CNS Langerhans cell histiocytosis: Common hematopoietic origin for LCH-associated neurodegeneration and mass lesions.

BACKGROUND: Central nervous system Langerhans cell histiocytosis (CNS-LCH) brain involvement may include mass lesions and/or a neurodegenerative disease (LCH-ND) of unknown etiology. The goal of this study was to define the mechanisms of pathogenesis that drive CNS-LCH. METHODS: Cerebrospinal fluid (CSF) biomarkers including CSF proteins and extracellular BRAFV600E DNA were analyzed in CSF from patients with CNS-LCH lesions compared with patients with brain tumors and other neurodegenerative conditions. Additionally, the presence of BRAFV600E was tested in peripheral mononuclear blood cells (PBMCs) as well as brain biopsies from LCH-ND patients, and the response to BRAF-V600E inhibitor was evaluated in 4 patients with progressive disease. RESULTS: Osteopontin was the only consistently elevated CSF protein in patients with CNS-LCH compared with patients with other brain pathologies. BRAFV600E DNA was detected in CSF of only 2/20 (10%) cases, both with LCH-ND and active lesions outside the CNS. However, BRAFV600E+ PBMCs were detected with significantly higher frequency at all stages of therapy in LCH patients who developed LCH-ND. Brain biopsies of patients with LCH-ND demonstrated diffuse perivascular infiltration by BRAFV600E+ cells with monocyte phenotype (CD14+ CD33+ CD163+ P2RY12- ) and associated osteopontin expression. Three of 4 patients with LCH-ND treated with BRAF-V600E inhibitor experienced significant clinical and radiologic improvement. CONCLUSION: In LCH-ND patients, BRAFV600E+ cells in PBMCs and infiltrating myeloid/monocytic cells in the brain is consistent with LCH-ND as an active demyelinating process arising from a mutated hematopoietic precursor from which LCH lesion CD207+ cells are also derived. Therapy directed against myeloid precursors with activated MAPK signaling may be effective for LCH-ND. Cancer 2018;124:2607-20. © 2018 American Cancer Society.

Potentially preventable infant and child deaths identified at autopsy; findings and implications.

PURPOSE: The purpose of the study was to determine the proportion of pediatric deaths investigated by HM Coronial autopsy which were potentially preventable deaths due to treatable natural disease, and what implications such findings may have for health policies to reduce their occurrence. METHODS: A retrospective study of 1779 autopsies of individuals between 7 days and 14 years of age requested by HM Coroner, taking place in one specialist pediatric autopsy center, was undertaken. Cases were included if they involved a definite natural disease process in which appropriate recognition and treatment was likely to have affected their outcome. Strict criteria were used and cases were excluded where the individual had any longstanding condition which might have predisposed them to, or altered the recognition of, acute illness, or its response to therapy. RESULTS: Almost 8% (134/1779) of the study group were potentially preventable deaths as a result of natural disease, the majority occurring in children younger than 2 years of age. Most individuals reported between 1 and 7 days of symptoms before their death, and the majority had sought medical advice during this period, including from general practitioners within working hours, and hospital emergency departments. Of those who had sought medical attention, around one-third had done so more than once (28%, 15/53). Sepsis and pneumonia accounted for the majority of deaths (46 and 34% respectively), with all infections (sepsis, pneumonia and meningitis) accounting for 110/134 (82%). CONCLUSION: Around 10% of pediatric deaths referred to HM Coroner are potentially preventable, being the result of treatable natural acute illnesses. In many cases medical advice had been sought during the final illness. The results highlight how a review of autopsy data can identify significant findings with the potential to reduce mortality, and the importance of centralized investigation and reporting of pediatric deaths.

Reference ranges for organ weights of infants at autopsy: results of >1,000 consecutive cases from a single centre.

BACKGROUND: Infancy is the most common period for childhood death, including both neonatal deaths from obstetric or medical complications and sudden unexpected infant deaths. The weighing of organs at autopsy is an established process and is recommended in current protocols. However, minimal contemporary data is available regarding reference ranges for organ weights of infants. METHODS: Organ weight data for consecutive infant autopsies over a 14 year period performed at a single tertiary centre, including >1,000 cases, were examined in order to provide up to date reference ranges across this age range, using linear regression modelling and the standard LMS method. RESULTS: 1,525 infant autopsies were analysed, of which 1,190 were subsequently used in the creation of linear regression models prior to performance of the LMS method. Organ weight charts were produced for the 5th, 25th, 50th, 75th and 95th centiles for the heart, lungs, liver, spleen, kidneys, pancreas, thymus gland and adrenal glands. CONCLUSION: This study provides the largest single centre contemporary dataset of infant autopsies allowing provision of up-to-date 'normal' ranges for all major organ weights across this age range.

Autopsy findings of co-sleeping-associated sudden unexpected deaths in infancy: relationship between pathological features and asphyxial mode of death.

AIM: Co-sleeping is associated with increased risk of sudden unexpected death in infancy (SUDI)/sudden infant death syndrome (SIDS). The aim of this study is to examine autopsy findings from a single U.K. specialist centre to determine the relationship between co-sleeping and cause of death. METHODS: Retrospective analysis of >1500 paediatric autopsies carried out by paediatric pathologists over a 10-year period. SUDI was defined as sudden unexpected death of an infant aged 7-365 days; deaths were categorised into explained SUDI (cause of death was determined) and unexplained SUDI (equivalent to SIDS). RESULTS: There were 546 SUDI; sleeping arrangements were specifically recorded in 314; of these, 174 (55%) were co-sleeping-associated deaths. Almost two thirds (59%) of unexplained SUDI were co-sleeping compared to 44% explained SUDI (95% confidence interval (CI) 1.0-27.2%, P=0.03); however, this difference remained statistically significant only for the first 5 months of life (95% CI 3.5-33.2%, P=0.01). In unexplained SUDI aged < 6 months, there were no significant differences between co-sleeping and non-co-sleeping deaths with respect to ante-mortem symptoms, intrathoracic petechiae, macroscopic lung appearances, pulmonary haemosiderin-laden macrophages, and isolation of specific bacterial pathogens; however, fresh intra-alveolar haemorrhage was reported more commonly in co-sleeping (54%) than in those that were not (38%; 95% CI 1.4-30.5%, P=0.03). CONCLUSIONS: Co-sleeping is associated with unexplained SUDI/SIDS in infants aged < 6 months, suggesting that co-sleeping is related to the pathogenesis of death in younger infants. The finding that intra-alveolar haemorrhage is more common in co-sleeping suggests that a minority of co-sleeping-associated deaths may be related to an asphyxial process.

Clinicopathological features of fatal cardiomyopathy in childhood: an autopsy series.

AIM: Cardiomyopathy, a group of primary myocardial disorders, is an uncommon, but important, cause of death in childhood. This study examines the demographic, clinical and pathological features of fatal cardiomyopathy in childhood with particular reference to its classification and autopsy findings. METHOD: The method of this study was a retrospective structured review of all paediatric autopsies performed at a single specialist centre from 1995 to 2009 inclusive, in order to determine the demographic, clinical and pathological features of fatal cardiomyopathy. RESULTS: From a total of 2229 autopsies performed at the centre during the study period on live-born infants and children, 34 confirmed cases of cardiomyopathy were identified (1.5%). More than half (59%) of these cases occurred in infants (less than 1 year of age). Heart weight of cardiomyopathy cases was significantly greater than those with normal hearts (P < 0.001), and 77% had heart weights above the 95th percentile of the normal expected range for age, including all of those over 1 year age. Of cardiomyopathy cases, 50% were primary dilated cardiomyopathy and 27% were primary hypertrophic cardiomyopathy. Twelve of 34 cases (35%) presented as sudden unexpected death, the diagnosis of cardiomyopathy being only made at autopsy. CONCLUSION: Cardiomyopathy is an uncommon cause of death in infancy and childhood. It can present as sudden unexpected death and encompasses a range of aetiologies. Heart weight above the 95th percentile at autopsy is present in most cases but heart weight may be within the normal range in infants.

Kikuchi-Fujimoto disease causing fever of unknown origin in a nine-year-old boy.

We describe a case of fever of unknown origin (FUO) in a 9-y-old boy finally diagnosed with Kikuchi-Fujimoto disease (KFD) and discuss the implications for the management of FUO in children. KFD should be considered in the differential diagnosis of patients presenting with FUO to prevent misdiagnosis and inappropriate treatment.

Disseminated langerhans cell histiocytosis-related sudden unexpected death in infancy.

Sudden unexpected death in infancy (SUDI) is defined as the sudden and unexpected death of an infant aged less than 1 year and comprises a heterogeneous group of deaths; in around one-third of cases a definite cause of death is identified at autopsy, while almost two-thirds of such deaths will remain unexplained despite a careful review of the circumstances of death and a detailed postmortem examination. We report a case of SUDI due to previously undiagnosed disseminated Langerhans cell histiocytosis (LCH) in a 10-month-old male, a disease characterized by a clonal proliferation of dendritic Langerhans cells. The diagnosis was established on histological examination, which revealed extensive infiltration by LCH of the skin, lymph nodes, thymus, spleen, and lungs. Despite a high mortality in disseminated disease, to our knowledge, this is the first reported case in the English-language literature of disseminated multisystem Langerhans cell disease presenting as SUDI. Furthermore, this case demonstrates the importance of routine microscopic tissue sampling in all SUDI, as the diagnosis required histological examination of the organs and might have been missed had histology not been performed.

Hepatic cirrhosis, dystonia, polycythaemia and hypermanganesaemia--a new metabolic disorder.

We report a new constellation of clinical features consisting of hypermanganesaemia, liver cirrhosis, an extrapyramidal motor disorder and polycythaemia in a 12 year-old girl born to consanguineous parents. Blood manganese levels were >3000 nmol/L (normal range <320 nmol/L) and MRI revealed signal abnormalities of the basal ganglia consistent with manganese deposition. An older brother with the same phenotype died at 18 years, suggesting a potentially lethal, autosomal recessive disease. This disorder is probably caused by a defect of manganese metabolism with the accumulation of manganese in the liver and the basal ganglia similar to the copper accumulation in Wilson disease. In order to assess the genetic basis of this syndrome we investigated two candidate genes: ATP2C2 and ATP2A3 encoding the manganese-transporting calcium-ATPases, SPCA2 and SERCA3, respectively. Genotyping of the patient and the family for microsatellite markers surrounding ATP2C2 and ATP2A3 excluded these genes. The patient was found to be heterozygous for both gene loci. Despite the unknown pathophysiology, we were able to develop a successful treatment regime. Chelation therapy with disodium calcium edetate combined with iron supplementation is the treatment of choice, lowering blood manganese levels significantly and improving clinical symptoms.

Immunohistochemical findings in embryonal small round cell tumors with molecular diagnostic confirmation.

The diagnosis of pediatric tumors relies heavily on immunohistochemical staining of small tissue biopsies, since many entities share a "small blue cell" phenotype. More recently, molecular genetic analysis for detection of specific gene fusion products has become available. With the increased use of such molecular techniques, the authors have noted that tumors with proven molecular diagnoses can exhibit unusual patterns of immunohistochemical staining. This study examines pediatric tumors with a "small blue cell" phenotype in which molecular diagnoses were available where applicable. A panel of immunohistochemical stains was performed (S100, CD56, NB84, CD99 [MIC2], Bcl-2, CD117, CD34, desmin, MNF116, and WT1). In the 370 sections from 37 cases, all primitive neuroectodermal tumors, with and without the presence of t(11;22), demonstrated uniform membranous membrane staining with CD99 (MIC2) and focal staining with CD56, NB84, MNF116, and WT1. All rhabdomyosarcomas, both alveolar and embryonal, demonstrated uniform desmin, CD56, and cytoplasmic WT1 immunostaining. Desmoplastic small round cell tumors showed positive cytokeratin staining, with half having "dot-like" cytoplasmic desmin and WT1 positivity; some showed focal positivity for NB84, CD99, and Bcl-2. The "undifferentiated" sarcomas showed the widest range of staining, with no marker staining all cases. Neuroblastomas exhibited uniform strong staining for CD56 and NB84 and marked cytoplasmic Bcl-2 positivity, and some cases showed cytoplasmic WT1 expression. Blastematous Wilms' tumors showed uniform strong membranous staining for CD56, uniform cytoplasmic staining for Bcl-2, and nuclear expression of WT1. Embryonal pediatric malignancies can demonstrate apparently nonspecific expression patterns for several antigens, which may reflect developmental immaturity rather than specific differentiation pathways.

Difficulties in interpretation of post-mortem microbiology results in unexpected infant death: evidence from a multidisciplinary survey.

BACKGROUND: Post-mortem (PM) microbiological investigations are recommended in cases of sudden unexpected death in infancy (SUDI), and infection is a recognised cause of such deaths, but no current evidence-based guidelines exist for the appropriate interpretation of results. AIM: To assess interpretive difficulties using a targeted cross-specialty questionnaire. METHODS: 109 consultant specialists involved in infant death management were given a questionnaire providing information on five hypothetical standardised SUDI cases, which differed only in their PM microbiology findings. Participants classified each case into categories: definite bacterial infection, probable bacterial infection, bacterial growth of uncertain significance and PM contamination. RESULTS: 63 (57%) specialists responded. There was no clinical scenario in which complete concordance in interpretation of PM microbiology results was established among participants. In cases with pure growth of Group 2 pathogens such as Group B ß-haemolytic Streptococcus, 96% of respondents agreed upon probable or definite bacterial infection. With mixed growth of Group 2 pathogens, 83% reported probable or definite bacterial infection. Growth of organisms such as Staphylococcus aureus caused the most difficulty, with almost equal numbers of participants interpreting the finding as significant or non-significant. There were no consistent differences in interpretation between different specialist groups. CONCLUSIONS: While there is general agreement in interpretation of PM microbiology findings in some SUDI scenarios, no consensus was achieved for any clinical setting, and variation in the presumed significance between specialists was apparent. In the absence of appropriate evidence-based guidelines, this has practical implications for the management of such deaths in a multidisciplinary setting.

Post-mortem interval and bacteriological culture yield in sudden unexpected death in infancy (SUDI).

It has been hypothesised that post-mortem translocation, the migration of micro-organisms from mucosal surfaces into the body after death, leads to microbial overgrowth in post-mortem samples, which is more frequently polymicrobial and which would be detected more frequently with increased post-mortem interval (PMI) from death to autopsy. This study aimed to evaluate the association between PMI and bacteriological yield in post-mortem examinations of sudden unexpected deaths in infancy (SUDI). A retrospective review of all microbiological findings from >500 SUDI autopsies (7-365 days of age) was performed as part of a larger review of >1500 paediatric autopsies over a 10-year period, 1996-2005. All autopsies were carried out in a single specialist centre by a small number of paediatric pathologists. For the 507 SUDI included in the analysis, there were 2079 samples collected for bacteriological culture. The median PMI was 2 days. The proportion of positive cultures decreased from 83% for samples taken within 24h of death, to 67% when taken five or more days after death (chi-square for linear trend=19.99, P<0.0001). Polymicrobial cultures decreased from 61% to 46% (chi-square for linear trend=12.88, P=0.0003), and cultures taken two or more days after death yielded significantly fewer isolates per sample than cultures taken less than 2 days after death (Mann-Whitney U-test, P=0.009). The findings of this study demonstrate that a PMI of several days' duration is neither associated with an increased frequency of positive cultures nor with an increased frequency of mixed-growth episodes as was hypothesised to occur with post-mortem translocation. Indeed, the opposite trend is observed, suggesting that a longer PMI may result in death of micro-organisms. However, these data do not allow assessment of the possibility of significant post-mortem translocation occurring within the first few hours after death. Whilst the interpretation of positive microbiological cultures in SUDI post-mortems remains difficult, a PMI of several days' duration is not associated with an increased risk of post-mortem translocation and routine microbiological sampling is recommended in all SUDI autopsies, even when there is a PMI of several days.

The frequency and significance of alveolar haemosiderin-laden macrophages in sudden infant death.

Alveolar haemosiderin-laden macrophages (HLMs) in histological sections of the lung represent evidence of previous pulmonary haemorrhage and in infants may be associated with features of non-accidental injury (NAI). The aim of this study is to establish the frequency of alveolar HLMs detected at post-mortem in a large series of sudden unexpected infant deaths, and to determine their clinical significance with particular regard to a possible association with NAI. A search was performed of a database of 1516 anonymised paediatric autopsies to identify all infants (<1 year of age) that died suddenly and unexpectedly in whom HLMs were demonstrated on routine histological examination of lung sections using special iron (Perls') stains. Clinical details and other post-mortem findings were then reviewed. During the study period (1996-2005 inclusive), there were 601 sudden unexpected infant deaths. Of the 536 autopsies in whom histological data regarding HLMs were recorded and slides were available for review, 29 (5%) demonstrated alveolar HLMs in lung sections. In 9 (31%) infants there were additional features of NAI; in 11 (38%) infants, there were features in the clinical history and/or on pathological examination of natural disease sufficient to potentially explain the presence of HLMs, and 9 (31%) represented otherwise unexplained infant deaths with no significant clinical history or other abnormalities. HLMs were present in 9 of the 27 (33%) total infant deaths with other features indicative of NAI, compared to only 9 of the 242 (4%) unexplained infant deaths without any other features of NAI or other contributory pathology (difference 29.6%, 95% CI 14.6-48.6%, p<0.0001; positive likelihood ratio 9.0, 95% CI 3.9-19.8). This association remained even if cases with rib fractures were excluded. Alveolar HLMs may be identified in a significant minority of sudden infant deaths following routine histological examination of the lungs with special stains for iron pigment. In most, there will be features in the clinical history or findings at post-mortem to indicate underlying natural disease which may account for their presence. However, in the absence of such features, alveolar HLMs, whilst not diagnostic, are associated with a significantly increased risk for the detection of other features of NAI; the presence of otherwise unexplained alveolar HLMs at autopsy should therefore prompt a careful exclusion of inflicted injury.

Rib fractures identified at post-mortem examination in sudden unexpected deaths in infancy (SUDI).

Rib fractures may be associated with non-accidental injury (NAI) in infancy, but the possible significance of fresh rib fractures in relation to resuscitation remains undetermined. Consequently, it is important to detect and confirm the presence of rib fractures when performing a post-mortem examination, particularly in the context of sudden unexpected death in infancy (SUDI). At our centre, it has been local policy to perform routine radiological skeletal surveys and detailed post-mortem examination of the ribs in all SUDI autopsies. The aim of this study is to establish the characteristics of all rib fractures identified at autopsy in the setting of SUDI from a large series of cases examined at a single specialist centre. As part of a larger review of paediatric post-mortem examinations performed at a single specialist institution over a 10-year period (1996-2005), all cases presenting as SUDI (aged 7-365 days) were identified and their anonymised records searched to identify all cases in which rib fractures were recorded. Over the 10-year period, 546 post-mortem examinations were performed for the indication of SUDI, including 94 forensic autopsies. Rib fractures were identified in 24 cases (4%). 15 infants (3% of SUDI) demonstrated healing rib fractures, of which 10 infants (67%) showed additional features suggestive of NAI. The other 9 infants (2% of SUDI) demonstrated fresh rib fractures only with no surrounding tissue reaction histologically; in 7 (78%) of these there were no other injuries and the fresh fractures were interpreted to have been caused by resuscitation-related trauma. All of the resuscitation-related fractures were situated in the anterolateral chest, in contrast to NAI-associated fractures, which were located in the anterolateral and/or posterior chest. Anterior costochondral junction fractures were also seen in a minority of NAI-associated cases, but such fractures were not seen in apparent resuscitation-related cases. Compared to healing rib fractures, which were detected on skeletal survey in 93%, fresh rib fractures were only detected in 22% of skeletal surveys. Rib fractures are uncommon in infancy and may indicate NAI, particularly when healed or healing, posterior or involving the costochondral junction. Fresh rib fractures may be missed on skeletal survey, but can be reliably detected at post-mortem examination following stripping of the pleura and detailed examination of each rib. Fresh anterolateral fractures, which may be multiple, contiguous and even bilateral, are highly likely to be related to resuscitation if there are no other associated injuries.

Sudden unexpected neonatal death in the first week of life: autopsy findings from a specialist centre.

OBJECTIVE: Sudden unexpected early neonatal death (SUEND) in the first week of life shares features with sudden unexpected death in infancy (SUDI) but is not included as SUDI, which is limited to post-perinatal deaths. The aim of this study was to review SUEND autopsies performed in a single specialist centre over a 10-year period, (1996-2005). METHODS: Retrospective analysis of >1500 consecutively performed paediatric autopsies performed by paediatric pathologists at one centre conducted according to a standard protocol including ancillary investigations. SUENDs were identified and autopsy findings reviewed. RESULTS: Of 1516 post-mortem examinations, 180 were first-week neonatal deaths, 55 (31%) presenting as SUEND. Thirty-two (58%) were explained following autopsy, whilst the remainder were unexplained; most deaths during sleep were associated with adult co-sleeping. Around 40% of explained deaths were associated with undiagnosed congenital abnormalities, mainly congenital heart disease. In addition, there were nine infection-related deaths and three deaths from unsuspected metabolic disease (fatty acid oxidation defects). CONCLUSION: There are distinct differences between SUEND and SUDI, with significantly more explained deaths in the former and a much greater proportion due to congenital abnormalities and metabolic disease.

Immunohistochemical nuclear positivity for WT1 in childhood acute myeloid leukemia.

Several studies have reported previously that acute myeloid leukemia (AML) may express WT1 detected by RT-PCR and/or Northern blotting. The diagnostic utility of WT1 expression in AML using immunohistochemistry has not been reported previously. Paraffin-embedded tissue sections from 55 AML, 12 acute lymphoblastic leukemia (ALL), and 10 normal bone marrow specimens were immunostained for WT1 (anti-N terminus antibody). 22/55 AML cases (40%) demonstrated nuclear immunopositivity for WT1, including 20/47 bone marrow trephines and 2/4 granulocytic sarcomas. All the ALL and normal bone marrow specimens were negative. A significant proportion of AML expresses nuclear immunostaining for WT1, a finding that has only been described previously in Wilms' tumor and desmoplastic small round cell tumor. This finding is important for the correct interpretation of immunohistochemical findings in the diagnosis of "small round cell" tumors of childhood, especially in cases of extramedullary deposits of AML, in which traditional myeloid markers may be negative.

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.