Infantile Hemangiomas and Vascular Anomalies.

Vascular anomalies represent a diverse group of disorders of abnormal vascular development or proliferation. Vascular anomalies are classified as vascular tumors and vascular malformations. Significant advances have been made in the understanding of the pathogenesis, natural history, and genetics of vascular anomalies, allowing for improvements in management including targeted molecular therapies. Infantile hemangiomas are the most common vascular tumor of childhood and follow a distinct natural history of proliferation and involution. Although benign, infantile hemangiomas can be associated with important complications. The use of beta-blockers has revolutionized the management of infantile hemangiomas. Other vascular tumors include pyogenic granulomas, congenital hemangiomas, and kaposiform hemangioendotheliomas, among others. Vascular malformations are categorized based on the type of involved vessel, including capillary malformations, venous malformations, lymphatic malformations, arteriovenous malformations, and mixed vascular malformations. Expert multidisciplinary management of vascular anomalies is critical to optimize outcomes in these patients. [Pediatr Ann. 2024;53(4):e129-e137.].

Sirolimus combined with glucocorticoids in the treatment of Kasabach-Merritt phenomenon in a neonate: A case report.

RATIONALE: Kaposiform hemangioendothelioma is an aggressive vascular tumor that is often associated with life-threatening coagulopathies and Kasabach-Merritt phenomenon. Pathologic biopsies can provide a good basis for diagnosis and treatment. Therapy with srolimus combined with glucocorticoids may offer patients a favorable prognosis. PATIENT CONCERNS: A large purplish-red mass on the knee of a child with extremely progressive thrombocytopenia and refractory coagulation abnormalities. Conventional doses of glucocorticoids alone failed to improve coagulation abnormalities and the child developed large cutaneous petechiae and scalp hematomas. DIAGNOSIS: Kaposiform hemangioendothelioma combined with Kasabach-Merritt phenomenon. INTERVENTIONS: The patient received prednisolone 2.0 mg/kg*d for 4 days. Blood products were transfused to ensure vital signs and to complete the pathologic biopsy. Sirolimus combined with prednisolone was given after clarifying the diagnosis of Kaposiform hemangioendothelioma. OUTCOMES: The tumor basically disappeared on examination and the ultrasound showed a subcutaneous hyperechoic mass with normal blood flow. LESSONS: Sirolimus combined with glucocorticoids is effective in controlling Kasabach-Merritt phenomenon and pathologic biopsy is important for definitive diagnosis.

How we use angiopoietin-2 in the diagnosis and management of vascular anomalies.

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.

Cost and effectiveness comparison of sirolimus versus standard treatment in Kasabach-Merritt phenomenon: a real-world evidence study in Thailand.

The conventional treatment of Kasabach-Merritt Phenomenon (KMP) consists of corticosteroids with vincristine/vinblastine or others. The aim of the study is to compare the first-year direct costs and effectiveness between sirolimus and conventional treatment. A retrospective case-control study of KMP patients was conducted at a mean age of 9 months (1 day to 12 years) between 2000 and 2022 from four tertiary centers in Thailand. The direct costs, hematologic and clinical complete response (HCR, CCR), hospitalization, length of stay, and complications were compared. Of 29 patients, 13 underwent sirolimus (four upfront and nine were refractory to the conventional). The first-year total cost had no statistically significant difference between sirolimus VS conventional treatment (8,852.63 VS 9,083.56 USD: p value: 0.94). The therapeutics achievement was the same in both HCR (244.75 VS 168.94 days; p value: 0.60) and CCR (419.77 VS 399.87 days; p value: 0.90). The subgroup analysis of the first-line sirolimus (n = 4) compared with the conventional (n = 25) showed a more reduced total cost (4,907.84 VS 9,664.05 USD; p value: 0.26) rendered net total cost of -4,756.21 USD per patient (cost saving). A more significant contrast of therapeutic achievement by reduction of both HCR (11.67 VS 224.20 days; p value: 0.36) and CCR (38.50 VS 470.88 days; p value: 0.04) was shown. The sirolimus had no difference in hospitalization, length of stay, and complications. Even though, it was unable to identify significant differences in cost-effectiveness. Sirolimus is suitable for all patients who have diagnosis of KMP either for rescue therapy or first-line treatment.

Treatment practices and response in kaposiform hemangioendothelioma: A multicenter cohort study.

BACKGROUND AND OBJECTIVES: Kaposiform hemangioendothelioma (KHE) and tufted angioma (TA) are rare vascular tumors in children historically associated with significant morbidity and mortality. This study was conducted to determine first-line therapy in the absence of available prospective clinical trials. METHODS: Patients from 17 institutions diagnosed with KHE/TA between 2005 and 2020 with more than 6 months of follow-up were included. Response rates to sirolimus and vincristine were compared at 3 and 6 months. Durability of response and response to other treatment modalities were also evaluated. RESULTS: Of 159 unique KHE/TA subjects, Kasabach-Merritt phenomenon (KMP) was present in 64 (40.3%), and only two patients were deceased (1.3%). Over 60% (n = 96) demonstrated treatment response at 3 months, and more than 70% (n = 114) by 6 months (no significant difference across groups). The vincristine group had higher radiologic response at 3 months compared to sirolimus (72.7% vs. 20%, p = .03), but there were no differences between these groups at 6 months. There were no differences in rates of recurrent or progressive disease between vincristine and sirolimus. CONCLUSIONS: In this large, multicenter cohort of 159 patients with KHE/TA, rates of KMP were consistent with historical literature, but the mortality rate (1.3%) was much lower. Overall treatment response rates were high (>70%), and there was no significant difference in treatment response or durability of disease comparing sirolimus to vincristine. Our results support individualized treatment decision plans depending on clinical scenario and patient/physician preferences. Response criteria and response rates reported here will be useful for guiding future treatment protocols for vascular tumors.

Kaposiform Hemangioendothelioma with Bone Destruction: A 16-Year Follow-Up Cohort Study of the Clinical Characteristics and Prognosis.

BACKGROUND: Kaposiform hemangioendothelioma (KHE) is a rare, locally aggressive vascular tumor that often occurs in infants and young children. The goal of this study was to analyze the clinical characteristics of KHE patients with bone destruction and provide clinical guidance for diagnosis and treatment. METHODS: We conducted a descriptive cohort study with follow-up from January 2007 to January 2023 to collect demographic information and tumor-related clinical information from KHE patients with bone destruction. RESULTS: A total of 269 KHE patients were included in the study, of whom 70 (26.0%) patients had tumors with bone destruction. The median age at diagnosis of patients with bone destruction was 19.0 months, which was much later than that of patients without bone destruction (P < 0.001). Patients with bone destruction were more likely to have a decreased range of motion (ROM) (P < 0.001). Metaphysis involvement was more likely to occur in the lower limb bones (P = 0.039), and the lower limb bones were more likely to be associated with decreased ROM (P = 0.001). Tumors involving extracompartmental bone were more likely to have decreased ROM (P = 0.003) and exhibit the Kasabach-Merritt phenomenon (P = 0.006). CONCLUSIONS: Based on the rarity and significant heterogeneity of KHE patients with bone destruction, we should give full play to the role of multidisciplinary teams in addressing disease to reduce the long-term complications of KHE with bone destruction and improve the quality of life of patients. TYPE OF STUDY: Prognostic Study. LEVEL OF EVIDENCE: Level II.

Kasabach-Merritt Syndrome: a case study of successful treatment with vincristine and propranolol.

Kasabach-Merritt syndrome is a rare condition, characterised by the presence of an enlarging vascular tumour associated with thrombocytopenia, microangiopathic haemolytic anaemia and consumptive coagulopathy. The syndrome manifests in infancy, with high morbidity and mortality rates. No standard guidelines have been established for the treatment of Kasabach-Merritt syndrome to date. To existing literature we add this report of a four-month-old female child with Kasabach-Merritt syndrome who was successfully treated with propranolol and vincristine. This drug combination helped reverse the severe thrombocytopenia as well as decrease in size of her haemangioma. Management of Kasabach-Merritt syndrome continues to be a challenge, with varying response to first line drugs. Early diagnosis and initiation of treatment in a closely monitored setting is essential to ensure good outcomes. Since this is a relatively rare condition and large studies are not feasible, documenting treatment experience for single cases or small series becomes even more important.

Late third trimester diagnosis of congenital giant hemangioma complicated by the Kasabach-Merritt phenomen: a case report and literature review.

Objective. To describe the case of a large cervical mass diagnosed in the late third trimester with development of Kasabach-Merritt phenomenon (KMP) in the immediate postnatal period, along with a literature review.Methods. Description of case-report and literature search through Medline/Pubmed, performed from inception to December 2022 for articles relating to the pre and postnatal diagnosis of KMP.Results. A 36-year-old multiparous woman was admitted to hospital for contractions at 40 weeks of gestation, in an otherwise uneventful pregnancy. Admission's ultrasound showed the presence of a voluminous mass of 14x15 cm of the posterior side of the neck, highly vascularized, and no signs of hemodynamic imbalance. Postnatally, blood tests showed the presence of severe anemia and thrombocytopenia requiring several transfusions of blood, plasma, platelets and clotting factors. Due to the association of congenital hemangioma and thrombocytopenia a diagnosis of KMP was made. After attempts of conservative treatment, surgical removal was needed to stop the hematological cascade with regression of symptoms. The review of the literature identified 14 articles including 9 cases of prenatally suspected KMP and 6 diagnosed in the immediate postnatal period and without signs of fetal hydrops. Adverse perinatal outcome, in terms of postnatal death/termination of pregnancy, was observed in 67% of cases (6/9) in the prenatally suspected group and 33% of cases in those with a postnatal diagnosis of KMP. Fetal hydrops was present in 83% of cases with adverse perinatal outcome.Conclusions. The Kasabach-Merrit syndrome is a rare condition, which can have a dangerous evolution when it develops in utero or in the immediate postnatal period carrying a risk of perinatal mortality of approximately 50%. Even if the fetus shows no signs of anemia or heart failure, the risk of developing it in the immediate postnatal period is high and should be mentioned to the couple.

Kaposiform hemangioendothelioma presented with raynaud phenomenon: a case report.

BACKGROUND: Kaposiform hemangioendothelioma (KHE) is a rare vascular neoplasm affecting infants or young children. KHE includes a spectrum of lesions, ranging from small and superficial tumors to large and invasive lesions with Kasabach-Merritt phenomenon (KMP). Currently, no published studies have reported a KHE presenting as thrombocytopenia and Raynaud phenomenon. CASE PRESENTATION: A 2-year-old boy with right hand swelling and thrombocytopenia was admitted to our hospital. His right hand turned swelling and red, even occasionally cyanotic. This condition became worse in response to cool environments and improved with warming, and platelet counts were between 50 ~ 80 × 10^9/L. Physical examination on admission revealed the swelling and frostbite-like rash of the right-hand fingers, and the skin temperature of the right hand was lower than the left. On day 3 of admission, chest CT results showed an irregular mass on the right side of the spine. The puncture biopsy demonstrated positive CD31, D2-40, and FLI1 immunohistochemical staining, but negative GLUT1 staining, confirming the diagnosis of KHE. Furthermore, endothelin-1 (ET1) expression levels significantly increased, and eNOS and A20 expression levels significantly decreased comparing with control patients. The patient received methylprednisolone and sirolimus treatments, and his condition gradually improved during the follow-up. CONCLUSIONS: We reported the first case of KHE presenting with thrombocytopenia and Raynaud phenomenon. The development of Raynaud phenomenon could be associated with increased ET-1 and reduced eNOS and A20 expressions. Careful differential diagnosis of hidden KHE should be considered in children with thrombocytopenia and Raynaud phenomenon.

Rare adult Kaposiform hemangioendothelioma with multiple-bone invasion - clinical experience and literature review.

BACKGROUND: Kaposiform hemangioendothelioma (KHE) is a borderline vascular tumor between hemangioma and malignant angiosarcoma. While KHE has strong local invasion with rare spontaneous regression, it is not observed with distant metastasis. Even if KHE is asymptomatic or without the Kasabach-Merritt phenomenon (KMP), bone or joint invasion should clearly receive proactive treatment. KHE commonly affects infants/children but is rarely seen in adults. CASE REPORT: We reported a rare adult KHE case with an invasion of >10 separate forearm/hand bones, who underwent multiple-lesion resection and finger amputation after tumor recurrence. Tumor recurrence and KMP were not observed during the 6-month follow-up after the final operation. During the hospitalization and follow-up period, the patient only received medications for infection prevention and pain relief. CONCLUSIONS: Multiple resectable lesions were found in the distal limb, for which complete resection might not present typical features (high-intensity T2-weighted MRI), which might fail to detect all KHE lesions. Therefore, complete excision is not optimal for multiple resectable KHE lesions.

Recurrent metastatic angiosarcoma presenting as Kasabach-Merritt syndrome.

Angiosarcoma is an incredibly rare type of malignancy, accounting for only 1%-2% of all soft-tissue sarcomas globally. It is clinically, pathologically and radiologically difficult to diagnose angiosarcoma owing to its varied presentation with little or no well-defined imaging findings.Kasabach-Merritt syndrome is also a lesser-heard entity which carries extremely poor prognosis. It is primarily seen in infants with vascular malformations and in kaposiform haemangioendothelioma. It is a condition of consumptive coagulopathy and only few of the cases have been reported so far in the adults with a background of angiosarcoma.This report presents the case of a male in his 70s who was diagnosed with metastatic angiosarcoma and experienced a complicated disease course due to Kasabach-Merritt syndrome.

Platelet functional abnormalities in pediatric patients with kaposiform hemangioendothelioma/Kasabach-Merritt phenomenon.

Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor of infancy that is commonly associated with a life-threatening thrombocytopenic condition, Kasabach-Merritt phenomenon (KMP). Platelet CLEC-2, tumor podoplanin interaction is considered the key mechanism of platelet clearance in these patients. Here, we aimed to assess platelet functionality in such patients. Three groups of 6 to 9 children were enrolled: group A with KHE/KMP without hematologic response (HR) to therapy; group B with KHE/KMP with HR; and group C with healthy children. Platelet functionality was assessed by continuous and end point flow cytometry, low-angle light scattering analysis (LaSca), fluorescent microscopy of blood smears, and ex vivo thrombi formation. Platelet integrin activation in response to a combination of CRP (GPVI agonist) and TRAP-6 (PAR1 agonist), as well as calcium mobilization and integrin activation in response to CRP or rhodocytin (CLEC-2 agonist) alone, were significantly diminished in groups A and B. At the same time, platelet responses to ADP with or without TRAP-6 were unaltered. Thrombi formation from collagen in parallel plate flow chambers was also noticeably decreased in groups A and B. In silico analysis of these results predicted diminished amounts of CLEC-2 on the platelet surface of patients, which was further confirmed by immunofluorescence microscopy and flow cytometry. In addition, we also noted a decrease in GPVI levels on platelets from group A. In KHE/KMP, platelet responses induced by CLEC-2 or GPVI activation are impaired because of the diminished number of receptors on the platelet surface. This impairment correlates with the severity of the disease and resolves as the patient recovers.

Kaposiform hemangioendothelioma of the heart: a case report and literature review.

Kaposiform hemangioendothelioma is a rare tumour of vascular origin that rarely occurs in the heart. We provided a rare case of a 26-day-old infant with tachypnoea. Echocardiography showed a solid tumour in the pericardial cavity and a large amount of pericardial effusion. The solid tumour was confirmed by surgery, and the pathology was kaposiform hemangioendothelioma. We analysed this case and reviewed the related literature to explore the clinical features and echocardiographic manifestations to improve the understanding, diagnosis, and treatment of this disease for clinicians and sonographers.

Kaposiform hemangioendothelioma of skull base with dura invasion in a pediatric patient: a case report.

Kaposiform hemangioendothelioma is an extremely rare vascular tumor which shows aggressive local growth. We present a case of rapid growing vascular skull tumor with dura invasion in a pediatric patient with neurofibromatosis type 1. A 14-year-old male complained of headache and dizziness for 1 month after minor head trauma. Brain magnetic resonance imaging (MRI) revealed a 5-cm-sized tumor in the left frontotemporal bone with internal hemorrhage and cystic changes. The gross total resection of tumor was done. At the 7-month follow-up, brain MRI revealed a recurrent skull tumor with intracranial dura mass. He underwent second surgery, and the pathologic diagnosis was suggestive of Kaposiform hemangioendothelioma. For this vascular proliferative tumor, mTOR inhibitor was treated for 6 months, and there was the recurred nodular-enhancing mass along the sphenoid ridge. After additional 2 months of medication, the following MRI revealed a decreased nodular-enhancing mass.

Efficacy of transcatheter arterial chemoembolization combined with sirolimus for treating Kasabach-Merritt phenomenon in infants, a retrospective study.

OBJECTIVE: This retrospective study aimed to observe the efficacy of transcatheter arterial chemoembolization (TACE) combined with sirolimus in the treatment of haemangioma combined with the Kasabach-Merritt phenomenon (KMP). METHODS: A total of 11 infants with KMP who were treated at our hospital from January 2016 to September 2021 were selected and treated with arteriosclerosis embolotherapy using a microsphere emulsion formed by bleomycin + ultra-fluid lipiodol + dexamethasone + contrast agent or bleomycin mixed microspheres as the embolising agent. The patients were administered sirolimus orally after TACE. The clinical efficacy and examination indicators before and after treatment were observed and compared. RESULTS: The 11 infants underwent TACE treatment by arteriosclerosis embolotherapy a total of 21 times; of these cases, 10 were cured, and 1 showed a moderate response. There were no cases of non-response or death. The platelet count rose from 10.0 (7.0, 18.0) x 109/L before TACE to 236.0 (188.0, 275.0) x 109/L six months after the first TACE, and the tumour size decreased from 49.0 (43.0, 111.7) cm3 before TACE to 7.0 (3.5, 17.0) cm3 six months after the first TACE. The differences were statistically significant (the Z values were -2.943 and -2.934, respectively, p < 0.05). CONCLUSION: The combination of TACE and sirolimus has significant efficacy on critical children with KMP.

Long-term outcomes of sirolimus treatment for kaposiform hemangioendothelioma: Continuing successes and ongoing challenges.

Treatment with sirolimus, an inhibitor of the mammalian target of rapamycin pathway, has improved the prognosis of patients with kaposiform hemangioendothelioma (KHE). However, the efficacy, durability and tolerability of long-term sirolimus treatment in patients with KHE have not been well elucidated. We performed efficacy and safety assessments based on more than 4.5 years of follow-up in patients receiving sirolimus therapy for KHE. One hundred sixty-seven patients were analyzed, including 102 (61.1%) patients with the Kasabach-Merritt phenomenon (KMP). Follow-up was conducted after a median of 56.0 months. A total of 154 (92.2%) patients had a durable response to sirolimus treatment. No difference in durable response was found between patients without KMP and patients with KMP (95.4% vs 90.2%; difference, 5.2%; 95% confidence interval [CI], -4.0% to 13.1%). Rebound growth occurred in 17.3% of patients upon sirolimus discontinuation. Early treatment discontinuation (odds ratio [OR]: 3.103; 95% CI: 1.529-6.299; P = .002) and mixed lesion type (OR: 2.271; 95% CI: 0.901-5.727; P = .047) were associated with tumor rebound growth. No KHE-related deaths occurred in this cohort. At the last follow-up, approximately 17.4% of patients had active disease and/or changes in body structures to a variable extent. Serious adverse events occurred most commonly during the first year of sirolimus therapy. Follow-up of almost 4.5 years demonstrated that the efficacy of sirolimus persisted over time and that long-term treatment with sirolimus was not associated with unacceptable cumulative toxicities. However, nonresponse, tumor relapse and long-term sequelae remained challenges despite intensified and prolonged sirolimus therapy.