Management of Symptomatic Hemorrhage From a Developmental Venous Anomaly.

Developmental venous anomalies (DVAs) are clinically benign, low-flow vascular malformations that classically hemorrhage only when associated with a cerebral cavernous malformation. It is very rare for an isolated DVA to hemorrhage. Resection of the DVA is generally contraindicated because of the high risk of venous infarct. We present the case of a large symptomatic hemorrhage stemming from an isolated DVA. The hematoma was evacuated and the hemorrhagic portion of the DVA was resected. This case demonstrates that in rare circumstances, careful resection can successfully treat hemorrhagic DVAs.

Targeted Next-Generation Sequencing Reveals Divergent Clonal Evolution in Components of Composite Pleomorphic Xanthoastrocytoma-Ganglioglioma.

Composite pleomorphic xanthoastrocytoma-ganglioglioma (PXA-GG) is an extremely rare central nervous system neoplasm with 2 distinct but intermingled components. Whether this tumor represents a "collision tumor" of separate neoplasms or a monoclonal neoplasm with divergent evolution is poorly understood. Clinicopathologic studies and capture-based next generation sequencing were performed on extracted DNA from all available PXA-GG at 2 medical centers. Five PXA-GG were diagnosed in 1 male and 4 female patients ranging from 13 to 25 years in age. Four arose within the cerebral hemispheres; 1 presented in the cerebellar vermis. DNA was sufficient for analysis in 4 PXA components and 3 GG components. Four paired PXA and GG components harbored BRAF p.V600E hotspot mutations. The 4 sequenced PXA components demonstrated CDKN2A homozygous deletion by sequencing with loss of p16 (protein product of CDKN2A) expression by immunohistochemistry, which was intact in all assessed GG components. The PXA components also demonstrated more frequent copy number alterations relative to paired GG components. In one PXA-GG, shared chromosomal copy number alterations were identified in both components. Our findings support divergent evolution of the PXA and GG components from a common BRAF p.V600E-mutant precursor lesion, with additional acquisition of CDKN2A homozygous deletion in the PXA component as is typically seen in conventional PXA.

Developmentally anomalous cerebellar encephalocele arising within the cerebellopontine angle and extending into the adjacent skull base in a pediatric patient.

Lesions of the cerebellopontine angle (CPA) in young children are rare, with the most common being arachnoid cysts and epidermoid inclusion cysts. The authors report a case of an encephalocele containing heterotopic cerebellar tissue arising from the right middle cerebellar peduncle and filling the right internal acoustic canal in a 2-year-old female patient. Her initial presentation included a focal left 6th nerve palsy. Magnetic resonance imaging was suggestive of a high-grade tumor of the right CPA. The lesion was removed via a retrosigmoid approach, and histopathologic analysis revealed heterotopic atrophic cerebellar tissue. This report is the first description of a heterotopic cerebellar encephalocele within the CPA and temporal skull base of a pediatric patient.

A Long-Term Survivor With Alveolar Capillary Dysplasia.

A patient with alveolar capillary dysplasia has survived more than 56 months with medical therapy. Intrauterine exposure to metformin potentially modified the severity of disease. In combination with other agents, endothelin receptor antagonists and amlodipine have been key medications in lowering pulmonary arterial pressure and managing right heart failure. (Level of Difficulty: Beginner.).

Myxoid glioneuronal tumor, PDGFRA p.K385-mutant: clinical, radiologic, and histopathologic features.

"Myxoid glioneuronal tumor, PDGFRA p.K385-mutant" is a recently described tumor entity of the central nervous system with a predilection for origin in the septum pellucidum and a defining dinucleotide mutation at codon 385 of the PDGFRA oncogene replacing lysine with either leucine or isoleucine (p.K385L/I). Clinical outcomes and optimal treatment for this new tumor entity have yet to be defined. Here, we report a comprehensive clinical, radiologic, and histopathologic assessment of eight cases. In addition to its stereotypic location in the septum pellucidum, we identify that this tumor can also occur in the corpus callosum and periventricular white matter of the lateral ventricle. Tumors centered in the septum pellucidum uniformly were associated with obstructive hydrocephalus, whereas tumors centered in the corpus callosum and periventricular white matter did not demonstrate hydrocephalus. While multiple patients were found to have ventricular dissemination or local recurrence/progression, all patients in this series remain alive at last clinical follow-up despite only biopsy or subtotal resection without adjuvant therapy in most cases. Our study further supports "myxoid glioneuronal tumor, PDGFRA p.K385-mutant" as a distinct CNS tumor entity and expands the spectrum of clinicopathologic and radiologic features of this neoplasm.

Neonatal cholestasis and hepatosplenomegaly caused by congenital dyserythropoietic anemia type 1: A case report.

BACKGROUND: Congenital dyserythropoietic anemia type 1 (CDA1) is an autosomal recessive disorder of ineffective erythropoiesis, resulting in increased iron storage. CDA1 is usually diagnosed in children and adolescents but can rarely present in the neonatal period with severe anemia at birth. There are no prior reports of neonatal liver histologic findings of CDA1. We report a case of CDA1 in a newborn presenting with severe anemia, cholestasis and liver failure, where liver biopsy helped confirm the diagnosis. CASE SUMMARY: A term infant, born via emergency Cesarean section, presented with cholestasis, hepatosplenomegaly, multiorgan failure and severe anemia at birth. A prior pregnancy was significant for fetal demise at 35 wk without autopsy or known etiology for the fetal demise. Parents are both healthy and there is no history of consanguinity. On further evaluation, the patient was found to have severe ferritin elevation and pulmonary hypertension. An extensive infectious and metabolic work-up was negative. Salivary gland biopsy was negative for iron deposition. At 2 wk of age, a liver biopsy showed findings consistent with CDA1. A genome rapid sequencing panel revealed novel variants in the CDAN1 gene. The patient's liver dysfunction, cholestasis and organomegaly resolved, however she remains transfusion-dependent. CONCLUSION: We report liver pathology findings of CDA1 with a novel genetic mutation for the first time in a newborn.

Accuracy of Suction Rectal Biopsy for Diagnosis of Hirschsprung's Disease in Neonates.

INTRODUCTION: Recent publications have questioned the sensitivity of suction rectal biopsy (SRB) for diagnosis of Hirschsprung's disease (HD) in newborns. A recent European survey reported that 39% of pediatric surgeons performed full-thickness transanal biopsies due to concerns about the accuracy of SRB. We sought to examine our contemporary SRB experience in infants. MATERIALS AND METHODS: A review was performed (2007-2016) of patients under 6 months of age who had a SRB at our children's hospital. The cohort was subdivided by postmenstrual age at time of SRB: preterm (< 40 weeks, A), term neonate (40-44 weeks, B), and infant (> 44 weeks, C). The pathology reports from endorectal pull-through were used as gold standard confirmation. One-year follow-up of patients with negative SRB was used to confirm accurate diagnosis. RESULTS: A total of 153 patients met the criteria and a total of 159 SRBs (< 2,500 g; n = 26) were performed (A = 60, B = 58, C = 35). Forty-three patients were diagnosed with HD (A = 25, B = 15, C = 3). A second SRB was performed in 6 (3.9%) patients due to inadequate tissue (A = 2, B = 2, C = 2) with HD diagnosed in 5. No complications occurred. Sensitivity and specificity of SRB was 100% in all age groups. Half of the patients with a negative SRB had at least 1 year follow-up, with none subsequently diagnosed with HD. CONCLUSION: SRB results in adequate tissue for evaluation of HD in nearly all patients less than 6 months of age on the first attempt and is highly accurate in the preterm and newborn infants. No complications occurred, even among infants less than 2,500 g.

C/EBPß-1 promotes transformation and chemoresistance in Ewing sarcoma cells.

CEBPB copy number gain in Ewing sarcoma was previously shown to be associated with worse clinical outcome compared to tumors with normal CEBPB copy number, although the mechanism was not characterized. We employed gene knockdown and rescue assays to explore the consequences of altered CEBPB gene expression in Ewing sarcoma cell lines. Knockdown of EWS-FLI1 expression led to a decrease in expression of all three C/EBPß isoforms while re-expression of EWS-FLI1 rescued C/EBPß expression. Overexpression of C/EBPß-1, the largest of the three C/EBPß isoforms, led to a significant increase in colony formation when cells were grown in soft agar compared to empty vector transduced cells. In addition, depletion of C/EBPß decreased colony formation, and re-expression of either C/EBPß-1 or C/EBPß-2 rescued the phenotype. We identified the cancer stem cell marker ALDH1A1 as a target of C/EBPß in Ewing sarcoma. Furthermore, increased expression of C/EBPß led to resistance to chemotherapeutic agents. In summary, we have identified CEBPB as an oncogene in Ewing sarcoma. Overexpression of C/EBPß-1 increases transformation, upregulates expression of the cancer stem cell marker ALDH1A1, and leads to chemoresistance.

Acute Leukemia and Concurrent Mediastinal Germ Cell Tumor: Case Report and Literature Review.

There is a known association of primary nonseminomatous mediastinal germ cell tumors (NSMGCT) and hematologic malignancy in younger males not linked to treatment. When combined these two rare entities convey a very poor prognosis. Here we report a 16-year-old male with an anterior mediastinal mass diagnosed as a malignant germ cell tumor based on elevation of serologic markers. He was found to have acute leukemia with megakaryocytic differentiation several days later. We focus our report on the pathologic findings, including a review of the literature, and a novel molecular analysis of the germ cell tumor.

Secondary osteosarcoma: is there a predilection for the chondroblastic subtype?

Osteosarcoma is the most common form of primary bone cancer in the adolescent and young adult patient population. Outcomes in patients with secondary osteosarcoma are inferior compared with outcomes in patients with primary osteosarcoma. The goal of this study was to investigate whether there is a predilection for the chondroblastic histologic subtype in secondary osteosarcoma. A retrospective chart review was performed to identify cases of secondary osteosarcoma treated at 1 institution from 1991 to 2012. Histologic subtypes were evaluated by a pathologist, and a review of the literature was also performed to identify the histologic subclassification of additional series of secondary osteosarcomas. Of a total of 131 cases of osteosarcoma, 9 (6.9%) were identified as a secondary malignancy. Only 2 cases (22%) were identified as chondroblastic variants, although 6 (67%) showed some degree of chondroid differentiation. Of the 3 cases meeting the criteria for postradiation osteosarcoma, 2 (67%) were identified as chondroblastic variants and all 3 showed some degree of chondroid differentiation. Five other studies evaluating histologic subtypes in postradiation osteosarcoma showed a cumulative frequency of 20% for the chondroblastic variant. Although the study results did not support the hypothesis of an association between secondary osteosarcoma and the chondroblastic subtype, the high proportion of cases of postradiation osteosarcoma with the chondroblastic subtype and the even higher proportion showing some degree of chondroid differentiation are noteworthy features of this disease.

Hirschsprung disease in the premature newborn: a population based study and 40-year single center experience.

BACKGROUND/PURPOSE: Understanding of Hirschsprung disease (HD) in premature newborns (PHD) is anecdotal. We have sought in this study to identify the demographic and clinical features of PHD. METHODS: All patients with HD 1970-2011 treated at our tertiary care children's hospital were identified. Patients with biopsy confirmed HD and EGA <37weeks were selected for further review. Prenatal and birth data, demographics, clinical signs, radiologic and pathologic data, and operative interventions were examined. The occurrence of PHD was observed using data from the Utah Department of Health database 1997-2011. RESULTS: 404 patients with HD from 1970 to 2011 were treated. Twenty-seven (6.7%) had PHD. Mean birth weight in PHD was 2196grams and mean gestational age 34 (range 29-36)weeks. Seven patients had Down syndrome. Nonchromosomal anomalies occurred in 25%. Median time from birth to biopsy diagnosis was 42days (range 2-316days). The most common presenting signs were abdominal distension and bilious emesis. The HD incidence in Utah for all births was 1/4322 (0.023%) and for premature infants 1/3885 (0.027%). CONCLUSIONS: PHD are similar to term infants with HD. Diagnosis of HD is often delayed in premature newborns, and associated anomalies are more common.

The effect of surgical margins on outcomes for low grade MPNSTs and atypical neurofibroma.

BACKGROUND AND OBJECTIVES: While convention defines atypical neurofibroma as benign and low-grade malignant peripheral nerve sheath tumors (MPNSTs) as malignant, sparse outcomes data exist for these tumors. This study reviews clinical outcomes of surgically resected low-grade MPNST and atypical neurofibroma, focusing on the effect of surgical margins on outcome. METHODS: This study is a retrospective review of 23 patients who underwent surgical resection of a low-grade MPNST or atypical neurofibroma. Treatment characteristics of adjuvant therapy and surgical margin were noted. Endpoints of local recurrence, presence of metastatic disease, disease-specific survival, and overall survival were reviewed. RESULTS: Eighteen of 23 patients (78%) had microscopically positive margins on the resection. Disease-specific survival was 100% for both atypical neurofibroma patients and those with low-grade MPNST, regardless of surgical margin. Local recurrence in terms of recurrence of measureable disease occurred in 2/12 (16.7%) of LGMPNST patients and 1/11 (9.1%) of atypical NF patients, all of whom had microscopically positive surgical margins. CONCLUSIONS: In a study dedicated exclusively to "intermediate" nerve sheath tumors, no patients developed metastatic disease nor died of disease despite a high rate of microscopically positive surgical margins (78%). While positive margins did lead to increased rates of local recurrence, these data suggest that surgeons potentially can temper their zeal for negative surgical margins in the setting of low-grade MPNST and atypical neurofibroma, as surgical morbidity may be more important than a presumed survival benefit of wide resection.

Molecular inversion probe analysis detects novel copy number alterations in Ewing sarcoma.

Ewing sarcoma (ES) is the second most common bone tumor in children and young adults, with dismal outcomes for metastatic and relapsed disease. To better understand the molecular pathogenesis of ES and to identify new prognostic markers, we used molecular inversion probes (MIPs) to evaluate copy number alterations (CNAs) and loss of heterozygosity (LOH) in formalin-fixed paraffin-embedded (FFPE) samples, which included 40 ES primary tumors and 12 ES metastatic lesions. CNAs were correlated with clinical features and outcome, and validated by immunohistochemistry (IHC). We identified previously reported CNAs, in addition to SMARCB1 (INI1/SNF5) homozygous loss and copy neutral LOH. IHC confirmed SMARCB1 protein loss in 7-10% of clinically diagnosed ES tumors in three separate cohorts (University of Utah [N = 40], Children's Oncology Group [N = 31], and University of Michigan [N = 55]). A multifactor copy number (MCN)-index was highly predictive of overall survival (39% vs. 100%, P < 0.001). We also identified RELN gene deletions unique to 25% of ES metastatic samples. In summary, we identified both known and novel CNAs using MIP technology for the first time in FFPE samples from patients with ES. CNAs detected by microarray correlate with outcome and may be useful for risk stratification in future clinical trials.

Premature closure of the foramen ovale secondary to congenital aortic valvular stenosis in a stillborn.

Premature closure of the foramen ovale is a rare and deleterious condition that can occur as an isolated defect or in association with other congenital and cardiovascular anomalies. We report on the pathologic findings in a 22-week stillborn male fetus with premature closure of the foramen ovale, severe aortic valve stenosis, cardiomegaly, intact atrial and ventricular septa, hypoplasia of the ascending aorta, and hypoplastic aortic arch with a preductal coarctation ridge. To the best of our knowledge, this is only the second report on this rare constellation of complex congenital cardiac defects.

Unilateral sclerocornea and tracheal stenosis: unusual findings in a patient with Goldenhar anomaly.

The Goldenhar anomaly (GA) is a heterogeneous field defect of uncertain cause and wide variability of expression, characterized by facial phenotypes, usually asymmetric and unilateral, accompanied by various combinations and gradations of cardiac, skeletal, renal, and central nervous system defects. We report the pathologic findings in a 5-month-old boy with GA, tracheal stenosis, and left unilateral sclerocornea. To the best of our knowledge this is the first description of sclerocornea in a patient with GA.

Recurrence of achondrogenesis type 2 in sibs: Additional evidence for germline mosaicism.

Achondrogenesis Type II (ACG2) is a lethal skeletal disorder caused by a dominant mutation in the type II collagen gene (COL2A1). Familial cases have been reported, suggesting both germline and somatic mosaicism. We report on two pregnancies from the same couple with gross, radiologic, and microscopic findings of ACG2. Molecular analysis of the second infant demonstrated heterozygosity for a c.2303G > A transition (p.Gly768Asp) in exon 33 of the COL2A1 gene. Although this mutation could not be proven by molecular studies in the first infant, identical findings in two affected pregnancies support germline mosaicism as the cause of ACG2 in this family.

Lipoblastoma (LPB): a clinicopathologic and immunohistochemical analysis of 59 cases.

Lipoblastoma (LPB) is a benign neoplasm that occurs predominantly in early childhood. We investigated clinicopathologic features, associated conditions, immunohistochemistry, and outcome in 59 LPB identified from surgical pathology and consultation files. Pathology materials, cytogenetics reports, and medical records were reviewed. Immunohistochemistry for S100 protein, CD34, and Mib-1 was performed on formalin-fixed, paraffin-embedded tissue using standard techniques. Fifty-nine patients had 74 samples, including 14 patients with one or more with local recurrences among the 30 patients who had available follow-up information. There were 37 males and 22 females (ratio 1.7). Age at diagnosis ranged from 3 months to 16 years with 22% in the first year, 68% at 1 to 9 years, and 10% at 10 to 16 years. Sixty-four percent arose on the trunk, 27% on the extremities, and 8% in the head/neck. Forty-six percent had one or more recurrences. Tumor diameter ranged from 1.2 to 15.5 cm. The white to yellow cut surface showed variable lobulation and myxoid change. Histologically, nodules of adipose and myxoid tissue were demarcated by bands of fibrous tissue. The cells displayed a range of differentiation from multivacuolated lipoblasts to mature adipocytes. Mitoses were nonexistent to rare. Histologic variations included a subtle zonal architecture of fat maturation, abundant myxoid material, primitive mesenchymal cells, a focal plexiform vascular pattern, and multinucleated cells. All cases tested were immunoreactive for S100 and CD34; Mib-1 reactivity was absent to low. Cytogenetic aberrations included chromosome 8 abnormalities in 8 cases, nonspecific numerical abnormalities in 1 case, and a normal karyotype in 1 case. Ten patients had other medical conditions including macrocephaly, seizures, developmental delay, autism, congenital anomalies, Sturge-Weber syndrome, or a family history of multiple lipomas. In summary, this large series of LPB demonstrates its occurrence in older children and adolescents, documents a recurrence rate of 46% and confirms that the degree of adipocytic differentiation does not predict biologic behavior. An unexpected finding was the presence in 17% of patients of central nervous system disorders such as seizures, autism, and developmental delay, congenital anomalies, Sturge-Weber syndrome, or a family history of lipomas. These observations raise the question of whether predisposing genetic or other constitutional factors contribute to the development of LPB or whether LPB is indicative of a syndrome.