Amy Lowichik

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.

How the Pediatric Autopsy Yields Valuable Information in a Vertically Integrated Health Care System

CONTEXT Although autopsy rates have declined significantly in recent decades, studies continue to validate the autopsy as an important source of clinically relevant information, a teaching tool, and a quality assurance measure. A recent review of autopsy series showed a decline in the number of serious errors likely to have affected clinical outcome detected at autopsy during the past 46 years, with a current major error rate of 8.4% to 24.4%. OBJECTIVE Our hypothesis was that the pediatric autopsy would uncover a significant number of major unexpected findings at the high end of the spectrum predicted by a recent review. This study assesses the unexpected findings at a pediatric hospital whose autopsy service handles both in-house (tertiary care) and referral (mostly perinatal) cases for a vertically integrated health care system. DESIGN Data were analyzed from an autopsy effectiveness report completed for all autopsies performed in 2000. The data from this series include concordance of premortem and postmortem diagnoses, with the autopsy considered the criterion standard. The autopsy effectiveness report also provided logistic information, such as problems with consents, medical records, specimen identification, and prosection. SETTING Pediatric autopsies were performed by members of the Pediatric Pathology Division in a freestanding childrens hospital in the Intermountain West of the United States with a large rural catchment area. This hospital is part of a large health maintenance organization serving the surrounding urban and rural areas. PATIENTS A sample of all in-house and referral autopsies for the year 2000 was examined. MAIN OUTCOME MEASURE The percentage of cases with a major or minor diagnostic discrepancy or unexpected pathologic finding using the autopsy as the criterion standard. RESULTS The overall autopsy rate was 40% (39 hospital autopsies and 15 forensic autopsies per 135 total deaths) and was 32% excluding forensic cases. Twenty-two additional referral autopsies from outside institutions were performed. Of 61 autopsies, 12 (20%) revealed a major diagnostic discrepancy or unexpected pathologic finding, 17 (28%) had a minor unexpected finding or additional diagnosis, 41 (67%) clarified the differential diagnosis, 46 (75%) confirmed or verified a major diagnosis, and 21 (34%) provided information regarding treatment effects. Additionally, 3 (5%) had problems with identification, and 12 (20%) had problems with consent, all of which were resolved prior to initiation of the autopsy. CONCLUSIONS These data confirm the value of the pediatric autopsy in a childrens hospital and a vertically integrated health care system. It is an important medical and quality assurance procedure for assessing the accuracy of diagnoses, clarifying differential diagnoses, yielding unexpected findings, and providing feedback regarding therapeutic outcomes.

Treatment Effects in Pediatric Soft Tissue and Bone Tumors Practical Considerations for the Pathologist

Dramatic improvements in survival for children with cancer have led to increased numbers of posttreatment pathologic specimens, particularly in bone and soft tissue sarcomas. Current therapeutic protocols in North America require specific pathologic classification and stratify patients based on clinical, biologic, and pathologic features. For osteosarcoma, the pathologic response to therapy predicts prognosis and modifies the treatment regimen. Ongoing studies aim to assess the response to therapy and outcome in other types of soft tissue and bone tumors. The pathologic evaluation of pretreatment and posttreatment specimens is critical for therapeutic decisions and prognostic assessment. A standardized approach to posttherapy pathologic specimens, with attention to appropriate use of ancillary tests, and assessment of clinical and biologic significance of therapy-induced pathologic changes has significance for patient management and treatment protocols.

Evidence by Spectral Karyotyping that 8q11.2 Is Nonrandomly Involved in Lipoblastoma

We report two cases of lipoblastoma with chromosome 8-related aberrations, ie, a 92,XXYY,t(7;8Xp22;q11.2)x2 [8]/46,XY[16] in Case 1 and a 46,XY,-8,-13,add(16) (q22),+mar, +r [cp13]/46,XY[7] in Case 2. Using spectral karyotyping and fluorescence in situ hybridization techniques, the karyotype of Case 2 was redesignated as 46,XY, r(8), del(13)(q12), der(16)ins(16;8)(q22; q24q11.2)[cp13]/46,XY[7]. This report delineates a new chromosome rearrangement, ie, der(16)ins(16;8)(q22; q24q11.2) in lipoblastoma, and also confirms the t(7; 8)(p22;q11.2), reported only once previously, as a recurrent translocation involved in such a tumor. These findings provide valuable information for clinical molecular cytogenetic diagnosis of lipoblastoma. Furthermore, this report highlights the value of cytogenetic and molecular cytogenetic analysis in differential diagnosis of childhood adipose tissue tumors and adds to the number of lipoblastomas reported with chromosomal abnormalities at 8q11.2.

The Stillbirth Collaborative Research Network (SCRN) placental and umbilical cord examination protocol.

The Stillbirth Collaborative Research Network (SCRN) was organized to study the scope and causes of stillbirth (SB) in the United States. The objective of this report is to describe the approach used for the placental examination performed as part of the study. The SCRN consists of a multidisciplinary team of investigators from five clinical sites, the National Institute of Child Health and Human Development, and the Data Coordination and Analysis Center. The study is a population-based cohort and nested case-control study, with prospective enrollment of women with SB and live births (LB) at the time of delivery. Detailed and standardized postmortem examination was performed on SB and placental examination in both groups. A total of 663 women with SB and 1932 women with LB were enrolled into the case-control study. In the SB group, there were 707 fetuses. Of these cases, 654 (98.6%) had placental examination. Of these LB controls, 1804 (93.4%) had placental examination. This is the largest prospective study to include population-based SB and LB, using standardized postmortem and placental examination, medical record review, maternal interview, collection of samples, and a multidisciplinary team of investigators collaborating in the analyses. Thus it has the potential to provide high-level evidence regarding the contribution of placental abnormalities to stillbirth.

Therapy associated changes in childhood tumors.

Summary: Contemporary treatment regimens for the common solid tumors of childhood have led to increased numbers of post‐treatment pathologic specimens from survivors. Current therapeutic strategies for childhood cancers in North America require an accurate pathologic diagnosis and stratify patients based on combinations of clinical, biological, and pathologic features. In several tumor systems, the pathologic response to therapy also modifies the treatment regimen. Accurate pathologic interpretation of such specimens is critical in providing useful prognostic information for therapeutic decisions. Standardized handling of post‐therapy pathologic specimens, appropriate use of molecular and genetic studies, consideration of the differential diagnoses, and assessment of the potential biologic significance of therapy‐induced pathologic changes are, therefore, critical for patient management and determination of treatment protocols.

Frozen Section Diagnosis in Pediatric Surgical Pathology: A Decade's Experience in a Children's Hospital

CONTEXT Intraoperative consultations, including frozen sections (FSs), are essential for patient care and are a key quality component in anatomic pathology. Little data exists about the use, frequency, and type of discrepancies and deferral rates of FS diagnoses in pediatric and adolescent surgical pathology. OBJECTIVE The purpose of this study was to analyze indications, discrepancies, and deferrals for all FSs performed at a childrens hospital during a 10-year period. DESIGN All FSs for 1995-2004 were reviewed for indications, discrepancies, deferred diagnoses, and turnaround time. Discrepancies were categorized into major and minor subtypes according to potential impact on patient care. RESULTS A total of 35,611 surgical pathology cases were accessioned, with 2839 intraoperative consultations, which included 2783 FSs and 56 nonmicroscopic consultations. Most frequent indications included questions related to neoplasms (tumor detection, specimen adequacy, triage, classification, and margins) and suspected Hirschsprung disease. In these consultations, 115 discrepancies (4%) were identified, of which 7 (0.2%) were major, with potentially significant clinical impact, and 108 (3.9%) were minor. The major discrepancies included tumor, ganglion cell, or organism detection. The minor discrepancies involved sampling error, reclassification of benign or malignant neoplasms without clinical consequences, tumor typing or grading, and ganglion cell identification without clinical impact. Deferrals in 718 FSs (25% deferral rate) included tumor classification from generic to specific, identification of organisms, and evaluation of lymph node biopsies for lymphoma. Turnaround time exceeded 20 minutes in 403 cases (14%). CONCLUSIONS The FS rate of 7.8% overall and 5% of surgical pathology cases is similar in childrens and general hospitals. The major discrepancy (discordance) rate is lower, which may reflect the different indications for FS in children and adolescents. Evaluation of colonic biopsies for ganglion cells is a diagnostic pitfall. The deferral rate of 25% reflects the definition of a deferred diagnosis. Traditional definitions of deferred and discordant FS diagnoses should be refined to reflect the increasing use of adjunct techniques, especially in tumor classification. These findings emphasize that, in children and adolescents, most FSs are performed for tumor classification, triage, detection, and specimen adequacy, and for possible Hirschsprung disease. In children and adolescents, FSs are used infrequently to identify normal or unknown tissue, to analyze a lesion in a radiographically directed specimen, or to detect lymph node metastases. The differences in pediatric and adolescent FS indications and use underscore the importance of focused education in pediatric surgical pathology.

Gastrointestinal polyposis in childhood: clinicopathologic and genetic features.

Gastrointestinal polyps and certain extraintestinal lesions in children may herald a hereditary polyposis syndrome, with an increased risk of neoplasia and other health problems for both children and their relatives. The availability of molecular/genetic screening tests has increased early diagnosis of younger members of known polyposis families. This article reviews the gross and microscopic features of polyposis syndromes of childhood and summarizes the molecular/genetic advances in this field. Clinical management is also briefly discussed.

Fetus with interstitial del(5)(p13.1p14.2) diagnosed postnatally with Cornelia de Lange syndrome

Cornelia de Lange (CdLS), also known as Brachmann de Lange, is a complex disorder that includes characteristic facial features, hirsutism, limb abnormalities, diaphragmatic hernia, preand postnatal growth retardation, and mental retardation. It is estimated to occur in 1 in 10,000 live births [Opitz, 1985]. CdLS is usually diagnosed by postnatal clinical findings; however, prenatal diagnosis has been made by the presence of congenital diaphragmatic hernia, characteristic limb abnormalities, and facial profile, as detected by fetal ultrasound [Urban and Hartung, 2001; Marino et al., 2002]. The gene responsible for CdLS, NIPBL, was recently identified, due in part to the clinical report of this case [Hulinsky et al., 2003] as well as an infant with a balanced de novo translocation (5;13)(p13.1;q12.1) [Krantz et al., 2004]. The proposita was the second child born to a nonconsanguineous Caucasian couple. The mother was referred at 20-week gestation to evaluate abnormal sonographic findings. Targeted ultrasound revealed multiple anomalies including diaphragmatic hernia, single umbilical artery, nuchal thickening, and abnormal upper extremities. Maternal serum screening was normal. The patient had one previous normal pregnancy with delivery at term of a healthy female. The family history was noncontributory. Due to the multiple congenital abnormalities, karyotype analysis by amniocentesis was performed at 20-week gestation. The karyotype was 46,XY,del(5)(p13.1p14.2) at 425 band level, and was confirmed by postnatal chromosome analysis (Fig. 1). Fluorescence in situ hybridization (FISH) analyses usingwhole-chromosome5paint and the cri-du-chat syndrome probe at 5p15.2 demonstrated a simple, interstitial deletion centromeric to the cri-du-chat syndrome deletion breakpoint. Parental karyotypes were normal. The couple was counseled extensively regarding poor prognosis, specifically in the context of a chromosome deletion, oligohydramnios, and diaphragmatic hernia. Follow-up ultrasounds at 26-, 30-, and 34-week gestation showed progressive reduction of amniotic fluid (there was no evidence of premature rupture of membranes) and progressive IUGR. Fetal echocardiogram at 26-week gestation was apparently normal. Precipitous delivery at 36-week gestation resulted in an infant born at home. The parents reported no movement or respiratory effort after delivery. Autopsy demonstrated a male infant with manifestations of Cornelia de Lange and the karyotype was confirmed by tissue biopsy. The facial features were consistent with CdLS, including low hairline, characteristic ‘‘penciled in’’ eyebrows without synophrys, long philtrum, thin lips, upturned nasal tip, and posteriorly rotated and abnormal ears (Fig. 2). Limb abnormalities were also consistent with a diagnosis of CdLS, which included micromelia and oligodactyly of the upper limbs with single forearm bones and short feet. Other external abnormalities consistent with a diagnosis of CdLS included cleft of the soft palate, hirsutism, and hypospadias. Internal abnormalities consistent with a diagnosis of CdLS included left-sided diaphragmatic hernia, and ventricular septal defect. Internal findings of unclear significance included hypoplastic

Bannayan-Riley-Ruvalcaba Syndrome: Spectrum of Intestinal Pathology Including Juvenile Polyps

ABSTRACT Bannayan-Riley-Ruvalcaba syndrome (BRRS) is a disorder that includes juvenile polyposis as part of its pathologic spectrum, and it recently has been shown to share phenotypic and genotypic features with Cowdens disease. In existing literature, descriptions of intestinal pathology in patients with BRRS are relatively sparse and occasionally erroneous. We describe the intestinal pathology in multiple specimens from three children with BRRS. Examination of gastrointestinal biopsies from these children revealed predominantly colonic and rectal polyps with the histology of juvenile polyps. Additionally, two cases with clusters of ectopic ganglion cells within the lamina propria, one in a colonic polyp and one in a duodenal biopsy, and an atypical polyp were observed. Bannayan-Riley-Ruvalcaba syndrome should be included in the list of differential diagnostic considerations when a child or young adult presents with a juvenile polyp, particularly if unusual histologic features such as atypical polyps or ectopic ganglion cells are encountered.