Diagnostic approach to hepatic vascular lesions: a paediatric perspective.

The pathological evaluation of hepatic vascular lesions in children requires special consideration. Inconsistent terminology, rarity of pathology specimens and overlapping pathological features between various lesions may pose a serious diagnostic challenge. In this review, we highlight the importance of using the International Society for the Study of Vascular Anomalies (ISSVA) classification scheme to characterise these lesions. Selected entities are discussed, including hepatic vascular tumours exclusively seen in the paediatric age group, hepatic infantile haemangioma and hepatic congenital haemangioma. Vascular malformations, with emphasis on their syndromic associations (venous malformation in blue rubber bleb naevus syndrome) and complications (hepatocellular nodules in Abernethy malformation) are also covered.

Assessing coagulopathy and endothelial dysfunction in pediatric venous malformation: A thromboelastometry and syndecan-1 study.

OBJECTIVE: The occurrence of unpredictable pain crises are the principal determinant of the quality of life for patients with venous malformations (VM). A definite coagulation phenomenon, characterized by an increase in D-dimer levels and the presence of phleboliths within the malformation, has been previously reported. By applying Virchow's triad and evaluating intralesional samples, our objective is to delineate the coagulation profile and the extent of endothelial dysfunction within the malformation. METHODS: With the authorization of the Ethics Committee, a research project was undertaken on intralesional and extralesional blood samples from 30 pediatric patients afflicted with spongiform VM. Thromboelastometry analyses were performed using ROTEM Sigma, and the concentration of syndecan-1 was determined by ELISA. RESULTS: In the ROTEM analyses, the A5, A10, and maximum clot firmness (MCF) values were below the established reference ranges in the intralesional samples in both the EXTEM and INTEM assays, indicating that intralesional clots had significant instability. Furthermore, during the investigation of the delayed fibrinolysis phase using recombinant tissue plasminogen activator (rtPA) in EXTEM analysis, widespread hyperfibrinolysis was observed intralesional. Additionally, analysis of syndecan-1 showed significant differences between extralesional and intralesional levels (p < .026) and controls (p < .03), suggesting differences in the state of endothelium. CONCLUSIONS: For the first time, we developed a comprehensive understanding of the coagulopathic profile of VM and the role of endothelial dysfunction in its pathogenesis. These findings will enable the implementation of targeted therapies based on the individual coagulation profiles.

The discriminative role of PROX-1 immunohistochemistry between venous malformation and lymphatic malformation of the deep type with no visible diagnostic surface skin lesion.

BACKGROUND: Venous malformations (VMs) are distinguished from lymphatic malformations (LMs) when specific diagnostic skin lesions are present. In the deep type, this is difficult by clinico-radiologic evaluation alone. We aimed to investigate the usefulness of lymphatic vessel endothelial cell (LEC) markers for the differential diagnosis of the deep VMs and LMs. METHODS: A retrospective study was conducted based on the medical records of patients with VMs and LMs who underwent biopsy with both D2-40 and PROX-1 immunohistochemistry. We compared the initial clinico-radiological diagnosis with the final pathological diagnosis and identified which ones showed a difference. RESULTS: From 261 patients who had VMs and LMs, 111 remained after the exclusion of those who showed definite surface diagnostic features. After pathological diagnosis with the expressions of D2-40 and PROX-1, 38 of 111 (34.2%) patients' final diagnoses were changed. Among these 38 cases, diagnosis was not changed by D2-40 positivity alone, but changed by PROX-1 positivity alone (52.6%) or by both (47.4%). The diagnostic changes were more frequent in the deep category (43.7%) than in the superficial category. CONCLUSIONS: Identifying the expression of D2-40, and especially PROX-1, in the differential diagnosis of VMs and LMs may provide important treatment guidelines and understanding their natural course.

Correlation between the miR-618 rs2682818 C>A polymorphism and venous malformation susceptibility.

Venous malformations are the most common congenital vascular malformations, and the incidence rate is high. Previous studies have confirmed that a variety of polymorphisms within the miRNA functional region are associated with tumor susceptibility. We examined the correlation between miR-618 rs2682818 C>A and risk of developing venous malformation in a southern Chinese population (1113 patients and 1158 controls). TaqMan genotyping of miR-618 rs2682818 C>A was conducted utilizing real-time fluorescent quantitative PCR. The miR-618 rs2682818 polymorphism was not correlated with susceptibility to venous malformation (CA/AA vs. CC: adjusted odds ratio [AOR] = 1.00, 95% confidence interval [CI] = 0.81-1.25, p = 0.994; AA vs. CC/CA: AOR = 1.10, 95% CI = 0.73-1.65, p = 0.646). Stratified analysis of different subtypes of venous malformation revealed that there was no significant difference in the rs2682818 C>A polymorphism genotypes across these subtypes. Our results indicate that miR-618 rs2682818 C>A polymorphism is not correlated with the susceptibility to venous malformation.

Venous malformations in children: comparison between magnetic resonance imaging and histopathological findings.

BACKGROUND: Among low-flow vascular malformations, venous malformations are relatively frequent. The pathological patterns vary in severity and are generally characterized by dilated vessels and low-flow blood that over time can organize into phleboliths. Sometimes small capillary and/or lymphatic vessels may be associated, micro- and/or macro-shunts may form alone or in different combinations, and finally adipose tissue may be interposed between the malformed vessels. Magnetic resonance imaging (MRI) is a crucial examination for confirming venous malformations because it can accurately identify different features of the lesions. OBJECTIVE: The aim of our study was to compare MRI and histopathological findings of venous malformations in children to assess the possibilities and limitations of MRI. MATERIALS AND METHODS: In a retrospective study, two observers independently evaluated the contrast-enhanced MRI of 26 children with venous malformations. Several radiological parameters were considered and compared with histopathological findings. The agreement between the interobserver radiological evaluation and between histopathological and radiological diagnosis was verified using Cohen's kappa. RESULTS: MRI interobserver agreement was excellent for micro-shunts and good for the remaining findings. The radiological-pathological agreement was perfect for the presence/absence of phleboliths and of macro-shunts and almost perfect for the presence of intralesional adipose tissue, lymphatic component, and micro-shunts. CONCLUSION: MRI in venous malformations can detect the presence of phleboliths, adipose tissue, and lymphatic components with excellent accuracy and good to excellent interobserver agreement. Furthermore, MR angiography can detect micro-shunts in simple and combined venous malformations with substantial agreement with histopathological findings.

Ileal venous malformation in a pediatric patient.

A 16-month-old girl presented with ileal venous malformation. Ultrasound facilitated a preoperative diagnosis, leading to a successful surgical resection. The study emphasizes the critical role of identifying sonographic features like intestinal wall thickening, a serpiginous mass with sluggish blood sinuses, and rich vascular flow for accurate diagnosis and timely treatment.

Blood within the bone: orbital intraosseous venous malformation.

PURPOSE: Description of clinical features, radiological characteristics, and management strategies in primary orbital intraosseous venous malformation (OIVM) with pertinent literature review. METHODS: A retrospective analysis including clinical, radiologic, operative, and histopathological data of six cases of histopathologically proven OIVM was done. A comprehensive literature review was conducted using online databases and augmented with manual search to identify reported cases of OIVM. RESULTS: Study data showed five females and one male in young to middle-age group, with an average age of 30 years (range: 20-48 years). Proptosis was noted in five cases (83.33%), and the duration of symptoms ranged from 6 months to 10 years. Frontal and zygomatic bones were most frequently affected and expansile bony lesion was the most common CT scan finding. Three patients underwent pre-operative embolization of feeders followed by en bloc excision of mass and surgical reconstruction (50%); one patient was managed with partial excision (16.66%) while two were regularly followed-up after incision biopsy (33.33%). Histopathology revealed vascular spaces with endothelial lining, separated by bony trabeculae in all patients. Follow-up periods ranged from 6 to 48 months and no recurrence or progression were noted. CONCLUSIONS: OIVM is an exceptionally rare disorder with a gradually progressive benign course. Ophthalmologists need to be mindful of this entity during patient evaluation as it has propensity for large volume blood loss intra-operatively, owing to its vascular nature. Complete excision with reconstruction of resultant defect is the preferred treatment strategy and without known recurrence.

Intraosseous venous malformation of the frontal bone with extension into the frontal sinus and orbit.

We present a novel case of intraosseous venous malformation of the frontal bone with dehiscence of the inner table of the frontal calvarium and extension into the frontal sinus and orbit. This case report discusses the surgical management of this intraosseous lesion achieved with a multidisciplinary approach involving otolaryngology and neurosurgical teams. We also present a review of the literature of the pathophysiology of venous malformations, the imaging modalities that aid in diagnosis of these lesions and the management options.

Vascular Anomalies Care in the United States: A Cross-Sectional National Survey.

OBJECTIVE: To characterize the current distribution, composition, and practice patterns of multidisciplinary vascular anomalies (VAs) teams in the US. STUDY DESIGN: This is a cross-sectional survey of children's hospitals in the US offering VAs care. We approached 142 children's hospitals that provided care for VAs via email. The survey evaluated VA clinic location, medical staffing, research participation, and treatments offered. The survey was administered between October 2021 and July 2022. RESULTS: Participants from 95 eligible hospitals responded to the survey (response rate = 67%). Large areas of the Midwest and Northwest US had no available multidisciplinary VA teams or clinics. Most respondents worked at academic centers (89%), with 66% at a freestanding children's hospital, and 56% reported having a multidisciplinary clinic. Most common physician participants in clinic included hematology-oncology (91%), interventional radiology (87%), dermatology (85%), plastic surgery (81%), and otolaryngology (74%). Only 38% of programs included medical geneticists. Smaller hospitals had fewer medical and ancillary staff and offered fewer therapeutic options. Research was available at most larger institutions (69%) but less commonly at smaller hospitals (34%). CONCLUSIONS: Major portions of the US lack multidisciplinary VA care. Furthermore, VA programs vary in composition and geneticists are absent from the majority of programs. These findings should inform efforts to address disparate access and develop standards of care for multidisciplinary VA care in the US.

Response to sirolimus in capillary lymphatic venous malformations and associated syndromes: Impact on symptomatology, quality of life, and radiographic response.

BACKGROUND: Capillary lymphatic venous malformations (CLVM) and associated syndromes, including Klippel-Trenaunay syndrome (KTS) and congenital lipomatous overgrowth, vascular malformation, epidermal nevi, skeletal, and spinal syndrome (CLOVES), are underrecognized disorders associated with high morbidity from chronic pain, recurrent infections, bleeding, and clotting complications. The rarity of these disorders and heterogeneity of clinical presentations make large-scale randomized clinical drug trials challenging. Identification of PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [gene]) mutations in CLVM has made targeted medications, such as sirolimus, attractive treatment options. The aim of this study was to investigate the safety and efficacy of sirolimus therapy in CLVM. PROCEDURE: A combined prospective and retrospective cohort of pediatric and young adult patients with CLVM treated with sirolimus was evaluated for disease response, including symptom improvement, quality of life (QOL), and radiologic response. Sirolimus dosing regimens and toxicities were also assessed. RESULTS: Twenty-nine patients with CLVM, including KTS and CLOVES, were included. Ninety-three percent of patients reported improved QOL, and 86% had improvement in at least one symptom. Most significantly, improvement was noted in 100% of patients with bleeding and 89% with thrombotic complications with corresponding decreases in mean D-dimer (p = .008) and increases in mean fibrinogen (p = .016). No patients had progressive disease on sirolimus. Most common side effects included neutropenia, lymphopenia, infection, and aphthous ulcers/stomatitis. No toxicities were life-threatening, and none required long-term discontinuation of sirolimus. CONCLUSION: Sirolimus appears to be effective at reducing complications and improving QOL in patients with CLVM and associated syndromes. In this patient cohort, sirolimus was well tolerated and resulted in few treatment-related toxicities.

Comprehensive analysis of exosomal circRNA, lncRNA, and mRNA profiles to identify the potential RNAs involved in the pathogenesis of venous malformation.

BACKGROUND: Venous malformation (VM) is a kind of congenital vascular anomaly with a high incidence of recurrence, detailed pathogenesis and standard treatment of VM still lack now. Increasing evidence showed exosomal RNA plays a pivotal role in various diseases. However, the underlying mechanism of VM based on the potential differentially exosomal RNAs remains unclear. METHODS: Comparative high-throughput sequencing with serum exosomes from three VM patients and three healthy donors was used to explore differentially expressed (DE) circRNAs, DE lncRNAs, and DE mRNAs involving the formation of VM. We identified and verified DE circRNAs, DE lncRNAs, and DE mRNAs via qRT-PCR assay. We explored the potential functions of these exosomal DE non-coding RNAs via performing further Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. Besides, circRNA/lncRNA-miRNA-mRNA linkages were also constructed to find their potential relationships in VM. RESULTS: A total of 121 circRNAs, 53 lncRNAs, and 42 mRNAs (|log2 FC| ≥ 2.0, FDR <0.05, n = 3) were determined to be differentially expressed. QRT-PCR validated that these top-changed DE circRNAs, lncRNAs, and mRNAs had significant expression changes. Functional studies demonstrated that DE circRNAs play a pivotal role in thyroid hormone signaling pathway, DE lncRNAs function as a key regulator in MAPK signaling pathway and DE miRNAs participate in the process of hepatocellular carcinoma mostly. CONCLUSION: Our study comprehensively depicted exosomal DE non-coding RNAs networks related to the pathogenesis of VM which can provide new insight into, a novel target for treating VM.

p-AKT/VPS4B regulates the small extracellular vesicle size in venous malformation endothelial cells.

OBJECTIVE: Small extracellular vesicle (sEV)-mediated intercellular communication is increasingly the key for the understanding of venous malformations (VMs). This study aims to clarify the detailed changes of sEVs in VMs. SUBJECTS AND METHODS: Fifteen VM patients without treatment history and twelve healthy donors were enrolled in the study. sEVs were isolated from both fresh lesions and cell supernatant, and were examined by western blotting, nanoparticle tracking analysis and transmission electron microscopy. Western blot analysis, immunohistochemistry and immunofluorescence were adopted to screening candidate regulator of sEV size. Specific inhibitors and siRNA were employed to validate the role of dysregulated p-AKT/vacuolar protein sorting-associated protein 4B (VPS4B) signaling on the size of sEVs in endothelial cells. RESULTS: The size of sEVs derived from both VM lesion tissues and cell model was significantly increased. VPS4B, whose expression level was mostly significantly downregulated in VM endothelial cells, was responsible for the size change of sEVs. Targeting abnormal AKT activation corrected the size change of sEVs by recovering the expression level of VPS4B. CONCLUSION: Downregulated VPS4B in endothelial cells, resulted from abnormally activated AKT signaling, contributed to the increased size of sEVs in VMs.

Topical injection of sclerosant to treat cheek subcutaneous venous malformation resulting in blindness: a case report.

Loss of vision after topical injection of sclerosant is a rare and uncommon complication. We describe a case with vision loss following the facial injections of physician-compounded (PCP) foam sclerotherapy which was created by room air. A 3-year-old boy underwent injection of 5ml polidocanol foamed with room air to treat the venous malformation on the cheek near the left orbit. The boy experienced the whole facial swelling on day 2 after the third injection, especially involving the left side, the visual acuity in the left eye was counting fingers at 30 cm and the swelling reduced at 7 days later after referral. Fundus examination on day 15 revealed hemorrhage inferior to the optic disc and fluorescein angiography revealed blocked fluorescein. The OCT on day 15 showed the edema of the nerve fiber layer beside the fovea. The patient's hearing was also impaired. PCP foam sclerotherapy with room air produced in typical concentrations, preparations as well as volumes always causes vision loss among children. Continued evaluation on the effects of product, gas, volume, and patient age identify optimal approaches will avoid the toxicity and side-effects caused by facial foam sclerotherapy.

Close Your Eyes and See: Stroke Sequelae versus Functional Neurological Disorder in a Physician.

The first author is a left-handed, 51-year-old nephrologist who experienced a neurologic event. She underwent neurosurgery complicated by hemorrhage. Postoperatively, she developed persistent vertigo and unilateral tongue pain which persisted for over 5 years. Early neuroimaging revealed expected encephalomalacia but no neuroanatomical basis for her symptoms. A functional neurological disorder was suspected, and she was seen by several psychiatrists and psychotherapists. However, she suspected a neuroanatomical lesion would better explain her unrelenting symptoms. After seeing many neurologists, a neuroanatomical diagnosis was finally made. The theory and practice of medicine mandate that subjective complaint guides the modality and interpretation of objective evidence. The final neurologist knew where on neuroimaging to look because she was guided by the patient's complaints - vertigo and unilateral tongue pain. In this case, detailed scrutiny of neuroimaging by a neurologist, after encephalomalacia and gliosis were fully completed, gave a more accurate neuroanatomical diagnosis and a more realistic prognosis.

Large scalp venous malformation in a pediatric patient managed with sclerotherapy and surgery: a case report and review of literature.

BACKGROUND: Venous malformations (VMs) are slow-flow vascular anomalies present at birth that enlarge during adolescence, subsequently causing thrombosis, hemorrhage, and pain. CASE PRESENTATION: We describe a case of an adolescent male presenting with a large scalp venous malformation. Given the size and location of the lesion, a hybrid approach employing both sclerotherapy and surgical resection was utilized. The VM was successfully removed without complication. CONCLUSION: A hybrid approach is a safe and effective treatment consideration for immediate management of large venous malformation in higher-risk locations.

Combined sclerotherapy followed by surgical resection of a large extracranial venous malformation in a 14-month-old child: preoperative workup and technical note.

INTRODUCTION: Venous malformations affect around 2 per 10,000 newborn and are the most common type of congenital vascular malformation. They are always present at birth and are often misdiagnosed with hemangiomas. Accurate diagnosis and adequate targeted therapy through a multidisciplinary approach is advocated for a successful treatment, considering a combination of modalities in complex cases. We present here the workup and treatment of a venous malformation in a 14 month old child by combining a preoperative sclerotherapy with sodium tetradecyl sulfate (STS) followed by complete surgical excision respecting the calvarium. CASE PRESENTATION: A large right extracranial fronto-parietal venous malformation and scalloping of the underlying calvarium, attached to the pericranium, surgically excised after preoperative sclerotherapy with STS in a 14-month-old child. RESULTS: The patient had an uneventful postoperative course with complete resection of the lesion, satisfying cosmetic appearance and no complications. Histopathological examination confirmed a venous malformation. CONCLUSION: We demonstrated the workup and the rationale of the combined sclerotherapy followed by surgical resection of a large growing extracranial venous malformation. Preoperative direct contrast injection and sclerotherapy allowed to rule out significative extracranial to intracranial venous inflow and reduce blood loss for the surgical procedure, respectively. Complete removal of the malformation minimized the impact on future growth of the calvarium.

Performance of a vascular anomaly center: a retrospective analysis of 461 cases over seven years.

BACKGROUND: Vascular malformations are rare diseases that are best managed in multidisciplinary vascular anomaly centers (VAC). So far, there are few published data on the logistic structure, patient allotment, and internal workflow in an interdisciplinary VAC. PURPOSE: To demonstrate the referral structure and patient allotment in a European VAC. MATERIAL AND METHODS: A retrospective cohort study was conducted. All patients treated in the VAC since its establishment in April 2014 until June 2020 were identified. A total of 461 patients were included in this study. RESULTS: Most often, a venous malformation was diagnosed (49.9%), followed by arteriovenous malformations (8.7%) and syndromal vascular malformations (8.2%). Only 45.1% of referral diagnoses were correct. Of referrals, 35.1% were internal on-campus references, 28.0% were external references through physicians in private practice, and 19.7% came via external cooperating hospitals. Of the patients, 17.1% were self-admissions without a referral. CONCLUSION: The most important referring clinics are internal medicine, pediatric, and vascular surgery. A substantial proportion of referrals came from private practices. Recruiting these cooperation partners should be considered a high priority when establishing a new VAC. The rate of misdiagnosis is high, and more education of fellow clinicians is urgently needed. Therefore, patients with vascular malformations should be referred to and treated in dedicated centers for vascular anomalies.

Radiomics-based machine learning approach in differentiating fibro-adipose vascular anomaly from venous malformation.

BACKGROUND: As a complex vascular malformation, fibro-adipose vascular anomaly was first proposed in 2014. Its overlap with other vascular malformations regarding imaging and clinical features often leads to misdiagnosis and improper management. OBJECTIVE: To construct a radiomics-based machine learning model to help radiologists differentiate fibro-adipose vascular anomaly from common venous malformations. MATERIALS AND METHODS: We retrospectively analyzed 178 children, adolescents and young adults with vascular malformations (41 fibro-adipose vascular anomaly and 137 common vascular malformation cases) who underwent MRI before surgery between May 2012 to January 2021. We extracted radiomics features from T1-weighted images and fat-saturated (FS) T2-weighted images and further selected features through least absolute shrinkage and selection operator (LASSO) and Boruta methods. We established eight weighted logistic regression classification models based on various combinations of feature-selection strategies (LASSO or Boruta) and sequence types (single- or multi-sequence). Finally, we evaluated the performance of each model by the mean area under the receiver operating characteristics curve (ROC-AUC), sensitivity and specificity in 10 runs of repeated k-fold (k = 10) cross-validation. RESULTS: Two multi-sequence models based on axial FS T2-W, coronal FS T2-W and axial T1-W images showed promising performance. The LASSO-based multi-sequence model achieved an AUC of 97%±3.8, a sensitivity of 94%±12.4 and a specificity of 89%±9.0. The Boruta-based multi-sequence model achieved an AUC of 97%±3.7, a sensitivity of 95%±10.5 and a specificity of 87%±9.0. CONCLUSION: The radiomics-based machine learning model can provide a promising tool to help distinguish fibro-adipose vascular anomaly from common venous malformations.

Impact of puberty on procedure frequency for treatment of simple head and neck lymphatic and venous malformations.

OBJECTIVE: Puberty has been shown to accelerate growth of vascular malformations, including lymphatic (LM) and venous malformations (VM). This study aims to compare the number of procedures performed before and after puberty in patients with LM and VM to assess whether the onset of puberty results in higher treatment frequency. METHODS: A retrospective review of head and neck LM and VM patients who were evaluated between January 2009 and December 2019 was performed. Patient demographics, lesion characteristics, and procedural details were recorded. For the purposes of this study, 11 years or older in females and 12 years or older in males were the established cut-offs for the onset of puberty. RESULTS: After initial screening of 357 patients, 83 patients were included in the study based on inclusion criteria. There were 34 patients with LM (41 %) and 49 with VM (59 %). The mean age at diagnosis was 6.1 ± 10.9 years (LM: 4.2 ± 7.0, VM: 7.4 ± 12.9, p = 0.489). 68 patients underwent treatments, which included sclerotherapy, surgical excision, and/or laser. For all patients, the average number of lifetime treatments when initiated before puberty was 3.78 ± 2.81 and when initiated after puberty was 2.17 ± 1.37 (p = 0.022). Patients diagnosed pre-puberty were more likely to undergo treatments vs. those diagnosed after puberty (OR 10.00, 95 % CI: 2.61-38.28, p < 0.001). CONCLUSION: We found that the number of treatments was fewer in those who started treatment after puberty. This finding suggests that providers may elect to proceed with observation in asymptomatic patients, given that waiting until after the onset of puberty has not shown an increase in the procedural load on patients.

Resection of an oropharyngeal venous malformation.

BACKGROUND: Venous malformations (VMs) are congenital vascular lesions caused by enlarged and ectatic venous channels. Current methods of treatment for VMs involve a combination of sclerotherapy, laser therapy, and surgical resection. While sclerotherapy remains the most commonly used treatment for small VMs, surgery remains an important tool for isolated VMs or larger VMs with higher flow due to potential local and systemic side effects associated with the use of certain sclerosing agents. METHODS/RESULTS: Here we present a case of a patient with a naso- and oropharyngeal venous malformation which was successfully resected with endoscopic-assisted transoral surgery. CONCLUSIONS: This is a low-fingerprint technique to tumors of the oropharynx with excellent visualization and maneuverability in cases where TORS is not an option. This technique does not require palate splitting or excessive retraction, allows multiple surgeons to work simultaneously, and is associated with significantly lower morbidity than transcervical techniques. LEVEL OF EVIDENCE: N/A.