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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.

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 β-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.

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.

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

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).Retrospective analysis of1500 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.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).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.

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

Background: The terminology applied to vascular anomalies has been variable in previously published literature making interpretation suboptimal. The International Society for the Study of Vascular Anomalies (ISSVA) has proposed a revised classification based on clinical features and histopathological findings. This classification is increasingly being accepted as clinically useful and a platform for future studies. Aims: To examine the extent to which the ISSVA classification can be practically applied to diagnostic histopathological specimens. Methods: Cutaneous vascular lesions received in a single paediatric pathology unit during a 2-year period (2004–5) were reviewed, including glucose transporter protein 1 (GLUT1) immunostaining where required, and lesions were reclassified according to the ISSVA classification. Results: 144 specimens were identified. Appropriate full clinical information was provided in only 17% of cases at submission. Infantile haemangiomas comprised 46% of cases, 18% of which were regressive type, initially inaccurately identified as vascular malformations before GLUT1 immunostaining. 30% of lymphatic malformations and all lymphovenous malformations were previously classified as vascular malformations, not otherwise specified. Conclusions: The ISSVA classification of vascular anomalies provides a useful framework for histopathologists to classify vascular anomalies. However, meaningful and appropriate use of such a system is dependent on the adequacy of clinical information provided and routine use of immunohistochemical markers.

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.

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.

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.

191 nfantile desmoid fibromatosis is the pediatric equivalent of adult musculoaponeurotic desmoid fibromatosis. Tumors are typically extraabdominal. Patients, who are predominantly male, present before the age of 8 years, usually in the first 2 years of life. Tumors are usually solitary, arising as a firm mass in skeletal muscle or adjacent fascia, aponeurosis, or periosteum. Lesions most frequently occur in the head and neck and usually involve the tongue, mandible, maxilla, or mastoids. The Imaging of Desmoid Fibromatosis in Pediatric Patients Catherine A. Kingston 1,2 , Catherine M. Owens 1 , Annmarie Jeanes 1 , Marian Malone 3

We report two infants with the acquired immunodeficiency syndrome (AIDS) and rectal bleeding due to cytomegalovirus (CMV) ileitis and colitis with minimal focal mucosal ulceration but with extensive leiomyolysis of the muscularis propria. Immunostaining and in situ hybridization for CMV showed numerous viral inclusions in the myocytes of the muscularis propria and vascular endothelium/smooth muscle with only occasional inclusions present in the muscularis mucosae. Colectomy was curative in one patient; in the other the bowel was only examined at postmortem.

We describe an intracardiac epithelial cyst in association with esophageal atresia. The case is unusual in that the cyst was symptomatic and ultimately fatal. In addition, there was no other cardiac anomaly, although a range of extrathoracic malformations was present. There are three types of intracardiac epithelial cysts: congenital polycystic tumor of the atrioventricular node, a cyst as part of a teratoma, and, as in this case, a gross cyst. All of them are very rare. The association of a cardiac cyst and esophageal atresia in our case supports the theory that intracardiac cysts are derived from misplaced foregut.

The histology of skin biopsies from 46 cases of different forms of congenital ichthyosis was reviewed. Sections were examined for hyperkeratosis, follicular keratosis, appearance of the granular layer, epidermal thickness, tonofilament clumps, epidermal vacuolation, spongiosis, bullae and dyskeratosis, appearance of the basal layer, inflammation, mitoses, and adnexae. A detailed description of the histological features of each type of ichtnyosis studied is presented. Some ichthyoses can be recognized on routine hematoxylin and eosin staining (bullous ichthyosiform erythroderma, Netherton's syndrome, and neutral lipid storage disease); some forms require frozen sections to demonstrate fat (neutral lipid storage disease) or enzyme activity (Sjögren-Larsson syndrome). Protein electrophoresis and enzymology are necessary for X-linked recessive ichthyosis. A close liaison with the clinicians is essential for the diagnosis of all types of ichthyosis, and combined studies including routine histopathology, electron microscopy, and frozen sections may be required for the diagnosis.

Acute leukaemia of infancy is associated with abnormalities at chromosome band 11q23, and has a poor prognosis. The gene involved. Mixed Lineage Leukaemia (MLL), has been identified and has the characteristics of a transcription factor. The BCL-2 gene responsible for blocking of programmed cell death is highly expressed in a number of haematological malignancies, both with and without the t(14;18) translocation. Those without the translocation include acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML) and chronic lymphocytic leukaemia (CLL). In these diseases the BCL-2 protein is implicated in drug resistance to apoptosis-inducing chemotherapeutic agents. High BCL-2 expression is also associated with autonomous growth of leukaemic blasts in culture and predicts a poor prognosis. The SEM cell line, established using blood lymphoblasts from a 5-year-old girl in first relapse with t(4;11) ALL, expresses lymphoid (CD19) and myeloid (CD13) cell surface markers. In cell culture, a subpopulation of cells (< 30%) express the BCL-2 protein. A reproducible model of true biphenotypic leukaemia in the SCID mouse has been established using the SEM-K2 cell line (a subclone of the SEM cell line). Between 5 and 50 million cells injected intravenously (i.v.) produce complete replacement of the murine bone marrow by day 30, associated with blood lymphoblastosis and infiltration of the spleen. No tumour masses were seen. Fluorescence in situ hybridization (FISH) analysis of the cell line and blood from the SCID-human (SCID-hu) chimaera has confirmed the presence of the t(4;11). Reverse transcriptional-polymerase chain reaction (RT-PCR) reveals that the breakpoint lies between exons 7 and 8 of the MLL-1 gene on chromosome 11 (the main breakpoint region). A further translocation, t(7;13), has been identified. Fluorescent antibody cell sorter (FACS) analysis of tumour material recovered from the SCID-hu model confirms expression of CD19 and CD13 identical to that of the cell line. In addition, BCL-2 expression in SCID-hu marrow is now seen in the majority of tumour cells. BCL-2 expression appears to confer a survival advantage to the blast cells in vivo. This reproducible model of biphenotypic leukaemia suggests that BCL-2 expression may play a role in leukaemogenesis. The model is suitable for the investigation of gene-targeted therapy, including antisense oligonucleotides, directed towards the MLL and BCL-2 genes.

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. 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. 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 (P0.001), 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. 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.

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.Retrospective analysis of1500 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).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 aged6 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).Co-sleeping is associated with unexplained SUDI/SIDS in infants aged6 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.

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.

Cytogenetic analyses on direct and short-term cultures from three peripheral primitive neuroectodermal tumors (PNET) showed only one tumor with the t(11;22)(q24;q12), a translocation reported as characteristic of this tumor type. A second tumor contained rearrangements including apparent deletions of chromosomes 11 and 22 between bands 11q21 and 11qter and between bands 22q11.2 and 22qter, respectively. A third tumor contained two normal copies of 11q but appeared to be monosomic for 22. We consider these findings in light of a survey of the PNET literature.

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 (

Cytogenetic reports of soft tissue sarcomas in children, other than rhabdomyosarcomas, are rare. We report the second cytogenetic analysis of a congenital fibrosarcoma. The tumor had a monoclonal karyotype of 49,XX,+7,+15,+del(17)(p12).

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.

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) results from defects of regulated insulin release from pancreatic (3 cells and is often refractory to medical treatment. Histological changes in the pancreas associated with PHHI may be focal or diffuse, and the intraoperative confirmation and siting of focal lesions would require frozen section diagnosis. The recognition of focal involvement and its distinction from diffuse disease by frozen section depends on the identification and distribution pattern of islet cells with large hyperchromatic nuclei. This study was designed to test the feasibility of using this parameter in PHHI to delineate focal from diffuse diseases prior to the introduction of frozen sections to guide intraoperative management in our institution. A total of 66 coded and randomized paraffin sections (from 18 PHHI and 4 postmortem pancreases) were scored by three independent observers into the following categories: a focal lesion (A), no large endocrine nuclei (B), few large endocrine nuclei (C), and frequent large endocrine nuclei (D). Interobserver concordance was complete in 88%, but there were minor discrepancies in the remaining 12%. When a focal lesion was present in one section no large endocrine nuclei were seen in sections from the rest of the pancreas. In four patients with diffuse PHHI, no or only very scanty large endocrine nuclei were seen. From this finding, and the observation that in other examples of diffuse disease, large endocrine nuclei were sparse even in large paraffin sections, we have reservations about using small frozen sections for reliable diagnosis.

Background: Langerhans' cell histiocytosis (LCH), a granulomatous disorder of unknown cause, most often affects the bony skeleton and skin. Obvious gut involvement is uncommon, and colon involvement has been cited in only a small number of case reports, probably because most patients who have LCH with diarrhoea and/or failure to thrive are not investigated by colonoscopy and biopsy. The current study was conducted to determine the incidence of symptomatic colon involvement among patients with multisystem LCH treated at a single institution. Method: A retrospective review of cases in hospital records and the literature. Results: Of the 275 children with LCH in the database, 5 were identified as having biopsy-confirmed colonic involvement. Another 14 cases were identified by a literature review. Conclusion: Colonic involvement in patients with multisystem LCH is probably more common than currently recognised. In addition to the other investigations recommended by the Writing Group of the Histiocyte Society, it is recommended that patients with any symptoms suggestive of gut involvement undergo colonoscopy and biopsy of the colonic mucosa.

We report a mother and daughter with features of Aagenaes syndrome. Unlike most previous cases, there is no Norwegian ancestry and the pedigree favours dominant rather than recessive inheritance.

Malignant tumors of the liver with rhabdoid features (MTR) are uncommon: Only 14 previous cases are reported in the literature. These tumors are characterised morphologically by sheets of large polygonal cells with abundant eosinophilic cytoplasm containing a periodic acid Schiff's-positive hyaline globular inclusion and vesicular nuclei with a central prominent nucleolus. Immunohistochemically, the inclusions at least show positivity for vimentin and epithelial markers and sometimes for other antigens. Ultrastructurally, the inclusions are composed of whorled intermediate filaments. Despite the superficial resemblance to cells of muscle origin implied in the term rhabdoid, there is no immunohistochemical or ultrastructural evidence to support such a derivation. We describe four additional children with tumors of this type, in three of whom tumor cells showed focal membrane positivity for MIC-2 on immunostaining. Its expression in an hepatic MTR may indicate neuroepithelial differentiation. Hepatic MTR should be considered in the differential diagnosis of an undifferentiated primary liver tumor in an infant in whom the alpha-fetoprotein concentration is normal or only slightly elevated for age.