Computed tomography symptomatology of liver hemangiomas]

The paper is concerned with analysis of CT-symptomatology of 72 liver hemangiomas in 43 patients. The authors employed standard and dynamic computerized tomography. All hemangiomas were divided into 2 groups: under 6 cm and over 6 cm. Small hemangiomas were characterized by clear-cut contours and regular density. Zones of low density, regular in structure with clear-cut contours were revealed by CT in hemangiomas over 6 cm. Morphologically, this zone corresponded to a hyaline structure (a hyaline slot) making it possible to differentiate hemangiomas from necrotic tumors. In serious cases dynamic CT with visual evaluation and plotting of time-density graphs was recommended. Visually hemangioma had a picture of contrast medium accumulation, beginning from a focal periphery. Graphically the time of appearance of a contrast medium and the time of reaching a maximum for hemangiomas is delayed as compared to the same intervals of contrast medium accumulation in the liver parenchyma. It tells hemangioma graphs from graphs of other tumors, of which intervals coincide with those of liver parenchyma graphs.     

Local serum levels of vascular endothelial growth factor in infantile hemangioma: Intriguing mechanism of endothelial growth

The pathogenesis of hemangiomas still remains poorly understood. Dysregulation of angiogenesis has been proposed to play a central role in hemangioma pathogenesis. The aim of our study was to determine the peripheral and local serum levels of VEGF in patients with hemangiomas and vascular malformations. Material and methods: The study group consisted of 52 children with infantile hemangioma (33 with proliferative lesions, 19 with involuting lesions), 14 children with vascular malformations and 36 healthy children. VEGF serum levels were analyzed by an ELISA assay and the values between the groups were compared. Results: The serum peripheral VEGF concentrations in children with proliferative hemangiomas were significantly higher than in patients with involuting hemangiomas, vascular malformations and controls. There was no correlation between the measured cytokine level, hemangioma size, and the age of the patients. The local serum VEGF levels in 29 children with hemangiomas were distinctly lower than in the peripheral blood, both in 20 proliferating hemangiomas (p < 0.0001) and 9 involuting ones (p = 0.007); and the difference between females and males was non-significant (NS p = 0.06). Conclusions: (1) VEGF serum levels vary in the different phases of hemangioma growth and may help to distinguish hemangiomas from vascular malformations; (2) obtained local results may support the intrinsic theory of endothelial cell proliferation in hemangiomas.     

Role of pigment epithelium-derived factor in the involution of hemangioma: Autocrine growth inhibition of hemangioma-derived endothelial cells

Hemangioma is a benign tumor derived from abnormal blood vessel growth. Unlike other vascular tumor counterparts, a hemangioma is known to proliferate during its early stage but it is followed by a stage of involution where regression of the tumor occurs. The critical onset leading to the involution of hemangioma is currently not well understood. This study focused on the molecular identities of the involution of hemangioma. We demonstrated that a soluble factor released from the involuting phase of hemangioma-derived endothelial cells (HemECs) and identified pigment epithelium-derived factor (PEDF) as an anti-angiogenic factor that was associated with the growth inhibition of the involuting HemECs. The growth inhibition of the involuting HemECs was reversed by suppression of PEDF in the involuting HemECs. Furthermore, we found that PEDF was more up-regulated in the involuting phase of hemangioma tissues than in the proliferating or the involuted. Taken together, we propose that PEDF accelerates the involution of hemangioma by growth inhibition of HemECs in an autocrine manner. The regulatory mechanism of PEDF expression could be a potential therapeutic target to treat hemangiomas.     

Karyotypic changes detected by comparative genomic hybridization in a stillborn infant with chorioangioma and liver hemangioma

BACKGROUND: Placental hemangioma (chorioangioma) and congenital hemangioma are relatively common tumors, which on rare occasions may occur together. Very little is known about the pathogenetic mechanisms underlying these lesions. CASE: Herein we describe a rare case of a stillborn infant with chorioangioma, placental mesenchymal dysplasia, and liver cavernous hemangioma. In addition, we present the findings of the karyotype analysis of these lesions, which was done with the bacterial artificial chromosome arrays using the comparative genomic hybridization method. The chromosomal abnormalities that we found were deletions at 2q13 and 7p21.1 and were common to both placental and liver lesions. CONCLUSIONS: None of the identified chromosomal aberrations have been previously associated with chorioangiomas or hemangiomas. Important genes that lie in these DNA regions may be implicated in the pathogenesis of congenital hemangiomas and mesenchymal dysplasia.     

Transcatheter Arterial Embolization Alone for Giant Hepatic Hemangioma

Giant hepatic hemangioma is a benign liver condition that may be treated using surgery. We studied the digital subtraction angiographic (DSA) characteristics of giant hepatic hemangioma, and the effectiveness of transcatheter arterial embolization (TAE) alone for its treatment. This was a retrospective study of 27 patients diagnosed with giant hepatic hemangioma and treated with TAE alone (using lipiodol mixed with pingyangmycin) at the Division of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University, between January 2010 and March 2013. The feeding arteries were identified using DSA. All patients were followed up for between three weeks and 12 months. Changes in tumor diameter and symptoms were observed. The 27 patients included had giant hepatic hemangiomas ranging from 5.3 to 24.5 cm (mean, 11.24±5.08 cm) in the right (n = 13), left (n = 1) or both (n = 13) lobes. Preoperative hepatic angiography showed multiple abnormal vascular lakes in the early phase, known as the “early leaving but late returning, hanging nut on a twig” sign. On the day after TAE, hepatic transaminase levels were increased (ALT: 22.69±17.95 to 94.88±210.32 U/L; ALT: 24.00±12.37 to 99.70±211.54 U/L; both P<0.05), but not total bilirubin. Six patients complained of abdominal pain, and 12 experienced transient fever. In the months after TAE, tumor size decreased (baseline: 11.24±5.08; 3 months: 8.95±4.33; 6 months: 7.60±3.90 cm; P<0.05), and the patients’ condition improved. These results indicated that TAE was effective and safe for treating giant hepatic hemangioma. TAE may be a useful alternative to surgery for the treatment of hepatic hemangioma.     

Increased circulating AC133+ CD34+ endothelial progenitor cells in children with hemangioma

Hemangioma is the most common soft-tissue tumor of infancy. Despite the frequency of these vascular tumors, the origin of hemangioma-endothelial cells is unknown. Circulating endothelial progenitor cells (EPCs) have recently been identified as vascular stem cells with the capacity to contribute to postnatal vascular development. We have attempted to determine whether circulating EPCs are increased in hemangioma patients and thereby provide insight into the role of EPCs in hemangioma growth. METHODS AND RESULTS: Peripheral blood mononuclear cells (PBMCs) were isolated from hemangioma patients undergoing surgical resection (N = 5) and from age-matched controls (N = 5) undergoing strabismus correction surgery. PBMCs were stained with fluorescent-labeled antibodies for AC133, CD34, and VEGFR2/KDR. Fluorescent-labeled isotype antibodies served as negative controls. Histologic sections of surgical specimens were stained with the specific hemangioma markers Glut1, CD32, and merosin, to confirm the diagnosis of common hemangioma of infancy. EPCs harvested from healthy adult volunteers were stained with Glut1, CD32, and merosin, to assess whether cultured EPCs express known hemangioma markers. Hemangioma patients had a 15-fold increase in the number of circulating CD34 AC133 dual-staining cells relative to controls (0.78+/-0.14% vs.0.052+/-0.017%, respectively). Similarly, the number of PBMCs that stained positively for both CD34 and KDR was also increased in hemangioma patients (0.49+/-0.074% vs. 0.19+/-0.041% in controls). Cultured EPCs stained positively for the known hemangioma markers Glut1, CD32, merosin. CONCLUSIONS: This is the first study to suggest a role for EPCs in the pathogenesis of hemangioma. Our results imply that increased levels of circulating EPCs may contribute to the formation of this vascular tumor.     

EZH2和CBX7在皮肤血管瘤中的异常表达及意义

目的探讨EZH2和CBX7在血管瘤中的的异常表达及临床意义。方法收集武汉大学人民医院病理科2005年9月一2009年12月皮肤毛细血管瘤存档蜡块50例,其中男性25例,女性25例。采用免疫组织化学S-P法检测50例皮肤血管瘤增生期、退化期及正常皮肤组织中EZH2和CBX7的表达水平,采用图像分析系统对EZH2和CBX7的表达进行定量分析,并用SPSS13．0软件对各组免疫组织化学反应阳性颗粒的平均光密度、阳性面积率做单因素方差分析和SNK（q）检验。结果增生期血管瘤血管内皮细胞中可见密集分布的棕黄色颗粒,EZH2和CBX7呈高表达,退化组及正常皮肤组血管内皮细胞中可见少量的棕黄色颗粒,EZH2和CBX7表达弱。增生期组EZH2和CBX7的表达明显高于退化期组和正常皮肤组（P〈0．05）,而后两组比较差异无统计学意义（P〉0．05）。结论EZH2和CBX7在血管瘤增生期均上调表达,表明EZH2和CBX7均与血管瘤内皮细胞的增殖密切相关。     

Somatic Activating Mutations in GNAQ and GNA11 Are Associated with Congenital Hemangioma

Congenital hemangioma is a rare vascular tumor that forms in utero. Postnatally, the tumor either involutes quickly (i.e., rapidly involuting congenital hemangioma [RICH]) or partially regresses and stabilizes (i.e., non-involuting congenital hemangioma [NICH]). We hypothesized that congenital hemangiomas arise due to somatic mutation and performed massively parallel mRNA sequencing on affected tissue from eight participants. We identified mutually exclusive, mosaic missense mutations that alter glutamine at amino acid 209 (Glu209) in GNAQ or GNA11 in all tested samples, at variant allele frequencies (VAF) ranging from 3% to 33%. We verified the presence of the mutations in genomic DNA using a combination of molecular inversion probe sequencing (MIP-seq) and digital droplet PCR (ddPCR). The Glu209 GNAQ and GNA11 missense variants we identified are common in uveal melanoma and have been shown to constitutively activate MAPK and/or YAP signaling. When we screened additional archival formalin-fixed paraffin-embedded (FFPE) congenital cutaneous and hepatic hemangiomas, 4/8 had GNAQ or GNA11 Glu209 variants. The same GNAQ or GNA11 mutation is found in both NICH and RICH, so other factors must account for these tumors’ different postnatal behaviors.     

Updated classification of hemangiomas and other vascular anomalies

Vascular anomalies comprise a widely heterogenous group of tumors and malformations. Great confusion has arisen because of the term hemangioma has been and is continued to be used to represent a multitude of vascular entities. This review presents the updated classification of vascular anomalies with the goal of clarifying the term hemangioma. In addition, newer clinical concepts in hemangiomas and other vascular tumors is presented. Hemangioma subtypes and hemangioma variants are also discussed, and a brief review of pyogenic granuloma and Kaposiform hemangioendothelioma is provided. Finally, the immunohistochemical marker GLUT1 is reviewed, a marker that heralds a new era in vascular anomalies research.     

MiR-200c-3p increased HDMEC proliferation through the notch signaling pathway

Excessive proliferation of vascular endothelial cells can cause hemangioma. Although typically benign, hemangiomas can become life-threatening. The microRNA miR-200c-3p is abnormally expressed in some types of tumors, but its expression, biological role, and mechanism of action in infantile hemangioma remain to be fully elucidated. The expression levels of miR-200c-3p in hemangioma tissue were compared with those in adjacent healthy tissue by using bioinformatics analyses and TargetScan. Western blot, enzyme-linked immunosorbent assay, and Cell Counting Kit 8 analyses were used to determine the biological function and site of action of miR-200c-3p in human dermal microvascular endothelial cells (HDMECs). MiR-200c-3p was one of the top 10 differentially expressed genes between healthy tissue, and hemangiomas tissues, having markedly decreased expression in hemangioma tissue. Reduction of miR-200c-3p expression in HDMECs through the transfection of a miR-200c-3p inhibitor significantly increased HDMEC proliferation. The addition of the Notch signaling pathway inhibitor DAPT to HDMECs transfected with the miR-200c-3p inhibitor eliminated the inhibitor-induced enhancement of proliferation in HDMECs. These findings indicate that miR-200c-3p targets the Notch signaling pathway to promote the proliferation of vascular endothelial cells, suggesting that miR-200c-3p plays an important role in the pathogenesis of hemangioma.     

Atypical vertebral hemangioma: an aggressive form of a benign disease. Case Report and Literature Review

Vertebral hemangiomas are an incidental and relatively common radiological finding and a benign tumor of vascular origin. VH are the most common spine tumors with an estimated incidence of 1.9-27% in the general population. Rarely, vertebral hemangiomas can exhibit extraosseous expansion with resulting compression of the spinal cord. Such lesions are termed aggressive or atypical vertebral hemangiomas (AVH) and account for less than 1% of spinal hemangiomas. A 68-year-old female was referred with progressive walking difficulty and sensory disturbances in her lower extremities. MRI imaging of the thoracic spine revealed a T1- and T2-weighted hyperintense lesion involving the T10 vertebra. Additionally, there was extraosseous extension of the tumor into the spinal canal, located both anterior and posterior to the spinal cord, causing severe spinal cord compression. A combined endovascular and surgical approach (arterial coil embolization and en bloc resection) for treatment was decided. Although vertebral hemangiomas are an incidental and relatively common radiological finding, the findings of our case were consistent with an aggressive hemangioma with atypical MRI and clinical prognostic characteristics. In summary, the present case highlights the need for multidisciplinary approach and in-depth knowledge of this rare pathologic entity.     

Further evaluation of the potential of the argon laser in the treatment of strawberry hemangiomas

Six cases of strawberry hemangioma have been presented in which some form of intervention in tumor progression was indicated. The argon laser was used. All six cases showed loss of surface vascularity. Growth was clearly arrested in four of the six. Premature regression could be definitely claimed in only one. The strong impression is presented that argon laser therapy, although often helpful in the more developed strawberry hemangiomas, as seen in this series, could be most effective if used when the lesion is first noted, before it has time to grow, especially in areas of high complication potential. Where feasible, further exploration into the use of the argon laser in very early strawberry hemangiomas is urged.     

Mice transgenic with SV40-late-promoter-driven Polyomavirus Middle T oncogene exclusively develop hemangiomas

In order to develop a model system of infantile hemangioma, transgenic mice were developed carrying the Polyomavirus Middle T (PyMT) gene driven by the SV40 late promoter. From the 520 fertilized eggs surviving microinjection, there were 25 live births. Three of these showed the hemangioma phenotype and carried and expressed the PyMT gene; the remaining descendants were normal. The tumors showed abnormal vascular proliferation with cavernous hemangioma-like structures in the skin surface, tongue, ear mucosa and gastric mucosal tissue in the transgenic mice with hemangioma phenotype. Immunohistochemical staining for Ki-67 was negative, showing the tumors were hemangiomas rather than angiosarcomas. None of the PyMT transgenic mice survived beyond 4 weeks. Previously reported PyMT transgenic mice under the control of various promoters induce many tumor types including hemangiomas. PyMT driven by the SV40 late promoter is an improved model system because it only induces hemangiomas. However, it is limited by the post-natal lethality. Thus, conditional variants of this model system would be desirable.     

Diagnosis of hepatic hemangiomas with 99mTc-labeled red blood cell scanning: value of SPECT.

99mTc-labeled red blood cell (RBC) scanning is considered a highly specific technique for the study of hepatic hemangiomas. However, planar imaging displays poor sensitivity for the identification of small lesions. The authors consider a survey group of 119 patients, of whom 66 with a presumed diagnosis of hepatic hemangioma, for a total of 77 lesions ranging from 0.8 to 15 cm in diameter. The study was conducted with three-phase planar imaging and single photon emission computed tomography (SPECT). The results, which confirm a high specificity of 99mTc-RBC scanning (100%) in the study of hepatic hemangiomas, show that SPECT significantly improves the detection of these lesions (71%) compared to the delayed static study (52%), with the largest gain for lesions between 2-3.5 cm (83% versus 51%). However, also SPECT has difficulty in detecting lesions of less than 2 cm. With regard to three-phase imaging, the authors point out that the pattern considered characteristic for hepatic hemangiomas (perfusion blood-pool mismatch) is infrequent (13%).     

Fine needle aspiration cytology of cellular hemangioma of infancy. A case report

BACKGROUND: Cellular hemangioma is a common benign vascular neoplasm of infants and children. The lesion typically occurs within the superficial dermis, where it is recognized as a strawberry nevus. Occasionally, this neoplasm is situated within deep soft tissues of the head or neck, with a particular predilection for the parotid gland region. Fine needle aspiration cytology (FNAC) of cellular hemangioma involving the parotid gland has been reported previously, but never confirmed by cytologic findings alone. We report the first case of infantile cellular hemangioma with sufficient characteristic cytologic features to be diagnosed by FNAC. CASE: A 3-month-old male presented with a rapidly enlarging, sensitive, solid, supraparotid mass. Ultrasound and computed tomography were performed but were nondiagnostic. Subsequent FNAC of the mass demonstrated a highly cellular specimen composed predominantly of elongated spindled cells arranged in three-dimensional coils and arcades. Immunohistochemistry demonstrated the endothelial origin of the spindled cells and confirmed the diagnosis of cellular hemangioma. CONCLUSION: Deeply situated cellular hemangiomas may pose a difficult diagnostic challenge to the clinician as well as to the radiologist. The infantile variant of this tumor enlarges rapidly, simulating an aggressive malignant tumor, and is occasionally accompanied by substantial compressive symptoms. Radiographic presentation of the lesion may be that of a solid tumor mass, unlike most other hemangiomas. Precise cytologic diagnosis of infantile cellular hemangioma can be rendered on aspirated material and is crucial in planning conservative medical treatment.     

Preliminary study of the vascular dynamics of port-wine hemangioma with therapeutic implications for argon laser treatment

The vascular dynamics of port-wine hemangioma have been studied in several ways in order to better understand blood flow factors. Utilizing a laser Doppler velocimeter, differential perfusion/blood flow was studied and contrasted to normal skin, compared to heat and cold challenges, and finally measured in relationship to argon laser treatment. Results indicate that port-wine hemangiomas do not necessarily have different perfusion than normal skin but respond less vigorously to heat challenges. Cooling showed no uniform response by port-wine hemangioma vessels, while injection with Xylocaine plus epinephrine resulted in a markedly decreased perfusion and vasoconstriction contrary to previously held theories. Argon laser treatment did not uniformly alter laser Doppler perfusion to a predictable degree. Laser Doppler velocimeter flow studies were not able to predict future good versus bad results of laser treatment.     

Rapamycin Inhibits Proliferation of Hemangioma Endothelial Cells by Reducing HIF-1-Dependent Expression of VEGF

Hemangiomas are tumors formed by hyper-proliferation of vascular endothelial cells. This is caused by elevated vascular endothelial growth factor (VEGF) signaling through VEGF receptor 2 (VEGFR2). Here we show that elevated VEGF levels produced by hemangioma endothelial cells are reduced by the mTOR inhibitor rapamycin. mTOR activates p70S6K, which controls translation of mRNA to generate proteins such as hypoxia inducible factor-1 (HIF-1). VEGF is a known HIF-1 target gene, and our data show that VEGF levels in hemangioma endothelial cells are reduced by HIF-1α siRNA. Over-expression of HIF-1α increases VEGF levels and endothelial cell proliferation. Furthermore, both rapamycin and HIF-1α siRNA reduce proliferation of hemangioma endothelial cells. These data suggest that mTOR and HIF-1 contribute to hemangioma endothelial cell proliferation by stimulating an autocrine loop of VEGF signaling. Furthermore, mTOR and HIF-1 may be therapeutic targets for the treatment of hemangiomas.     

Transscleral diode photocoagulation of large retinal and choroidal vascular lesions

BACKGROUND: Transscleral retinal photocoagulation with a diode laser is used in glaucoma refractory to medical and surgical treatment. Our main research question was how the technique performed in large vascular lesions associated with hemangiomas of the retina and choroid. METHODOLOGY/CLINICAL FINDINGS: Patient charts were retrieved from the hospital files for patients who underwent the procedure and were followed for at least 24 months. Five patients (6 eyes) fit the criteria. Cases included Von Hippel's disease (2 eyes), Coats' disease (1 eye) and choroidal hemangioma (3 cases). Transscleral diode laser treatment was performed under retrobulbar and topical anesthesia with a retinopexy probe (IRIS DioPexy, IRIS Medical Instruments, Mountain View, CA) applied transsclerally under indirect ophthalmoscope visualization. We found an improvement in best-corrected visual acuity at 24 months postoperatively. CONCLUSIONS/SIGNIFICANCE: Transscleral photocoagulation may have a clinical application in these diseases as an alternate to the high cost of photodynamic therapy with photosensitizing agents.     

A possible mechanism of spontaneous involution of infantile hemangioma

Infantile hemangiomas are common vascular tumours which exhibit a rapid proliferating phase followed by spontaneously involuting for a long time. The formation and development mechanisms are not clear yet. Recent studies show that hemangioma-derived stem cells have multipotential differentiation abilities, including endothelial and mesenchymal differentiation. In addition, mesenchymal stem cell has the capability of inducing endothelial cell apoptosis, differentiating into adipocytes and triggering the involution of hemangiomas. Thus we hypothesize that mesenchymal stem cell may be the source of spontaneously regression of hemangiomas. Further investigations may be needed to develop potential therapeutic implications of mesenchymal stem cell in treating hemangiomas.