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ABSTRACT: Introduction Efficient intestinal peristalsis is a function of intact enteric nervous system, muscle, and connective muscularis propria tissue. Malfunction of any component results in impaired peristalsis. Hirschsprung disease (HD) as prototypic enteric neural migration disorder is increasingly well characterized. More recently, intestinal myopathies and particularly defects of myenteric collagenization have entered the focus of attention. However, detailed development of muscularis propria connective tissue is not well known. The aim of this study was to morphologically characterize intestinal connective tissue in fetal and postnatal development and intestinal pseudo-obstruction.Materials and Methods In this study, 130 archival specimens of fetal autopsies, intestinal resections, and biopsies were analyzed. Patients' age was 10th gestational week (gw) to 70 years. Muscularis mucosae, muscle layers, collagen tissue, and enteric plexus were analyzed. Picrosirius red stains, enzyme histochemistry, and immunohistochemistry for collagens I, III, and IV were performed.Results Total 89 normal intestinal specimens were from fetal autopsies or intestinal resections; 41 patients showed a primary structural colon wall defect (HD, desmosis). Our results showed a constant increase in tunica muscularis propria thickness with age. Separation into circular and longitudinal muscle layer first occurred in the 11th gw. A tendinous collagen plexus layer first arose in the 10th gw and showed a steady caliber increase. Muscularis mucosae first appeared in the 10th gw and grew independent of any primary gastrointestinal disease. In the 11th gw, enteric ganglia were fully developed. In desmosis, a collagen plexus layer was absent. In contrast, in HD, muscularis mucosae showed hypertrophy, but the collagen plexus layer was intact in the aganglionic segment. In intestinal neuronal dysplasia and hypoganglionosis, nerve cell development was disturbed; connective tissue and muscle layers were well developed.Conclusion Our comprehensive study of intestinal connective tissue development in comparison to neural intestinal wall components in normal and pathological conditions showed that tendinous tissue develops parallel to muscularis propria and arises early in embryogenesis. In enteric nervous system disorders, ganglionic lesions develop independently of impaired collagen network, whereas mucosal biopsies serve for diagnosis of HD, seromuscular biopsies are required to prove desmosis in gastrointestinal dysmotility disorders.
European Journal of Pediatric Surgery 08/2012; · 0.81 Impact Factor
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ABSTRACT: Vascular anomalies in children and adolescents are the most common soft tissue lesions and include reactive, malformative, and neoplastic tumefactions, with a full spectrum of benign, intermediate, and malignant neoplasms. These lesions are diagnostically challenging because of morphologic complexity and recent changes in classification systems, some of which are based on clinical features and others on pathologic findings. In recent decades, there have been significant advances in clinical diagnosis, development of new therapies, and a better understanding of the genetic aspects of vascular biology and syndromes that include unusual vascular proliferations. Most vascular lesions in children and adolescents are benign, although the intermediate locally aggressive and intermediate rarely metastasizing neoplasms are important to distinguish from benign and malignant mimics. Morphologic recognition of a vasoproliferative lesion is straightforward in most instances, and conventional morphology remains the cornerstone for a specific diagnosis. However, pathologic examination is enhanced by adjunctive techniques, especially immunohistochemistry to characterize the type of vessels involved. Multifocality may cause some uncertainty regarding the assignment of "benign" or "malignant." However, increased interest in vascular anomalies, clinical expertise, and imaging technology have contributed greatly to our understanding of these disorders to the extent that in most vascular malformations and in many tumors, a diagnosis is made clinically and biopsy is not required for diagnosis. The importance of close collaboration between the clinical team and the pathologist cannot be overemphasized. For some lesions, a diagnosis is not possible from evaluation of histopathology alone, and in a subset of these, a specific diagnosis may not be possible even after all assembled data have been reviewed. In such instances, a consensus diagnosis in conjunction with clinical colleagues guides therapy. The purpose of this review is to delineate the clinicopathologic features of vascular lesions in children and adolescents with an emphasis on their unique aspects, use of diagnostic adjuncts, and differential diagnosis.
Pediatric and Developmental Pathology 01/2012; 15(1 Suppl):26-61. · 0.99 Impact Factor
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ABSTRACT: Records of 24 pregnancies with fetal polydactyly were reviewed for the type of polydactyly, family history, associated sonographic findings, genetic testing, and postnatal/postmortem examination findings. The importance of fetal polydactyly can be mainly elucidated by the family history and absent or associated anomalies on a specialized malformation scan. Fetal karyotyping diagnoses frequent chromosomal anomalies in about half of cases with additional malformations, and array comparative genomic hybridization may be a future means of detecting cryptic chromosomal aberrations. Syndromic disorders of monogenic origin demand a careful interdisciplinary clinical assessment for establishing a clinical diagnosis and prognosis for the outcome of the child.
Journal of ultrasound in medicine: official journal of the American Institute of Ultrasound in Medicine 07/2011; 30(7):1021-9. · 1.25 Impact Factor
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ABSTRACT: An 8-year-old boy was admitted for excision of a putative 'blue nevus' on the left foot. Histological examination and immunohistochemistry revealed a Bednar tumour, the pigmented variant of dermatofibrosarcoma protuberans. Surgical options considered by a multidisciplinary team included wide local excision, Mohs micrographic surgery or a staged excision with examination of several histological sections. The third alternative procedure was chosen after consideration of tumour and patient factors to achieve the best possible clinical, cosmetic and functional outcome. After the final surgical procedure with resection of the third metatarsal bone, all peripheral margins were free of tumour, and the interdigital space was reconstructed with a pedicled pulpa flap. Three years after surgery, there was no tumour recurrence, and further long-term follow-up for this patient will be provided.
Journal of Plastic Reconstructive & Aesthetic Surgery 06/2011; 64(12):1697-701. · 1.49 Impact Factor
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ABSTRACT: INTRODUCTION: Odontogenic myxomas are benign but locally invasive tumours originating from primordial mesenchymal tooth forming tissues which do not metastasise. We present a series of two paediatric and two adult cases and focus on differences in diagnostic and therapeutic approaches between children and adults based on our own experience and a critical review of the literature.
Journal of cranio-maxillo-facial surgery: official publication of the European Association for Cranio-Maxillo-Facial Surgery 05/2011; 40(3):271-6. · 1.25 Impact Factor
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Charles H Knowles,
Roberto De Giorgio,
Raj P Kapur, Elisabeth Bruder,
Gianrico Farrugia,
Karel Geboes,
Greger Lindberg,
Joanne E Martin,
William A Meier-Ruge,
Peter J Milla,
Virpi V Smith,
Jean Marie Vandervinden,
Béla Veress,
Thilo Wedel
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ABSTRACT: Guidelines on histopathological techniques and reporting for adult and paediatric gastrointestinal neuromuscular pathology have been produced recently by an international working group (IWG). These addressed the important but relatively neglected areas of histopathological practice of the general pathologist, including suction rectal biopsy and full-thickness intestinal tissue. Recommendations were presented for the indications, safe acquisition of tissue, histological techniques, reporting and referral of such histological material.
Consensual processes undertaken by the IWG and following established guideline decision group methodologies.
This report presents a contemporary and structured classification of gastrointestinal neuromuscular pathology based on defined histopathological criteria derived from the existing guidelines. In recognition of its origins and first presentation in London at the World Congress of Gastroenterology 2009, this has been named 'The London Classification'. The implementation of this classification should allow some diagnostic standardisation, but should necessarily be viewed as a starting point for future modification as new data become available.
Gut 07/2010; 59(7):882-7. · 10.11 Impact Factor
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ABSTRACT: We report a rare case of a woman with bilateral papillary cystadenomata of the broad ligament with von Hippel-Lindau disease (VHL) (other manifestations: capillary hemangioblastomas of the spinal cord). Patient surveillance is important, because in the course of VHL-associated tumors malignant lesions may arise that are relevant for the prognosis.
Archives of Gynecology 02/2010; 282(3):343-6. · 0.91 Impact Factor
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ABSTRACT: Gastrointestinal motility disorders and chronic constipation are common pediatric problems. Symptoms of abdominal discomfort are frequently encountered in the daily practice of pediatricians and pediatric surgeons. Normal peristalsis depends on the interaction between muscles, nerve cells, and tendinous connective tissue of muscularis propria. Malfunction of any of these components results in a motility disorder. Aganglionosis, typically of the left distal colon, is the cause of Hirschsprung disease. Hypoganglionosis constitutes another gastrointestinal motility disorder. In hypoplastic hypoganglionosis, the number of nerve cells and the size of ganglia of the enteric nervous system are reduced, resulting in symptoms similar to aganglionosis. In intestinal neuronal dysplasia type B, submucous plexus development is disturbed. Immaturity of the enteric nervous system, but also ganglioneuromatosis, can be the underlying cause of chronic constipation. Chronic constipation may be caused by a myopathy. Aplasia or atrophy of the tendinous connective tissue of muscularis propria may cause desmosis, which may result in an aperistaltic syndrome. In severe chronic constipation, a histopathological diagnosis of the underlying cause is useful. In the diagnostic approach for most of these causes of chronic constipation, enzyme histochemistry is an efficient tool to complement conventional immunohistochemical and selected molecular technologies. An interdisciplinary approach of a gastrointestinal working group is beneficial in the management of these difficult patients.
Seminars in Pediatric Surgery 11/2009; 18(4):206-11. · 2.93 Impact Factor
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ABSTRACT: Hypoxia and other adverse conditions are commonly encountered by rapidly growing cells. The RNA-binding protein RBM3 (RNA-binding motif protein 3), which is transcriptionally induced by low temperature and hypoxia, has recently been implicated in survival of colon cancer cells by mechanisms involving cyclooxygenase-2 (COX-2) signaling. Immunohistochemically, we found strong RBM3 expression in a variety of malignant and proliferating tissues but low expression in resting and terminally differentiated cells. RBM3 expression in fibroblasts and human embryonal kidney (HEK293) cells subjected to serum deprivation or contact inhibition closely paralleled proliferation rates, assessed by real-time RT-PCR and immunoblotting. siRNA-mediated RBM3 knockdown reduced cell viability and finally led to cell death, which did not involve caspase-3-mediated apoptosis, cell cycle arrest, or COX-2 regulation. In contrast, RBM3 over-expression rescued cells from death under serum starvation. This was associated with increased translation rates, as measured by C serine and H phenylalanine incorporation. Together, RBM3 is a critical factor providing cellular survival advantages in an adverse microenvironment presumably by restoring translation efficacy.
Pediatric Research 09/2009; 67(1):35-41. · 2.70 Impact Factor
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Charles H Knowles,
Roberto De Giorgio,
Raj P Kapur, Elisabeth Bruder,
Gianrico Farrugia,
Karel Geboes,
Michael D Gershon,
John Hutson,
Greger Lindberg,
Joanne E Martin,
William A Meier-Ruge,
Peter J Milla,
Virpi V Smith,
Jean Marie Vandervinden,
Béla Veress,
Thilo Wedel
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ABSTRACT: The term gastrointestinal neuromuscular disease describes a clinically heterogeneous group of disorders of children and adults in which symptoms are presumed or proven to arise as a result of neuromuscular, including interstitial cell of Cajal, dysfunction. Such disorders commonly have impaired motor activity, i.e. slowed or obstructed transit with radiological evidence of transient or persistent visceral dilatation. Whilst sensorimotor abnormalities have been demonstrated by a variety of methods in these conditions, standards for histopathological reporting remain relatively neglected. Significant differences in methodologies and expertise continue to confound the reliable delineation of normality and specificity of particular pathological changes for disease. Such issues require urgent clarification to standardize acquisition and handling of tissue specimens, interpretation of findings and make informed decisions on risk-benefit of full-thickness tissue biopsy of bowel or other diagnostic procedures. Such information will also allow increased certainty of diagnosis, facilitating factual discussion between patients and caregivers, as well as giving prognostic and therapeutic information. The following report, produced by an international working group, using established consensus methodology, presents proposed guidelines on histological techniques and reporting for adult and paediatric gastrointestinal neuromuscular pathology. The report addresses the main areas of histopathological practice as confronted by the pathologist, including suction rectal biopsy and full-thickness tissue obtained with diagnostic or therapeutic intent. For each, indications, safe acquisition of tissue, histological techniques, reporting and referral recommendations are presented.
Acta Neuropathologica 05/2009; 118(2):271-301. · 9.32 Impact Factor
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ABSTRACT: Aberrant wnt signaling caused by mutations in CTNNB1 occurs in about 15% of Wilms tumors, and these mutations appear to be dependent on the concomitant mutational inactivation of the zinc-finger protein WT1. Nuclear beta-catenin protein, a substitute marker of active wnt signaling, has been detected in an even higher proportion (>50%) of Wilms tumors, suggesting alternative genetic pathways leading to beta-catenin activation. Thus, targeting wnt signaling may become an important future therapeutic strategy in Wilms tumor patients. Currently, chemically induced rat nephroblastomas provide the only available rodent model for this tumor. To determine the contribution of active wnt signaling in this model, we investigated 24 chemically induced rat nephroblastomas for beta-catenin protein expression and for Ctnnb1 and WT1 mutations. Immunohistochemistry showed focal strong nuclear accumulation of beta-catenin protein in 18 of 24 tumors, although in a heterogenous pattern. Blastemal and mesenchymal compartments displayed nuclear-positive cells more frequently than areas of epithelial differentiation. Interestingly, we found no mutation of exon 3 of Ctnnb1 and no mutation within the zinc-finger region of WT1 in any of the 24 tumors analyzed. In conclusion, our findings suggest activation of wnt signaling in the majority (63%) of chemically induced rat nephroblastomas. Nuclear expression of beta-catenin in the absence of Ctnnb1 mutations implies, however, alternate mutational targets in rat nephroblastomas.
Pediatric and Developmental Pathology 04/2009; 13(1):1-8. · 0.99 Impact Factor
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ABSTRACT: Vascular lesions of bone are rare and their terminology is not standardized. Herein, we report 77 patients with such lesions in order to characterize their morphologic spectrum and the applicability of the International Society for the Study of Vascular Anomalies (ISSVA) classification. In this system, malformations are structural anomalies distinguishable from tumors, which are proliferative. The radiologic images/reports and pathologic materials from all patients were reviewed. All lesions were either restricted to bone or had minimal contiguous soft tissue involvement with the exception of some multifocal lymphatic lesions that extensively affected soft tissue and/or viscera. We found that certain lesions of bone often regarded as tumors should be classified as malformations. Malformations (n = 46) were more common than tumors (n = 31); lymphatic and venous malformations were equally frequent. In the tumor category, hemangioendothelioma and epithelioid hemangioma were the most common. We also describe new vascular entities that arise in or involve bone. Utilizing the ISSVA approach, the diverse and often contradictory terminology of vascular lesions of bone can be largely eliminated. Standardized nomenclature is critical for scientific communication and patient management, and we hereby recommend the ISSVA classification be applied to vascular lesions of bone, just as for skin, soft tissue, and viscera.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 01/2009; 454(2):161-79. · 2.49 Impact Factor
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ABSTRACT: Milk contains too little arginine for normal growth, but its precursors proline and glutamine are abundant; the small intestine of rodents and piglets produces arginine from proline during the suckling period; and parenterally fed premature human neonates frequently suffer from hypoargininemia. These findings raise the question whether the neonatal human small intestine also expresses the enzymes that enable the synthesis of arginine from proline and/or glutamine. Carbamoylphosphate synthetase (CPS), ornithine aminotransferase (OAT), argininosuccinate synthetase (ASS), arginase-1 (ARG1), arginase-2 (ARG2), and nitric-oxide synthase (NOS) were visualized by semiquantitative immunohistochemistry in 89 small-intestinal specimens.
Between 23 weeks of gestation and 3 years after birth, CPS- and ASS-protein content in enterocytes was high and then declined to reach adult levels at 5 years. OAT levels declined more gradually, whereas ARG-1 was not expressed. ARG-2 expression increased neonatally to adult levels. Neurons in the enteric plexus strongly expressed ASS, OAT, NOS1 and ARG2, while varicose nerve fibers in the circular layer of the muscularis propria stained for ASS and NOS1 only. The endothelium of small arterioles expressed ASS and NOS3, while their smooth-muscle layer expressed OAT and ARG2.
The human small intestine acquires the potential to produce arginine well before fetuses become viable outside the uterus. The perinatal human intestine therefore resembles that of rodents and pigs. Enteral ASS behaves as a typical suckling enzyme because its expression all but disappears in the putative weaning period of human infants.
BMC Developmental Biology 12/2008; 8:107. · 2.79 Impact Factor
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Sylvia C Wetli,
Ivo Leuschner,
Dieter Harms,
Alex Rufle,
Anja Foerster,
Michel Bihl,
Norbert Graf,
Roikos Furtwaengler,
Michael Paulussen,
Jakob Briner,
Charalampos Aslanidis,
Gerd Schmitz,
Luigi Tornillo,
Michael J Mihatsch,
Inti Zlobec, Elisabeth Bruder
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ABSTRACT: Nephroblastoma prognosis has dramatically improved, but an unfavourable prognostic subgroup warrants development of novel therapeutic strategies. Selective KIT, PDGFRalpha and epidermal growth factor receptor (EGFR) tyrosine kinase inhibition evolved as powerful targeted therapy for gastrointestinal stromal tumours and non-small-cell lung cancer. To investigate a potential role for tyrosine kinase inhibition, we analyzed 209 nephroblastomas for immunohistochemical KIT and EGFR expression, 63 nephroblastomas for mutations in KIT exons 9, 11, 13, EGFR exons 18, 19, 20 and 21, and all 209 nephroblastomas for PDGFRalpha exons 12, 14 and 18. Twenty-two tumours (10.5%) expressed KIT, 31 (14.8%) EGFR, and 10 (4.8%) both KIT and EGFR, respectively. KIT expression was relatively more common among high-risk tumours (6/27; 22.3%) compared to low-/intermediate-risk tumours (26/181; 14.4%). Nine patients deceased, four of which had high-risk tumours with KIT expression in two of four and EGFR expression in one of four. There were no KIT, PDGFRalpha or EGFR mutations. Our results suggest no significant contribution of KIT, EGFR or PDGFRalpha mutations to nephroblastoma pathogenesis. Despite a trend towards association of immunohistochemical KIT and EGFR expression with poor outcome in high-risk nephroblastomas, statistical analysis did not yield significant correlations in this subgroup. Therefore, it remains open if KIT, PDGFRalpha or EGFR tyrosine kinase inhibition constitute a therapeutic target in nephroblastoma in the absence of KIT, PDGFRalpha or EGFR mutations.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 07/2008; 452(6):637-50. · 2.49 Impact Factor
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ABSTRACT: Enzyme histochemistry serves as a link between biochemistry and morphology. It is based on metabolization of a substrate provided to a tissue enzyme in its orthotopic localization. Visualization is accomplished with an insoluble dye product. It is a sensitive dynamic technique that mirrors even early metabolic imbalance of a pathological tissue lesion, combined with the advantage of histotopographic enzyme localization. With the advent of immunohistochemistry and DNA-oriented molecular pathology techniques, the potential of enzyme histochemistry currently tends to be underrecognized. This review aims to draw attention to the broad range of applications of this simple, rapid and inexpensive method. Alkaline phosphatase represents tissue barrier functions in brain capillaries, duodenal enterocyte and proximal kidney tubule brush borders. Decrease in enzyme histochemical alkaline phosphatase activity indicates serious functional impairment. Enzyme histochemical increase in lysosomal acid phosphatase activity is an early marker of ischemic tissue lesions. Over the last four decades, acetylcholinesterase enzyme histochemistry has proven to be the gold standard for the diagnosis of Hirschsprung disease and is one of the most commonly applied enzyme histochemical methods today. Chloroacetate esterase and tartrate-resistant phosphatase are both resistant to formalin fixation, EDTA decalcification and paraffin embedding. Early enzyme histochemical insight into development of a pathologic tissue lesion and evaluation of function and vitality of tissue enhance our understanding of the pathophysiology of diseases. In this process, enzyme histochemistry constitutes a valuable complement to conventional histology, immunohistochemistry and molecular pathology for both diagnostic and experimental pathology.
Pathobiology 02/2008; 75(4):233-43. · 1.18 Impact Factor
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Sylvia C. Wetli,
Ivo Leuschner,
Dieter Harms,
Alex Rufle,
Anja Foerster,
Michel Bihl,
Norbert Graf,
Roikos Furtwaengler,
Michael Paulussen,
Jakob Briner,
Charalampos Aslanidis,
Gerd Schmitz,
Luigi Tornillo,
Michael J. Mihatsch,
Inti Zlobec, Elisabeth Bruder
[show abstract]
[hide abstract]
ABSTRACT: Nephroblastoma prognosis has dramatically improved, but an unfavourable prognostic subgroup warrants development of novel
therapeutic strategies. Selective KIT, PDGFRα and epidermal growth factor receptor (EGFR) tyrosine kinase inhibition evolved
as powerful targeted therapy for gastrointestinal stromal tumours and non-small-cell lung cancer. To investigate a potential
role for tyrosine kinase inhibition, we analyzed 209 nephroblastomas for immunohistochemical KIT and EGFR expression, 63 nephroblastomas
for mutations in KIT exons 9, 11, 13, EGFR exons 18, 19, 20 and 21, and all 209 nephroblastomas for PDGFRα exons 12, 14 and 18. Twenty-two tumours (10.5%) expressed KIT, 31 (14.8%) EGFR, and 10 (4.8%) both KIT and EGFR, respectively.
KIT expression was relatively more common among high-risk tumours (6/27; 22.3%) compared to low-/intermediate-risk tumours
(26/181; 14.4%). Nine patients deceased, four of which had high-risk tumours with KIT expression in two of four and EGFR expression
in one of four. There were no KIT, PDGFRα or EGFR mutations. Our results suggest no significant contribution of KIT, EGFR or PDGFRα mutations to nephroblastoma pathogenesis. Despite a trend towards association of immunohistochemical KIT and EGFR expression
with poor outcome in high-risk nephroblastomas, statistical analysis did not yield significant correlations in this subgroup.
Therefore, it remains open if KIT, PDGFRα or EGFR tyrosine kinase inhibition constitute a therapeutic target in nephroblastoma
in the absence of KIT, PDGFRα or EGFR mutations.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 01/2008; 452(6):637-650. · 2.49 Impact Factor
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Elisabeth Bruder,
Holger Moch,
David Ehrlich,
Ivo Leuschner,
Dieter Harms,
Pedram Argani,
Jakob Briner,
Norbert Graf,
Barbara Selle,
Alex Rufle,
Michael Paulussen,
Robert Koesters
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ABSTRACT: Renal cell carcinomas in young patients constitute a morphologically and genetically heterogeneous group. Twenty percent belong to the newly recognized Xp11.2 translocation-associated family and rare tumors arise from nephroblastoma. Aberrant Wnt signaling through beta-catenin mutation has been implicated in nephroblastoma pathogenesis and has been found to synergize with WT1 mutations. To characterize Wnt signaling activity in renal cell carcinomas in young patients, we gathered 34 tumors (three clear cell, ten Xp11.2 translocation associated, five papillary, two chromophobe, two collecting duct, one neuroblastoma associated, eight unclassified renal cell carcinomas, and three carcinomas combined with nephroblastoma) from patients less than 22 years. Expression of beta-catenin, its homologue gamma-catenin, and of WT1 was assessed by immunohistochemistry in 30 tumors, and sequence analysis of CTNNB1, CTNNG1, and WT1 genes was performed in 25 tumors. Cytoplasmic beta-catenin accumulation was demonstrated in two papillary carcinomas, one neuroblastoma-associated carcinoma, and two carcinomas arising from nephroblastoma. The pattern of gamma-catenin expression paralleled that of beta-catenin but its signal intensity was lower in 22, equal in 7, and stronger only in 1 tumor, respectively. Four tumors showed nuclear WT1 expression. One Xp11.2 translocation-associated carcinoma presented a rare intronic CTNNB1 single nucleotide polymorphism and cytoplasmic beta-catenin accumulation. There were no further CTNNB1 or CTNNG1 sequence alterations. A WT1 mutation was found in the nephroblastoma component of a carcinoma arising from nephroblastoma. These findings suggest Wnt signaling pathway activation only in a minority of renal cell carcinomas in young patients. CTNNB1 mutations are rare events. Cytoplasmic beta-catenin accumulation in an Xp11.2-associated carcinoma suggests potential interaction of Wnt signaling components with microphthalmia transcription factor family also in Xp11.2 translocation carcinomas. WT1 mutation in the nephroblastoma component of a mixed-type renal cell carcinoma provides direct evidence for clonal independence of nephroblastoma and carcinoma components in this exceptional tumor.
Modern Pathology 01/2008; 20(12):1217-29. · 4.79 Impact Factor
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ABSTRACT: Pulmonary surfactant is essential to maintain alveolar patency, and invariably fatal neonatal lung disease has been recognized to involve mutations in the genes encoding surfactant protein-B or ATP-binding cassette transporter family member ABCA3. The lipid transporter ABCA3 targets surfactant phospholipids to lamellar bodies that are lysosomal-derived organelles of alveolar type II cells. ABCA3-/- mice have grossly reduced surfactant phosphatidyl glycerol levels and die of respiratory failure soon after birth. We studied lung biopsy samples of two siblings with a novel homozygous ABCA3 mutation at nucleotide position 578 (c.578C>G), leading to a Pro193Arg amino-acid exchange, who died at 55 and 105 days of age. Light microscopy revealed thickened alveolar septa with abundant myxoid interstitial matrix, marked hyperplasia of type II pneumocytes, desquamation of alveolar macrophages and focal alveolar proteinosis. Surfactant protein-B was detected by immunohistochemistry after antigen retrieval. Transmission electron microscopy showed rare cytoplasmic inclusions with concentric membranes and eccentrically placed electron-dense aggregates. These 'fried-egg'-appearing lamellar bodies differed both from normal lamellar bodies and the larger, poorly formed composite bodies with multiple vesicular inclusions observed in surfactant protein-B deficiency. In conclusion, our findings underscore that the implications of interstitial lung disease in infant lungs differ from those in adults. In infants with a desquamative interstitial pneumonitis pattern, surfactant or ABCA3 mutations should be evaluated. Importantly, these findings support the notion that electron microscopy is useful in distinguishing between surfactant protein-B and ABCA3 deficiency, and has an important role in evaluating biopsies or autopsies of term infants with unexplained severe respiratory failure and interstitial lung disease.
Modern Pathology 10/2007; 20(10):1009-18. · 4.79 Impact Factor
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ABSTRACT: Pulmonary surfactant is essential to maintain alveolar patency, and invariably fatal neonatal lung disease has been recognized to involve mutations in the genes encoding surfactant protein-B or ATP-binding cassette transporter family member ABCA3. The lipid transporter ABCA3 targets surfactant phospholipids to lamellar bodies that are lysosomal-derived organelles of alveolar type II cells. ABCA3-/- mice have grossly reduced surfactant phosphatidyl glycerol levels and die of respiratory failure soon after birth. We studied lung biopsy samples of two siblings with a novel homozygous ABCA3 mutation at nucleotide position 578 (c.578C>G), leading to a Pro193Arg amino-acid exchange, who died at 55 and 105 days of age. Light microscopy revealed thickened alveolar septa with abundant myxoid interstitial matrix, marked hyperplasia of type II pneumocytes, desquamation of alveolar macrophages and focal alveolar proteinosis. Surfactant protein-B was detected by immunohistochemistry after antigen retrieval. Transmission electron microscopy showed rare cytoplasmic inclusions with concentric membranes and eccentrically placed electron-dense aggregates. These 'fried-egg'-appearing lamellar bodies differed both from normal lamellar bodies and the larger, poorly formed composite bodies with multiple vesicular inclusions observed in surfactant protein-B deficiency. In conclusion, our findings underscore that the implications of interstitial lung disease in infant lungs differ from those in adults. In infants with a desquamative interstitial pneumonitis pattern, surfactant or ABCA3 mutations should be evaluated. Importantly, these findings support the notion that electron microscopy is useful in distinguishing between surfactant protein-B and ABCA3 deficiency, and has an important role in evaluating biopsies or autopsies of term infants with unexplained severe respiratory failure and interstitial lung disease.Keywords: neonatal pneumonia, surfactant, lamellar bodies, ABCA3 mutation, ultrastructure
Modern Pathology 07/2007; 20(10):1009-1018. · 4.79 Impact Factor
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ABSTRACT: We report on a newborn infant with complex congenital heart disease (CHD) featuring double outlet right ventricle and hypoplastic left ventricle who had postductal oxygen saturation well above 95% and thus eluded pulse oximetry screening for CHD.
European Journal of Pediatrics 07/2007; 166(6):625-6. · 1.88 Impact Factor
