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.].

Comprehensive phenotypic and genomic characterization of venous malformations.

Venous malformations (VMs) are the most common vascular malformations. TEK and PIK3CA are the causal genes of VMs, and may be involved in the PI3K/AKT pathway. However, the downstream mechanisms underlying the TEK or PIK3CA mutations in VMs are not completely understood. This study aimed to identify a possible association between genetic mutations and clinicopathological features. A retrospective clinical, pathological, and genetic study of 114 patients with VMs was performed. TEK, PIK3CA, and combined TEK/PIK3CA mutations were identified in 49 (43%), 13 (11.4%), and 2 (1.75%) patients, respectively. TEK-mutant VMs more commonly occurred in younger patients than TEK and PIK3CA mutation-negative VMs (other-mutant VMs), and showed more frequent skin involvement and no lymphocytic aggregates. No significant differences were observed in sex, location of occurrence, malformed vessel size, vessel density, or thickness of the vascular smooth muscle among the VM genotypes. Immunohistochemical analysis revealed that the expression levels of phosphorylated AKT (p-AKT) were higher in the TEK-mutant VMs than those in PIK3CA-mutant and other-mutant VMs. The expression levels of p-mTOR and its downstream effectors were higher in all the VM genotypes than those in normal vessels. Spatial transcriptomics revealed that the genes involved in "blood vessel development", "positive regulation of cell migration", and "extracellular matrix organization" were up-regulated in a TEK-mutant VM. Significant genotype-phenotype correlations in clinical and pathological features were observed among the VM genotypes, indicating gene-specific effects. Detailed analysis of gene-specific effects in VMs may offer insights into the underlying molecular pathways and implications for targeted therapies.

Progressive vascular tumor in infant: A case report and literature review of PIK3CA vascular malformation.

PURPOSE: Vascular anomalies are classified as either vascular tumors or vascular malformations. Vascular malformations can be difficult to diagnose and treat in the pediatric population and can masquerade as malignant processes. Understanding the genetics behind vascular malformations can lead to identification of specific mutations which can be treated with targeted immunotherapy. METHODS: Our case presents a pediatric patient with progressively enlarging vascular malformation despite multiple surgical resections and systemic medical treatments who underwent genetic evaluation and was found to have PIK3CA mutation. RESULTS: After identification of PIK3CA mutation, our patient was successfully treated with the p110ɑ-specific inhibitor, alpelisib, with both shrinkage of malformation on follow-up imaging as well as gains in her developmental milestones. CONCLUSION: Progressive vascular malformations in the pediatric population can be hard to diagnose and treat and are thought to arise from somatic mutations. Our case highlights a patient with progressive malformation despite multiple surgical resections who was successfully treated with targeted immunotherapy after proper identification of genetic mutation.

Venous malformations of the lower limb with severe localized intravascular coagulopathy treated with radiofrequency ablation and resection.

Diffuse venous malformations (VMs) are relatively rare, especially the lesions locting special anatomical sites, and they are prone to casuse localized intravascular coagulopathy (LIC). Diffuse VMs can also cause bleeding and life-threatening disseminated intravascular coagulopathy (DIC) from trauma, surgery, and improper treatments. Thus, the treatment of diffuse VMs with LIC is quite tough. We report of a diffuse VMs with severe LIC that was treated with the combined use of minimally invasive treatment and open surgery.

Jejunal arteriovenous malformation and multiple acquired extrahepatic portosystemic shunts in a juvenile dog, presenting with melena.

A juvenile dog referred with a 1-month history of persistent melena and severe anaemia, was diagnosed with a jejunal arteriovenous malformation, and multiple acquired extrahepatic portosystemic shunts. A midline coeliotomy was performed, the jejunal arteriovenous malformation was localised intraoperatively and was successfully removed via an enterectomy. Histopathology confirmed a true arteriovenous malformation. Despite the initial improvement, the patient developed seizure episodes secondary to hepatic encephalopathy 8 months after surgery. Fifteen months after surgery, the owner opted for euthanasia due to the ongoing seizure episodes. Post-mortem histologic examination of the liver showed features consistent with portal vein hypoplasia. A congenital arteriovenous malformation should be considered as a differential diagnosis in juvenile patients with a chronic history of haemorrhage from the gastrointestinal tract. In addition, acquired portosystemic shunts may occur in patients with portal vein hypoplasia and jejunal arteriovenous malformations.

ErbB signaling is a potential therapeutic target for vascular lesions with fibrous component.

Background: Sporadic venous malformation (VM) and angiomatosis of soft tissue (AST) are benign, congenital vascular anomalies affecting venous vasculature. Depending on the size and location of the lesion, symptoms vary from motility disturbances to pain and disfigurement. Due to the high recurrence of the lesions, more effective therapies are needed. Methods: As targeting stromal cells has been an emerging concept in anti-angiogenic therapies, here, by using VM/AST patient samples, RNA-sequencing, cell culture techniques, and a xenograft mouse model, we investigated the crosstalk of endothelial cells (EC) and fibroblasts and its effect on vascular lesion growth. Results: We report, for the first time, the expression and secretion of transforming growth factor A (TGFA) in ECs or intervascular stromal cells in AST and VM lesions. TGFA induced secretion of vascular endothelial growth factor (VEGF-A) in paracrine fashion, and regulated EC proliferation. Oncogenic PIK3CA variant in p.H1047R, a common somatic mutation found in these lesions, increased TGFA expression, enrichment of hallmark hypoxia, and in a mouse xenograft model, lesion size, and vascularization. Treatment with afatinib, a pan-ErbB tyrosine-kinase inhibitor, decreased vascularization and lesion size in a mouse xenograft model with ECs expressing oncogenic PIK3CA p.H1047R variant and fibroblasts. Conclusions: Based on the data, we suggest that targeting of both intervascular stromal cells and ECs is a potential treatment strategy for vascular lesions having a fibrous component. Funding: Academy of Finland, Ella and Georg Ehnrooth foundation, the ERC grants, Sigrid Jusélius Foundation, Finnish Foundation for Cardiovascular Research, Jane and Aatos Erkko Foundation, GeneCellNano Flagship program, and Department of Musculoskeletal and Plastic Surgery, Helsinki University Hospital.

Fibroadipose vascular anomaly: a clinicopathological study of 75 cases.

AIMS: Fibroadipose vascular anomaly (FAVA) is a complex vascular malformation that is likely to be under-recognised. In this study we aimed to report the pathological features and somatic PIK3CA mutations associated with the most common clinicopathological features. METHODS AND RESULTS: Cases were identified by reviewing the lesions resected from patients with FAVA registered at our Haemangioma Surgery Centre and unusual intramuscular vascular anomalies in our pathology database. There were 23 males and 52 females, who ranged in age from 1 to 51 years. Most cases occurred in the lower extremities (n = 62). The majority of the lesions were intramuscular, with a few disrupting the overlying fascia and involving subcutaneous fat (19 of 75), and a minority of the cases had cutaneous vascular stains (13 of 75). Histopathologically, the lesion was composed of anomalous vascular components that were intertwined with mature adipocytic and dense fibrous tissues and vascular components with: (a) clusters of thin-walled channels, some with blood-filled nodules and others with thin walls resembling pulmonary alveoli; (b) numerous small vessels (arteries, veins and indeterminate channels) - proliferative small blood vessels were often mixed with adipose tissue; (c) larger abnormal venous channels usually irregularly and sometimes excessively muscularised; (d) lymphoid aggregates or lymphoplasmacytic aggregates were usually observed; and (e) lymphatic malformations were sometimes seen as minor elements. All patients had their lessons subjected to PCR, and 53 patients had somatic PIK3CA mutations (53 of 75). CONCLUSIONS: FAVA is a slow-flow vascular malformation with specific clinicopathological and molecular characteristics. Its recognition is fundamental for its clinical/prognostic implications and for targeted therapy.

Symptomatic Developmental Venous Anomaly: State-of-the-Art Review on Genetics, Pathophysiology, and Imaging Approach to Diagnosis.

Developmental venous anomalies (DVAs) are the most common slow-flow venous malformation in the brain. Most DVAs are benign. Uncommonly, DVAs can become symptomatic, leading to a variety of different pathologies. DVAs can vary significantly in size, location, and angioarchitecture, and imaging evaluation of symptomatic developmental venous anomalies requires a systematic approach. In this review, we aimed to provide neuroradiologists with a succinct overview of the genetics and categorization of symptomatic DVAs based on the pathogenesis, which forms the foundation for a tailored neuroimaging approach to assist in diagnosis and management.

Orbital Vascular Malformations: Relationship Between Enophthalmos and Clinically Apparent Distensibility with Valsalva.

PURPOSE: Determining the hemodynamic characteristics of an orbital vascular malformation is a critical step in management. The purpose of this study is to assess the relationship between enophthalmos and clinically apparent distensibility of orbital vascular malformations, to optimize imaging and treatment. METHODS: In this cross-sectional cohort study consecutive patients at a single institution were screened for study entry. Data extracted included age, sex, Hertel measurements, presence or absence of distensibility during the Valsalva maneuver, whether lesions were primarily venous or lymphatic based on imaging, and location of the lesion relative to the globe. Enophthalmos was defined as ≥ 2 mm difference from the opposite side. Parametric and nonparametric statistics were used, and linear regression was performed to examine factors predictive of Hertel measurement. RESULTS: Twenty-nine patients met the inclusion criteria. Relative enophthalmos ≥2 mm was significantly associated with distensibility ( p = 0.03; odds ratio = 5.33). Distensibility and venous dominant morphology were the 2 most important factors associated with enophthalmos on regression analysis. The relative position of the lesion anterior or posterior to the globe did not have a significant bearing on baseline enophthalmos. CONCLUSIONS: The presence of enophthalmos increases the likelihood that an orbital vascular malformation is distensible. This group of patients was also more likely to be characterized by venous dominant malformations. Baseline clinical enophthalmos may serve as a useful surrogate marker for distensibility and venous dominance, which may be useful in guiding the selection of appropriate imaging.

Vascular Malformations: A Histopathologic and Conceptual Appraisal / Malformaciones vasculares: un enfoque histopatológico y conceptual

In the field of vascular anomalies, distinguishing between vascular malformations and tumors has become crucial for a correct therapeutic approach. However, the differential diagnosis between these two groups is not always well explained in classical texts, mainly because many vascular malformations are still known with old names that suggest a tumoral nature. Also, genetic and pathogenic knowledge of these entities has greatly increased in recent decades, so researchers and clinicians now have a better understanding of vascular malformations. In this paper, we present the main histopathological tips to recognize and identify a vascular malformation as such. We also contextualize such information in the clinical and pathogenic knowledge for a better understanding of these entities (AU)

En el campo de las anomalías vasculares, distinguir entre malformaciones vasculares y tumores vasculares se ha vuelto esencial para un enfoque terapéutico correcto. Sin embargo, el diagnóstico diferencial entre estos dos grupos no está siempre correctamente explicado en los textos clásicos, principalmente porque a muchas malformaciones vasculares se las conoce todavía con nombres antiguos que sugieren tumores vasculares. Asimismo, el conocimiento genético y patogénico de estas entidades se ha incrementado notablemente en las décadas recientes, de tal manera que investigadores y clínicos tienen ahora una mejor comprensión de las malformaciones vasculares. En este artículo, presentamos las principales claves histopatológicas para reconocer las malformaciones vasculares e identificarlas como tal. También contextualizamos tal información en el conocimiento clínico y patogénico para mejor comprensión de estas entidades (AU)

[Artículo traducido] Malformaciones vasculares: un enfoque histopatológico y conceptual / Vascular Malformations: A Histopathologic and Conceptual Appraisal

En el campo de las anomalías vasculares, distinguir entre malformaciones vasculares y tumores vasculares se ha vuelto esencial para un enfoque terapéutico correcto. Sin embargo, el diagnóstico diferencial entre estos dos grupos no está siempre correctamente explicado en los textos clásicos, principalmente porque a muchas malformaciones vasculares se las conoce todavía con nombres antiguos que sugieren tumores vasculares. Asimismo, el conocimiento genético y patogénico de estas entidades se ha incrementado notablemente en las décadas recientes, de tal manera que investigadores y clínicos tienen ahora una mejor comprensión de las malformaciones vasculares. En este artículo, presentamos las principales claves histopatológicas para reconocer las malformaciones vasculares e identificarlas como tal. También contextualizamos tal información en el conocimiento clínico y patogénico para mejor comprensión de estas entidades (AU)

In the field of vascular anomalies, distinguishing between vascular malformations and tumors has become crucial for a correct therapeutic approach. However, the differential diagnosis between these two groups is not always well explained in classical texts, mainly because many vascular malformations are still known with old names that suggest a tumoral nature. Also, genetic and pathogenic knowledge of these entities has greatly increased in recent decades, so researchers and clinicians now have a better understanding of vascular malformations. In this paper, we present the main histopathological tips to recognize and identify a vascular malformation as such. We also contextualize such information in the clinical and pathogenic knowledge for a better understanding of these entities (AU)

Cochlear implantation in a patient with congenital microtia, cochlear hypoplasia, venous anomalies of the temporal bone and laryngomalacia: Challenges and surgical considerations.

RATIONALE AND PATIENT CONCERNS: Congenital hearing loss is often caused by an inner ear malformation, in such cases, the presence of other anomalies, such as microtia, and venous anomalies of the temporal bone and laryngomalacia makes it challenging to perform cochlear implantation surgery. DIAGNOSES: This study reports the case of a 28-month-old girl with congenital profound hearing loss, laryngomalacia, and malformed inner ear, who received cochlear implantation surgery. The bony structure, vessels and nerves were first assessed through magnetic resonance imaging and computed tomography before exploring the genetic basis of the condition using trio-based whole exome sequencing. Perioperative evaluation and management of the airway was then performed by experienced anesthesiologist, with the surgical challenges as well as problems encountered fully evaluated. INTERVENTIONS: Cochlear implantation was eventually performed using a trans-mastoid approach under uneventful general anesthesia. OUTCOMES: Due to the small size of the cochlea, a short electrode FLEX24 was inserted through the cochleostomy. LESSONS: Considering the high risk of facial nerve injury and limited access to the cochlea when patients present significant bony and venous anomalies, cochlear implantation in such patients require careful preoperative evaluation and thoughtful planning. In these cases, airway assessment, magnetic resonance venography, magnetic resonance arteriography, and magnetic resonance imaging and computed tomography can be useful to minimize the risks. Intraoperative facial nerve monitoring is also recommended to assist in the safe location of facial nerve.

Approach to clinically significant vascular anomalies in children.

Vascular anomalies consist of tumours or malformations made up of abnormal growth or collections of blood vessels that can result in functional or cosmetic problems. While many vascular anomalies are present at birth, some do not appear until later in life, making diagnosis more challenging. Although many vascular anomalies are benign, some are associated with serious complications and may involve multiple organ systems. This article highlights the important features of clinically significant vascular anomalies to help physicians promptly identify and refer these cases to a specialised multidisciplinary team for evaluation and management. The discussion includes the various presenting complaints of vascular anomalies in children, namely, rapidly growing birthmarks, painful lesions, seizures/neurological manifestations, bleeding diathesis, cardiac/airway abnormalities and part of an overgrowth syndrome.

Endothelial cell expression of mutant Map2k1 causes vascular malformations in mice.

Extracranial arteriovenous malformation (AVM) is a congenital vascular anomaly causing disfigurement, bleeding, ulceration, and pain. Most lesions are associated with somatic MAP2K1 activating mutations in endothelial cells (ECs). The purpose of this study was to determine if EC expression of mutant activated MAP2K1 is sufficient to produce vascular malformations in mice. We generated mice with a ROSA26 allele containing a lox-stop-lox gene trap (GT), Map2k1 cDNA with an activating p.K57N missense mutation, an internal ribosomal entry site, and green fluorescent protein cDNA (R26GT-Map2k1-GFP). We expressed mutant MAP2K1 and GFP in ECs of fetal and newborn mice using Tg-Cdh5Cre or Tg-Cdh5CreER alleles. Tg-Cdh5Cre+/-;R26GT-Map2k1-GFP/+ animals that express mutant MAP2K1 in ECs in utero developed diffuse vascular abnormalities and died by embryonic (E) day 16.5. Tg-Cdh5CreER+/-;R26GT-Map2k1-GFP/+ animals in which mutant MAP2K1 expression was induced in ECs by tamoxifen at postnatal (P) day 1 developed vascular malformations in the brain, ear, and intestines by P23. The lesions consisted of abnormal networks of blood vessels containing recombined and non-recombined ECs. In conclusion, expression of MAP2K1 p.K57N is sufficient to cause vascular malformations in mice. This model can be used to study the malformation process and for pre-clinical pharmacologic studies.

Successful Surgical Resection and Reconstruction of a Giant Facial Vascular Malformation in an Elderly Patient.

Venous vascular malformations can be challenging, especially in an elderly patient. As these lesions can present with ulceration, deformity, pain, and swelling resulting from thrombi formed due to low flow (palpable phleboliths), removing them can be important for the well-being of the patient. A 79-year-old patient presented with a giant venous malformations occupying the left hemiface and a deprivation amblyopia in his left eye. Successful surgical resection and reconstruction was achieved and the patient was very pleased with his new appearance. Despite his age and surgical risks, we consider that never is late to improve a disfigured face.

Intravascular Endothelial Hyperplasia of the Foot.

Intravascular endothelial hyperplasia is a benign soft tissue mass rarely reported in the foot. Advanced imaging and confirming a benign diagnosis are critical for any soft tissue mass. This paper identifies 2 patients that developed intravascular endothelial hyperplasia tumors which required surgical excision. A 17-year-old male patient presented to clinic complaining of a painful bump to the arch of his right foot which he related to an injury 9 months prior. Magnetic resonance imaging of the right foot revealed a mass within the plantar subcutaneous fat that was serpiginous in nature similar to adjacent branching vessels favoring a low-flow vascular malformation. A 38-year-old female with Multiple Sclerosis presented with complaints of persistent symptoms of pain to the 1st interspace, difficult ambulation and neuritis. Ultrasound and MRI observed solid, multilobulated mass, with internal vascular malformation, MRI describing intrinsic involvement along the abductor musculature and flexor tendons. Both lesions were surgically excised and sent for pathology. Pathology report indicated a diagnosis of intravascular papillary endothelial hyperplasia or Masson's tumor in both cases. Pathology diagnosis of intravascular papillary endothelial hyperplasia is generally good with wide resection leading to low recurrence rates. Both patients in the current study have progressed postoperatively with resolution of symptoms and without recurrence.

Hemangiolinfangioma mesentérico: reporte de un caso / Mesenteric hemangiolymphangioma: case report

El hemangiolinfangioma es un tipo muy raro de malformación del sistema vascular, caracterizado histológicamente por la presencia de vasos venosos y linfáticos dilatados quísticamente, cuyas células endoteliales de revestimiento son positivas para marcadores de inmunohistoquímica como CD31, CD34 y D2-40. El compromiso extenso retroperitoneal y del tracto gastrointestinal es infrecuente. Se presenta el caso de una paciente femenina de 24 años con antecedente de dolor pélvico crónico, con exacerbación de síntomas. El diagnóstico imagenológico mostró una masa retroperitoneal multiquística. Se hizo hemicolectomía derecha y resección de la masa, encontrándose que dicha lesión estaba íntimamente adherida al mesenterio con compromiso extenso del tracto gastrointestinal, y cuyo estudio histopatológico reveló un hemangiolinfangioma, con mejoría clínica posterior a la resección quirúrgica. Aportamos a la literatura mundial, la caracterización de los hallazgos clínicos, imagenológicos e histopatológicos de este tipo de malformaciones

Hemangiolymphangioma is a very rare type of malformation of the vascular system, characterized histologically by the presence of cystically dilated venous and lymphatic vessels, whose lining endothelial cells are positive for immunohistochemical markers such as CD31, CD34 and D2-40. Extensive retroperitoneal and gastrointestinal tract involvement is uncommon. We present the case of a 24-yearold female patient with a history of chronic pelvic pain with exacerbation of symptoms. The imaging diagnosis revealed a multicystic retroperitoneal mass. A right hemicolectomy and resection of the mass was performed, finding that the lesion was intimately adherent to the mesentery with extensive involvement of the gastrointestinal tract, and whose histopathological study revealed a hemangiolymphangioma, with clinical improvement after surgical resection. We contribute to the world literature with the characterization of the clinical, imaging and histopathological findings of this type of malformations