Portia A. Kreiger

Losses of chromosomes 1p and 19q are rare in pediatric oligodendrogliomas

Pediatric oligodendrogliomas are rare neoplasms and have not been characterized extensively either pathologically or genetically. Given the recent interest in the significance of chromosomal losses in predicting the clinical course and in establishing uniform diagnoses of adult oligodendrogliomas, we reviewed the pathological and clinical features of a series of pediatric oligodendrogliomas and determined their 1p and 19q status using fluorescence in situ hybridization. Of 19 tumors originally diagnosed as oligodendroglioma, 7 were oligodendroglioma, 3 were anaplastic oligodendroglioma, 3 were oligoastrocytoma, and 6 were reclassified. Only one tumor, an anaplastic oligodendroglioma, had 1p loss; none had 19q loss. The single patient whose tumor had 1p loss did not have a particularly favorable clinical course. These results suggest that pediatric oligodendrogliomas arise by molecular alterations distinct from adult oligodendrogliomas, and such molecular alterations do not hold immediate promise as an adjunct to the diagnosis of pediatric oligodendrogliomas.

Current Imaging of Prenatally Diagnosed Congenital Lung Lesions

Congenital lung lesions refer to a spectrum of pulmonary developmental anomalies including, but not limited to, bronchial atresia, congenital pulmonary airway malformation (formerly known as congenital cystic adenomatoid malformation) and bronchopulmonary sequestration. These anomalies comprise about 90% of the anomalies seen in clinical practice. The advent of prenatal sonography and, more recently, fetal magnetic resonance imaging has changed our understanding and practice in the evaluation of congenital lung lesions. Postnatal imaging using low-dose computed tomography angiography (CTA) is extremely useful as it may provide information essential for differential diagnosis by allowing multiplanar reconstructions of the airway, lung parenchyma, and vasculature. The use of iodine in CTA permits the application of low-dose radiation protocols in these young patients. The purpose of this article is to emphasize the technical factors that may optimize low-dose CTA evaluation of these lesions. We also provide a description of prenatal imaging findings and helpful diagnostic clues that may be useful for the characterization of the most commonly encountered prenatally diagnosed pulmonary developmental anomalies.

Loss of INI1 expression defines a unique subset of pediatric undifferentiated soft tissue sarcomas

Malignant rhabdoid tumor has traditionally been defined by its histologic phenotype. However, genetic investigations of malignant rhabdoid tumor have revealed a characteristic loss of or mutation in the INI1 gene on chromosome 22q. The occurrence and significance of soft tissue tumors meeting genetic criteria for malignant rhabdoid tumor but with an undifferentiated non-rhabdoid histology is poorly characterized. Seventeen undifferentiated sarcomas, lacking rhabdoid histology were identified either through the surgical pathology files of The Childrens Hospital of Philadelphia (1980–2005) or in consultation. Immunohistochemistry for the INI1 protein showed a loss of nuclear expression within tumor cells in five of these cases. On histologic review, these five tumors had a featureless sheet-like architecture; four were small round blue cell tumors, and one showed focal spindling. Although they had variably prominent nucleoli, classic rhabdoid morphologic features were not identified in any of these cases at primary presentation. Additional immunohistochemistry showed a polyphenotypic profile. Four of the five tumors showed genetic abnormalities involving the INI1 gene by a combination of fluorescent in situ hybridization, reverse transcription-polymerase chain reaction, and/or mutational analysis. Patient ages ranged from 1 week to 5 years. Four patients were male, and one was female. Sites included two neck tumors, two extremity tumors, and one paraspinal tumor. Two patients are alive and well over 15 years from the time of diagnosis; the remaining four are alive and well but with less than 2 years follow-up. Thus, alterations of the INI1 gene with consequent loss of expression identified a population of undifferentiated sarcomas lacking classic rhabdoid morphology in young patients, with evidence of favorable survival. Whether these undifferentiated sarcomas represent a clinicopathologic entity distinct from classic malignant rhabdoid tumor requires further investigation.

Congenital high airway obstruction syndrome: MR/US findings, effect on management, and outcome

BackgroundCongenital high airway obstruction syndrome (CHAOS) is a rare disorder defined as any fetal abnormality that obstructs the larynx or trachea. Prompt airway intervention at delivery after accurate prenatal diagnosis may allow survival of this otherwise fatal condition.ObjectiveTo identify prenatal MRI findings in CHAOS, to compare these findings with those of fetal US, to determine if imaging alters diagnosis and management decisions, and to correlate prenatal with postnatal imaging findings.Materials and methodsRecords and MRI scans of ten fetuses with CHAOS were reviewed, and the findings correlated with outside and same-day fetal US and postnatal imaging findings. Fetal lung volumes were measured on MRI scans.ResultsLarge lung volumes were found in 90% of the fetuses. Increased lung signal intensity, inverted diaphragm, and a dilated, fluid-filled lower airway were identified in all. The obstruction level was identified in 90%. MRI changed screening US diagnosis in 70%, but was concordant with the tertiary care US imaging in 90%. Seven fetuses were terminated or died in utero, and three fetuses survived after ex utero intrapartum tracheostomy placement. Autopsy or bronchoscopy performed in 60% confirmed CHAOS. Postnatal chest radiographs and CT showed hyperinflation, while US and fluoroscopy showed diminished diaphragmatic motion.ConclusionMRI demonstrates large lung volumes, increased lung signal intensity, inverted diaphragm, and dilated fluid-filled lower airway, and usually identifies the obstruction level. The degree of correlation between MRI and tertiary prenatal US is high, but CHAOS is frequently misdiagnosed on screening US. Correct diagnosis may enable planned airway management. Voluminous lungs and diaphragmatic abnormalities persist on postnatal imaging.

Interferon-γ mediates anemia but is dispensable for fulminant toll-like receptor 9-induced macrophage activation syndrome and hemophagocytosis in mice.

OBJECTIVE Macrophage activation syndrome (MAS) is a devastating cytokine storm syndrome complicating many inflammatory diseases and characterized by fever, pancytopenia, and systemic inflammation. It is clinically similar to hemophagocytic lymphohistiocytosis (HLH), which is caused by viral infection of a host with impaired cellular cytotoxicity. Murine models of MAS and HLH illustrate that interferon-γ (IFNγ) is the driving stimulus for hemophagocytosis and immunopathology. This study was undertaken to investigate the inflammatory contributors to a murine model of Toll-like receptor 9 (TLR-9)-induced fulminant MAS. METHODS Wild-type, transgenic, and cytokine-inhibited mice were treated with an IL-10 receptor blocking antibody and a TLR-9 agonist, and parameters of MAS were evaluated. RESULTS Fulminant MAS was characterized by dramatic elevations in IFNγ, IL-12, and IL-6 levels. Increased serum IFNγ levels were associated with enhanced IFNγ production within some hepatic cell populations but also with decreased numbers of IFNγ-positive cells. Surprisingly, IFNγ-knockout mice developed immunopathology and hemophagocytosis comparable to that seen in wild-type mice. However, IFNγ-knockout mice did not become anemic and had greater numbers of splenic erythroid precursors. IL-12 neutralization phenocopied disease in IFNγ-knockout mice. Interestingly, type I IFNs contributed to the severity of hypercytokinemia and weight loss, but their absence did not otherwise affect MAS manifestations. CONCLUSION These data demonstrate that both fulminant MAS and hemophagocytosis can arise independently of IFNγ, IL-12, or type I IFNs. They also suggest that IFNγ-mediated dyserythropoiesis, not hemophagocytosis, is the dominant cause of anemia in fulminant TLR-9-induced MAS. Thus, our data establish a novel mechanism for the acute anemia of inflammation, but suggest that a variety of triggers can result in hemophagocytic disease.

Hamartomatous tongue lesions in children

The incidence and spectrum of tongue lesions in children, in particular tongue hamartomas, is relatively unknown. We report a retrospective review of all tongue lesions seen at a major tertiary care childrens hospital over an 18-year period with an emphasis on describing tongue hamartomas. A total of 135 tongue lesions were identified. Vascular/lymphatic lesions (36/135) were the most common followed by mucus extravasation phenomenon (22/135). Interestingly, hamartomatous lesions (18/135) were the third most common lesion category identified. Lingual hamartomas were predominantly submucosal in location and were classified histologically by tissue composition as follows: neurovascular (2/18), smooth muscle predominant (5/18), fat predominant (1/18), and smooth muscle and fat containing (10/18). All 5 smooth muscle predominant hamartomas also contained vasculature, and 1 case additionally contained salivary gland tissue. The single fat predominant hamartoma additionally contained vessels and salivary gland. The final 10 hamartomas contained varying amounts of both smooth muscle and fat, and also admixed combinations of vessels, nerves, and salivary glands. Two of these 10 cases additionally contained foci of choristomatous elements, including cutaneous adnexal structures and cartilage. Most patients with hamartomatous lesions were young, 2 years or less. Eight cases were congenital in origin. Females outnumbered males by 2:1. The majority of lesions (16/18) were dorsal in location, and 4 patients had a syndromic association, all oral-facial-digital syndrome.

Giant cell tumor of tendon sheath: largest single series in children.

Giant cell tumors of tendon sheath (GCTTS) are rare in children. We hypothesized that GCTTS in children probably behave in a similar manner to the adult lesions, with regard to clinical features, imaging characteristics, histology, and recurrence rates after surgical excision. We retrospectively reviewed 29 children diagnosed and treated for GCTTS during a 16-year period and evaluated the above characteristics to compare these results with published data for adult patients. A telephone questionnaire survey was also conducted to assess the current symptoms and function, satisfaction with procedure, and incidence of recurrence. In children, we noted similar predilection for lesions in both upper and lower extremities. Most cases, 28 (96%) of 29, presented with a gradual enlarging soft tissue mass. Plain radiography demonstrated soft tissue swelling in 50% of cases. Magnetic resonance imaging features were noted to be variable, although low signal intensity on T1- and T2-weighted images was noted in most lesions. Incisional biopsy with intraoperative frozen section and histological evaluation was the gold standard for accurate diagnosis. We noted no recurrence at final follow-up in any of our cases. Twenty-two (75%) of these 29 patients had follow-up of more than 2 years, with no recurrence, and the remaining 7 had follow-up between 1 to 2 years, which may seemingly be adequate from perspective of expected time interval for early recurrences. Meticulous dissection and excision with appropriate use of magnifying surgical loupes are likely factors that may help to minimize the recurrence rate.

Eosinophilic Gastroenteritis and Colitis: a Comprehensive Review

Eosinophilic gastrointestinal disorders, including eosinophilic esophagitis, gastroenteritis, and colitis, refer to a spectrum of clinical diseases that present with variable degrees of infiltration of the gastrointestinal tract by eosinophils in the absence of other known causes of tissue eosinophilia. Clinical symptoms and laboratory findings are usually non-specific and may or may not be accompanied by peripheral blood eosinophilia. The extent of eosinophilic infiltration of the gastrointestinal wall varies from mucosal to transmural and serosal involvement. Diagnosis requires presence of gastrointestinal symptoms, demonstration of gastrointestinal eosinophilia by biopsy, and exclusion of other known causes of tissue eosinophilia. Many studies have pointed toward the eosinophil as the major offender; however, the exact functional role of the eosinophil in the pathogenesis of eosinophilic gastrointestinal disorders remains unclear. The roles of T-helper-2 cytokines and other mediators, such as eotaxin-1 and interleukin-5, have gained significant importance in the pathobiology of eosinophilic gastrointestinal disorders. Current understanding of treatment is based on case reports and a few case series, as there is a lack of large prospective studies. Steroids are currently the mainstay of therapy, but the roles of other drugs such as leukotriene inhibitors, mast cell stabilizers, interleukin-5 inhibitors, and anti-immunoglobulin E, along with other targets in the immune pathway, are currently being explored.

Fetal Lung Interstitial Tumor (FLIT): A Proposed Newly Recognized Lung Tumor of Infancy to Be Differentiated From Cystic Pleuropulmonary Blastoma and Other Developmental Pulmonary Lesions

The differential diagnosis of congenital lung lesions includes a variety of pulmonary malformations, and uncommon or rare neoplasms such as the pleuropulmonary blastoma (PPB) and congenital peribronchial myofibroblastic tumor (CPMT). Although most of the congenital lesions have a predominantly cystic appearance, the exceptions of a more solid process are the type 3 congenital cystic adenomatoid or pulmonary airway malformation (CCAM-CPAM) and the CPMT. The clinical and pathologic features of a unique solid or mixed solid/cystic lung mass composed of immature interstitial mesenchyme in association with irregular airspace-like structures mimicking abnormal incompletely developed lung are presented in this report of 10 infants (7 males, 3 females) whose tumor-like lesions were detected in the prenatal period to 3 months of age (median, 1-day old). A lobectomy was done in all 10 infants and 1 infant received adjuvant chemotherapy. One of the surgical resections occurred as an ex utero, antenatal procedure because of fetal ascites. There have been no reported recurrences in those patients with greater than 12 months of follow-up ranging from 15 to 182 months (9 cases). Because of the morphologic resemblance of this mass-like lesion to fetal lung at 20 to 24 weeks gestation (as though any further pulmonary development was arrested in these localized lesions), we are proposing the designation of fetal lung interstitial tumor (FLIT) whose pathogenetic relationship, if any, to type 1 (cystic) pleuropulmonary blastoma remains uncertain to date.

Fetal pulmonary malformations: defining histopathology.

Although classification schemes have sought to categorize congenital cystic lung malformations, studies including the pathology of pulmonary malformations occurring specifically during the fetal period are limited. To better characterize such histopathology, we reviewed a total of 23 fetal lung malformations seen at the Childrens Hospital of Philadelphia from 1996 to 2004. Twenty-one of the 23 fetal pulmonary malformations could be categorized into 1 of 3 groups based upon the predominant histologic features present within each lesion. Group 1 (9/21) demonstrated tubular airspaces lined by columnar epithelium. Group 2 (6/21) contained airspaces lined by cuboidal epithelium and surrounded by smooth muscle with abundant interstitial mesenchyme. Group 3 (6/21) showed a mixture of relatively mature-appearing airspaces lined by flattened epithelium and scattered dilated bronchiole-like structures. Cysts were of variable size but in all cases showed a respiratory-type lining. Gestational ages ranged from 21 5/7 to 38 2/7 weeks. Patients in groups 1 and 2 were generally younger than those in group 3; however, morphology did not seem to correlate entirely with normal stages of fetal lung development, and group 2 lesions in particular were the least akin to normal fetal lung. In 4 cases a systemic vascular supply to a lobe of lung was identified, providing evidence that such vasculature is embryonic in origin. The histopathology of fetal lung malformations highlights the variability seen in such lesions at all ages, and it is hoped that continued investigations will provide further insight into these enigmatic lesions.