The presentation and management of multiple paraganglioma in head and neck.

OBJECTIVE: We report the presentation and management of an 18-year-old male, who presented with bilateral carotid body paragangliomas and a unilateral jugular body paraganglioma. METHOD: A comprehensive review of the medical literature concerning paragangliomas in the pediatric and adult population is discussed. RESULTS: Presentations of multiple paragangliomas in an 18-year-old have never been described. CONCLUSION: This is the first case of multiple paragangliomas in a 18-year-old male, who was treated with embolisation and surgical resection and remains disease free 2 years from surgery.

Infantile hemangiomas involving the neuraxis: clinical and imaging findings.

BACKGROUND AND PURPOSE: The neuroradiology and neurosurgery literature is replete with references to "hemangioma" involving the central nervous system (CNS). However, the number of cases of true infantile hemangiomas in the CNS reported to date is 15. Our purpose was to delineate the definition of infantile hemangiomas, determine their prevalence in the neuraxis, and describe their imaging characteristics and associations in this location. MATERIALS AND METHODS: We reviewed our Vascular Anomalies Center data base from 1999 through May 2008 to assess the prevalence of intracranial or intraspinal involvement within the total cohort of infantile hemangiomas. Fifteen patients were identified with infantile hemangiomas that involved the neuraxis. Two board-certified neuroradiologists reviewed the available imaging of these 15 patients, and a board-certified pathologist reviewed the available histopathology. Clinical records of all 15 patients were reviewed to identify the type of treatment and the treatment response. RESULTS: Of the 1454 patients listed with infantile hemangioma, 15 (approximately 1.0%) had involvement of the CNS. Eight patients had intracranial infantile hemangioma, 6 had intraspinal hemangioma, and 1 had both. In most instances, there was continuous extension into the neuraxis from an extracranial or extraspinal lesion. There were no cases of a CNS hemangioma without an accompanying extra-CNS tumor. Two patients had findings consistent with posterior fossa anomalies, cervicofacial hemangioma, arterial anomalies, cardiac defects, ocular abnormalities, and associated sternal or ventral defect. Of note, there were no brain or spinal parenchymal signal-intensity abnormalities, and there was no evidence of parenchymal invasion. CONCLUSIONS: CNS involvement by infantile hemangiomas is an unusual occurrence, which, when recognized, can help optimize patient management.

Comparative analysis of D2-40 and LYVE-1 immunostaining in lymphatic malformations.

Identification of lymphatic vessels in normal tissue and vascular malformations has been considerably enhanced by the recently discovered lymphatic endothelial markers D2-40 and LYVE-1. However, comparative analysis of these two antibodies in the evaluation of lymphatic malformations has not been widely reported. We evaluated twenty lymphatic malformations of skin/subcutis/soft tissue with immunostaining for D2-40 and LYVE-1. Ten high-power fields from each section were scored for total number of immunopositive vessels using identical fields with both markers. Vessels were grouped by diameter (< 225 microm and > 225 microm), with each vessel categorized according to the percentage of its lumen showing immunopositivity (< 25, 26-75, or > 75). Endothelial staining intensity was graded low or high in each case. We found no significant difference between total number of vessels stained with D2-40 or LYVE-1 or between the 2 markers in terms of the percentage of luminal circumference stained or intensity in vessels smaller than 225 microm. LYVE-1 stained a higher percentage of luminal circumference of channels greater than 225 microm at both low and high intensities. Large channels stained much less and sometimes not at all with either antibody. D2-40 and LYVE-1 are both effective for highlighting endothelium of lymphatic malformations, staining similar percentages of channels. LYVE-1 provides more luminal staining in channels larger than 225 microm but is less specific also staining macrophages and adipocytes. Both markers are expressed less strongly or sometimes not at all in large channels.

Multifocal rapidly involuting congenital hemangioma: a link to chorangioma.

Common infantile hemangioma is intriguing because of its variable presentation, rapid postnatal growth and slow regression in childhood. Interest in this tumor has increased with the recognition that it can be associated with structural anomalies in the craniofacial and ventral-caudal regions. The phenotype has expanded by characterization of rare vascular tumors that arise in the fetus and manifest at birth as rapidly involuting congenital hemangioma (RICH) or non-involuting congenital hemangioma (NICH). We describe a boy born with three RICH on the abdominal wall; one extended into the base of the umbilical cord. Two weeks later a small, infantile hemangioma arose on his neck. This patient stimulated a review of what is known about placental vascular tumors and their possible relationship to fetal and infantile hemangiomas. We suggest that chorangioma and umbilical cord hemangioma are clinically and histopathologically similar to cutaneous and hepatic RICH. These placental vascular tumors can also occur in conjunction with solitary and multiple infantile hemangiomas.

Vascular tumors of the heart in infants and children: case series and review of the literature.

Primary tumors of the heart are rare in children, of which vascular tumors comprise a small subgroup. We present the clinical, histopathologic, and imaging findings in six children with vascular tumors of the heart and review the findings of 36 previously published cases. We observed three intramuscular hemangiomas of the small-vessel type in older children, two congenital hemangiomas in infants, and one malignant polymorphous hemangioendothelioma. Intramuscular hemangiomas did not respond to corticosteroid and were biologically distinct from the congenital hemangiomas, both of which exhibited regression with pharmacotherapy. Age at diagnosis appears to predict histologic type, tumor location, and clinical presentation.

[Skeletal vascular lesions in childhood and adolescence]. / Angiomatöse Skelettläsionen im Kindesalter.

Currently, vascular lesions are being classified either as tumors with inherent proliferative potential or as vascular malformations with early manifestation and growth commensurate with the growth of the child. This new classification is also applicable to skeletal vascular lesions. 30% of all skeletal vascular lesions manifest in the first two decades of life, with a preponderance of malformations. They are attributed to disturbances in the complex cascade of angiogenesis and a minority may be hereditary. Multiple cutaneous vascular malformations are associated with mutations of the TIE2- and Glomulin-Genes. Vascular malformations with involvement of multiple skeletal elements may pursue an aggressive course and manifest as massive osteolysis. Among the epithelioid vascular tumours of bone, also in young patients, benign epithelioid hemangioma can be distinguished on a morphological basis from epithelioid hemangioendothelioma as an entity with low malignant potential.

PLAG1 alterations in lipoblastoma: involvement in varied mesenchymal cell types and evidence for alternative oncogenic mechanisms.

Lipoblastomas are rare soft tissue tumors that occur primarily in young children. They typically contain variably differentiated adipocytes, primitive mesenchymal cells, myxoid matrix, and fibrous trabeculae. Abnormalities in chromosome 8, leading to rearrangements of the PLAG1 gene, were demonstrated recently in four lipoblastomas. In the present report, we determine the frequency of PLAG1 alterations in 16 lipoblastomas from children aged 13 years or younger, and we also evaluate the stages of lipoblastoma differentiation at which PLAG1 genomic alterations are found. Eleven lipoblastomas (69%), including those with either classic or lipoma-like histology, had rearrangements of the 8q12 PLAG1 region. Another three lipoblastomas had polysomy for chromosome 8 in the absence of PLAG1 rearrangement. Only two cases (13%) lacked a chromosome 8 abnormality. Notably, the lipoblastomas with chromosome 8 polysomy had up to five copies of chromosome 8 as an isolated cytogenetic finding in an otherwise diploid cell. We also demonstrate that PLAG1 alterations are found in a spectrum of mesenchymal cell types in lipoblastomas, including lipoblasts, mature adipocytes, primitive mesenchymal cells, and fibroblast-like cells. This finding is consistent with neoplastic origin in a primitive mesenchymal precursor and with variable differentiation to a mature adipocyte end-point. Hence, our studies provide biological validation for the clinical observation that lipoblastomas can evolve into mature, lipoma-like, lesions. They also suggest that PLAG1 dosage alterations caused by polysomy 8 might represent an alternative oncogenic mechanism in lipoblastoma.

Aggressive multimodal treatment of pleuropulmonary blastoma.

Pleuropulmonary blastoma is a rare intrathoracic neoplasm almost solely confined to childhood. Survival is poor. The authors report 2 children with extensive intrathoracic disease who are long term survivors after multimodal therapy. Both children received multiagent neoadjuvant chemotherapy, followed by surgical resection to remove all gross tumor. Postoperative chemotherapy was given to both children; radiotherapy was also given in the second case because of a question of positive tumor margins. Experience supports the use of multimodal therapy, including an aggressive surgical approach in the potentially curative treatment of this tumor.

Noninvoluting congenital hemangioma: a rare cutaneous vascular anomaly.

The authors studied a rare, congenital, cutaneous vascular anomaly that grows proportionately with the child and does not regress. A total of 53 patients were compiled from three vascular anomaly centers. These patients' lesions were analyzed for presentation, physical findings, radiologic and histopathologic characteristics, natural history, and outcome after resection. The lesions occurred slightly more often in male patients, always appeared alone, and were located (in order of frequency) in the head/neck region, extremities, and trunk. They were round-to-ovoid in shape, were plaque-like or bossed, occurred in variable shades of pink to purple, and had an average diameter of 5 cm. The overlying skin was frequently punctuated by coarse telangiectasia, often with central or peripheral pallor. The lesions were warm on palpation; fast-flow was further documented by Doppler ultrasonography. Magnetic resonance imaging and angiographic findings were similar to those of common hemangioma of infancy. All lesions were easily excised without recurrence.Histologic examination revealed lobular collections of small, thin-walled vessels with a large, often stellate, central vessel. Interlobular areas contained predominantly dilated, often dysplastic veins; arteries were also increased in number. Small arteries were observed "shunting" directly into lobular vessels or into abnormal extralobular veins. "Hobnailed" endothelial cells lined the small intralobular vessels. Mast cells were increased. Tests for glucose transporter-1, a recently reported reliable marker for common hemangioma of infancy, were negative in all 26 specimens examined. In conclusion, the authors think these clinicopathologic and radiologic features define a rare vascular lesion for which the term "noninvoluting congenital hemangioma" is proposed. These lesions of intrauterine onset may be a variant of common hemangioma of infancy or another hemangiomatous entity with persistent fast-flow.

Pulmonary dysplasia, Denys-Drash syndrome and Wilms tumor 1 gene mutation in twins.

While a genetic basis for the association of developmental lung and kidney defects has been suspected, the involvement of specific genes in this process is under active investigation. We report such a possible genetic linkage present in identical twins with a mutant Wilms tumor (WT1) gene. Twin girls, born at 35 weeks gestation, manifested symptoms of congenital nephrotic syndrome, renal failure, and severe respiratory abnormalities refractory to assisted ventilation. Both died at 1 month of age. Renal biopsies and autopsy kidney tissue from both the girls revealed diffuse mesangial sclerosis (DMS). Autopsy lung tissue revealed pulmonary dysplasia and hypoplasia in both twins. The WT1 gene from renal tissue in both twins was analyzed for mutations using polymerase chain reaction (PCR) amplification and the single-strand conformation polymorphism (SSCP) technique. Both twins possessed an identical missense mutation in exon 8 of the WT1 gene, resulting in replacement of arginine by histidine at amino acid 366 (arg366his) in the WTI protein. This mutation has previously been described in Denys-Drash syndrome. The WT1 gene plays a role in mesenchymal epithelial (ME) interactions in the developing urogenital system, and possibly has a similar role during lung morphogenesis. We propose that this WT1 gene mutation contributes to both DMS and developmental pulmonary abnormalities by altering ME interactions in both organs.

Giant cell angioblastoma: three additional occurrences of a distinct pathologic entity.

Giant cell angioblastoma was described previously in a single case report as a congenital soft-tissue tumor with a unique morphology. In the current report, we describe three cases of giant cell angioblastoma found in three infants; one case was congenital and located in the hand, one appeared neonatally in the palate, and one on the scalp of an infant. Clinical findings and results of light microscopy, immunohistochemistry, and electron microscopy were evaluated. All tumors were ulcerated; the hand and palate tumors also infiltrated soft tissue and bone. They exhibited a solid, nodular, and plexiform proliferation of oval-to-spindle cells with a frequent striking, concentric aggregation around small vascular channels. These cells had characteristics of undifferentiated mesenchymal cells, fibroblasts, myofibroblasts, and pericytes. Co-mingled with these cells were large mononuclear and multinucleate giant cells with histiocytic features. The palatal giant cell angioblastoma, excised with positive margins, was managed with interferon-alpha and showed no progression after nearly 5 years. The hand tumor diminished in size after management with interferon-alpha, was subtotally excised, and did not progress after 27 months. Follow-up data are unavailable for the patient with the scalp lesion. Our findings validate the classification of giant cell angioblastoma as a distinct and rare entity that is locally infiltrative but slow growing. The morphology and diverse cellular differentiation are consistent with an unusual form of neoplastic angiogenesis.

Identification of a basal/reserve cell immunophenotype in benign and neoplastic endometrium: a study with the p53 homologue p63.

BACKGROUND: Metaplastic differentiation, including squamous, mucinous, and tubal (ciliated), is common in both benign and neoplastic endometrium, and the cell of origin for this pathway is poorly understood. In this study, expression of a marker for basal and reserve cells in cervical squamous mucosa, designated p63, was investigated in a spectrum of endometrial alterations. METHODS: One hundred ninety different endometria from 132 patients were examined, including fetal (6), premenarchal (3), benign cyclic (29) and noncyclic (54), hyperplastic (14), and neoplastic (93) endometrial glandular epithelia. The latter included conventional endometrioid carcinomas with and without mucinous, ciliated, and squamous metaplasia, and uterine papillary serous carcinoma (UPSC). RESULTS: p63 expression was identified in basal/subcolumnar cells in the fetal endometrium in a distribution similar to that in basal/reserve cells of the cervix. Staining was confined to individual scattered basal and suprabasal cells in cycling endometrium. In polyps and postmenopausal endometria, focal clusters of p63-positive cells were identified in inactive glands or surface epithelium. Metaplastic (squamous or mucinous) epithelia, either alone or in conjunction with hyperplasias or carcinomas, exhibited the most intense staining, primarily in basal or subcolumnar cells. In some cases, immediately adjacent nonmetaplastic columnar epithelium also stained positive. UPSCs contained only rare scattered p63-positive cells. CONCLUSIONS: Cells with a basal or reserve cell phenotype exist in the endometrium during fetal life, are not conspicuous during the reproductive years, but may emerge during shifts in differentiation. Whether these cells signify specialized multipotential endometrial cells is not clear, but the similarity of these cells to basal/reserve cells of the cervix and their association with neoplasia merit further study.

PLAG1 fusion oncogenes in lipoblastoma.

Lipoblastomas are pediatric neoplasms resulting from transformation of adipocytes. These benign tumors are typically composed of adipose cells in different stages of maturation within a variably myxoid matrix, and they contain clonal rearrangements of chromosome band 8q12. Because lipoblastomas resemble embryonic adipose tissue, characterization of their transforming mechanisms might reveal biological pathways in physiological adipogenesis. Herein, we demonstrate that lipoblastoma chromosome 8q12 rearrangements bring about promoter-swapping events in the PLAG1 oncqgene. We show that the hyaluronic acid synthase 2 (HAS2) or collagen 1 alpha 2 (COL1A2) gene promoter regions are fused to the entire PLAG1 coding sequence in each of four lipoblastomas. PLAG1 is a developmentally regulated zinc finger gene whose tumorigenic function has been shown previously only in epithelial salivary gland cells. Our findings reveal that PLAG1 activation, presumably resulting from transcriptional up-regulation, is a central oncogenic event in lipoblastoma.

Clinical course of postinfectious bronchiolitis obliterans.

We performed a prospective observational study to define the clinical course and the prognostic factors of 31 patients with postinfectious bronchiolitis obliterans. All patients presented with an episode of acute bronchiolitis in the first 2 years of life, and respiratory symptoms and signs persisted since then. Other diseases which may cause chronic airflow obstruction were excluded. The patients were followed after their inclusion in the study and the clinical findings were recorded in a standardized questionnaire and form. Repeated chest radiographs and lung perfusion scans were obtained in all 31 patients and semiannual spirometry was performed in 8 older patients. Eight patients had lung biopsies. The clinical course varied in the 31 patients during a mean of 3.5 years of follow-up. The outcome of the patients included clinical remission (22.6%), persistence of respiratory symptoms and signs (67.7%), and death (9.7%). An older age at onset of illness and presence of atopy as suggested by an elevated serum IgE appeared to predispose to a poor prognosis.

Pulmonary hypertension associated with nonketotic hyperglycinaemia.

Nonketotic hyperglycinaemia (NKH) is an autosomal recessive disorder characterized by defective glycine degradation by the mitochondrial glycine cleavage system. The clinical features include lethargy, hypotonia, apnoea, seizures and severe psychomotor retardation, all attributed to the accumulation of glycine in the nervous system. Pulmonary hypertension (PHN) has not been reported in NKH. We describe four patients with NKH who had PHN in addition to the characteristic manifestations of NKH. This newly recognized association might provide additional insight into the underlying pathophysiology of PHN.

Soft-tissue vascular anomalies: utility of US for diagnosis.

PURPOSE: To determine the ultrasonographic (US) features that distinguish soft-tissue hemangioma from vascular malformation and one type of malformation from another. MATERIALS AND METHODS: Eighty-seven vascular anomalies were evaluated by means of US. Lesions were assessed for the presence of solid tissue and abnormal arteries, veins, or cysts. Vessel density, peak flow velocities, and resistive indexes were compared. RESULTS: There were 49 hemangiomas and 38 vascular malformations. A significantly greater proportion of hemangiomas (48 of 49) compared with vascular malformations (zero of 38) consisted of a solid-tissue mass (P < .001). Vessel density was comparable for hemangioma and arteriovenous malformation (AVM) but significantly greater compared with the other vascular malformations (P < .001 in each case). No differences in mean arterial peak velocity were detected between hemangiomas and malformations. Mean venous peak velocity was significantly higher for AVM than for other vascular malformations and hemangioma. Mean resistive index was greater for lymphatic malformation than for hemangioma or AVM. Abnormal veins, arteries and veins, or cysts were univariate predictors for distinguishing between venous, arteriovenous, and lymphatic malformations (P < .001 in all cases). Solid-tissue mass was the only multivariate predictor for differentiating hemangioma from vascular malformation (likelihood ratio test = 109.8, P < .001). CONCLUSION: US can be used to distinguish hemangioma from vascular malformation and detect arterial flow. These distinctions are critical for subsequent management and assessing prognosis.

Residual lesions after Kasabach-Merritt phenomenon in 41 patients.

BACKGROUND: Kasabach-Merritt phenomenon (KMP) is the association of a vascular tumor and thrombocytopenic coagulopathy. Vascular tumors are either kaposiform hemangioendothelioma or tufted angioma but not "true" common hemangioma of infancy. There is a conspicuous absence in the literature regarding the late outcome and possible residual lesions after apparent clinical cure of KMP. OBJECTIVE: The purpose of the study was to analyze these residua in a large number of patients. METHODS: Clinical data on 41 patients who had KMP were accrued in an international cooperative study. The emphasis was on the residual lesions after resolution of the thrombocytopenia and other coagulation abnormalities. Imaging studies (follow-up magnetic resonance imaging studies available for 10 patients) and histologic specimens (30 specimens available for 26 patients, 18 biopsies done during the KMP and 12 concerning the sequelae) were reviewed. RESULTS: Residual lesions after "cure" of KMP were common. They exhibited 3 clinical patterns: type I lesions (n = 28) showed a cutaneous red stain, with or without associated red papules. The stain might overlap a minor fibrotic infiltration or a significant poorly delineated diffuse fibrotic infiltration. These cutaneous vascular lesions varied in size and appearance over time and were occasionally painful. Type II lesions were telangiectatic streaks and swelling (n = 5), and type III lesions showed a minor, firm, irregular, subcutaneous mass assessed by palpation or deep infiltration evidenced by computed tomography or magnetic resonance imaging (n = 8). A fourth feature was sequelae in muscles and/or joints. Histologically, tufted angioma was more common in the specimens from residual lesions, whereas kaposiform hemangioendothelioma was more common during the active phase of KMP. Imaging findings were remarkably reproducible and revealed a persistent vascular tumor. CONCLUSION: Residua of tumors associated with KMP are common after the resolution of thrombocytopenia and coagulopathy. They are (more or less) prominent dormant vascular tumors, not "scars" and, clinically as well as histologically, they differ markedly from involuted hemangioma.