- [Show abstract] [Hide abstract] ABSTRACT: Endoglin (CD105) and endothelial nitric oxide synthase (eNOS) assist in regulating vascular development. Variation in expression of these factors is linked to errors in vascular growth and remodeling in invasive lesions. To clarify the role of endoglin and eNOS in the growth of extracranial head and neck arteriovenous malformations (AVMs), an invasive and high-flow vascular anomaly. Immunohistochemistry and Western blot study at an academic research center. Frozen and formalin-fixed paraffin-processed human AVMs (n = 14) were examined for expression of CD105 and eNOS. Expression in infantile hemangiomas (n = 9) and in normal skin with subcutaneous tissue (n = 9) was used for comparison. Quantitative assessment and localization of CD105 and eNOS protein expression were performed on each specimen by immunohistochemistry and Western blot analysis. Protein expression levels were compared with β-actin level and were semiquantitatively assessed. Abundant CD105 protein was found in AVMs but was not present in infantile hemangiomas or normal skin with subcutaneous tissue. Expression of eNOS protein in AVMs and infantile hemangiomas was similar (P = .20) and was significantly greater than that in normal skin with subcutaneous tissue (P < .001 and P = .008, respectively). Immunohistochemistry demonstrated that CD105 and eNOS are predominantly located in AVM vascular endothelial cells. CD105 and eNOS are present and significantly expressed in head and neck AVMs. Expression of CD105 and eNOS may have an important role in the angiogenesis and vascular remodeling of AVMs. CD105 can be used as a specific marker for AVM endothelial cells.
- [Show abstract] [Hide abstract] ABSTRACT: This article reviews the most current practice guidelines in the diagnosis and treatment of infantile hemangiomas. Several systemic conditions that can be associated with hemangiomas, such as PHACES syndrome, are also discussed. Propranolol has become an effective first-line treatment, and protocols for its use as well as its potential risks are outlined.
- [Show abstract] [Hide abstract] ABSTRACT: To examine the location and degree of endothelial nitric oxide synthase (eNOS) protein expression in hemangioma growth, involution, and during propranolol therapy. Cross-sectional study. University hospital. Pediatric patients with hemangiomas. Fresh human hemangioma specimens at various stages of development were harvested. Effective propranolol therapy had been implemented in some patients. Quantitative assessment and localization of eNOS protein expression was performed on each specimen by Western blot analysis and immunohistochemical analysis, respectively. Hemangiomas in a proliferative phase (group 1: n = 4; mean [SD] age, 4.25 [2.06] months), an early involuting phase (group 2: n = 6; 12.00 [1.64] months), and a late involuting phase (group 3: n = 6; 23.30 [1.97] months) were harvested. The mean (SD) eNOS protein expression was 0.88 (0.41) in group 1, 0.26 (0.26) in group 2, and 0.15 (0.08) in group 3, respectively. A statistically significant decrease in eNOS protein expression was observed between proliferating and involuting hemangiomas (group 1 vs group 2 and group 3; P ≤ .01) but not between early and late phases of involution (P = .17). In a separate propranolol treatment group (n = 7), the eNOS protein level was significantly lower than in age-matched controls (n = 7; 0.08 [0.1] vs 0.45 [0.45]; P = .03). Immunohistochemical analysis demonstrated eNOS to be predominately in endothelial cells lining mature blood vessels. Expression of eNOS protein decreases during the hemangioma lifecycle. Propranolol may suppress hemangioma growth by inhibiting expression of eNOS protein and subsequent production of nitric oxide.
- [Show abstract] [Hide abstract] ABSTRACT: To develop an in vivo mouse model of human microcystic lymphatic malformations (LMs) and provide a tool for investigating the biological mechanisms and treatment of microcystic disease. Animal model and histologic analysis. Tertiary referral center. Fresh microcystic LM from human subjects were harvested and xenografted in the immunologically naïve nude mice (Athymic Nude- Foxn1(nu)). Specimens were divided (5 × 5 × 5 mm) and secured in 4 quadrants subcutaneously along the dorsum of 4 nude mice. Weekly observations for volume, color, and texture of the grafts were performed with sequential harvesting from each quadrant at 30-day intervals. All grafts (n = 16) were sectioned and stained with hematoxylin-eosin. Comparative pathologic evaluation of the grafts and native LM was performed by 2 blinded pathologists. Immunohistochemical analysis for D2-40 (a known lymphatic endothelial cell marker), Ki-67, and human-specific nuclear antigen was performed. Near complete microcystic LM xenograft survival (n = 13 [81%]) was achieved in the mouse irrespective of the period of implantation. Xenografts underwent a brief growth phase to day 20 to 30 and were quiescent until approximately day 65 but ultimately had a gradual loss of volume following transplant. Histologic analysis revealed structural characteristics matching the native LM tissue. Immunohistochemical analysis found that 10 (77%) of the surviving xenografts (77%) were positive for D2-40, 9 (69%) were positive for human-specific nuclear antigen, and 8 (62%) were positive for Ki-67. This preliminary in vivo model suggests that microcystic LM can survive in the athymic nude mouse. The presence of markers for human antibodies, lymphatic endothelium, and cellular proliferation demonstrates the stability of native tissue qualities within the xenografts.
- [Show abstract] [Hide abstract] ABSTRACT: To develop an in vitro model of human lymphatic malformations (LM) that reflects histological characteristics of native LM. Fresh human LM (n = 6) were harvested, sectioned, explanted into a fibrinogen gel, and cultured. A total of 25 explants were developed and observed for primary and peripheral cellular growth. On days 9 to 10, the cultured tissues and gels were collected and fixed in 10% formalin. Primary LM and surrounding gel matrix were sectioned and stained for H&E analysis. Immunohistochemistry was performed for Prox-1 and D2-40, known markers for lymphatic endothelium, and Ki-67, a marker of cellular proliferation. On culture day 3, cells were observed to grow into the gel surrounding the primary tissue explants. Persistent and significant growth into the gel matrix was observed for each specimen at subsequent measurement intervals (day 6 and day 10, P < .0001). H&E staining of all the LM explants demonstrated survival and intact organization and cellular structure reflective of the original LM specimens. Microchannels were observed in the surrounding gel suggesting the presence of newly formed lymphatic vessels. Positive-immunohistochemical staining for D2-40 and Prox-1 revealed organized lymphatic endothelia within each specimen and associated microchannels distal to the explants in the gel matrix. Scattered cells in the gel matrix stained positive for Ki-67. This experimental model suggests that human LM can be preserved and observed to grow in vitro with structural characteristics, and immunohistologic qualities similar to native LM. This model may provide a facile tool for basic and translational research on LM.
- [Show abstract] [Hide abstract] ABSTRACT: Objective: 1) Establish a xenograft animal model of arteriovenous malformation (AVM), an uncommon and often incurable vascular anomaly. 2) Observe the morphological alterations and histological characteristics of xenograft AVM.
- [Show abstract] [Hide abstract] ABSTRACT: To analyze the operative benefit of preoperative sclerotherapy of facial venous malformations and assess long-term patient outcome. Preoperative sclerotherapy was performed in 24 consecutive patients referred before resection of facial venous malformation. Pretreatment imaging was reviewed for malformation dimensions (length, width, and height), and volumes were estimated. Sclerotherapy was performed with 3% sodium tetradecyl in the first 15 patients and 98% dehydrated alcohol in the remaining 9 patients. Operative blood loss, operative time, transfusion requirement, and hospital stay were recorded. Operative time per lesion volume and operative blood loss per lesion volume were calculated. Results were compared with 15 historical control patients who underwent resection of facial venous malformations without preoperative sclerotherapy. Long-term follow-up of study and control patients was performed. Compared with controls, patients undergoing preoperative venous sclerotherapy were significantly older (P = .0206) and had larger lesions in all three dimensions (height, P = .0002; length, P = .0010; width, P = .0004). Patients receiving sclerotherapy had shorter operative time per lesion volume (P < .0001) and reduced blood loss per lesion volume (P < .0001). Neither hospital stay nor the need for blood transfusion differed from the control patients (P = .2449 and P = .6857). Mild periprocedural complications were encountered in 12.5% of cases, and nerve paresis occurred in 8.3% of cases. Long-term follow-up revealed retreatment was required in 2 of 24 patients (8.3%). Preoperative sclerotherapy of venous malformations was associated with less operative time per lesion volume and less operative blood loss per lesion volume. Long-term follow-up revealed a low need for retreatment.
- [Show abstract] [Hide abstract] ABSTRACT: To quantify the efficacy of vincristine and vinblastine in the treatment of complicated hemangiomas. Retrospective review. Charts were reviewed to identify patients treated with vincristine or vinblastine for complicated hemangiomas from August 2002 to October 2007. Only patients who received both a pre and post-treatment magnetic resonance imaging (MRI) were considered. A database was created which includes patient gender, age at treatment initiation, rationale for treatment, hemangioma location, number of cycles of chemotherapy received, and complications of treatment. A single pediatric radiologist calculated lesion volumes from both pre and post-treatment MRI which were compared to quantify treatment response. Seven patients (2 male, 5 female) met criteria. Mean age at treatment initiation was 20 weeks (median 14, range 5-60). Rationale for treatment included four patients (57%) with proptosis/orbital compromise and one patient each (14%) with heart failure, airway compression, and hemangiomatosis with rapid growth of multiple lesions. Patients received a mean of 2.86 cycles of chemotherapy (median 3, range 1-5). Twelve lesions were identified and analyzed for pre and post-treatment volume on MRI in the seven patients. Eleven of twelve (92%) lesions decreased in size after treatment. The mean volume ratio of hemangiomas at the conclusion of chemotherapy was 0.45 compared to pre-treatment size (median 0.18, range 0-2.19) Orbital compromise, airway compression, and cardiac failure either improved or resolved in all patients. Three complications of treatment were seen in seven patients (42%) including bacteremia with anemia, peripheral neuropathy and motor delay. All complications resolved after cessation of chemotherapy. Treatment of complicated hemangiomas with vincristine or vinblastine can control growth and improve symptoms in the majority of patients. Treatment often requires multiple cycles of chemotherapy. Complications of treatment are common, but reversible.
- [Show abstract] [Hide abstract] ABSTRACT: Objectives: The neodymium:yttrium-aluminum-garnet (Nd:YAG) laser is a powerful tool in treating venous malformations (VMs) involving the upper airway. If left untreated, laryngeal VMs can lead to life-threatening airway obstruction. We aimed to evaluate the efficacy of endoscopic management of laryngeal VMs with the Nd:YAG laser. Methods: We performed a 12-year retrospective review in a tertiary referral center. Patient records were reviewed for demographics, presenting symptoms, area of involvement, age at first Nd:YAG laser therapy, total number of treatments, time between treatments, and treatment response. Results: Seventeen patients were treated endoscopically with an Nd:YAG laser for laryngeal VMs. The mean age at first treatment was 23.0 years (range, 18 to 45 years). The majority of patients presented with obstructive sleep apnea (58.8%), and 17.5% of patients presented with acute airway obstruction or stridor. The remaining patients presented with minor symptoms, including chronic cough and voice changes. The VMs involved the supraglottis, glottis, or both in 29%, 35%, and 35% of patients, respectively. An average of 4 treatments were required per patient (median, 3.5; range, 1 to 9). The time between treatments increased with each consecutive laser therapy, starting at a mean of 3.8 months between the first and second treatments to 21.7 months between the third and fourth. A marked reduction in VM size and symptom improvement were achieved in each patient after Nd:YAG therapy. Two complications (3%) were encountered among 66 total procedures. Conclusions: Endoscopic management of VMs using an Nd:YAG laser appears to be both effective and relatively safe. Multiple treatments are often required, but increased time can elapse between consecutive therapies. Use of the Nd:YAG laser for laryngeal VMs helps avoid tracheotomy and open surgical resection.
- [Show abstract] [Hide abstract] ABSTRACT: Propranolol has recently been introduced as a novel pharmacologic treatment for infantile hemangiomas. Systematic examination of this treatment in a tertiary care setting has not been described. This study explores the impact of propranolol on both proliferative and involuting hemangiomas at a tertiary vascular anomalies center. Retrospective single institution review. We reviewed children treated with propranolol for problematic hemangiomas followed by a blinded prospective analysis of serial photographs taken during the course of their therapy. Parental questionnaires were obtained to evaluate perceived therapeutic response and complications to oral propranolol. Thirty-two children with complete photo documentation were treated with oral propranolol for infantile hemangiomas between September 2008 and June 2009. Twenty-seven patients began therapy during the proliferative phase of their lesions (mean age, 4.9 months), whereas five patients began during the involutional phase (mean age, 19.4 months). Ninety-seven percent of patients displayed improvement in the quality of their hemangiomas during propranolol therapy. Patients were determined to be excellent responders (n = 16, 50%), partial responders (n = 15, 47%), or nonresponders (n = 1, 3%). Partial and nonresponders received adjuvant therapy (75%, laser therapy; 31%, steroid injections). Ten patients experienced minor but reportable side effects to propranolol, including somnolence (27.2%), gastroesophageal reflux (9.1%), respiratory syncytial virus exacerbation (4.5%), and rash (4.5%). Propranolol may revolutionize the treatment of problematic hemangiomas that cause imminent functional or cosmetic sequelae. At therapeutic doses, propranolol is safe and effective in the majority of patients. Adjunctive therapies may still be required. Minor side effects, expected from beta-blocker therapy, are common but easily managed.
- [Show abstract] [Hide abstract] ABSTRACT: Oral Diseases (2010) 16, 405–418 Vascular anomalies are congenital errors in vascular development. They frequently involve the head, neck, and oral cavity. Subdivided into vascular tumors (hemangiomas) and vascular malformations, vascular anomalies remain poorly understood. However, growing interest and recent advances in the diagnosis, management, and molecular characterization of these lesions are improving treatment strategies. The role of the multidisciplinary team cannot be overstated. This review provides both basic and up-to-date knowledge on the most common vascular anomalies encountered by physicians and practitioners. Because treatment options for vascular anomalies are widely variable and often debated, this report aims to provide a comprehensive approach to these lesions based upon current concepts and practical clinical experience.
- [Show abstract] [Hide abstract] ABSTRACT: Infantile hemangiomas are the most common benign tumors of infancy and the majority of them occur in the head and neck. Recent literature has described propranolol for the treatment of these vascular tumors. Propranolol was serendipitously found to induce early involution in hemangiomas even during the proliferative phase of the hemangioma cycle. First reported in June 2008, and presented at the International Society for the Study of Vascular Anomalies meeting in Boston that same month, propranolol has stirred much interest in the physicians who treat these types of lesions. Early case report data are now appearing in the literature, and are verifying the findings of the initial studies as an effective treatment for hemangiomas. Our institution has the privilege of maintaining a high volume vascular center and we have begun treating patients with problematic hemangiomas with propranolol as well. The present article will briefly review the literature and give some of our preliminary experience with the drug. Research regarding propranolol is in its infancy but, should the initial results and safety record be borne out, it is likely to revolutionize how we manage infantile hemangiomas.
- [Show abstract] [Hide abstract] ABSTRACT: Venous malformations are rare congenital aberrations of vein development frequently presenting in the head and neck. Without treatment, venous malformations cause progressive disfigurement, dysfunction, and bleeding. In this study, we analyzed a cohort of pediatric patients with cervicofacial venous malformations (CFVM), with the goal of developing a treatment algorithm for these complex lesions. Eleven-year retrospective chart review. The setting was a vascular anomalies center at a pediatric tertiary hospital. Nineteen patients (10 male, 9 female), aged 11 months to 17 years, presented with CFVM. Patient charts were reviewed for demographics, signs and symptoms, timing of first and subsequent interventions, total number and type of interventions performed, and procedural complications. A family questionnaire supplemented outcome measures by determining the perception of disease control. Presenting symptoms for CFVM include growth (100%), disfigurement (63%), pain (58%), respiratory compromise (42%), and dysphagia (32%). A mean of 6.7 interventions were performed per patient (median, 6; range, 2-12), requiring a mean of 0.8 excisions, 4.6 laser treatments, and 1.3 sclerotherapy injections. Average age at first procedure was 8.5 years. Time between treatments averaged 8.9 months. Four complications occurred in 127 procedures (3.1%). Questionnaire responses indicated subjective improvement following therapy. A management algorithm could be developed from therapeutic outcomes. Treatment of CFVM can be safely and successfully performed with a combination of laser therapy, sclerotherapy, and surgical excision. A treatment algorithm involving multiple procedures during childhood can lead to successful management of CFVM.
- [Show abstract] [Hide abstract] ABSTRACT: Infantile hemangiomas arising in the trachea are rare. These lesions pose a management dilemma as several treatment options can provide safe management. Propranolol, a nonselective beta-blocker, has recently been introduced as a novel modality for the treatment of proliferating hemangiomas. This report illustrates the successful management of tracheal hemangiomas using oral propranolol in a young patient with otherwise treatment-resistant airway lesions. Despite various endoscopic therapeutic attempts, the patient remained stridulous with airway disease that persisted into the involution phase of the average hemangioma cycle. Within 6 weeks of beginning oral propranolol (2 mg/kg/day), her airway compromise was eliminated and she had complete resolution of endoscopically visible disease. No side effects from propranolol occurred. We propose that oral propranolol should be considered for use in airway hemangiomas.
- [Show abstract] [Hide abstract] ABSTRACT: To identify hormone receptors within vascular malformations (arteriovenous malformations [AVMs], venous malformations [VMs], and lymphatic malformations [LMs]) of the head and neck. Immunohistochemical staining for estrogen receptor (ER) and progesterone receptor (PR) was performed on archival vascular malformation tissue collected from both pediatric and adult patients. Tertiary referral center from 2006 to 2008. Twelve AVM, 10 VM, and eight LM specimens were stained for both ER and PR. Ten breast carcinoma specimens were used as controls, with the carcinoma cells serving as positive controls, and the endothelium and smooth muscle cells of the blood vessels serving as negative controls. Five normal supraglottic mucosal samples served as head and neck controls. The Fisher exact test was used for statistical analysis. Ten of the 12 (83%) AVM specimens stained diffusely positive for PR within the nuclei of the endothelium and smooth muscle of the malformed vessels (P < 0.0001). Five of the 10 (50%) VM specimens stained positive for PR (2 [20%] focal, 3 [30%] diffuse) within the nuclei of the endothelium and smooth muscle of the malformed vessels (P = 0.0325). Four of the eight (50%) LM specimens stained focally positive for PR within the nuclei of the endothelium of the malformed vessels (P = 0.0229). None of the vascular malformation specimens stained positive for ER. Our data suggest that PR, but not ER, is expressed in AVMs, VMs, and LMs of the head and neck.
- [Show abstract] [Hide abstract] ABSTRACT: To evaluate the safety and efficacy of CO(2) laser resurfacing in the symptomatic treatment of intraoral lymphatic malformations (LM). Retrospective review. Charts were reviewed on 26 patients (16 male, 10 female) from January 1997 to July 2007 who underwent CO(2) laser resurfacing for symptomatic treatment of intraoral LM. A questionnaire was given in order to elucidate effectiveness in controlling symptoms and speed of postoperative recovery. Mean age at time of first treatment was 9.2 years (median 6.8). Mean number of treatments was 3.0 (median 2.5). Average time between treatments was 9.7 months (median 5.6). Questionnaires were returned for 17 patients (65%). Common preoperative symptoms included swelling, bleeding, vesicle formation, and pain. All 17 patients reported symptomatic improvement after laser treatment. Five patients (29%) tolerated oral intake immediately, 10 (59%) the following day, and 1 (6%) was gastric tube dependent. Four patients (24%) returned to normal activity immediately after treatments, six (35%) by the following day, six (35%) within a few days, and one (6%) within a week. No postoperative complications were seen. CO(2) laser resurfacing appears to be both safe and efficacious in treatment of symptoms related to intraoral LM. Intermittent treatments for recurrent symptoms is expected.
- [Show abstract] [Hide abstract] ABSTRACT: To investigate the expression of vascular endothelial growth factor (VEGF) and its receptor (VEGF-R2) in port-wine stains (PWSs). An immunohistochemistry (IHC) study on formalin-fixed, paraffin-embedded specimens. Representative sections from surgical resection specimens of 12 PWS patients and 12 control specimens stained with routine IHC by using polyclonal anti-VEGF and anti-VEGF-R2 antibodies. Slides were evaluated semiquantitatively for the intensity of staining for VEGF and VEGF-R2 by using a scoring system varying from 0 to 3+. PWS specimens showed statistically significant overexpression of both VEGF and VEGF-R2 molecules when compared with control specimens (P < 0.005). VEGF and its receptor may play an important role in the pathogenesis of PWS. It is possible that PWS may progress by hyperplasia in addition to hypertrophy. VEGF-R blockade may have a potential role as a targeted approach in the treatment of this disfiguring condition in the future.
- [Show abstract] [Hide abstract] ABSTRACT: Problem Port-wine stains (PWS) are vascular anomalies that may cause significant functional and psycho-social ramifications worsening by age. Traditional management of port-wine stains involves pulsed dye laser treatments, however only 10% of these lesions show complete response and 35% of these recur even after complete response. Therefore, there is still a need for an effective treatment for PWS. Vascular endothelial growth factor (VEGF) -a potent angiogenic molecule-has been shown to be associated with various vascular anomalies such as hemangiomas and arterio-venous malformations. However, the possible pathophysiological relationship of VEGF and PWS has not been investigated previously. The purpose of this study is to investigate if VEGF and VEGF-receptors are overexpressed in PWS as a key step in developing a potential targeted treatment approach for this disfiguring disease.
- [Show abstract] [Hide abstract] ABSTRACT: Objective 1) To demonstrate the natural history of arteriovenous malformation (AVMs) when left untreated or inadequately managed. 2) To demonstrate the need for major treatment to patients, families, healthcare providers, and insurance companies.
- [Show abstract] [Hide abstract] ABSTRACT: Intense pulsed light (IPL) systems are being presented as an alternative to conventional laser therapy for the treatment of vascular lesions. Broad spectral emission, radiant exposure, and pulse time are the key parameters for any IPL system used in clinical practice. Herein, we present the concept of using multi-pulse delivery to improve the vascular damage caused by IPL light.The result of our animal study shows an increase in tissue temperature that depends on the number of applied IPL pulses. However, this temperature increase is not a function of heat accumulation. In our study, the peak temperature after each pulse decreased to baseline prior to each successive pulse. A temperature increase of 25°C is possible with five consecutive 30ms pulses of 18J/cm2 with a 9s time interval. We show that in healthy, human-like skin, multi-pulse IPL can achieve selective vascular and perivascular damage with little thermal injury to the epidermis and dermis after proper cooling during treatment. The thermal damage of the vessels could have been enhanced due to an increased blood perfusion that is caused by the multiple pulses. The IPL system provides the clinician a treatment modality with more adjustable parameters to improve the clinical response of various skin types and vascular lesions. We theorize that port-wine stains should respond to multi-pulse IPL therapy in a similar fashion to our healthy, human skin model.
University of Arkansas for Medical Sciences
Little Rock, Arkansas, United States
- Department of Radiology