partial response (PR) for 14 cases, progressive disease (PD) for 2 cases and stable disease (SD) was only detected once. Lesions decreased in two PD patients after administration of oral sirolimus. No serious adverse reactions were observed., Conclusion: This study indicates that both propranolol and sirolimus were effective drugs for the treatment of children with IHHE at SCMC., (Copyright © 2020 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

Kaposiform lymphangiomatosis (KLA) is a rare, life-threatening congenital lymphatic malformation. Diagnosis is often delayed due to complex indistinct symptoms. Blood angiopoietin-2 (ANG2) levels are elevated in KLA and may be useful as a biomarker to monitor disease status. We report a 7-year-old male child with easy bruising, inguinal swelling, and consumptive coagulopathy, diagnosed with KLA. A multimodal treatment regimen of prednisone, sirolimus, vincristine, and adjunctive zoledronate was used. Plasma ANG2 levels were highly elevated at diagnosis but decreased during treatment. The patient showed significant clinical improvement over a 38-month period and normalization of ANG2 levels correlated with resolution of the coagulopathy., (© 2020 Wiley Periodicals, Inc.)

A full-term newborn with kaposiform hemangioendothelioma (KHE) affecting the right thigh with thrombocytopenia due to Kasabach-Merritt phenomenon (KMP) was referred to our center. After biopsy, he rapidly evolved to severe thrombocytopenia and severe coagulopathy. Standard therapy was initiated with prednisolone and vincristine. His coagulopathy worsened to life-threatening hemorrhage necessitating aggressive blood products replacement. Sirolimus was added; he became transfusion independent with no further bleeding and reduction in tumor size. Addition of sirolimus to treatment of vascular anomalies with hemostatic complications should be considered as part of early treatment for patients with KMP/KHE., (© 2018 Wiley Periodicals, Inc.)

Kasabach-Merritt phenomenon (KMP) occurred uniquely in patients with kaposiform hemangioendothelioma (KHE) and tufted angioma (TA). We report the clinical characteristics of two patients with KHE involving the right upper arm. The patients demonstrated rapid enlargement of the lesion with severe KMP shortly after vaccination. Sirolimus was used to treat the KHE with KMP. The patients showed a quick normalization of the platelet level. The follow-up examination revealed that the size of the mass was significantly decreased. This report raises the intriguing possibility that extrinsic factors may contribute to the development of KMP in the context of an already existing KHE., (© 2018 Japanese Dermatological Association.)

Kasabach-Merritt phenomenon (KMP) is a rare life-threatening vascular condition of infancy. Prognosis factors and long-term follow-up data are lacking. We retrospectively analysed the records of 24 infants (10 females, 14 males) treated for KMP in the Department of Dermatology of Necker-Enfants Malades Hospital, Paris, France, from 1984 to 2012. Mean duration of thrombocytopaenia (2,000-38,000 platelets/mm3, mean 10,500/µl) was 8.8 months (range 3 days-84 months), which correlated with tumour infiltration depth on imaging. D-dimer levels were always elevated, even before KMP onset. Each patient received a mean of 4.8 different treatments (range 1-10). Median follow-up was 6.5 years (range 2 months-22 years). All infants had residual cutaneous lesions, along with inflammatory manifestations (n = 9), elevated D-dimer (n = 5) and orthopaedic sequelae (n = 5). The permanent coagulopathy (elevated D-dimer) even after resolution of KMP suggests the presence of chronic low-grade platelet trapping, with possible sudden worsening, and raises the possibility of prophylactic anti-platelet therapy.

Background: Antiphospholipid antibody syndrome is an autoimmune disorder associated with pregnancy complications, venous and/or arterial thrombosis and the presence of antiphospholipid antibodies. This syndrome is known to present with various cutaneous features, but association with reactive angioendotheliomatosis has been described rarely in the literature., Results: A woman in her thirties with a past history of three consecutive abortions developed purpuric, ulcerative plaque over the plantar aspect of the foot. Her biopsy showed marked expansion of dermal vasculature due to intravascular cellular proliferation suggestive of reactive angioendotheliomatosis. The intravascular cells stained positive for CD31. Her blood investigations showed positive lupus anticoagulant, antiphospholipid antibodies and anticardiolipin antibodies, leading to a diagnosis of antiphospholipid syndrome also known as Hughes syndrome., Conclusion: We suggest that a hypercoagulable state caused the formation of intravascular thrombi leading to reactive angioendotheliomatosis. We report a case of Hughes syndrome with reactive angioendotheliomatosis as the first clinical cutaneous manifestation and treated satisfactorily with anticoagulants and immunomodulators., (© The Author(s) 2015.)

Background: Kaposiform hemangioendothelioma (KHE) with Kasabach-Merritt phenomenon (KMP) still remains a particular and life-threatening disease. The purpose of this study was to evaluate the efficacy of vincristine (VCR) and the possibility of replacement with steroids in the treatment of steroid-resistant KHE with KMP., Procedure: We retrospectively reviewed the medical records of 37 patients with steroid-resistant KHE who were treated at the Children's Hospital of Fudan University between March 2003 and March 2013., Results: The age of initial diagnosis with KHE was between 1 day and 10 months. Eight and 29 cases were located in the superficial and deep soft tissues, respectively. Thirty-seven KHE lesions did not respond well to steroids before starting VCR treatment. Twenty-six KHE lesions achieved complete remission, with platelet counts reaching normal levels within7.6 ± 5.2 weeks after VCR treatment. The vascular tumor began to decrease in size or soften at an average of 4.9 ± 2.7 weeks. Two KHE lesions had partial responses and one remains in treatment. Eight KHE lesions had no apparent response to VCR and thus received other therapies. Twenty-eight patients have ended treatment with VCR; the average length of treatment was 31.2 ± 5.9 weeks. Side effects occurred in 48.6% of patients who received steroids, and in 11.4% of patients who received VCR treatment. The mean follow-up time was 3.5 years. No recurrences have been reported., Conclusions: VCR appears to be a safe and effective treatment option in the management of steroid-resistant KHE with KMP, and recommended as first-choice treatment., (© 2014 Wiley Periodicals, Inc.)

Kaposiform hemangioendothelioma (KHE), a borderline tumor of endothelial origin, is associated with Kasabach-Merritt phenomenon, characterized by profound thrombocytopenia and consumptive coagulopathy resulting from the localized intravascular coagulation (LIC) in the tumor. Previous studies have suggested that the trapping of blood components, including platelets, may underlie the LIC in KHE. However, more evidence is needed to support this hypothesis. In this study, one case of a Chinese infant with a KHE in the left arm was complicated by Kasabach-Merritt phenomenon. The tumor was partially resected and the sample was used for ultrastructural observation and immunohistochemistry staining of Glut-1. Ultrastructural observation found the trapping of erythrocytes, platelets, macrophages, and lymphocytes in the slit-like channels of the tumor nodules, and phagocytic vesicles in the cytoplasm of neoplastic cells. Immunohistochemistry staining further showed numerous Glut-1(+) erythrocytes in the channels. In conclusion, our results provided compelling morphological evidence of the trapping of blood components in KHE, which may interpret the LIC in the tumor and subsequent consumptive coagulopathy.

Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor and has a high mortality in newborns when associated with Kasabach-Merritt syndrome (KMS). In two newborns with KHE and severe KMS refractory to medical treatment, emergency embolization led to clinical improvement in the acute neonatal setting by reducing tumor volume, increasing the platelet count, and improving other clotting parameters. Systemic vincristine treatment was added for further tumor control. Both patients remained symptom-free at long-term follow-up., (Copyright © 2012 SIR. Published by Elsevier Inc. All rights reserved.)

Sirolimus (Rapamune), a mammalian target of Rapamycin (mTOR) inhibitor, which has been used extensively in children following solid organ transplantation, has been demonstrated to have anti-angiogenic activity in pre-clinical models. Limited experience suggests that it may have application to the treatment of vascular lesions. We describe our experience with a 1-year-old female with a kaposiform hemangioendothelioma and Kasabach-Merritt phenomenon who had rapid and dramatic response to sirolimus (0.1 mg/kg/day). This case provides further rationale for clinical trials of sirolimus in the treatment of vascular lesions.

Infantile hemangioendothelioma is the most common hepatic vascular tumor in infants less than 6 months of age, with a prevalence of 1%. Serum alpha-fetoprotein levels have been used as an important tumor marker for hepatoblastoma, hepatocellular carcinoma, and germ cell tumors. It is rarely elevated in hepatic hemangioendothelioma. The authors report an infant with a hepatic hemangioendothelioma associated with elevation of serum alpha-fetoprotein who was treated with corticosteroids. In young infants, a solitary hepatic mass and elevated serum AFP level may not always be associated with hepatoblastoma. Infantile hemangioendothelioma must be differentiated by MRI or other radiological techniques before performing invasive procedures.

Two patients with hemangioendothelioma and elevated plasma vascular endothelial growth factor (VEGF) levels are presented. A reduction in the plasma VEGF level after therapeutic intervention correlated with a successful clinical response. Conversely, a stable plasma VEGF level correlated with therapeutic failure.

Infantile hemangioendothelioma is the most common vascular tumor in infancy. A three-month-old infant was admitted to the hospital for hepatomegaly. Abdominal ultrasonography, a CT-scan, and MRI studies demonstrated bilateral diffuse hepatic nodules, which were characteristic of hepatic hemangioendothelioma. A highly elevated alpha-fetoprotein (AFP) level misled us to an impression of hepatoblastoma, but the pathology report through an open biopsy disclosed a liver hemangioendothelioma. The patient responded to methylprednisolone therapy. A follow-up sonogram revealed regression of the hepatic masses. This case emphasizes that an elevated AFP level of up to 400 ng/ml is normally found in some neonates until two months of age. Careful interpretation of this value is very important, especially when it is associated with a hepatic tumor. Herein, we present a case of infantile hemangioendothelioma in a three-month-old boy with a highly elevated serum AFP.

We report a case of primary epithelioid hemangioendothelioma arising in the liver. There were no specific findings or signs except for the deformity and multiple lesions of the liver at imaging procedures, which included magnetic resonance imaging. The key to the diagnosis was histological examination of liver biopsy specimens obtained under laparoscopy. Plasma factor VIII activity was elevated, which was also helpful in the diagnosis.

The clinical course of five infants with heptic hemangioendothelioma is reviewed. Hemodynamic abnormalities observed at cardiac catheterization included an increased cardiac output (range, 9.2 to 10.5 liters/min/sq m) with over 50% of this output being shunted through the arteriovenous malformation, an elevated right and left end diastolic pressure (8 to 10 mm Hg and 9 to 15 mm Hg respectively), a small systolic pressure gradient across the pulmonary outflow tract (4 to 6 mm Hg), and mild elevation of pulmonary artery pressure (range, 35/16 to 37/12 mm Hg). All four patients treated with prednisone improved while on therapy; three are well one to three years after cessation of therapy. One patient died from unrecognized congestive heart failure following discontinuation of prednisone and another before prednisone was started. We conclude that prednisone in high doses (2 to 4 mg/kg/day) with the addition of digitalis and diuretics for control of congestive heart failure is an effective treatment regimen for infants with hepatic hemangioendothelioma.

Three of 42 (7%) monkeys given aflatoxin B1 (AFB1) for longer than 2 years have developed primary malignant neoplasms of the liver. Liver biopsies performed at intervals during aflatoxin administration revealed that neoplasia was preceded by pathologic lesions of the liver, including toxic hepatitis, proliferation of pseudotubules, and hyperplastic nodules. Serum alpha-fetoprotein levels, monitored in one of the monkeys by radioimmunoassay, paralleled tumor growth and recurrence of the hepatocellular carcinoma. Normal serum alpha-fetoprotein levels were noted for a monkey with hemangioendothelial sarcoma. Our results implicate AFB1 as a liver carcinogen in monkeys and add additional support to the hypothesis that humans exposed to this substance may be at risk of developing liver cancer.

A case of infantile hemangioendothelioma of the liver presenting with congestive heart failure and massive hepatomegaly in a two-mth old baby is described. Serum alpha-fetoprotein was elevated in this patient and clinically the lesion might not be distinguishable from other, commoner hepatic tumours in children. Histologically the tumour showed a type II pattern as defined by Dehner. The significance of classifying this tumour into two histologic types is discussed. Only 3 cases reported in the English literature were studied by electron microscopy; two of them were type I while the other was a type II lesion. In our case the endothelial cells appeared ultrastructurally less differentiated and architecturally more disorganized than in type I lesions. Like the previous case, the basal lamina showed marked thickening and reduplication. The significance of these findings is discussed.

The effects of prolonged p.o. administration of quinoline or 2-chloroquinoline on rat liver were examined histologically. Hepatocellular carcinomas and hemangioendotheliomas were observed in the livers of rats fed a basal diet containing 0.05, 0.10, or 0.25% quinoline for about 16 to 40 weeks. However, no neoplastic changes were seen in the livers of rats fed a basal diet containing 0.05, 0.10, or 0.25% 2-chloroquinoline for 40 weeks. In groups that received low concentrations of quinoline, the incidences of hepatocellular carcinomas were higher and the incidences of hemangioendotheliomas were lower than in the group that received a high concentretion of quinoline. The liver tumors induced by quinoline were classified histologically as hemangioendotheliomas or hemangiosarcomas and trabecular hepatocellular carcinomas. Typical nodular hyperplasias were occasionally seen in the livers of rats treated with quinoline. 2-Chloroquinoline did not induce any nodular hyperplasia or other neoplastic changes, but it caused diffuse fatty changes of parenchymal cells. Oval cell infiltration and bile duct proliferation were slight or moderate. Cirrhotic changes were rare in the livers of rats treated with either quinoline or 2-chloroquinoline. The serum levels of glutamic oxaloacetic transaminase and alkaline phosphatase were slightly changed in groups treated with quinoline, but no other remarkable changes were detected.

An autposy case of a 30-year-old house wife with malignant hemangiothelioma of the heart was reported. This case was also accompanied by marked anemia, thrombocytopenia, leukoerythremoid reaction and hypofibrinogenemia. The spread of tumor was so wide that only the alimentary tract and the skin were free from metastases of the tumor. Many of the metastatic foci showed marked hemopoiesis intra tumori. A short discussion was made on the hematological abnormalities associated with vascular tumors.