Micro-CT yields high image quality in human fetal post-mortem imaging despite maceration.

BACKGROUND: Current clinical post-mortem imaging techniques do not provide sufficiently high-resolution imaging for smaller fetuses after pregnancy loss. Post-mortem micro-CT is a non-invasive technique that can deliver high diagnostic accuracy for these smaller fetuses. The purpose of the study is to identify the main predictors of image quality for human fetal post-mortem micro-CT imaging. METHODS: Human fetuses were imaged using micro-CT following potassium tri-iodide tissue preparation, and axial head and chest views were assessed for image quality on a Likert scale by two blinded radiologists. Simple and multivariable linear regression models were performed with demographic details, iodination, tissue maceration score and imaging parameters as predictor variables. RESULTS: 258 fetuses were assessed, with median weight 41.7 g (2.6-350 g) and mean gestational age 16 weeks (11-24 weeks). A high image quality score (> 6.5) was achieved in 95% of micro-CT studies, higher for the head (median = 9) than chest (median = 8.5) imaging. The strongest negative predictors of image quality were increasing maceration and body weight (p < 0.001), with number of projections being the best positive imaging predictor. CONCLUSIONS: High micro-CT image quality score is achievable following early pregnancy loss despite fetal maceration, particularly in smaller fetuses where conventional autopsy may be particularly challenging. These findings will help establish clinical micro-CT imaging services, addressing the need for less invasive fetal autopsy methods.

Maceration determines diagnostic yield of fetal and neonatal whole body post-mortem ultrasound.

OBJECTIVES: To determine factors in nondiagnostic fetal and neonatal post-mortem ultrasound (PMUS) examinations. METHODS: All fetal and neonatal PMUS examinations were included over a 5-year study period (2014-2019). Nondiagnostic image quality by body parts (brain, spine, thorax, cardiac, and abdomen) was recorded and correlated with patient variables. Descriptive statistics and logistic regression analyses were performed to identify significant factors for nondiagnostic studies. RESULTS: Two hundred sixty-five PMUS examinations were included, with median gestational age of 22 weeks (12-42 wk), post-mortem weight of 363 g (16-4033 g), and post-mortem interval of 8 days (0-39 d). Diagnostic imaging quality was achieved for 178/265 (67.2%) studies. It was high for abdominal (263/265, 99.2%), thoracic (264/265, 99.6%), and spine (265/265, 100%) but lower for brain (210/265, 79.2%) and cardiac imaging (213/265, 80.4%). Maceration was the best overall predictor for nondiagnostic imaging quality (P < .0001). Post-mortem fetal weight was positively associated with cardiac (P = .0133) and negatively associated with brain imaging quality (P = .0002). Post-mortem interval was not a significant predictor. CONCLUSIONS: Fetal maceration was the best predictor for nondiagnostic PMUS, particularly for brain and heart. Fetuses with marked maceration and suspected cardiac or brain anomalies should be prioritised for post-mortem MRI.

Ultrastructural features of neuroblastic tumours in relation to morphological, and molecular findings; a retrospective review study.

BACKGROUND: Neuroblastoma is the most common solid tumour of infancy and is responsible for 15% of childhood cancer deaths. Presence of amplified MYCN in neuroblastoma is associated with poor prognosis and rapid tumour progression. The aim of this study was to examine and compare the ultrastructural features of high-risk MYCN amplified neuroblastomas, with lower-risk non-MYCN amplified tumours. METHODS: This was a retrospective study evaluating archival diagnostic tissue samples, in which Fluorescence in-situ hybridisation (FISH) had been used at diagnosis to establish MYCN status. 22 (11 MYCN amplified tumours and 11 non-MYCN amplified) tumours of similar light microscopic appearance (poorly differentiated neuroblastoma) were then selected for ultrastructural examination. RESULTS: There is a relationship between ultrastructural features in neuroblastoma and MYCN status, although with marked overlap between groups. MYCN amplified tumours generally exhibited a 'less differentiated' ultrastructural phenotype, with significantly smaller neurotubules (NT) in the cell body (p < 0.002). Non-MYCN amplified tumours show increased features of neuronal differentiation, with fewer neurosecretory granules (NSG) and NT in the cytoplasm. CONCLUSIONS: MYCN amplification is associated with a less differentiated ultrastructural phenotype, and lack of MYCN amplification with relative ultrastructural neuronal differentiation.

Consensus Definition of Fetal Growth Restriction in Intrauterine Fetal Death: A Delphi Procedure.

CONTEXT.­: Fetal growth restriction is a risk factor for intrauterine fetal death. Currently, definitions of fetal growth restriction in stillborns are heterogeneous. OBJECTIVES.­: To develop a consensus definition for fetal growth restriction retrospectively diagnosed at fetal autopsy in intrauterine fetal death. DESIGN.­: A modified online Delphi survey in an international panel of experts in perinatal pathology, with feedback at group level and exclusion of nonresponders. The survey scoped all possible variables with an open question. Variables suggested by 2 or more experts were scored on a 5-point Likert scale. In subsequent rounds, inclusion of variables and thresholds were determined with a 70% level of agreement. In the final rounds, participants selected the consensus algorithm. RESULTS.­: Fifty-two experts participated in the first round; 88% (46 of 52) completed all rounds. The consensus definition included antenatal clinical diagnosis of fetal growth restriction OR a birth weight lower than third percentile OR at least 5 of 10 contributory variables (risk factors in the clinical antenatal history: birth weight lower than 10th percentile, body weight at time of autopsy lower than 10th percentile, brain weight lower than 10th percentile, foot length lower than 10th percentile, liver weight lower than 10th percentile, placental weight lower than 10th percentile, brain weight to liver weight ratio higher than 4, placental weight to birth weight ratio higher than 90th percentile, histologic or gross features of placental insufficiency/malperfusion). There was no consensus on some aspects, including how to correct for interval between fetal death and delivery. CONCLUSIONS.­: A consensus-based definition of fetal growth restriction in fetal death was determined with utility to improve management and outcomes of subsequent pregnancies.

Indoleamine 2,3-dioxygenase expression in gestational trophoblastic disease: implications for development of immunotherapeutic approaches.

OBJECTIVE: To examine the immunoexpression of indoleamine 2,3-dioxygenase (IDO) in gestational trophoblastic neoplasia (GTN), including hydatidiform moles and gestational trophoblastic tumors. STUDY DESIGN: GTN cases were identified from a referral center for trophoblastic disease, and sections were immunostained with anti-IDO antibody and classified as positive or negative for trophoblast staining relative to normal chorionic villi. RESULTS: Fifty-two cases were included: 10 nonmolar hydropic miscarriages (HA), 11 partial moles (PHM), 9 complete moles (CHM), 15 choriocarcinoma cases (CC) and 7 placental site trophoblastic tumors (PSTT). All HA, PHM and CHM demonstrated IDO staining; 2 of 15 CC were strongly positive, 6 demonstrated focal positivity (< 10% of tumor cells), and the remainder were negative. Of the 7 PSTT, only 2 showed focal weak positivity; the others were negative. CONCLUSION: Hydatidiform moles express IDO, but the majority of gestational trophoblastic tumors, despite arising from villous or nonvillous trophoblast, do not express this enzyme, suggesting that IDO-mediated immunoregulation is unlikely to be a major component of the malignant phenotype in these tumors. Immunotherapeutic approaches involving IDO might represent ancillary approaches in a minority of patients with GTN.

Implications of placental pathology for disease mechanisms; methods, issues and future approaches.

Pathological examination of the placenta is a well-established investigation following delivery in order to investigate the underlying mechanisms of a range of pregnancy related complications. Several recommendations and guidelines are available regarding the indications for such placental testing. The immediate clinical rationale for this process is to identify underlying disease processes which may have an impact on the management of either the infant or the mother in future pregnancies. Additional benefits include improved understanding of the pathophysiological processes of disease and potential medicolegal implications in cases with adverse outcome, including regarding possible timing of lesions. However, interpretation of findings in specific cases remains difficult for several methodological reasons. Future progress requires the use of high quality, well phenotyped tissue collections, with blinded assessment using consensus criteria. In addition, it is likely that novel discovery-based approaches will significantly change the concept of how placental disease is investigated, making tissue sampling even more important across a wide range of pregnancy-related diseases. This will be associated with more stringent conditions for placental evaluation and sampling, including strict definitions of sample site and interval post-delivery, the effects of which will vary depending on the precise assays and methodologies used.

De Novo PTEN Mutation in a Young Boy with Cutaneous Vasculitis.

Phosphatase and tensin homolog (PTEN) is the protein encoded by the PTEN gene (10q23.3). PTEN mutations are related to a variety of rare diseases referred to collectively as PTEN hamartoma tumor syndromes (PHTS), which include Cowden Syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus Syndrome, and Proteus-like syndrome. These diseases are associated with an increased risk of malignancy and for this reason an accurate and early diagnosis is essential in order to institute cancer surveillance. PTEN is a regulator of growth and homeostasis in immune system cells, although there are limited data describing immune dysregulation caused by PTEN mutations. We describe a case of PHTS syndrome caused by a de novo mutation in PTEN detected using a targeted next generation sequencing (NGS) gene panel which was instigated for workup of cutaneous vasculitis. We highlight the diagnostic utility of this approach and that mutations in PTEN may be associated with immune-dysregulatory features such as vasculitis in young children.

Juvenile papillomatosis of the breast in a male infant with Noonan syndrome, café au lait spots, and family history of breast carcinoma.

Juvenile papillomatosis (JP) of the breast is a rare condition, usually affecting women under 30 years of age. Although this is considered a benign lesion, follow-up is recommended for the patient and family since there is an association with a family history of breast carcinoma and increased risk of development of breast carcinoma. We report an infant with JP, Noonan syndrome (NS), café au lait spots, and family history of breast carcinoma. Seven previously reported cases of JP in males exist, two occurring in infants. The association between JP and NS has not been previously reported.

Intravascular inflammatory myofibroblastic tumors in infancy.

Inflammatory myofibroblastic tumor (IMT), previously described as inflammatory pseudotumor, can occur at any age but is a recognized soft tissue tumor of childhood. Less than 10 previous cases have been described of IMT affecting the heart, in patients ranging from 5 months to 17 years of age. We present three unusual, but similar, cases of IMT in infants, which were all predominantly intravascular in location, one of which was associated with death due to angiodestructive lesions of the coronary and cerebral arteries. These cases demonstrate an apparently distinct phenotype, with a predominant intravascular location of the tumor. Furthermore, this series highlights the difficulty in categorizing such lesions as benign versus malignant on histological grounds alone. IMT should be considered in the differential diagnosis of unusual pediatric intravascular spindle cell lesions.

Sclerosing rhabdomyosarcoma in childhood: case report and review of the literature.

Rhabdomyosarcoma is the most common soft tissue malignancy in children but is rare in adults. The latest World Health Organization classification of soft tissue tumors recognizes embryonal, alveolar, and pleomorphic rhabdomyosarcomas. More recently, a sclerosing variant of rhabdomyosarcoma has been recognized and reported in seven adult patients. We describe a pediatric case of sclerosing rhabdomyosarcoma presenting as a sacral mass in a 3-year-old girl. Morphologically, the tumor showed a prominent sclerosing hyaline matrix and demonstrated pseudovascular and microalveolar architectural foci. Focal positivity was seen with desmin, smooth muscle actin, and myogenin. MyoD1 showed uniform diffuse nuclear staining. Fusion transcripts were not demonstrated by reverse transcriptase-polymerase chain reaction analysis. The histology, immunohistochemistry, and molecular genetics matched those reported in the seven adult cases of sclerosing rhabdomyosarcoma. This is the first case report, to our knowledge, of this rare tumor arising in the pediatric age group, and we compare the features with those reported in adult sclerosing rhabdomyosarcoma.

Aberrant immunohistochemical expression in nonrhabdomyosarcoma soft tissue sarcomas of infancy: retrospective review of clinical material.

Malignant soft tissue tumors other than rhabdomyosarcoma (RMS) are uncommon in infancy, representing approximately 5% of pediatric sarcomas. The pathological categorization of non-RMS soft tissue malignancies from these young patients is complicated by variation in both morphologic and immunohistochemical features. A search covering an 11-year period identified 19 patients presenting at birth or in infancy with a clinical or referral diagnosis of soft tissue sarcoma. After histologic and immunohistochemical review, nine of these tumors were classified as primitive neuroectodermal tumor (PNET), three as infantile hemangiopericytoma (HPC), two as infantile fibrosarcoma (FS), and five as undifferentiated sarcoma. Those identified as undifferentiated sarcomas showed an atypical spindle and ovoid cell morphology, with cellular pleomorphism and high mitotic rate, but lacking the fascicular growth pattern of classic infantile fibrosarcoma. Immunohistochemical staining in this group showed variable weak positivity for a range of markers (desmin, smooth muscle actin, Myo-D1, PGP, NSE, S100, CO56, cytokeratin, and CD99), and did not fit readily into any distinct diagnostic category. In this series, tumors classified as soft tissue PNETs had a poor prognosis despite aggressive treatment. However, once RMS, PNET, and other rare specific lesions are excluded, the remaining undifferentiated sarcomas, despite their unusual morphology and immunohistochemistry, appear to behave in a similar favorable manner to infantile fibrosarcoma.