Noninvoluting Congenital Hemangioma Research Articles

Construction and applications of the EOMA spheroid model of Kaposiform hemangioendothelioma

BackgroundKaposiform hemangioendothelioma (KHE) is a rare intermediate vascular tumor with unclear pathogenesis. Recently, three dimensional (3D) cell spheroids and organoids have played an indispensable role in the study of many diseases, such as infantile hemangioma and non-involuting congenital hemangiomas. However, few research on KHE are based on the 3D model. This study aims to evaluate the 3D superiority, the similarity with KHE and the ability of drug evaluation of EOMA spheroids as an in vitro 3D KHE model.ResultsAfter two days, relatively uniform morphology and high viability of EOMA spheroids were generated by the rotating cell culture system (RCCS). Through transcriptome analysis, compared with 2D EOMA cells, focal adhesion-related genes such as Itgb4, Flt1, VEGFC, TNXB, LAMA3, VWF, and VEGFD were upregulated in EOMA spheroids. Meanwhile, the EOMA spheroids injected into the subcutaneous showed more obvious KMP than 2D EOMA cells. Furthermore, EOMA spheroids possessed the similar characteristics to the KHE tissues and subcutaneous tumors, such as diagnostic markers (CD31 and LYVE-1), cell proliferation (Ki67), hypoxia (HIF-1α) and cell adhesion (E-cadherin and N-cadherin). Based on the EOMA spheroid model, we discovered that sirolimus, the first-line drug for treating KHE, could inhibit EOMA cell proliferation and downregulate the VEGFC expression. Through the extra addition of VEGFC, the effect of sirolimus on EOMA spheroid could be weakened.ConclusionWith a high degree of similarity of the KHE, 3D EOMA spheroids generated by the RCCS can be used as a in vitro model for basic researches of KHE, generating subcutaneous tumors and drug screening.

Novel organoid construction strategy for non-involuting congenital hemangioma for drug validation

BackgroundNon-involuting congenital hemangiomas (NICHs) are fully formed vascular tumors at birth with distinctive clinical, radiologic, and histopathological profiles. In the literature, there is no effective therapy strategy for patients with NICH except surgery. Currently, no cell line or animal model exists for studying the mechanism of NICH and drug validation. We plan to construct a new strategy by constructing NICH organoids for further study.ResultHere, we report a novel NICH organoid system construction and optimization process. Both HE and immunohistological staining exactly matched NICH tissue. We further performed transcriptome analysis to elucidate the characteristics of NICH organoids. Both NICH tissue and NICH organoids manifested similar trends in download sites. NICH organoids display novel features to new cells derived from organoids and show spectacular multiplication capacity. In the preliminary verification, we found that cells splitting from NICH organoids were human endothelial cells. Drug validation demonstrated that trametinib, sirolimus, and propranolol showed no inhibitory effects on NICH organoids.ConclusionOur data show that this new NICH-derived organoid faithfully captured the features of this rare vascular tumor. Our study will boost further research on the mechanism of NICH and drug filtering in the future.

Newborn with Giant Non-Involuting Congenital Hemangioma: Mechanisms of Allodynia, Hyperalgesia and Treatment

Newborn with Giant Non-Involuting Congenital Hemangioma: Mechanisms of Allodynia, Hyperalgesia and Treatment

Management of a Gluteal Noninvoluting Hemangioma With Glue Embolization and Excision.

Noninvoluting congenital hemangiomas (NICHs) persist in a high-flow state into childhood and often require surgical excision. The inherent vascular nature of these tumors make effective surgical treatment challenging. Here we report on a patient that underwent intraoperative glue embolization and complete excision of a large gluteal NICH. Concurrent glue embolization followed by complete excision allows for decreased intraoperative blood loss and easier discrimination between the tumor and surrounding structures. Treating difficult vascular tumors with a multidisciplinary approach and subsequent intraoperative glue embolization with surgical excision allows for an effective, single-stage approach to NICHs.

Percutaneous Cryoablation for Symptomatic Peripheral Congenital Hemangioma

Congenital hemangiomas (CHs) are rare, benign vascular tumors that are present at birth. They are divided into 3 major subtypes: rapidly involuting CHs, partially involuting CHs, and noninvoluting CHs (NICHs). There is a paucity of data in the literature regarding NICH and its management. Most symptomatic patients with NICH are managed with surgery. However, endovascular embolization, direct percutaneous sclerotherapy, or laser treatment can be used on a case-by-case basis. In this report, 3 cases with peripheral symptomatic NICH treated with percutaneous cryoablation are presented.

Spontaneous evolution patterns of focal congenital hepatic hemangiomas: a case series of 25 patients.

Hepatic hemangiomas are the most common benign liver tumors of infancy. They are termed congenital if fully developed at birth or infantile if they appear in the first weeks of life. Previous studies suggested that most focal hepatic hemangiomas are congenital in nature, exhibit no postnatal growth and have an evolution that parallels their cutaneous counterparts. They are subdivided by pattern of involution, whether rapidly involuting (RICH), partially involuting (PICH) or non-involuting (NICH) congenital hemangiomas. In our experience, some focal hepatic hemangiomas show postnatal growth, behaving like infantile forms. To analyze the spontaneous evolution of focal congenital hepatic hemangiomas with quantification of tumor volume changes over time and to identify initial postnatal ultrasound (US) imaging biomarkers predictive of their evolution pattern. A retrospective review of clinical, imaging and pathology data of children diagnosed with focal congenital hepatic hemangioma (prenatal diagnosis or age at diagnosis <7days and/or glucose transporter protein 1 [GLUT1]-negative tumor) diagnosed between 2000 and 2018 was performed with analysis of tumor volume changes over time. Exclusion criteria were treatment inducing a tumor volume change (hepatic artery embolization, propranolol, or corticosteroids), imaging follow-up less than 1month or fewer than two US examinations. Volumetric analysis was based on US and cross-sectional imaging. Lesion volumes were estimated using the standard ellipsoid formula. A 35% margin of error was assumed for tumor volume variation to account for variability in measurements. Imaging studies, including US, computed tomography, and magnetic resonance imaging, were reviewed and initial postnatal US features were correlated with evolution pattern. Twenty-five patients with focal congenital hepatic hemangiomas were included. The median follow-up time was 46.5months (range: 4-144months). Eight (32%) lesions showed postnatal growth before involuting, without signs of intralesional hemorrhage, as do cutaneous infantile hemangiomas. The other 17 (68%) lesions exhibited a strict decrease in volume with age, of which 15 underwent complete involution (8 before age 18months and 7 after age 18months) and 2 underwent partial involution. The different evolution patterns of focal congenital hepatic hemangiomas showed overlapping imaging features and we found no initial US feature to be significantly associated with postnatal growth. However, large vascular spaces with marked vascularity at US were noted in three of the eight rapidly involuting lesions. Focal congenital hepatic hemangiomas are not the equivalent of cutaneous RICH, as some may increase in size and tumor regression may be rapid or slow. The different evolution patterns of focal congenital hepatic hemangiomas show overlapping US features.

Abstract No. 81 Bleomycin-soaked bio-resorbable particle embolization of benign vascular anomalies

Report our early experience using bleomycin-soaked, bio-resorbable particles via trans-arterial embolization to treat benign vascular tumors/malformations refractory to medical therapy and not amenable to surgical resection. Between January 2019 and July 2020, 8 patients (median age: 7 years [range: 2-15 years], median weight: 26 kg [range: 12-81 kg]) underwent trans-arterial embolization of non-involuting congenital hemangiomas (n = 3), infantile hemangiomas (n = 3), and intra-muscular capillary high-flow malformations (n = 2). Median number of treatments was 2 (range: 1-5). Indications for treatment: pain, worsening function in extremity/affected body part, swelling and dysmorphic overgrowth. The particles (300-500μm) were prepared with the bleomycin solution (dose: 1 unit/kg; maximum 15 units reconstituted in 4mL normal saline) and allowed to soak for 20-30 minutes prior to endovascular delivery. Particles were delivered via micro-catheter (2.5F) into the affected locations (lip = 5; leg = 1; posterior chest wall = 1; face = 1). 8 patients underwent 19 embolization procedures. Technical success (pruning/elimination of the lesion’s arterial supply and diminished lesional blush) was achieved in all procedures. There were no major or minor complications. Angiographic follow-up was available in 6 patients, with all patients showing angiographic improvement or resolution. Clinical success, defined as symptomatic and/or functional improvement, was achieved in all 7 patients for which clinical follow-up was available (1 patient lost to follow-up). Average clinical follow-up: 8 months (range: 2-17). Arterial embolization of benign vascular tumors/malformations with bleomycin-soaked, bio-resorbable particles is technically feasible with a seemingly favorable safety profile in appropriately selected patients. Further investigation is warranted to assess long-term efficacy.

Repidly involuting congenital hemangioma

Congenital hemangiomas are rare benign vascular tumors that develop in utero and are fully formed by the time of birth. Depending on the ability to involution, there are three subtypes: RICH (repidly involuting congenital hemangioma), NICH (non involuting congenital hemangioma), PICH (partially involuting congenital hemangioma). PICH may be accompanied by thrombocytopenia and consumption coagulopathy. Despite clearly defined clinical and histological characteristics, it can be difficult to make a differential diagnosis between congenital hemangiomas and other vascular tumors (infantile hemangioma, kaposiform hemangioendothelioma/“fascicular” angioma and others). The clinical case in the article of a vascular tumor in a newborn complicated by thrombocytopenia and consumption coagulopathy was regarded as Kazabach-Merritt syndrome, which is based on kaposiform hemangioendothelioma/“fascicular” angioma. Rapid regression of the tumor and recovery of hemogram and coagulogram parameters, as well as anamnesis of the disease and initial characteristics of the tumor forced to reconsider the diagnosis. Based on the histological picture, the diagnosis of congenital hemangioma, RICH, was confirmed. Verification of the diagnosis made it possible to change therapeutic tactics and avoid chemotherapy. A giant hemangioma, accompanied by thrombocytopenia and consumption coagulopathy, may have a very favorable outcome – a complete resolution of the pathological process inherent in its natural course. The patient's parents agreed to use the information, including the child's photo, in scientific research and publications. 

HEAD AND NECK VASCULAR ANOMALIES OUR CLINICAL EXPERIENCE AND LITERATURE REVIEW.

Abstract Background- Head and neck vascular anomalies are a spectrum of lesion ranging from simple asymptomatic malformations to life-threatening airway vascular tumors. Management of these lesion poses a real challenge to even most experienced otolaryngologists.Systematic evaluation and prompt diagnosis and judicial choice of treatment are essential for proper management of these lesions. Material and methods-A retrospective review of the head and neck vascular anomalies over three years, from 2017 to 2019 in a tertiary referral centre. Clinical features, radiology, treatment and follow-up data were studied.We did a literature review to give a comprehensive analysis regarding the diagnosis and treatment of the vascular anomalies of the head and neck region. Results- A total of 25 patients were managed in our department in two years. Of these 25 patients, three patients had infantile haemangioma(12%), six patient had congenital haemangioma(24%), six patients had lymphatic malformation(24%), four patient had an arteriovenous malformation (16%), and six patient had venous malformation (24%). Sixpatients (24%) underwent surgery as treatment, which includes one case of noninvoluting congenital hemangioma (NICH) of the temporal bone, one facial AVM, twolateral neck lymphangiomas, one skull base lymphangioma and a venous neck malformation. All the infantile h a ema n gi oma s we rema n a g e d w i t h o ra l propranolol, three lymphatic malformations underwent sclerotherapy, while the three Arteriovenous malformations (AVM), 􀃶ve congenital haemangiomas and four Venous malformations (VM) were under observation. Conclusion-Managing a vascular anomaly requires a prompt diagnosis based on the ISSVA classi􀃶cation, patients' symptoms and the location of the lesion. Not all vascular anomaly requires active management. Careful case selection and a multidisciplinary team are essential for adequate management of the vascular anomalies. Key Words: Vascular Malformation, Hemangioma, Lymphangioma

Benign vascular anomalies: A transition from morphological to etiological classification

The International Society for the Study of Vascular Anomalies (ISSVA) devised a multidisciplinary etiopathogenesis based approach to classify benign vascular anomalies into tumors and malformations. This classification scheme has major therapeutic and prognostic implications as treatment modalities differ for both the categories. Inappropriate usage of the term “hemangioma” for etiopathogenetically distinct entities is commonly seen in clinical practice leading to delivery of incorrect treatment to the patients. We aimed to study the histomorphological and immunohistochemical features of benign vascular anomalies for their precise histopathological classification. A total of 48 cases diagnosed over a period of 3.5 years were reviewed and reclassified into vascular tumors and malformations based on ISSVA classification and prototypical histopathological features. Biopsies were reviewed based on 5 histopathological criteria viz. endothelial morphology, mitotic activity, intralesional nerve bundles, intralesional inflammation, and prominent vessel type. A panel of GLUT-1, WT-1, and Ki-67 was performed in each case. Seven cases of infantile hemangioma, 4 cases each of non-involuting congenital hemangioma and pyogenic granuloma, and 33 cases of vascular malformations were diagnosed. Endothelial cell morphology (p < 0.001), mitotic activity (p < 0.001), and intralesional nerve bundles (p < 0.001) were found to be statistically significant in differentiating hemangioma from malformations. GLUT-1 (p < 0.001) and Ki-67 labeling index (p < 0.001) were useful to distinguish infantile hemangioma from vascular malformations. To conclude, the ISSVA classification of benign vascular anomalies can be reliably done on histopathology. However, every case must be interpreted in the light of clinical and radiological features.

A case series of tardive expansion congenital hemangioma: A variation of noninvoluting congenital hemangioma or a new hemangiomatous entity?

Congenital hemangiomas present fully grown at birth and share a remarkably similar lack of disproportionate or accelerated postnatal proliferation. We report a series of unusual congenital hemangiomas that arise prenatally and initially exhibit a proportional growth pattern similar to that of noninvoluting congenital hemangioma. However, a tardive expansion of the lesion, similar to the proliferation phase of infantile hemangioma, occurs later during childhood. A total of 11 unusual congenital hemangiomas were reviewed in regard to clinical presentation, imaging, and pathologic characteristics. The infants included 9 boys and 2 girls. The tumors were located in the head and neck (n=10) and abdominal wall (n=1). Spontaneous expansion began at the age of 12 months to 61 months, as determined from clinic notes and paired follow-up photographs. Uniform parenchymal masses and fast-flow vessels were confirmed by imaging examination. There are both histopathological overlap and distinction between these lesions and other congenital hemangiomas. Only a small number of cases were identified. We propose that these lesions be denominated "tardive expansion congenital hemangioma (TECH)" to indicate their specific clinical and histological distinctiveness. Recognition of these distinct lesions will contribute to a better understanding of congenital hemangiomas.

Giant Congenital Hemangioma: An Entity of Intermediate Behavior Between Rapidly Involuting Congenital Hemangioma and Non-Involuting Congenital Hemangioma. Presentation of A Case and Review of the Literature

Giant Congenital Hemangioma: An Entity of Intermediate Behavior Between Rapidly Involuting Congenital Hemangioma and Non-Involuting Congenital Hemangioma. Presentation of A Case and Review of the Literature

RICH (Rapidly Involuting Congenital Hemangioma) with Fetal Involution

A term newborn was evaluated for the presence of a lesion resembling an involuting hemangioma; dermoscopy showed some residual ectasic capillaries, consistent with the diagnosis. At 5 months, lesion appeared in further light regression, comparable to that of a classical capillary hemangioma at 2 years of life. Pediatric hemangiomas are classified into infantile and congenital hemangioma. Infantile hemangiomas typically are very pale at birth, proliferate in the first months of life and then gradually involute throughout childhood. Congenital hemangiomas are further subclassified into rapidly involuting (RICH) and non-involuting (NICH) congenital hemangioma. Recently, a new variant of RICH showing fetal involution has been described. The prominent part of the life cycle of this variant of RICH (ie, proliferation and rapid involution) seems to start prenatally, whereas regression in typical RICH usually occurs in early infancy.Our case seems to confirm the existence of such variant of RICH.

Non-involuting congenital hemangiomas (NICH) with postnatal atypical growth: A case series.

Non-involuting congenital hemangiomas (NICH) are fully formed vascular tumors at birth, with a distinctive clinical, radiologic, and histopathological profile, and classically lack expansion or involution over time. We describe a series of NICH cases with atypical postnatal growth. The authors retrospectively analyzed all NICH cases diagnosed from 2007 to 2017. We reviewed charts and photographic databases from our Vascular Anomalies Clinic. We included in the study all NICH with an atypical postnatal growth. Clinical data, imaging, and histopathology were analyzed. Eighty cases of NICH were identified. Nine presented with atypical postnatal growth after a stable period, at ages from 2 to 10years (mean: 5.3years). Two patients had associated pain; 5 patients showed new red papules on the surface of the lesion; 2 reported bleeding from the papules; and 1 developed a pyogenic granuloma. All patients had Doppler ultrasound and/or MRI compatible with NICH, and a confirmatory biopsy was performed in 4 cases. In treatment, 2 patients received endovascular embolization, and one required further surgery. Non-involuting congenital hemangiomas (NICH) may develop significant postnatal growth over time (10% in our series), requiring closer follow-up for longer periods. The development of red papules, pyogenic granulomas, and superficial bleeding may be observed. Since this is a small series, we were not able to establish risk factors for NICH with postnatal growth.

Angiographic and Clinical Features of Noninvoluting Congenital Hemangiomas.

While infantile hemangiomas are very common, congenital hemangiomas are rare and less understood. Congenital hemangiomas are present at birth. They fall into 2 major categories: rapidly involuting congenital hemangioma and noninvoluting congenital hemangioma. Noninvoluting congenital hemangioma is the rarer of the 2 entities. If not recognized and treated appropriately, noninvoluting congenital hemangioma can lead to considerable morbidity. There is a paucity of literature regarding noninvoluting congenital hemangiomas. In this article, we will outline our experience with this condition, focusing on clinical and angiographic features. There is a distinct angiographic appearance of noninvoluting congenital hemangiomas involving an arterial-capillary web, a dense tumor blush with identifiable feeding arteries, no arteriovenous shunting, and variably present draining veins. Our experience with endovascular embolization and direct percutaneous treatment is the largest for this entity to date. Endovascular embolization and/or direct percutaneous sclerotherapy of this lesion may obviate subsequent surgical resection.

Rapidly involuting congenital hemangioma with complete resolution In Utero

There are three types of congenital hemangioma - rapidly involuting congenital hemangioma (RICH), partially involuting congenital hemangioma, and noninvoluting congenital hemangioma. We report a case of RICH on the back of a 4-month-old Caucasian male infant, based on ultrasound and magnetic resonance imaging findings in the antenatal period, skin changes at birth, and a normal ultrasound after birth. He was born with an atrophic plaque at the site of the vascular swelling depicted on the scans, suggesting the complete involution of the lesion in the antenatal period.

Prenatal diagnosis of rapidly involuting congenital hemangioma: a case report and review of the literature

Abstract Congenital hemangiomata are rare benign vascular tumors, presenting as fully mature lesions at birth. Three types have been described; the “rapidly involuting congenital hemangioma” (RICH), the “non-involuting congenital hemangioma” (NICH)and the “partially involuting congenital hemangioma” (PICH). We herein report on a RICH type congenital hemangioma, identified during a fetal morphology ultrasound performed at 19 weeks’ gestation. Early diagnosis allowed close surveillance of the fetus and neonate and observation of the natural course of this lesion. Although being a potentially life-threatening condition, no intervention was required. It presented as a 4 cm vascular tumor on the forehead at time of the cesarean section and diminished rapidly over the first 4 neonatal months, resulting in some skin excess and discoloration which is expected to entirely resolve by 14 months of age.

The pigment epithelium-derived factor (PEDF): an important potential therapeutic agent for infantile hemangioma.

In previous studies, the expression and the role of proangiogenic factors in infantile hemangiomas have been well studied. However, the role of angiogenic inhibitors has been revealed rarely. The expression of PEDF, as the strongest and safe endogenous inhibitor, is still unrecognized until the current study. In order to investigate the expression and significance of the pigment epithelium-derived factor (PEDF) in the proliferating and regressing phases of infantile hemangiomas, the expression of PEDF, VEGF, Ki-67, and CD34 protein in hemangioma tissues was examined with immunohistochemical polymer HRP method in 42 cases during the proliferative phase, 40 cases during the regressing phase, and 11 cases of non-involuting congenital hemangiomas (NICHs). Meanwhile, the mRNA expression of these factors was detected with quantitative realtime RT-PCR. We found the protein and mRNA expression of PEDF in regressing phase was significantly higher than those in proliferative phase and NICHs (P < 0.001), while the protein and mRNA expression of VEGF were much lower (P < 0.001). The microvessel density (MVD), Ki-67 changes, and the expression of PEDF and VEGF were found significantly correlated. These results indicated that the reduction of VEGF and increase in PEDF are causative to the evolution of infantile hemangioma. PEDF may play a key role in the spontaneous regression of infantile hemangioma and may become an important potential therapeutic agent for infantile hemangioma.

Congenital hemangiomas.

Congenital hemangiomas are rare solitary vascular tumors that do not proliferate after birth. They are characterized as either rapidly involuting congenital hemangiomas (RICHs) or noninvoluting congenital hemangiomas (NICHs) based on their clinical progression. NICHs have no associated complications, but are persistent. RICH, while usually asymptomatic, may ulcerate or bleed early in their presentation, but involute quickly during the first few months of life. Hepatic RICHs are not associated with cutaneous RICHs, but may result in high-output cardiac failure due to arteriovenous or portovenous shunting. In the following review, the clinical characteristics and current management specific to congenital hemangiomas is discussed.

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.