Judy Mae Pascasio

FOXO1–FGFR1 fusion and amplification in a solid variant of alveolar rhabdomyosarcoma

Rhabdomyosarcoma is the most common pediatric soft tissue malignancy. Two major subtypes, alveolar rhabdomyosarcoma and embryonal rhabdomyosarcoma, constitute 20 and 60% of all cases, respectively. Approximately 80% of alveolar rhabdomyosarcoma carry two signature chromosomal translocations, t(2;13)(q35;q14) resulting in PAX3–FOXO1 fusion, and t(1;13)(p36;q14) resulting in PAX7–FOXO1 fusion. Whether the remaining cases are truly negative for gene fusion has been questioned. We are reporting the case of a 9-month-old girl with a metastatic neck mass diagnosed histologically as solid variant alveolar rhabdomyosarcoma. Chromosome analysis showed a t(8;13;9)(p11.2;q14;9q32) three-way translocation as the sole clonal aberration. Fluorescent in situ hybridization (FISH) demonstrated a rearrangement at the FOXO1 locus and an amplification of its centromeric region. Single-nucleotide polymorphism-based microarray analysis illustrated a co-amplification of the FOXO1 gene at 13q14 and the FGFR1 gene at 8p12p11.2, suggesting formation and amplification of a chimerical FOXO1–FGFR1 gene. This is the first report to identify a novel fusion partner FGFR1 for the known anchor gene FOXO1 in alveolar rhabdomyosarcoma.

Development of autoimmune hepatitis in a child with systemic-onset juvenile idiopathic arthritis during therapy with etanercept.

Autoimmune hepatitis is a progressive chronic inflammatory liver disease of unknown etiology. The diagnosis and classification is based on histologic abnormalities and the presence of abnormal serum autoantibodies and globulins. We report the case of a patient with systemic-onset juvenile idiopathic arthritis (JIA) who developed type 1-autoimmune hepatitis while receiving etanercept, a tumor necrosis factor (TNF)-blocker.

Histological Study of Osteoid Osteoma's Blood Supply

The osteoid osteoma is a painful lesion with a special predilection for the femur and tibia of young patients. Although the lesion has been described as richly innervated, its vascular supply has not been critically appraised to date in the pathology literature. To this end, we have undertaken a morphological study of 16 archival cases of osteoid osteoma, focusing primarily on the patterns of vascularization, utilizing traditional histological and immunohistochemical approaches. The study demonstrated that a prominent arterial and arteriolar blood supply was a constant finding within the various zones of soft tissues, skeletal muscle, and bone surrounding the nidus. It also showed that the caliber of the vessels underwent gradual attenuation throughout their centripetal course toward the nidus, where the vessels lost their muscularis as they merged into the capillary network of the nidus. Immunostaining with antibodies to neurofilament and S100 proteins revealed a pattern of innervation that was overall less exuberant than that described in some reports and that was virtually absent from the nidus. Taken together with data reported in the radiological literature, our findings lead us to wonder whether the osteoid osteoma may represent a response to the local stimulation of bony tissue by a primarily aberrant vasculature, a hypothesis that warrants further elucidation using state-of-the-art imaging approaches.

Malignant peripheral nerve sheath tumor arising from an adrenal ganglioneuroma in a 6-year-old boy.

This report describes the youngest patient to develop a malignant peripheral nerve sheath tumor arising from a ganglioneuroma (MPNST ex Ganglioneuroma). The patient, a 6-year-old boy, was never irradiated and had no history or stigmata of neurofibromatosis. The report also includes a review of the previously published related cases, and an analysis of the immunohistochemistry and electron microscopy data available to date on the subject.

Recognition of Crohn disease on incidental gastric biopsy in childhood.

The role of gastric biopsy in the diagnosis of Crohn disease (CD) in the pediatric population has not been well described. We assessed the use of gastric biopsies in the diagnosis of CD using specific histopathologic parameters: granulomata, focal gland injury with neutrophils (glandulitis or glandular abscesses), and/or focal concomitant eosinophilic infiltrates. Multiple (438) consecutive pediatric biopsies with inflammation spanning a 5-year period were identified from archival material in patients ages 2 months to 16 years. A total of 56 CD cases were confirmed using colon biopsies and clinical and radiologic data as the gold standards of diagnosis. Review of hematoxylin and eosin (H&E) slides and Diff-Quik stained slides (negative for Helicobacter pylori) isolated 53 cases which suggested CD on gastric biopsy: 20 cases with granulomata, 14 cases with focal glandulitis and glandular abscesses, and 19 cases of focal glandulitis/glandular abscesses with eosinophilic infiltrates. Seventy-seven percent (43/56) were correctly identified as patients with CD. Twenty-three percent (13/56) of CD cases were not identified primarily because of concurrent H. pylori infection identified on Diff-Quik stain with a superimposed nonspecific diffuse gastritis. The use of Diff-Quik stain to identify H. pylori cases after all other factors are considered was significant (P = 0.0145); a negative stain, combined with the identified histopathologic features indicative of CD, significantly increased the accuracy of CD diagnosis. CD was mimicked by other gastric granulomatous diseases (actinomyces, 1 case; chronic granulomatous disease of childhood, 1 case). Gastric biopsy can be used to identify or support the diagnosis of CD in children in the appropriate clinicopathologic setting.

Glioneuronal phenotype in a diencephalic pilomyxoid astrocytoma.

We report the presence of divergent populations of cells in a hypothalamic/chiasmatic pilomyxoid astrocytoma of an 11-month-old male, exhibiting differential immunohistochemical localizations for glial fibrillary acidic protein (GFAP) and synaptophysin. The tumor cells were negative for Neu-N and neurofilament protein. Ultrastructurally, the tumor comprised 2 cell types, one with features attributable to a neuronal phenotype alongside cells exhibiting an overt astroglial phenotype. This composite organization was confirmed by confocal microscopy, which revealed 2 distinct, albeit tightly interwoven, populations of GFAP and synaptophysin-labeled tumor cells. Our results indicate that a subset of the so-called pilomyxoid astrocytomas of the hypothalamic/chiasmatic region may represent phenotypically mixed glioneuronal neoplasms distinct from the pilocytic astrocytomas.

Study of an ovarian sclerosing stromal tumor presenting as vaginal bleeding in a 7-month-old.

This communication describes the histological, immunohistochemical, ultrastructural, and cytogenetic study of an ovarian sclerosing stromal tumor resected from a 7-month-old girl who presented with vaginal bleeding. The tumor is very rare, its pathogenesis is not clear, and its hormonal activity has been subject to debate. In addition, it has been rarely seen in children and never in infants, with the youngest patient reported being 10 years of age. Histological study of the tumor showed a process of multinodular asynchronous growth followed by gradual loss of cells, hyalinization, and eventual transformation into corpora albicantia–like structures, thus indicating that the process may be more akin to an ovarian nodular follicular hyperplasia than to a classical neoplasm. The study also documented an elevated proliferative MIB-1 index in the process, which had not been investigated in earlier reports, and illustrated the immunohistochemical reactivity of some of its stromal cells to progesterone receptors.

Co‐occurrence of non‐mosaic trisomy 22 and inherited balanced t(4;6)(q33;q23.3) in a liveborn female: Case report and review of the literature

Trisomy 22 is the third most common autosomal trisomy occurring in about 0.4% of all clinically recognized pregnancies. Complete non‐mosaic trisomy 22 is extremely rare in live births. Most affected children die before one year of age. To date, only 29 liveborn cases have been reported and none has carried an additional genetic lesion. In this report, we describe the clinical presentation, cytogenetic, and cytogenomic findings in a liveborn female with complete non‐mosaic trisomy 22 as well as a paternally inherited, balanced reciprocal chromosomal rearrangement t(4;6)(q33;q23.3). The proband manifested features commonly seen in individuals with non‐mosaic trisomy 22 such as intrauterine growth retardation (IUGR), single umbilical artery, cranial abnormalities, short neck, cleft lip and palate, dysmorphic ears, hypoplastic nipples, digital malformation, congenital heart defects, dysplastic kidneys, and genital anomalies. In addition, she had lobar holoprosencephaly, aqueductal stenosis, and limb and eye problems that have not been associated with complete trisomy 22 in previous reports. She died at 35 days of age of complex heart disease and renal failure. We are hereby expanding the cytogenetic and clinical spectrum of this rare chromosome disorder. Clinical features of liveborn children with non‐mosaic trisomy 22 are reviewed and compared to those in our proband. The impact of genomic content in relation to the survival of trisomies in humans is also discussed.

Malignant glioma with primitive neuroectodermal tumor-like component (MG-PNET): novel microarray findings in a pediatric patient.

Central nervous system (CNS) tumors exhibiting dual features of malignant glioma (MG) and primitive neuroectodermal tumor (PNET) are rare and diagnostically challenging. Previous studies have shown that MG-PNET carry MYCN or MYC gene amplifications within the PNET component concomitant with glioma-associated alterations, most commonly 10q loss, in both components [9]. Here we confirm and extend the profile of molecular genetic findings in a MG-PNET involving the left frontal lobe of a 12-year-old male. Histologically, the PNET-like component showed morphological features akin to anaplastic medulloblastoma highlighted by widespread immunoreactivity for βIII-tubulin (TUBB3) and nonphosphorylated neurofilament protein, and to a lesser degree, Neu-N, synaptophysin, and CD99, whereas the gliomatous component was demarcated by glial fibrillary acidic protein (GFAP) labeling. Immunohistochemical labeling with an anti-H3K27M mutant-specific antibody was not detectable in either gliomatous and/or PNET-like areas. Interphase fluorescent in situ hybridization (FISH) study on touch preparations from frozen tumor and formaldehyde-fixed, paraffin-embedded histological sections showed amplification of MYC in both PNET-like and gliomatous areas. Single nucleotide polymorphism (SNP) microarray analysis revealed that the tumor carried gains of multiple chromosomes and chromosome arms, losses of multiple chromosomes and chromosome arms, gains of multiple chromosomal segments (not limited to amplification of chromosomal segments 4q12 including PDGFRA, and 8q24.21 including MYC), and a hitherto unreported chromothripsis-like abnormality on chromosome 8. No mutations were identified for IDH1, IDH2, or BRAF genes by sequence analysis. The molecular genetic findings support the presence of a CNS-PNET as an integral part of the tumor coupled with overlapping genetic alterations found in both adult and pediatric high-grade gliomas/glioblastoma. Collectively, microarray data point to a complex underpinning of genetic alterations associated with the MG-PNET tumor phenotype.
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Tetrasomy 13q32.2qter Due to an Apparent Inverted Duplicated Neocentric Marker Chromosome in an Infant with Hemangiomas, Failure to Thrive, Laryngomalacia, and Tethered Cord

BACKGROUND Approximately 100 small supernumerary marker chromosomes (sSMCs) with a non-α-satellite neocentromere structure have been reported in the literature. Of the few derived from chromosome 13, five have consisted of inverted duplicated segment 13q32qter. CASE REPORT We herein describe the sixth case, characterized by genome wide SNP array, conventional cytogenetics and FISH studies. The de novo occurrence of the marker, the poor prognosis and the presence of hemangiomas are consistent with previous cases. CONCLUSION We hereby expand the clinical spectrum of this rare cytogenetic disorder and suggest a possible mechanism for the pathogenesis of associated congenital vascular malformations.