Extracranial arteriovenous malformations demonstrate dysregulated TGF-ß/BMP signaling and increased circulating TGF-ß1.

Extracranial arteriovenous malformations (AVMs) are characterized by anomalous arterial-to-venous connections, aberrant angiogenesis, local inflammation and hypoxia, and disorganized histological architecture; however, the precise molecular perturbations leading to this phenotype remain elusive. We hypothesized that extracranial AVM tissue would demonstrate deregulation of the TGF-ß/BMP signaling pathway, which may serve as a potential target in the development of molecular-based therapies for AVMs. AVM tissue was harvested during resection from 10 patients with AVMs and compared to control tissue. Blood was collected from 14 AVM patients and 10 patients without AVMs as controls. Expression of TGF-ß/BMP pathway components was analyzed using RT-PCR, western blotting, and immunohistochemistry. Circulating levels of TGF-ß1 were analyzed by ELISA. Paired t tests were utilized to perform statistical analysis. The mRNA levels of TGF-ß1, ALK1, Endoglin (ENG), Smad6, Smad7, and Smad8 were significantly elevated in AVM tissue when compared to controls. Protein levels of TGF-ß1 and Smad3 were elevated in AVM tissue while protein levels of BMP-9, ALK1, Smad1, Smad6, and Smad8 were significantly decreased in AVMs. Immunohistochemistry demonstrated increased TGF-ß1 in the perivascular cells of AVMs compared to normal controls, and circulating levels of TGF-ß1 were significantly higher in AVM patients. Patients with AVMs demonstrate aberrant TGF-ß/BMP expression in AVM tissue and blood compared to controls. Targeting aberrantly expressed components of the TGF-ß/BMP pathway in extracranial AVMs may be a viable approach in the development of novel molecular therapies, and monitoring circulating TGF-ß1 levels may be a useful indicator of treatment success.

Bronchogenic cyst of the posterior neck mimicking lymphatic malformation.

Bronchogenic cysts are embryologic malformations of the foregut and are rarely found head and neck region. Here we present a case of an upper scapular/lower posterior neck cystic mass which was initially suspicious for lymphatic malformation but confirmed by pathology to be an ectopic bronchogenic cyst.

Venous malformation vessels are improperly specified and hyperproliferative.

Venous malformations (VMs) are slow-flow malformations of the venous vasculature and are the most common type of vascular malformation with a prevalence of 1%. Germline and somatic mutations have been shown to contribute to VM pathogenesis, but how these mutations affect VM pathobiology is not well understood. The goal of this study was to characterize VM endothelial and mural cell expression by performing a comprehensive expression analysis of VM vasculature. VM specimens (n = 16) were stained for pan-endothelial, arterial, venous, and endothelial progenitor cell proteins; proliferation was assessed with KI67. Endothelial cells in the VM vessels were abnormally orientated and improperly specified, as seen by the misexpression of both arterial and endothelial cell progenitor proteins not observed in control vessels. Consistent with arterialization of the endothelial cells, VM vessels were often surrounded by multiple layers of disorganized mural cells. VM endothelium also had a significant increase in proliferative endothelial cells, which may contribute to the dilated channels seen in VMs. Together the expression analysis indicates that the VM endothelium is misspecified and hyperproliferative, suggesting that VMs are biologically active lesions, consistent with clinical observations of VM progression over time.

NOTCH pathway activation in infantile hemangiomas.

OBJECTIVE: The objective of this study was to characterize the role of NOTCH signaling cascade activation in the angiogenic drive of infantile hemangioma (IH) tissue. METHODS: Both IH tissue and normal skin were collected from 55 surgical patients. Of these, 14 were proliferating hemangiomas, 14 were stationary, 14 were involuted, and 13 had been treated with propranolol. Protein and RNA were extracted from all tissues and subjected to Western blotting and reverse transcription-polymerase chain reaction, respectively, for components of the NOTCH signaling pathway. RESULTS: Compared with normal skin from the same patients, proliferating IHs contained higher levels of messenger RNA and protein for the majority of NOTCH receptors and ligands as well as the downstream coactivator MAML1. Expression of NOTCH receptor ligand messenger RNA and protein was significantly lower in involuting and propranolol-treated IHs. CONCLUSIONS: Perturbations in NOTCH signaling follow the natural course and treatment outcome of IHs, suggesting a critical role in their pathogenesis.

Abnormal elastin and collagen deposition is present in extracranial arteriovenous malformations: A comparison to intracranial disease.

BACKGROUND: Vascular malformations are characterized by anomalous vascular channels with fragile walls and a propensity to bleed. Arteriovenous malformations (AVMs) in particular have disorganized vascular spaces with intervening fibrosis. Characterization of the structural abnormalities of these vessels has not been comprehensively evaluated. We hypothesize that AVMs are likely to demonstrate altered elastic and collagen fiber organization and distribution, reflecting their fragility, vascular instability, and abnormal development. METHODS: Fifteen AVMs were histologically evaluated by H&E, elastin and trichrome staining. To identify potential differences between extracranial and intracranial AVMs, 5 AVMs were harvested from the brain (n=5) and 10 from extracranial sites involving the skin and deep soft tissue (n=10). RESULTS: The elastin staining demonstrated reduplication, fragmentation and disruption of internal elastic lamina as well as irregular thickness, and inconsistent vascular density of all AVM specimens. Trichrome staining revealed thickening of the intimal layers of AVM arteries and demonstrated an irregular thickness of venous walls within the malformation and some areas of medial degeneration. Intracranial AVMs are characterized by more intramural inflammation with predominant neutrophil and lymphocyte infiltration. In contrast, extracranial AVMs display more extravascular inflammation with mast cell and neutrophil infiltration. Microvascular proliferations intervening between larger blood vessels were also noted in both types of AVMs, but more obvious in extracranial AVMs. CONCLUSION: These observed histologic anomalies of AVMs demonstrate disorganized deposition of elastin and collagen that point to the clinically observed vascular instability and fragility of these lesions.

A novel surgical treatment for posterior glottic stenosis using thyroid ala cartilage - A case report and literature review.

Posterior glottic stenosis (PGS) describes a laryngeal disorder in which worsening degrees of scarring limit abduction of the vocal folds and/or arytenoids. It can be congenital or acquired. Generally, the acquired form is the result of chronic endotracheal tube trauma to the posterior larynx. Symptoms of acquired PGS usually begin four to eight weeks after extubation, and present as gradually worsening stridor and shortness of breath as the laryngeal obstruction becomes more severe. Without intervention, PGS can cause total obstruction and respiratory failure. The mainstay of treatment for PGS is surgery. We present a case in which an infant patient with PGS was treated with a posterior cricoid split and insertion of a thyroid ala graft. The graft was bolstered in place with an appropriately-sized endotracheal tube during a six-day period of postoperative intubation. We report this as a novel surgical approach, as a literature review did not uncover that this technique has been previously described. Our patient has had excellent airway and voice outcomes. His swallow outcomes have been difficult to assess, as the patient has shown signs of global delay.

Eosinophilic esophagitis in children under the age of 5 years: Clinical characteristics.

OBJECTIVES/HYPOTHESIS: To delineate clinical characteristics and treatment outcomes of eosinophilic esophagitis (EoE) in the youngest of children. STUDY DESIGN: Retrospective chart review. METHODS: A 7-year retrospective chart review of children with clinicopathologic diagnosis of EoE was performed with specific analysis of patients under 5 years old. EoE was defined as the presence of symptoms of esophageal dysfunction with pathologically proven eosinophilic inflammation (≥15 eosinophils per high-power field [EOS/HPF]) unresponsive to reflux therapy. Patient parameters and clinical results were systematically reviewed. RESULTS: Of 558 children diagnosed with EoE, 127 (22.8%) were younger than 5 years old (mean age 2.5 years). This subgroup presented with reflux symptoms (90.1%), vomiting (86.2%), diarrhea (55.3%), liquid dysphagia (52.0%), and constipation (50.0%), whereas food impaction (1.6%) was rare. Liquid dysphagia was present at all ages but significantly more common in younger children (P = .0101). The most common food and environmental allergens were egg whites (39.7%), cow's milk (36.5%), peanuts (34.9%), animal dander (15.1%), and weed pollen (11.1%). Patients were managed with antireflux medication (100%), elimination diet (83.5%), and steroid medication (68.5%). After treatment, 86% of parents reported symptom improvement. Mean reduction of EOS in pos-treatment biopsy was 33.5 EOS/HPF (P < .0001), and 67 patients showed histologic resolution of EoE (56.8%, P < .0001). CONCLUSIONS: Approximately one-quarter of children with EoE present under 5 years of age with multiple esophageal symptoms, comorbidities, and allergen-sensitization profiles. These patients demonstrate substantial clinicohistologic improvement following therapy. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:798-805, 2018.

Current status, pitfalls and future directions in the diagnosis and therapy of lymphatic malformation.

Lymphatic malformations are complex congenital vascular lesions composed of dilated, abnormal lymphatic channels of varying size that can result in significant esthetic and physical impairment due to relentless growth. Lymphatic malformations comprised of micro-lymphatic channels (microcystic) integrate and infiltrate normal soft tissue, leading to a locally invasive mass. Ultrasonography and magnetic resonance imaging assist in the diagnosis but are unable to detect microvasculature present in microcystic lymphatic malformations. In this review, we examine existing tools and elaborate on alternative diagnostic methods in assessing lymphatic malformations. In particular, photoacoustics, low-toxicity nanoparticles and optical clearing can overcome existing challenges in the examination of lymphatic channels in vivo. In combination with photothermal scanning and flow cytometry, Photoacoustic techniques may provide a versatile tool for lymphatic-related clinical applications, potentially leading to a single diagnostic and therapeutic platform to overcome limitations in current imaging techniques and permit targeted theranostics of microcystic lymphatic malformations.