Expression of endoglin (CD105) and endothelial nitric oxide synthase in head and neck arteriovenous malformations.

IMPORTANCE: 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. OBJECTIVE: 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. DESIGN AND SETTING: Immunohistochemistry and Western blot study at an academic research center. SPECIMENS: 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. MAIN OUTCOME MEASURES: 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 ß-actin level and were semiquantitatively assessed. RESULTS: 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. CONCLUSIONS AND RELEVANCE: 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.

Current management of infantile hemangiomas and their common associated conditions.

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.

A pilot in vivo model of human microcystic lymphatic malformations.

OBJECTIVE: 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. DESIGN: Animal model and histologic analysis. SETTING: Tertiary referral center. SUBJECTS: Fresh microcystic LM from human subjects were harvested and xenografted in the immunologically naïve nude mice (Athymic Nude- Foxn1(nu)). MAIN OUTCOME MEASURES: 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. RESULTS: 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. CONCLUSIONS: 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.

Preliminary investigation of human lymphatic malformations in vitro.

PURPOSE: To develop an in vitro model of human lymphatic malformations (LM) that reflects histological characteristics of native LM. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Preoperative sclerotherapy of facial venous malformations: impact on surgical parameters and long-term follow-up.

PURPOSE: To analyze the operative benefit of preoperative sclerotherapy of facial venous malformations and assess long-term patient outcome. MATERIALS AND METHODS: 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. RESULTS: 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%). CONCLUSIONS: 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.

Endoscopic management of airway venous malformations with Nd:YAG laser.

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.

Propranolol for infantile hemangiomas: early experience at a tertiary vascular anomalies center.

OBJECTIVES/HYPOTHESIS: 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. STUDY DESIGN: Retrospective single institution review. MATERIALS AND METHODS: 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. RESULTS: 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%). CONCLUSIONS: 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.

Diagnosis and management of pediatric cervicofacial venous malformations: retrospective review from a vascular anomalies center.

OBJECTIVES/HYPOTHESIS: 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. STUDY DESIGN: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Propranolol treatment for infantile hemangiomas.

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: 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.

CO2 laser resurfacing of intraoral lymphatic malformations: a 10-year experience.

OBJECTIVE: To evaluate the safety and efficacy of CO(2) laser resurfacing in the symptomatic treatment of intraoral lymphatic malformations (LM). DESIGN: Retrospective review. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Intralesional steroid injection for proliferative parotid hemangiomas.

OBJECTIVE: To evaluate the efficacy of proliferative phase intralesional steroid injections in the treatment of parotid hemangiomas. DESIGN: Retrospective analysis of pediatric patients with parotid hemangiomas treated with intralesional steroid injections during the proliferative phase. SETTING: Vascular Anomalies Center, University of Arkansas for Medical Sciences, Arkansas Children's Hospital, Little Rock, Arkansas, USA. PATIENTS: Twenty-one pediatric patients, ages 4-39 months. METHODS: Between 2001 and 2006, 21 patients received steroid injections for 23 parotid hemangiomas (bilateral in 2 patients). A total of 1-3 injections over the first year of life were given at 6-25 week intervals. RESULTS: Main outcome measures included softening, decreased growth rate, and/or decrease in size. After injection, achievement of outcome measures occurred with all lesions. No incidence of tissue atrophy or facial nerve injury was seen. Four of 21 (19%) patients developed failure to thrive (FTT). CONCLUSION: Parotid hemangiomas can be effectively controlled with proliferative phase intralesional steroid injections. Injections may limit the need for future extensive surgery. Further prospective randomized trials are needed to support these claims. Failure to thrive may be a potential complication of intralesional steroid injection. Endocrine/growth monitoring should be considered when treating with intralesional steroids.

Use of recombinant factor VIIa during excision of vascular anomalies.

BACKGROUND: The surgical excision of vascular anomalies is often accompanied with significant perioperative bleeding. Novel hemostatic agents, including recombinant factor VIIa (rVIIa), have been shown to reduce bleeding in hemophilia and trauma patients along with decreasing blood loss during various surgical procedures. The role of rVIIa during excision of vascular anomalies has not been examined. METHODS: A retrospective chart review of patients from 2001 to 2003 who received perioperative rVIIa during excision of vascular anomalies at one institution. RESULTS: Nine patients were identified who received perioperative rVIIa during removal of their vascular anomalies (7 venous malformations, 1 lymphatic-venous malformation, 1 arteriovenous malformation). All patients received at least one dose of rVIIa during the perioperative period (2/9 received 2 doses). An accurate account of hourly blood loss was reported, and could be graphed, in three patients. These patients displayed significant reductions in hourly blood loss after the administration of rVIIa. These cases are detailed in this report. Surgeons reported subjective improvements in operative bleeding, efficiency, and operative time in six of six patients after the administration of rVIIa intraoperatively. Reduced postoperative bleeding was reported in two patients who received rVIIa for persistent drain output. CONCLUSION: rVIIa may be an effective adjunct in improving the surgical efficiency and outcome of excised vascular anomalies.

Arteriovenous malformations of the tongue: a spectrum of disease.

OBJECTIVES: To examine our vascular anomalies team's experience with tongue arteriovenous malformations (AVM) with specific emphasis on the spectrum on disease and surgical management. METHODS: Retrospective chart review of 11 patients (10 female, 1 male), discovered from 1997 to 2005 with histological, radiographic, and clinical characteristics consistent with tongue AVM. RESULTS: Four patients displayed advanced disease with malformations involving the tongue, floor of mouth, and neck. Contributions from multiple feeding arteries were identified by angiography as each patient reported a prior history of surgical or embolic procedures. These lesions required preoperative embolization and extensive resection with complex reconstruction (mean operating time, 10.9 hr). One patient had evidence of recurrent disease (mean follow-up, 24.6 mo). In contrast, seven patients presented with discreet tongue malformations with a single feeding lingual artery. These patients reported no prior intervention, required only one resection (mean operating time, 2.8 hr), and have shown no evidence of recurrence (mean follow-up, 11 mo). Slight histologic differences between advanced versus focal tongue AVM were identified. CONCLUSIONS: This study suggests that tongue AVM can occur within a spectrum of disease with different clinical presentations, radiographic findings, and histology among patients with focal versus advanced lesions. Inadequate treatment is thought to contribute to collateral flow and disease progression in advanced AVM, making further management difficult. However, focal tongue AVM may represent early lesions that are more amenable to surgical management.

Mathematical modeling of selective photothermolysis to aid the treatment of vascular malformations and hemangioma with pulsed dye laser.

Pulsed dye lasers (PDL) are the standard of care in the treatment of cutaneous vascular disorders such as the port-wine strains or hemangiomas of infancy. Nonetheless, there is still uncertainty regarding the specific laser parameters that are likely to yield optimal clinical outcomes. Using mathematical modeling, we explain and associate clinical outcomes with laser wavelength, radiant exposure, and pulse time and shape. The model's prediction that a continuous PDL pulse of 0.45 ms with a radiant exposure of 6 J/cm(2) is equivalent to delivering a 1.5-ms pulse consisting of three pulses with a radiant exposure of 12 J/cm(2) is in agreement with clinical studies. The model also suggests that for vascular malformations involving vessel diameters in the range of 150-500 microm, one should use a PDL at a wavelength of 595 nm with a radiant exposure of at least 12 J/cm(2) and pulse time of 1.5 ms, delivered in three pulses. Whereas it is calculated that malformations with vessels smaller than 50 microm will not respond to PDL in any clinical setting, an excellent response to PDL treatment at either a 585- or 595-nm wavelength can be expected for malformations with vessel diameters of 50-150 microm. Epidermal cooling is highly recommended for all settings to minimize pain and the risk of side effects. Finally, the model is used to generate a reference table that suggests specific PDL parameters for the treatment of various malformations and hemangiomas. The table cannot replace a clinician's experience with respect to which and how parameters should be changed, but provides a defined window of parameters that should be tried to improve clinical response.

Update on hemangiomas and vascular malformations.

PURPOSE OF REVIEW: Our knowledge base in the area of vascular anomalies is growing rapidly. With greater understanding of classification and diagnosis, as well as with the numerous areas of research bringing further awareness on the complexity of these lesions, we are improving our ability to treat them. We will attempt in this article to summarize the developments in the field of vascular anomalies over the last year. RECENT FINDINGS: Emphasis on correct classification is still a high priority in the literature and yet there remains a great deal of misinformation. Many new developments in the basic science of these lesions are allowing better understanding of why these lesions occur while improving our management in these patients. Advances in laser surgery as well as sclerotherapy techniques have improved our ability to treat extensive lesions and also improve patients' quality of life. SUMMARY: Many new and exciting areas of discovery occur almost daily in the field of vascular anomalies. Due to the breadth of this topic, it is certain that not all articles can be reviewed however the author has tried to present the most recent and clinically relevant breakthroughs in the field.