Multidisciplinary Multiagent Treatment of Complex Lymphatic Anomalies with Severe Bone Disease: A Single-Site Experience.

Background: Complex lymphatic anomalies (CLA) are a group of conditions that pose diagnostic and therapeutic challenges due to their rarity and overlapping clinical findings. This case series describes the complex pathology and novel combination therapies of three patients diagnosed with various types of CLA. Methods and Results: A retrospective review of medical records was performed for three patients treated for CLA between 2011 and 2019. Diagnostics, imaging, treatment, and follow-up were reviewed in the electronic medical record and combined with the literature review within the analysis. One patient had involvement of her skull base and ear canals, diagnosed after ear canal abnormalities were detected on computed tomography following meningitis. The second patient had involvement of her posterior ribs and T7-T12 vertebral bodies, with thoracic instability requiring a back brace. The third patient had involvement of his left lower extremity and hemipelvis, necessitating a left above the knee amputation. Case 1 progressed on sirolimus and pamidronate but responded to zoledronic acid (ZA). She developed flares of coagulopathy and cellulitis that required reinforcement with vincristine and steroid pulses. Similarly, case 2 progressed on sirolimus and ZA alone, but achieved stable disease with added vincristine. Upon further disease progression, stabilization was obtained by the reinforcement of ZA. Case 3 required a combination of surgery as well as medical management with sirolimus and pamidronate. All three patients now have stable disease. Conclusion: This case series depicts a multidisciplinary and multiagent approach to the management of CLA with severe bony involvement using sirolimus, bisphosphonates, vincristine, and steroids.

Conformal Radiation Therapy for Pediatric Patients with Low-Grade Glioma: Results from the Children's Oncology Group Phase 2 Study ACNS0221.

PURPOSE: To determine the rate of marginal relapse, progression-free survival (PFS), and overall survival (OS) in patients with pediatric low-grade glioma (PLGG) treated with conformal radiation therapy (CRT) with a clinical target volume (CTV) margin of 5 mm in the Children's Oncology Group trial ACNS0221. METHODS AND MATERIALS: Patients aged 3 to 21 years with unresectable progressive, recurrent, or residual PLGG were eligible for this study. Patients younger than 10 years were required to have received at least 1 chemotherapy course. Patients with neurofibromatosis type I were not eligible. All patients underwent magnetic resonance imaging-based planning and received 54 Gy CRT in 30 fractions with a 5-mm CTV margin. RESULTS: Of 85 eligible patients (median age, 13.6 years) treated between March 2006 and December 2010, 14 were younger than 10 years and 36 received prior chemotherapy. Sixty-six had pilocytic astrocytoma, 15 had other histologic subtypes, and 4 had unbiopsied chiasmatic lesions. Events included 23 relapses (19 central, 4 distant, and no marginal) and 7 deaths. At a median follow-up of 5.15 years, 5-year PFS was 71% ± 6% and OS was 93% ± 4%. Male sex (P = .068) and large tumor size (P = .050) trended toward significance for association with decreased PFS. Age, histology, tumor location, time between diagnosis and study entry, and MIB-1 status were not associated with PFS. OS was negatively associated with male sex (P = .064), non-pilocytic astrocytoma histology (P = .010), and large tumor size (P = .0089). CONCLUSIONS: For patients with PLGG, CRT with a CTV margin of 5 mm yields an acceptable PFS and does not lead to a high rate of marginal relapse.

Intracerebral schwannomas: a rare disease with varying natural history.

Although intracerebral schwannomas are typically regarded as benign intracranial tumors, malignancy and recurrence have been reported among patients harboring such neoplasms. The available literature consists of case reports and small series that present variable characteristics distinguishing these unusual lesions. Little advancement has been made to further the understanding and management of these tumors. The authors present 3 cases from their institution that highlight the difference between typical benign intracerebral schwannomas and histopathological variants that may portend more aggressive behavior. Also provided is a review of the literature in the hope of gaining a better understanding of these rare tumors.

DNA fragmentation simulation method (FSM) and fragment size matching improve aCGH performance of FFPE tissues.

Whole-genome copy number analysis platforms, such as array comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) arrays, are transformative research discovery tools. In cancer, the identification of genomic aberrations with these approaches has generated important diagnostic and prognostic markers, and critical therapeutic targets. While robust for basic research studies, reliable whole-genome copy number analysis has been unsuccessful in routine clinical practice due to a number of technical limitations. Most important, aCGH results have been suboptimal because of the poor integrity of DNA derived from formalin-fixed paraffin-embedded (FFPE) tissues. Using self-hybridizations of a single DNA sample we observed that aCGH performance is significantly improved by accurate DNA size determination and the matching of test and reference DNA samples so that both possess similar fragment sizes. Based on this observation, we developed a novel DNA fragmentation simulation method (FSM) that allows customized tailoring of the fragment sizes of test and reference samples, thereby lowering array failure rates. To validate our methods, we combined FSM with Universal Linkage System (ULS) labeling to study a cohort of 200 tumor samples using Agilent 1 M feature arrays. Results from FFPE samples were equivalent to results from fresh samples and those available through the glioblastoma Cancer Genome Atlas (TCGA). This study demonstrates that rigorous control of DNA fragment size improves aCGH performance. This methodological advance will permit the routine analysis of FFPE tumor samples for clinical trials and in daily clinical practice.

Proliferative and metabolic markers in incompletely excised pediatric pilocytic astrocytomas--an assessment of 3 new variables in predicting clinical outcome.

Although pilocytic astrocytoma (PA) is the most common brain tumor diagnosed in children, few prognostic variables have been delineated that stratify the risk of clinical progression in patients with this tumor. In this study, the MIB-1 labeling index was compared with 2 other immunohistochemical markers of cell proliferation, phospho-histone H3 (PHH3) and mini-chromosomal maintenance protein 2 (MCM2) in 80 incompletely resected PAs to see which was best able to identify patients at risk for tumor progression. 0(6)-Methylguanine-DNA methyltransferase (MGMT) protein expression, which has been predictive of progression-free survival (PFS) in high-grade gliomas in children, was also evaluated in these cases. The mean follow-up period was 7.81 ± 3.9 years, and 42.8% of tumors have shown progression at the time of censoring. A MIB-1 labeling index ≥2.0 was associated with shortened PFS as a grouped variable by log-ranked analysis (P = .03) and by Cox regression analysis as a continuous variable (P = .007). None of the other potential biomarkers was significantly predictive of PFS. Although the amount of MCM2 staining correlated with the MIB-1 labeling index (P < .001), MCM2 reactivity was not independently associated with outcome. We conclude that MIB-1 labeling remains the best predictor of PFS in pediatric PAs.

Wilms tumor in a child with L-2-hydroxyglutaric aciduria.

We report a male infant with L-2-hydroxyglutaric aciduria and Wilms tumor. L-2-hydroxyglutaric aciduria is a rare, autosomal-recessive, inborn error of metabolism characterized by a variable degree of progressive encephalopathy. Of the fewer than 100 cases reported in the literature, at least 9 patients have developed tumors of the central nervous system. To our knowledge, the present case is the 1st example of an extracranial tumor associated with L-2-hydroxyglutaric aciduria. This observation potentially widens the tumor spectrum in this metabolic disorder and may lead to further insight into the relationship between L-2-hydroxyglutaric acid and cellular transformation.

Primary renal lymphoma presenting with hypertension.

Primary renal lymphoma (PRL) is a rare lymphoma which usually presents with hematuria, flank pain, abdominal mass, and weight loss. PRL is more diagnosed in adults than children. We describe an asymptomatic child who presented with hypertension and was subsequently diagnosed with primary renal lymphoma. This case represents an atypical presentation for PRL.

Pediatric renal cell carcinomas with Xp11.2 rearrangements are immunoreactive for hMLH1 and hMSH2 proteins.

Alveolar soft part sarcoma and pediatric renal cell carcinoma share a similar chromosomal abnormality, t(X;17)(p11.2;q25). Recently, it has been suggested that the inactivation of DNA mismatch repair genes hMLH1 and hMSH2 may play an additional role in the pathogenesis of alveolar soft part sarcoma. Immunohistochemical expression of the proteins hMLH1 and hMSH2 is indicative of the activation status of the corresponding genes. We performed immunohistochemistry for hMLH1 and hMSH2 in 4 cases of pediatric renal cell carcinomas with Xp11.2 rearrangements. All cases showed nuclear immunoreactivity for both proteins, although the staining was patchy. Our study demonstrates that inactivation of the DNA mismatch repair genes hMLH1 and hMSH2 does not appear to play a role in the tumorigenesis of pediatric renal cell carcinomas with Xp11.2 rearrangements.

Renal metanephric adenoma with previously unreported cytogenetic abnormalities: case report and review of the literature.

We report a case of a renal metanephric adenoma in a 10-year-old boy, in which cytogenetic analysis showed a balanced translocation, t(9;15)(p24;q24) and a balanced paracentric inversion of chromosome 12, inv(12)(q13q15). Immunohistochemically, the tumor showed diffuse reactivity for cytokeratin AE1/AE3, CAM5.2, CD57, and WT1; patchy reactivity for CD56; and focal reactivity for cytokeratin 7, epithelial membrane antigen, and CD10. Tumor cells were entirely nonreactive for alpha-methyl acyl coenzyme A racemase. Published cytogenetic data for metanephric adenomas are limited, and this is the first report of these cytogenetic abnormalities. The involvement of the chromosome region 9p24 is particularly interesting because of the recent identification of a tumor suppressor gene, KANK (kidney ankyrin repeat-containing protein), at this locus.

Hepatic mesenchymal hamartoma with translocation involving chromosome band 19q13.4: a recurrent abnormality.

We report a case of mesenchymal hamartoma of the liver in an 8-month-old male child, in which the cytogenetic analysis revealed a balanced translocation, t(11;19)(q13;q13.4). This is the fifth description of a cytogenetic abnormality in mesenchymal hamartoma and is similar to the four cases reported previously in that one of the breakpoints involved chromosome band 19q13.4.

Study of the MIB-1 labeling index as a predictor of tumor progression in pilocytic astrocytomas in children and adolescents.

PURPOSE: The pilocytic astrocytoma (PA) is the most common childhood brain tumor. This report examines the MIB-1 labeling index (LI) as a predictor of progression-free survival (PFS) among childhood PAs. PATIENTS AND METHODS: Consecutive PAs were examined to determine whether the MIB-1 LI was associated with tumor progression. Other variables evaluated included tumor location, use of adjuvant therapy, extent of resection, and age at diagnosis. RESULTS: One hundred forty-one children were identified (mean +/- SD age, 7.6 +/- 4.7 years; range, 0.43 to 18.56 years); 118 children had adequate tissue for MIB-1 immunohistochemistry. The 5-year PFS was 61.25%. By log-rank analysis, an MIB-1 LI of more than 2.0 was associated with shortened PFS (P =.035). Patients with PAs who underwent complete surgical resection, had tumors located in the cerebellum, and were treated with surgery only also had more prolonged PFS (P =.001 for all). Tumors in the optic pathways were associated with a shorter PFS (P =.001). Restricting the evaluation of MIB-1 LI to only incompletely resected tumors revealed an insignificant trend of MIB-1 LI of more than 2.0 having a shortened PFS. Multivariate analysis demonstrated completely resected tumors and tumors located in the cerebellum as less likely to progress (P =.001 and.019, respectively). CONCLUSION: Children with PAs with an MIB-1 LI of more than 2.0 have a shortened PFS. PAs that are completely resected and are located in the cerebellum have a prolonged PFS. This initial study suggests that the MIB-1 LI identifies a more aggressive subset of PAs. Further work should focus on elucidating features of pilocytic astocytomas that will identify prospectively children at risk for progression.

Cystic fibrosis and Chiari type I malformation: autopsy study of two infants with a rare association.

Cystic fibrosis (CF), an epithelial cell transport disorder caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, is not generally associated with malformations of the central nervous system (CNS). This report describes two African-American children who died at less than 2 years of age with known Chiari I malformations and were found, unexpectedly at autopsy, to have the classic pancreatic and respiratory changes of CF. Both patients had suffered from failure to thrive that had been attributed to their CNS malformations. One child also had recurrent pneumonia and died with Pseudomonas sepsis. Mutational analysis for > 70 common CFTR mutations identified a single delta F508 mutation in one patient and a single 3120+1G to A mutation in the other. Their second CFTR mutations were not identified. The association of CF with Chiari I malformation is not likely to be purely coincidental, as the probability of such an occurrence in African-Americans is greater than one in 7,500,000 patients. It is possible that the CFTR gene may play a previously unrecognized role in CNS development. Alternatively, this CNS abnormality may be acquired due to the metabolic and electrolyte imbalances that characteristically occur in CF.

Prognostic factors in children and adolescents with low-grade oligodendrogliomas.

Few reports exist describing the progression-free and overall survival of children with low-grade (WHO grade II) oligodendrogliomas treated uniformly with aggressive surgery but without adjuvant chemotherapy or radiation therapy. Furthermore, significant prognostic features, including the MIB-1 labeling index (LI), have not been reported for children with oligodendrogliomas. The medical records of 20 consecutive patients with low-grade oligodendrogliomas were reviewed. All patients had been treated with aggressive surgical resection. Adjuvant chemotherapy and radiation therapy were reserved for radiographic or clinical progression. These patients have been followed for a median of 5.5 years (range 0.5-11.5 years) after diagnosis. To date, there have been no patient deaths. Six of the 20 patients experienced tumor progression at a median of 2.2 years (range 0.4-4.8 years) following the initial surgery. The MIB-1 LI was infrequently greater than 5. Of several prognostic factors for subsequent tumor progression that were examined, only tumors located within the parietal lobes were associated with a worse progression-free survival. Other risk factors, including presenting symptoms, age at diagnosis, MIB-1 LI and the extent of tumor resection, were not associated with an increased frequency of tumor progression.

Placental histopathology of congenital syphilis.

OBJECTIVE: To evaluate the contribution of placental histopathology to the diagnosis of congenital syphilis. METHODS: From January 1, 1986, through December 31, 1998, all pregnant women presenting to a large, urban Dallas County labor and delivery unit with untreated syphilis at delivery and who had placental evaluation performed were identified. Women were clinically staged, and the infants were evaluated for congenital syphilis using a standard protocol. Each placenta was evaluated by two independent pathologists. Histologic characteristics of the placenta related to congenital syphilis in live-born and stillborn infants were then analyzed. RESULTS: Sixty-seven women met the study criteria: 33 (49%) stillborn and 18 (27%) live-born infants with congenital syphilis, 15 (22%) uninfected live-born infants, and one uninfected stillborn fetus diagnosed by current criteria. There were no differences between the groups with regard to demographic characteristics, prenatal care, or stage of syphilis. Stillborn infants were more likely to deliver preterm (P <.001). Controlling for gestational age, histopathology revealed necrotizing funisitis, villous enlargement, and acute villitis associated with congenital syphilis. Erythroblastosis was more common in stillborn infants with congenital syphilis than all live-born infants (odds ratio 16, 95% confidence interval 1, 370). The addition of histologic evaluation to conventional diagnostic evaluations improved the detection rate for congenital syphilis from 67% to 89% in live-born infants, and 91% to 97% in stillborn infants. CONCLUSION: Our results show that histopathologic examination of the placenta is a valuable adjunct to the contemporary diagnostic criteria used to diagnose congenital syphilis.

Apoptosis and white matter injury in preterm infants.

White matter injury in premature infants with or without intraventricular hemorrhage (IVH) remains an important cause of neonatal mortality and neurologic morbidity. The contribution of apoptosis to the cellular death in white matter injury in the preterm infant is unclear. The objective of this study was to determine whether apoptosis contributes to the cellular death in premature infants with cranial ultrasound (US) evidence of IVH and asymmetric periventricular echogenicity (PVE). Brain tissue incorporating frontoparietal white matter was obtained from 21 infants: 6 infants with severe IVH and asymmetric PVE (grade 1V IVH) on US (group 1); 9 infants with minimal IVH or normal US who died within 21 days (group II); and 6 infants with minimal IVH or normal US who died later (group III). The presence of DNA fragmentation, typical of apoptosis, was determined using a terminal deoxytransferase-mediated dUTD nick-end labeling (TUNEL) assay. The TUNEL index for group I infants was significantly greater, i.e., 2.75 +/- 1.94% versus 0.84 +/- 0.70% for group II and 0.42 +/- 0.22 for group III infants (P = 0.004). Most cells showing reactivity had morphologic characteristics consistent with astrocytes and oligodendroglia. The number of white matter cells showing morphologic changes consistent with apoptosis, such as nuclear blebs and karyorrhexis, was also quantitated and was significantly more numerous in group I than in group II infants, i.e., 0.51 +/- 0.64% versus 0.02 +/- 0.05% (P = 0.0005), and group III infants, i.e., 0.10 +/- 0.18% (P = 0.03). These findings implicate apoptosis as a contributing mechanism for the cellular death in infants with IVH and asymmetric PVE. Strategies aimed at preventing the white matter injury will need to incorporate methods of inhibiting the ongoing process of apoptosis.