Pediatr Dev Pathol [journal]
- Terminal Deoxynucleotidyl Transferase (TdT)-negative Lymphoblastic Leukemia in Pediatric Patients: Incidence and Clinical Significance. [JOURNAL ARTICLE]
- Pediatr Dev Pathol 2016 Aug 12.
Pediatric TdT-negative precursor B- or T-lymphoblastic leukemia/lymphoma (ALL) cases are rare and their prognostic significance remains controversial. We aimed to determine the frequency of TdT-negative ALL in the community hospital setting. Between 2005 and 2015, 43 pediatric patients were diagnosed with ALL at our Institution, of which six (14%) were characterized as TdT-negative by flow cytometric analysis. Four of these six patients had B-ALL and the other two had T-ALL. Two of the six TdT-negative patients also had undetectable CD34 expression by flow cytometry (TdT/CD34 double-negatives). Subsequent paraffin immunohistochemistry confirmed the negative CD34 expression in both cases. By contrast, all the six patients had TdT-like immunoreactivity in their marrow despite the negative flow cytometric analysis. Furthermore, neither TdT/CD34-negative cases showed myc rearrangement by FISH, ruling our Burkitt leukemia as a differential diagnostic consideration. We conclude that TdT-negative pediatric ALL cases (especially those that are TdT/CD34 double-negative) may pose diagnostic challenge to hematopathologists, and ancillary studies (paraffin immunohistochemistry to detect TdT and FISH to exclude myc rearrangement) may be instrumental in reaching the correct diagnosis.
- Decidual Vasculopathy: Placental Location and Association with Ischemic Lesions. [JOURNAL ARTICLE]
- Pediatr Dev Pathol 2016 Aug 11.
Decidual vasculopathy (DV) is a general term for a number of lesions involving uteroplacental vessels. It is often seen in preeclamptic placentas and indicates a disorder of uteroplacental malperfusion and is associated with placental ischemia and infarction. Although some have advocated submitting special sections in order to better document DV, it is unclear which placental sections have the highest yield in demonstrating these abnormal vessels. 76 consecutive cases of decidual vasculopathy were identified and evaluated for location of DV, as well as presence of other lesions of ischemic change, infarcts and retroplacental hematomas. Sections reviewed were the membrane roll, full thickness sections of the placental disc, and sections specifically of the basal plate. DV was found in the membrane roll (MR) in 67.1% of cases, in full thickness sections (FT) in 32.9% and in the basal plate (BP) in 25.0% of cases (p value = 0.004). DV was exclusive to the MR in 53.9%, the FT in 14.5% and the BP in 9.2%. DV was present in 2 locations in 19.7% and in all 3 locations in 2.6%. The presence of DV in any location (MR, FT, BP) was associated with placental ischemic change but not specifically with infarcts or retroplacental hematomas. The specific location of DV showed no difference in the presence of placental lesions. Our findings indicate DV is often present in one location, and is associated with lesions of malperfusion. It is recommended that when clinically indicated, additional sections are submitted to demonstrate decidual vasculopathy.
- Post Mortem Diagnostic Exome Sequencing Identifies a de novo TUBB3 Alteration in a Newborn with Prenatally Diagnosed Hydrocephalus and Suspected Walker-Warburg Syndrome. [JOURNAL ARTICLE]
- Pediatr Dev Pathol 2016 Aug 4.
Herein we report a case of a deceased newborn with prenatally detected hydrocephalus. Postnatal findings included abnormal brain imaging and electroencephalogram (EEG), optic nerve abnormalities, and elevated creatine kinase (CK). No underlying genetic etiology had been previously identified for the proband, despite testing with a congenital muscular dystrophy gene panel.Diagnostic exome sequencing (DES) was performed on the proband-parents trio, and candidate alterations were confirmed using automated fluorescence dideoxy sequencing.Exome sequencing of the proband, mother and father identified a previously unreported apparently de novo heterozygous tubulin, beta-3 (TUBB3) c.523G>C (p.V175L) alteration in the proband.Overall, DES established a likely molecular genetic diagnosis for a post-mortem case after traditional testing methods were uninformative. The DES results allowed for reproductive options, such as preimplantation genetic diagnosis (PGD) and/or prenatal diagnosis, to be available to the parents in future pregnancies.
- CONGENITAL CYSTIC LUNG LESIONS: EVOLUTION FROM IN-UTERO TO PATHOLOGY DIAGNOSIS - A MULTIDISCIPLINARY APPROACH. [JOURNAL ARTICLE]
- Pediatr Dev Pathol 2016 Aug 4.
Congenital cystic lung lesions (CCLL) are a group of rare pathologies that are usually diagnosed in the pre-natal period. The majority of these lesions are diagnosed at pathology examination as congenital pulmonary airway malformations (CPAM) and bronchopulmonary sequestration (BPS). These lesions are typically managed by surgical intervention within the first year of life and have an excellent prognosis. We examined the evolution of imaging appearances from prenatal diagnosis to postnatal work-up of these lesions and correlate imaging and pathological findings. An 8-year retrospective review of the perinatal and pathology database of a single tertiary care center identified 42 cases of CCLL of which 36 had known prenatal ultrasound and prenatal course available. Final pathologic diagnoses were: 15 CPAM (41%), 7 BPS (19%) and 9 hybrid BPS and CPAM lesions (25%). Five cases with bronchial atresia were also identified (either in isolation or associated with CPAM or BPS). The overall characteristics of these lesions by prenatal ultrasound, postnatal imaging, and ultimate histopathologic diagnosis are described.
- Ewing Sarcoma and Atypical Teratoid Rhabdoid Tumor: A FISH and Immunohistochemical Comparison. [JOURNAL ARTICLE]
- Pediatr Dev Pathol 2016 Jul 28.
Ewing sarcoma (ES)/primitive neuroectodermal tumor (PNET) and atypical teratoid rhabdoid tumor (ATRT) are high-grade malignancies of childhood, each of which is associated with genetic abnormalities on chromosome 22. ES is typically characterized by rearrangement of the EWSR1 locus and ATRT by deletion of SMARCB1. We report a case with an unusual FISH signal pattern consistent with EWSR1 rearrangement that was shown to have loss of INI1 expression by immunohistochemistry due to deletion in the long arm of one chromosome 22. In light of the unusual findings in this case as well as the proximity of the EWSR1 locus and SMARCB1 locus on chromosome 22 and frequent CD99 staining in both tumors, we examined 16 ES cases and 17 ATRT, renal rhabdoid tumor (RRT), and extrarenal rhabdoid tumor (ERRT) cases for CD99 and INI1 staining and for EWSR1 rearrangement. Staining with INI1 was negative in ATRT, RRT, and ERRT and positive in ES cases; CD99 was positive in ES cases and variable in ATRT cases. All but 2 cases of ES, and no cases of ATRT, showed rearrangement of EWSR1. The present case appears to be best classified as a unique variant of ATRT based on immunohistochemistry, EWSR1 FISH and RT-PCR, and SMARCB1 gene sequencing.
- A Rare Case of Pediatric Chronic Myelogenous Leukemia Presenting with Severe Thrombocytosis without Leukocytosis. [JOURNAL ARTICLE]
- Pediatr Dev Pathol 2016 Jul 25.
Pediatric chronic myelogenous leukemia (CML) is uncommon. We report a pediatric patient with CML presenting with a normal white blood cell count and no circulating immature myeloid cells. The patient presented with extreme thrombocytosis (platelet count range: 2,175-3,064 x 109/L) noted incidentally. No splenomegaly was found. Examination of the bone marrow aspirate (BMA) revealed normal cellularity and normal myeloid: erythroid ratio with marked megakaryocytic hyperplasia. Molecular studies on the BMA detected both the major BCR/ABL1p210 fusion transcript (9,280 copies; p210/ABL1 ratio: 38.2%) and the minor p190 transcript (below limit of quantitation). The platelet count normalized within 2 weeks after treatment with the second-generation tyrosine kinase inhibitor dasatinib. Follow-up 3 months later revealed a 1.87 log reduction in p210 transcripts compared to diagnosis and no detectable p190 transcripts. This case highlights the need to include BCR/ABL1 fusion testing to accurately diagnose pediatric patients presenting with isolated thrombocytosis.
- Advancing clinicopathologic diagnosis of high-risk neuroblastoma using computerized image analysis and proteomic profiling. [JOURNAL ARTICLE]
- Pediatr Dev Pathol 2016 Jul 21.
A subset of patients with neuroblastoma are at extremely high risk for treatment failure, though they are not identifiable at diagnosis and therefore have the highest mortality with conventional treatment approaches. Despite tremendous understanding of clinical and biological features that correlate with prognosis, neuroblastoma at ultra-high risk for treatment failure remains a diagnostic challenge. As a first step towards improving prognostic risk stratification within the high-risk group of patients, we determined the feasibility of using computerized image analysis and proteomic profiling on single slides from diagnostic tissue specimens. After expert pathologist review of tumor sections to ensure quality and representative material input, we evaluated multiple regions of single slides as well as multiple sections from different patients' tumors using computational histologic analysis and semi-quantitative proteomic profiling. We found that both approaches determined that intertumor heterogeneity was greater than intratumor heterogeneity. Unbiased clustering of samples was greatest within a tumor, suggesting a single section can be representative of the tumor as a whole. There is expected heterogeneity between tumor samples from different individuals with a high degree of similarity among specimens derived from the same patient. Both techniques are novel to supplement pathologist review of neuroblastoma for refined risk stratification, particularly since we demonstrate these results using only a single slide derived from what is usually a scarce tissue resource. Due to limitations of traditional approaches for upfront stratification, integration of new modalities with data derived from one section of tumor hold promise as tools to improve outcomes.
- Placental Pathologic Associations with Morbidly Adherent Placenta: Potential insights into Pathogenesis. [JOURNAL ARTICLE]
- Pediatr Dev Pathol 2016 Jul 21.
The pathology that underlies morbidly adherent placenta (MAP) is poorly understood. The objective of this study was to describe the placental pathology, especially implantation site pathology, associated with MAP.This was a single institution, retrospective case-control study design examining placentas of patients who delivered between January 2008 and September 2013. MAP cases were defined by the need for clinical intervention at delivery beyond spontaneous placental delivery or simple manual extraction of the placenta. Controls consisted of patients with placentas sent for examination due to a history of maternal malignancy with no clinical suspicion of accreta. Placental pathologic findings of maternal vascular underperfusion (MVU), acute inflammation, chronic inflammation, fetal vascular obstruction and hemorrhage were recorded and compared using bivariable and multivariable analyses.Three categories of pathologic changes were seen more commonly in MAP placentas (N=101) than control placentas (N=110): chronic basal inflammation, villous changes of MVU and retromembranous and retromembranous/intervillous hemorrhage. In multivariable analyses adjusted for confounders, chronic basal villitis (aOR 5.6, 1.73-18.18), plasma cell deciduitis (aOR 2.63, 1.08-6.39), increased syncytial knots (aOR 3.92, 1.57-9.75), villous agglutination (aOR 24.85, 2.78-221.75), increased perivillous fibrin (aOR 5.08, 1.49-17.34), and the presence of subchorionic/intervillous thrombi (aOR 4.01, 1.63-9.86) remained associated with MAP.MAP is highly associated with evidence of intraparenchymal placental hemorrhage villous changes of MVU, and a lymphoplasmacytic infiltrate at the implantation site. The contribution of this basal chronic inflammatory infiltrate to MAP requires further investigation.
- Primary Epithelioid Sarcoma of the Zygomatic Bone. [JOURNAL ARTICLE]
- Pediatr Dev Pathol 2016 Jul 21.
Primary epithelioid sarcoma of bone is extremely rare with only two reported cases in the English literature. A previously healthy 18-year-old male presented with a six-month history of right facial numbness and tingling and right eye diplopia. CT scan revealed an ill-defined mass with dense osseous matrix centered in the right zygomatic bone. An outside biopsy was read as osteosarcoma. The resection specimen revealed large epithelioid and spindle cells embedded in a prominent hyalinized matrix with focal metaplastic bone formation. The tumor cells were strongly and diffusely positive for AE1/AE3 and epithelial membrane antigen, but a definitive diagnosis of epithelioid sarcoma was not immediately reached due to the presence of dense hyalinized matrix and weak expression of SAT2B by tumor cells. Deficient INI1 protein expression by immunohistochemistry and homozygous loss of the SMARCB1 gene by chromosomal microarray analysis ultimately justified this tumor's designation as epithelioid sarcoma.
- Pediatric intraocular immature teratoma associated with sacrococcygeal teratoma: case report and review of the literature. [JOURNAL ARTICLE]
- Pediatr Dev Pathol 2016 Jul 6.
Intraocular teratomas are rare neoplasms with only three previously reported cases. We present the fourth case of intraocular teratoma and the second associated with sacrococcygeal teratoma. While the nature of the association between intraocular teratomas and sacrococcygeal teratomas is unclear it suggests a need for careful ophthalmologic follow-up of infants with congenital sacrococcygeal teratomas.