Reticular infantile hemangioma of the limb can be associated with ventral-caudal anomalies, refractory ulceration, and cardiac overload.

We describe six patients with an uncommon variant of infantile hemangioma that we have termed reticular, occurring in the extremity, which were associated with intractable ulceration, anogenito-urinary-sacral anomalies, and sometimes cardiac overload. The extreme end of the spectrum is exemplified by a male neonate who presented with a stained, enlarged, pulsatile lower extremity, and cardiac failure. He also had hepatic hemangiomas and ambiguous genitalia. Progressive soft tissue necrosis and bony destruction necessitated amputation. The histopathologic features differed from those of typical infantile hemangioma: infiltrative (not lobular) and involving fascia, muscle, and bone. The mid-spectrum is illustrated by five females with reticular infantile hemangioma of the lower limb, buttock, and perineum. Four of these infants had a ventral-caudal anomaly, including omphalocele, recto-vaginal fistula, solitary/duplex kidney, imperforate anus, and tethered cord; one infant also had hepatic hemangiomas. Deep ulcerations healed following corticosteroid therapy; one patient required skin graft for closure of a thigh wound. The minor end of the spectrum is exemplified a patchy lesion in the distal limb. The reticular variant of infantile hemangioma can be confused with other vascular anomalies in the limb, such as capillary malformation, cutis marmorata telangiectasia congenita, diffuse arteriovenous malformation (Parkes Weber syndrome) and capillary-lymphatico-venous malformation (Klippel-Trenaunay syndrome). The macular network-like appearance of the tumor and coexisting ventral-caudal structural anomalies is analogous to the association of posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities association in the craniofacial region.

Cardiac conduction through engineered tissue.

In children, interruption of cardiac atrioventricular (AV) electrical conduction can result from congenital defects, surgical interventions, and maternal autoimmune diseases during pregnancy. Complete AV conduction block is typically treated by implanting an electronic pacemaker device, although long-term pacing therapy in pediatric patients has significant complications. As a first step toward developing a substitute treatment, we implanted engineered tissue constructs in rat hearts to create an alternative AV conduction pathway. We found that skeletal muscle-derived cells in the constructs exhibited sustained electrical coupling through persistent expression and function of gap junction proteins. Using fluorescence in situ hybridization and polymerase chain reaction analyses, myogenic cells in the constructs were shown to survive in the AV groove of implanted hearts for the duration of the animal's natural life. Perfusion of hearts with fluorescently labeled lec-tin demonstrated that implanted tissues became vascularized and immunostaining verified the presence of proteins important in electromechanical integration of myogenic cells with surrounding re-cipient rat cardiomyocytes. Finally, using optical mapping and electrophysiological analyses, we provide evidence of permanent AV conduction through the implant in one-third of recipient animals. Our experiments provide a proof-of-principle that engineered tissue constructs can function as an electrical conduit and, ultimately, may offer a substitute treatment to conventional pacing therapy.

Increased expression of urinary matrix metalloproteinases parallels the extent and activity of vascular anomalies.

OBJECTIVE: Matrix metalloproteinases (MMPs) and the angiogenic proteins basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) have been implicated in mechanisms of human cancer and metastasis. Assays were conducted on the urine of patients with vascular anomalies (tumors and malformations), relatively common and occasionally life-threatening disorders for which few therapies exist. We sought to determine whether these angiogenesis modulators are present in the urine and whether their expression is associated with the extent and clinical course of the vascular lesion. METHODS: A total of 217 patients with vascular anomalies and 74 age-matched control subjects participated. Urinary MMP expression was determined by substrate gel electrophoresis. Urinary bFGF and VEGF levels were measured by enzyme-linked immunosorbent assay. Each patient was assigned to 1 of 2 categories (tumor or malformation) and 1 of 9 specific groups. Extent of the vascular lesion and activity were scored by a blinded clinician. RESULTS: Urinary high molecular weight (hMW) MMPs and bFGF were significantly increased in patients with vascular tumors (53%) and vascular malformations (41%), compared with control subjects (22%). These percentages increased as a function of extent of the lesion and disease activity. hMW MMPs were increased in 4 groups: infantile hemangioma, other vascular neoplasms, lymphatic malformation and capillary-lymphaticovenous malformations, and extensive and unremitting capillary malformation and arteriovenous malformation. No significant differences among the groups were detected for low molecular weight MMPs or VEGF. CONCLUSIONS: Expression patterns of hMW MMPs and bFGF in the urine of patients with tumors and malformations are consistent with their different clinical behavior. These data represent the first evidence that MMPs are elevated in the urine of children with vascular anomalies. These data also suggest that the increased expression of urinary MMPs parallels the extent and activity of vascular anomalies in children. In addition to tumors, vascular malformations are angiogenesis dependent, suggesting that progression of a vascular malformation might be suppressed by angiogenic inhibitors, which would target bFGF and MMPs.

Current management of hemangiomas and vascular malformations.

This article outlines the classification of vascular anomalies, which include vascular tumors and vascular malformations. We describe the nomenclature, diagnosis, and management of the different types of anomalies. Specific indications for pharmacologic and surgical intervention are discussed.

Pulmonary capillary hemangiomatosis with atypical endotheliomatosis: successful antiangiogenic therapy with doxycycline.

We report here our experience in achieving remission in a 20-year-old man with pulmonary capillary hemangiomatosis (PCH) with atypical endotheliomatosis following therapy with doxycycline. PCH is a rare disorder characterized by proliferating capillaries that invade the pulmonary interstitium and alveolar septae, and occlude the pulmonary vasculature. The patient's symptoms, lung function, and radiographic findings had worsened despite treatment with both prednisone and alpha-interferon. He was considered to be a candidate for transplantation. Given the elevated levels of basic fibroblast growth factor (bFGF) in urine and the capillary proliferation noted on biopsy specimens, we elected to treat the patient with doxycycline, a matrix metalloproteinase and angiogenesis inhibitor. Following several weeks of therapy, a gradual resolution of symptoms was noted, with normalization of pulmonary function test results and urine bFGF levels. After 18 months of therapy, the patient remains in complete remission.

Circular excision of hemangioma and purse-string closure: the smallest possible scar.

Localized cutaneous infantile hemangioma acts like a tissue expander. This rapidly growing tumor can destroy elastic fibers or cause ulceration resulting in telangiectases, cutaneous laxity, scarring, and fibrofatty residuum. Although surgeons may dispute indications and timing, most would agree that the scar of resection should be minimized. For this reason, circular excision and purse-string closure is particularly applicable for hemangioma at any stage of its evolution. The purposes of this study were to: (1) analyze the results of circular excision/purse-string closure in all three phases of the life cycle of hemangioma; (2) quantify dimensional changes after resection; and (3) compare the scars after theoretical single-stage lenticular excision with those after staged circular excision/purse-string closure. The authors retrospectively analyzed their experience in 25 children with localized hemangioma who underwent circular excision/purse-string closure from 1997 to 2000. Each hemangioma was measured preoperatively and the scars were measured at most recent follow-up (minimum, 6 months). Preoperative and postoperative dimensions were analyzed using SPSS statistical software. The study included 22 girls and three boys, with an average time to follow-up evaluation of 13.1 months. Twenty-one lesions were in the face and scalp, and five were in the extremity. Five tumors were resected in the proliferative phase (either because of ulceration, bleeding, or visual complications) and 21 were excised in the involuting or involuted phase. Six patients had a second-stage procedure: three had another circular excision and three had later lenticular excision. After single circular excision/purse-string closure, the mean long-axial diameter (length) decreased by 45 percent, the mean short-axial width (width) decreased by 73 percent, and the mean scar area was only 15 percent of the original area. All these differences were statistically significant (p = 0.001). The average width/length ratio decreased by 50 percent, indicating a tendency for scars to linearize. There was no difference in linearization for the three phases of hemangioma (p > 0.05); extremity scars became more linear that those on the face (p = 0.01). The authors devised a formula for scar length after lenticular excision/linear closure, assuming a conventional excisional ratio of 3:1 for a circular lesion. Using this equation, the authors predicted that mean scar length after circular excision, followed by lenticular excision, would be 72 percent shorter than the calculated scar that would result from conventional lenticular excision. In three patients who underwent this two-stage approach, the resultant scar was 69 percent shorter. Circular excision of hemangioma and purse-string closure reduces both the longitudinal and transverse dimensions and converts a large circular lesion into a small ellipsoid scar. If subsequent revision to a linear scar is desirable, its length will be the same or slightly less than the diameter of the original lesion. No other excision and closure technique results in a smaller scar. Another advantage of this method is minimal distortion of surrounding structures.

Prenatal diagnosis of vascular anomalies.

BACKGROUND/PURPOSE: Vascular anomalies are diagnosed prenatally with increasing frequency. The authors reviewed a group of children treated at their center who had an abnormal prenatal diagnosis to determine (1) fetal age at which the vascular anomaly was detected, (2) general diagnostic accuracy, and (3) impact on ante- and postnatal care. Their findings are compared with reported cases and series. The authors clarify appropriate terminology and underscore the need for interdisciplinary participation of specialists in the field of vascular anomalies. METHODS: Patients referred during prenatal life and children with a history of abnormal antenatal findings seen at our vascular anomalies center during a 1-year period (September 1999 through August 2000) were included in this study. The fetal age at diagnosis, pre- and postnatal diagnoses, antenatal course, and neonatal outcome were obtained from the parents, through chart reviews, and through telephone interviews with the treating obstetricians. RESULTS: Twenty-nine patients with vascular anomalies were identified: 17 had a correct prenatal diagnosis, and 12 had an incorrect diagnosis, an overall diagnostic accuracy of 59%. Capillary-lymphatic-venous malformations (CLVM) most often were correctly diagnosed (67%), followed by lymphatic malformation (LM, 62%) and hemangioma (59%). In the infants who received correct diagnoses in utero, there were no fetal deaths and there was no neonatal morbidity. Maternal steroids were administered for a fetus with an intrahepatic hemangioma and deteriorating cardiac function, with subsequent stabilization and successful delivery of a healthy neonate. Among infants with incorrect diagnoses, there was 1 postnatal death, 1 case of erroneous gender assignment, 1 case of unnecessary fetal surgical intervention, 1 unnecessary neonatal laparotomy, and 1 delay in diagnosis of a malignancy. Cesarean section was done for 65% of correctly diagnosed cases, (including 2 ex utero intrapartum [Exit] procedures) and for 33% of incorrectly diagnosed cases. Most diagnoses were made during the mid- to late second trimester and third trimester; only 4 cases (14%) were detected before 20 weeks. CONCLUSIONS: In this series, accurate diagnosis optimized antenatal care by providing an opportunity for planning deliveries, for pharmacologic fetal intervention in 1 case, and for appropriate parental counselling. Inaccurate diagnosis was associated with significantly increased morbidity and mortality. Finally, the intrauterine diagnosis of LM should be distinguished from posterior nuchal translucency, an obstetric term applied to fetal lymphatic abnormalities detected in the first and second trimesters that do not manifest as postnatal LM.

Successful antiangiogenic therapy of giant cell angioblastoma with interferon alfa 2b: report of 2 cases.

We describe 2 cases of angioblastoma, a rare, destructive pediatric tumor, treated with interferon alfa 2b (IFNalpha2b). The first patient is a 10-month-old male who presented with an ulcerated palatal neoplasm that could not be completely resected. The second is a male neonate with a congenital tumor of the right hand that invaded the hypothenar eminence, destroying the fourth and fifth metacarpals. Biopsy in both patients was interpreted as giant cell angioblastoma. Angioblastoma is rare; there is only 1 reported case that necessitated amputation of an upper extremity, also initially recommended for our patient. Because there is little experience with chemotherapy, permission was granted to employ an antiangiogenic regimen of IFNalpha2b. The angiogenic protein, basic fibroblast growth factor (bFGF), was abnormally elevated in both patients. Both patients received IFNalpha2b. In the first child, it was used after incomplete resection, because biopsy-proven tumor was present at the margin and in the nasopharynx. Biopsies 15 months after initiation of IFN2alphab were negative for tumor. Therapy was stopped after 3 years. Eighteen months later, the patient remains disease-free. In the second child, IFNalpha2b was started after debridement of the ulcerated tumor. Over 11 months, the tumor completely regressed and there was bony regeneration of the metacarpals. The fifth digit was amputated because of damage to the metacarpophalangeal joint by the tumor. IFNalpha2b therapy was discontinued after 1 year of treatment, and the child remains disease-free 2 years and 8 months later. In conclusion, this report demonstrates that: 1) a bFGF-overexpressing low-grade tumor can respond to IFNalpha2b in a manner similar to life-threatening infantile hemangiomas, 2) urinary bFGF levels can help guide IFNalpha dosage in such patients, and 3) although bFGF-mediated tumor angiogenesis is inhibited by IFNalpha, physiologic angiogenesis seems to be unaffected.