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.

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.

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.

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.

Renal cell carcinomas in children and young adults: increased incidence of papillary architecture and unique subtypes.

Renal cell carcinomas in children and young adults are rare, and the pathologic features of these tumors have not been well described. We reviewed 24 renal cell carcinomas in children and young adults ages 6 to 29 years, 14 of whom were younger than 18 years of age. Fourteen were female. In 19 (79%) of 24 cases, the tumor met histologic criteria for papillary renal cell carcinoma, with at least 50% papillary architecture. Four of the remaining five cases were typical clear cell tumors in patients known to have von Hippel Lindau syndrome, and one case was of chromophobe type. In the papillary tumors, calcifications, high nuclear grade, extracapsular extension (American Joint Commission on Cancer stage T3), and lymph node metastases were common. Among these papillary tumors, four distinct histologic patterns could be identified. Collecting duct-like tumors (two cases) involved the large collecting ducts, were multifocal and predominantly papillary, and had focal tubular and solid areas. These tumors were reactive for epithelial membrane antigen (EMA) and keratins, including CK7, but negative for Ulex europeaus and high molecular weight keratin 34BE12. Voluminous cell tumors (four cases) were composed of cells with extremely voluminous clear cytoplasm and, although predominantly papillary, had areas that also resembled clear cell tumors. These tumors were reactive for keratins AE1/AE3 but were otherwise negative for all other keratins, EMA, and U. europeaus. One of these tumors showed an X;7 translocation. Adult type tumors (12 cases) resembled papillary tumors of adults. These tumors were reactive for EMA and keratins, including CK7, and all but one were negative for U. europeaus and keratin 34BE12. This last case had trisomies of chromosomes 7, 16, 17, and 20. The final neuroendocrinelike case was multifocal, organoid, and composed of nests of small cells in a neuroendocrinelike pattern. Three of 13 patients were alive with disease at last follow-up, and three additional patients died of disease, all within 2 years. Progression was highly associated with lymph node involvement at the time of resection. We conclude that the clinicopathologic features of renal cell carcinomas in children and young adults differ from those arising in older adults. These tumors are characteristically high-grade, high-stage, papillary tumors with numerous calcifications, and several subtypes can be identified based on histologic, immunohistochemical, and cytogenetic features. Some subtypes appear to be unique to this age group.

The pericentromeric inversion, inv (6)(p25q13), is a novel diagnostic marker in chondromyxoid fibroma.

Chondromyxoid fibroma is a benign bone tumor that arises most commonly in the metaphysis of long bones in young adults. The cytogenetic features of this tumor are not well known. In this study, four chondromyxoid fibromas were karyotyped after short-term cell culture. All of the tumors contained clonal rearrangements of chromosome 6, and each of these rearrangements involved band 6q13. Two tumors contained a pericentromeric inversion, inv (6)(p25q13), which was described recently in chondromyxoid fibroma. 6q13 rearrangements are not associated with other types of bone and soft tissue tumors, and the inv (6)(p25q13) is reported only in chondromyxoid fibroma. Hence, this cytogenetic marker might be helpful in distinguishing chondromyxoid fibroma from chondrosarcoma and other histologic mimics. The consistent occurrence of 6q13 rearrangements suggests a specific oncogenic mechanism in chondromyxoid fibroma, most likely involving oncogene activation.

Congenital mesoblastic nephroma t(12;15) is associated with ETV6-NTRK3 gene fusion: cytogenetic and molecular relationship to congenital (infantile) fibrosarcoma.

Morphological, cytogenetic, and biological evidence supports a relationship between congenital (infantile) fibrosarcoma (CFS) and congenital mesoblastic nephroma (CMN). These tumors have a very similar histological appearance, and they are both associated with polysomies for chromosomes 8, 11, 17, and 20. Recently, CFS was shown to contain a novel t(12; 15)(p13;q25) translocation resulting in ETV6-NTRK3 gene fusion. The aims of this study were to determine whether congenital mesoblastic nephroma contains the t(12;15)(p13;q25) translocation and ETV6-NTRK3 gene fusion and whether ETV6-NTRK3 fusions, in CMN and CFS, antedate acquisition of nonrandom chromosome polysomies. To address these aims, we evaluated 1) ETV6-NTRK3 fusion transcripts by reverse transcriptase polymerase chain reaction and sequence analysis, 2) genomic ETV6-region chromosomal rearrangement by fluorescence in situ hybridization, and 3) chromosomal polysomies by karyotyping and fluorescence in situ hybridization. We report ETV6-NTRK3 fusion transcripts and/or ETV6-region rearrangement in five of six CMNs and in five of five CFSs. The ETV6-NTRK3 fusion transcripts and/or ETV-region chromosome rearrangements were demonstrated in two CMNs and one CFS that lacked chromosome polysomies. These findings demonstrate that t(12;15) translocation, and the associated ETV6-NTRK3 fusion, can antedate acquisition of chromosome polysomies in CMN and CFS. CMN and CFS are pathogenetically related, and it is likely that they represent a single neoplastic entity, arising in either renal or soft tissue locations.

Pleural effusions in lymphoblastic lymphoma: a diagnostic alternative.

BACKGROUND: Children with large anterior mediastinal masses frequently present with severe respiratory compromise and often pose a difficult diagnostic dilemma. A biopsy is preferred for diagnosis before treatment can begin; however, many of these children are at risk of acute clinical deterioration and cardiovascular arrest with the induction of anesthesia. The authors noted a correlation between pleural effusions and lymphoblastic lymphoma and recently diagnosed three cases of lymphoblastic lymphoma in children with a large anterior mediastinal mass and pleural effusion through cytological and flow cytometric examination of the pleural fluid. METHODS: To focus on this problem, 101 pediatric patients presenting with an anterior mediastinal mass between January 1980 and September 1994 were reviewed to determine if pleural effusions occur more frequently at initial presentation with lymphoblastic lymphoma than with Hodgkin's disease, thus offering a means of diagnosis in children with severe respiratory compromise. The patients' chest radiographs and/or computed tomograms for the 88 cases in which they were available were reviewed retrospectively in a blinded fashion to identify those children with pleural effusions at the time of presentation. RESULTS: In this study, 71% of patients with lymphoblastic lymphoma (10 of 14) had a pleural effusion at presentation, whereas only 11.7% of patients with Hodgkin's disease (7 of 60) had a pleural effusion on initial presentation. (P < .002 Fisher's Exact test). CONCLUSION: This retrospective review suggests that there is a significantly greater association of pleural effusions in patients with lymphoblastic lymphoma than with Hodgkin's disease. Our experience supports the conclusion that thoracentesis may provide a means of diagnosis in children presenting in severe respiratory compromise obviating the need for anesthesia and open biopsy.