Lineage Assignment in Acute Leukemia: A Challenging Case in a Pediatric Patient.

We report a case of a 2-year-old girl who was diagnosed with natural killer cell acute lymphoblastic leukemia and treated with an acute lymphoblastic leukemia chemotherapy regimen. Two months posttherapy, the disease relapsed with a myeloid immunophenotype. Complete response was then achieved with acute myeloid leukemia therapy followed by unrelated donor umbilical cord allogenic stem cell transplant. Retrospectively, reanalysis of the diagnostic specimen showed minimal myeloperoxidase expression that was called negative by conventional single parameter linear gating but better appreciated on histogram overlays. This case illustrates that even low levels of myeloperoxidase expression should be considered significant in lineage assignment in acute leukemia.

Conservative management of urachal anomalies.

PURPOSE: The purpose of this study was to evaluate trends in management of urachal anomalies at our institution and the safety of nonoperative care. METHODS: Based on our experience managing urachal remnants from 2000 to 2010 (reported in 2012), we adopted a more conservative approach, including preoperative antibiotic use, refraining from using voiding cystourethrograms (VCUG), postponing surgery until at least six months of age, and considering nonoperative management. A retrospective analysis of urachal anomaly cases was conducted (2011-2016) to assess trends in practice. Charts indicating anomalies of the urachus were pulled and trends in management (nonoperative versus surgical treatment), VCUG and antibiotic use, and outcomes were reviewed. RESULTS: Data from 2000-2010 and 2013-2016 were compared. Our findings indicate care has shifted towards nonoperative management. A smaller proportion of patients from 2013-2016 was treated surgically compared to 2000-2010. Patients receiving nonoperative treatment exhibited lower rates of complication relative to surgically managed cases. VCUGs were eliminated as a diagnostic tool for evaluating urachal anomalies. Prophylactic preoperative antibiotic use was standardized. No patients with a known urachal remnant presented later with an abscess or sepsis. CONCLUSIONS: We find that a shift towards nonoperative treatment of urachal anomalies did not adversely affect overall outcomes. We recommend observing minimally symptomatic patients, especially those under six months old. STUDY TYPE: Performance improvement. LEVEL OF EVIDENCE: Level IV.

Flow Cytometric Characteristics of Extrathymic Thymocytes in Adenoid Tissue: A Case Report and Comparison to Normal Thymus and Thymoma.

BACKGROUND: Normal thymocyte precursors in secondary lymphoid organs have previously been described. It is important to recognize normal thymocyte precursors by flow cytometry to differentiate them from T-cell lymphoblastic leukemia. METHODS: A 3-year-old boy status 2 years postallogenic cardiac transplant underwent adenoidectomy to exclude post-transplant lymphoproliferative disorder. Microscopic, immunohistochemical, and flow cytometry analyses of the adenoid were performed. RESULTS: By flow cytometry, a population of CD45+(dim)/CD7+(bright)/CD3- cells were observed at 1.0% of lymphocytes. These cells expressed CD10, partial CD34 and exhibited acquisition of CD4 followed by CD8. Within the brighter CD45+ lymphocytes, a population of CD3-/CD4+/CD8+ thymocytes and a similarly sized population of CD4+/CD8+ cells exhibiting acquisition of low-density CD3 were identified. By immunostaining, clusters of TdT+/CD1a+/CD4+/CD8+ T-cells were identified in the interfollicular areas. Compared to normal thymus, thymocytes in the adenoid tissue lacked the classic CD4xCD8 winged differentiation profile but showed a normal early precursor pattern. CONCLUSIONS: Thymocytes in adenoid show a similar differentiation pattern to thymus and thymoma. However, the classic winged pattern of common thymocyte differentiation may not be readily apparent in thymocytes differentiating outside of the thymus. Recognition of the early thymocyte precursor antigen acquisition profile can be crucial to correct interpretation. © 2017 International Clinical Cytometry Society.

Flow cytometric characteristics of extrathymic thymocytes in adenoid tissue: A case report and comparison to normal thymus and thymoma.

BACKGROUND: Normal thymocyte precursors in secondary lymphoid organs have previously been described. It is important to recognize normal thymocyte precursors by flow cytometry to differentiate them from T-cell lymphoblastic leukemia. METHODS: A 3-year-old boy status 2 years post-allogenic cardiac transplant underwent adenoidectomy to exclude post-transplant lymphoproliferative disorder. Microscopic, immunohistochemical, and flow cytometry analyses of the adenoid were performed. RESULTS: By flow cytometry, a population of CD45+(dim)/CD7+(bright)/CD3- cells were observed at 1.0% of lymphocytes. These cells expressed CD10, partial CD34, and exhibited acquisition of CD4 followed by CD8. Within the brighter CD45+ lymphocytes, a population of CD3-/CD4+/CD8+ thymocytes and a similarly sized population of CD4+/CD8+ cells exhibiting acquisition of low-density CD3 were identified. By immunostaining, clusters of TdT+/CD1a+/CD4+/CD8+ T-cells were identified in the interfollicular areas. Compared to normal thymus, thymocytes in the adenoid tissue lacked the classic CD4xCD8 winged differentiation profile but showed a normal early precursor pattern. CONCLUSIONS: Thymocytes in adenoid show a similar differentiation pattern to thymus and thymoma. However, the classic winged pattern of common thymocyte differentiation may not be readily apparent in thymocytes differentiating outside of the thymus. Recognition of the early thymocyte precursor antigen acquisition profile can be crucial to correct interpretation. © 2017 International Clinical Cytometry Society.

Myhre syndrome: Clinical features and restrictive cardiopulmonary complications.

Myhre syndrome, a connective tissue disorder characterized by deafness, restricted joint movement, compact body habitus, and distinctive craniofacial and skeletal features, is caused by heterozygous mutations in SMAD4. Cardiac manifestations reported to date have included patent ductus arteriosus, septal defects, aortic coarctation and pericarditis. We present five previously unreported patients with Myhre syndrome. Despite varied clinical phenotypes all had significant cardiac and/or pulmonary pathology and abnormal wound healing. Included herein is the first report of cardiac transplantation in patients with Myhre syndrome. A progressive and markedly abnormal fibroproliferative response to surgical intervention is a newly delineated complication that occurred in all patients and contributes to our understanding of the natural history of this disorder. We recommend routine cardiopulmonary surveillance for patients with Myhre syndrome. Surgical intervention should be approached with extreme caution and with as little invasion as possible as the propensity to develop fibrosis/scar tissue is dramatic and can cause significant morbidity and mortality.

Trends in surgical management of urachal anomalies.

PURPOSE: We have noted an increasing frequency of diagnosed urachal anomalies. The purpose of this study is to evaluate this increase, as well as the outcomes of management at our institution over 10 years. METHODS: A retrospective analysis of urachal anomalies at our institution was performed. Inclusion criteria were Anomalies of Urachus (ICD 753.7) or Urinary Anomaly NOS (ICD 753.9) between January 2000 and December 2010. Exclusion criteria were having an asymptomatic urachal remnant incidentally excised. RESULTS: Eighty-five patients (49 male, 36 female) presented between 0 and 17 years of age (mean 1.5 years). Diagnoses increased from 0 in 2000 to 21 in 2010. Zero was surgically managed in 2000 while 21 were managed in 2010 (p=0.0145). Fifteen patients (17.6%) were observed with 13 (13/15, or 15.3%) resolving without complication while 2 were operated on. Average time to resolution (clinical or radiologic) was 4.9 months (Range: 0.4-12.6). A total of seventy-two patients (84.7%) underwent excision. Thirty-nine (54%) surgical cases were outpatient while 33 (46%) were admitted. Thirteen (18%) had post-operative complications. Ten (77%) of the complications were wound infections. Patients under 6 months of age accounted for 60% (6 of 10) of all wound infections and 52% (17 of 33) of hospitalizations. CONCLUSIONS: Our experience and review of the literature suggest a high complication rate with surgical management in young patients, mostly from infections and support non-operative management of all non-infected urachal remnants in children.

Retropharyngeal thymus and parathyroid gland: a case report.

Cervical ectopic thymus occurs when thymic tissue arrests during its embryologic descent through the neck to the upper mediastinum. Most often it presents as an asymptomatic neck mass. Rarely does it present with airway compromise, particularly in neonates. A neonate presented with a retropharyngeal mass causing dynamic upper airway obstruction, mimicking a venolymphatic malformation. Ultimately this proved to be aberrant ectopic thymus with an associated parathyroid gland. While there have been isolated reports of thymus or parathyroid in the retropharyngeal space, none of the prior reports found both within the same patient.

Molecular and clinical characterization of the myopathic form of mitochondrial DNA depletion syndrome caused by mutations in the thymidine kinase (TK2) gene.

Mitochondrial DNA (mtDNA) depletion syndromes (MDSs) are a clinically and molecularly heterogeneous group of mitochondrial cytopathies characterized by severe mtDNA copy number reduction in affected tissues. Clinically, MDSs are mainly categorized as myopathic, encephalomyopathic, hepatocerebral, or multi-systemic forms. To date, the myopathic form of MDS is mainly caused by mutations in the TK2 gene, which encodes thymidine kinase 2, the first and rate limiting step enzyme in the phosphorylation of pyrimidine nucleosides. We analyzed 9 unrelated families with 11 affected subjects exhibiting the myopathic form of MDS, by sequencing the TK2 gene. Twelve mutations including 4 novel mutations were detected in 9 families. Skeletal muscle specimens were available from 7 out of 11 subjects. Respiratory chain enzymatic activities in skeletal muscle were measured in 6 subjects, and enzymatic activities were reduced in 3 subjects. Quantitative analysis of mtDNA content in skeletal muscle was performed in 5 subjects, and marked mtDNA content reduction was observed in each. In addition, we outline the molecular and clinical characteristics of this syndrome in a total of 52 patients including those previously reported, and a total of 36 TK2 mutations are summarized. Clinically, hypotonia and proximal muscle weakness are the major phenotypes present in all subjects. In summary, our study expands the molecular and clinical spectrum associated with TK2 deficiency.

Hepatic fibrosis persists and progresses despite biochemical improvement in children treated with intravenous fish oil emulsion.

OBJECTIVES: Intestinal failure-associated liver disease (IFALD) is a multifactorial process, which can culminate in cirrhosis and need for transplantation. Fish oil-based lipid emulsions (FOE) reportedly reverse hyperbilirubinemia, but there are little data on their effect on the histopathology of IFALD. METHODS: We blindly examined sequential liver biopsy data on 6 children receiving FOE, with scoring of cholestasis, inflammation, fibrosis, and ductal proliferation based on standardized systems. This information was correlated with biochemical and clinical data to determine any possible relations between biologic and histologic improvement. RESULTS: The median gestational age was 35 weeks, median birth weight 2064 g, and common most reason for intestinal loss was gastroschisis (5/6 children). Median intestinal length was 26 cm beyond the ligament of Treitz and most children had roughly 2 of 3 of their colonic length. It was observed that although hyperbilirubinemia reversed and hepatic synthetic function was preserved across timepoints, fibrosis was persistent in 2 cases, progressive in 3 cases, and regressed in only 1. It remained severe (grade 2 or higher) in 5 of 6 children at last biopsy. Histologic findings of cholestasis improved in all patients and inflammation improved in 5 of 6 children. There were mixed effects on ductal proliferation and steatosis. CONCLUSIONS: In children treated with FOE, reversal of hyperbilirubinemia is not reflected by a similar histologic regression of fibrosis at the timepoints studied. Children with IFALD should have active ongoing treatment and be considered for early referral to an Intestinal Failure Program even with a normalized bilirubin.

Pathologic changes in biliary dyskinesia.

PURPOSE: For children with upper abdominal pain and evaluation for acalculous biliary disease, laparoscopic cholecystectomy is an accepted treatment with inconsistent outcomes. The purpose of this study was to identify predictors of outcomes. METHODS: One hundred sixty-seven children underwent laparoscopic cholecystectomy at a single children's hospital. Radiographic findings, histopathology, family history, and demographics (sex, age, height, weight, body mass index-for-age percentile) were evaluated as predictors of postoperative symptomatic resolution using a binomial probability model. The data for radiologic studies and pathologic specimens were obtained via re-review in a blinded fashion. RESULTS: Of 167 children, 43 (25.7%) had a preoperative diagnosis of biliary dyskinesia and 41 (95.3%) had documented follow-up. Mean follow-up was 8.4 months. Twenty-eight patients (68.3%) had symptom resolution. Ejection fraction less than or equal to 15%, pain upon cholecystokinin injection, and a family history of biliary disease were not predictors of symptomatic resolution. Nonoverweight patients (body mass index-for-age <85th percentile) were more likely to have symptom resolution than their overweight counterparts (odds ratio, 2.13). Most patients (68.3%) had a pathologic gallbladder on blinded review. However, this did not correlate with outcome. CONCLUSIONS: Most gallbladders removed for biliary dyskinesia are pathologic. Being overweight can be considered a relative contraindication to cholecystectomy for biliary dyskinesia.

Teaching pediatric laboratory medicine to pathology residents.

CONTEXT: Laboratory data are essential to the medical care of fetuses, infants, children, and adolescents. However, the performance and interpretation of laboratory tests on specimens from these patients, which may constitute a significant component of the workload in general hospitals and integrated health care systems as well as specialized perinatal or pediatric centers, present unique challenges to the clinical pathologist and the laboratory. Therefore, pathology residents should receive training in pediatric laboratory medicine. OBJECTIVE: Children's Health Improvement through Laboratory Diagnostics, a group of pathologists and laboratory scientists with interest and expertise in pediatric laboratory medicine, convened a task force to develop a list of curriculum topics, key resources, and training experiences in pediatric laboratory medicine for trainees in anatomic and clinical pathology or straight clinical pathology residency programs and in pediatric pathology fellowship programs. DATA SOURCES: Based on the experiences of 11 training programs, we have compiled a comprehensive list of pediatric topics in the areas of clinical chemistry, endocrinology, hematology, urinalysis, coagulation medicine, transfusion medicine, immunology, microbiology and virology, biochemical genetics, cytogenetics and molecular diagnostics, point of care testing, and laboratory management. This report also includes recommendations for training experiences and a list of key texts and other resources in pediatric laboratory medicine. CONCLUSIONS: Clinical pathologists should be trained to meet the laboratory medicine needs of pediatric patients and to assist the clinicians caring for these patients with the selection and interpretation of laboratory studies. This review helps program directors tailor their curricula to more effectively provide this training.