Elisabeth Bruder

Morphologic and molecular characterization of renal cell carcinoma in children and young adults

A new WHO classification of renal cell carcinoma has been introduced in 2004. This classification includes the recently described renal cell carcinomas with the ASPL-TFE3 gene fusion and carcinomas with a PRCC-TFE3 gene fusion. Collectively, these tumors have been termed Xp11.2 or TFE3 translocation carcinomas, which primarily occur in children and young adults. To further study the characteristics of renal cell carcinoma in young patients and to determine their genetic background, 41 renal cell carcinomas of patients younger than 22 years were morphologically and genetically characterized. Loss of heterozygosity analysis of the von Hippel-Lindau gene region and screening for VHL gene mutations by direct sequencing were performed in 20 tumors. TFE3 protein overexpression, which correlates with the presence of a TFE3 gene fusion, was assessed by immunohistochemistry. Applying the new WHO classification for renal cell carcinoma, there were 6 clear cell (15%), 9 papillary (22%), 2 chromophobe, and 2 collecting duct carcinomas. Eight carcinomas showed translocation carcinoma morphology (20%). One carcinoma occurred 4 years after a neuroblastoma. Thirteen tumors could not be assigned to types specified by the new WHO classification: 10 were grouped as unclassified (24%), including a unique renal cell carcinoma with prominently vacuolated cytoplasm and WT1 expression. Three carcinomas occurred in combination with nephroblastoma. Molecular analysis revealed deletions at 3p25-26 in one translocation carcinoma, one chromophobe renal cell carcinoma, and one papillary renal cell carcinoma. There were no VHL mutations. Nuclear TFE3 overexpression was detected in 6 renal cell carcinomas, all of which showed areas with voluminous cytoplasm and foci of papillary architecture, consistent with a translocation carcinoma phenotype. The large proportion of TFE3 “translocation” carcinomas and “unclassified” carcinomas in the first two decades of life demonstrates that renal cell carcinomas in young patients contain genetically and phenotypically distinct tumors with further potential for novel renal cell carcinoma subtypes. The far lower frequency of clear cell carcinomas and VHL alterations compared with adults suggests that renal cell carcinomas in young patients have a unique genetic background.

The London Classification of gastrointestinal neuromuscular pathology: report on behalf of the Gastro 2009 International Working Group

Objective 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. Design Consensual processes undertaken by the IWG and following established guideline decision group methodologies. Results and conclusion 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.

Gastrointestinal neuromuscular pathology: guidelines for histological techniques and reporting on behalf of the Gastro 2009 International Working Group

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.

Population-based study of renal cell carcinoma in children in Germany, 1980-2005: more frequently localized tumors and underlying disorders compared with adult counterparts.

Childhood renal cell carcinomas (RCCs) differ histologically and biologically from their adult counterparts. The characteristics of RCC‐affected children and their tumors, the influence of treatment, and outcome have so far not been studied in a nonselected, population‐based cohort.

Vascular lesions of bone in children, adolescents, and young adults. A clinicopathologic reappraisal and application of the ISSVA classification

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.

Intestinal Neuronal Dysplasia Type B: One Giant Ganglion is Not Good Enough:

In this “Current Practice in Pediatric Pathology” article, 2 experts in the field and an associate editor of Pediatric and Developmental Pathology discuss the definition, diagnosis, clinical significance, and management of intestinal neuronal dysplasia type B. Intestinal neuronal dysplasia type B has constituted a diagnostic challenge ever since its first description more than 30 years ago. Intestinal neuronal dysplasia type B is regarded by many as a subtle malformation of the enteric nervous system that is limited to the submucosal plexus of the colon. The precise etiology remains unknown, and, to date, no specific diagnostic test exists other than morphology. Over time, with increasing experience, obligate pathological features have been adapted and refined, leading to contemporary diagnostic criteria that are enunciated in this review and placed into context with prior published data. Rigorous application of these criteria, under standardized laboratory conditions, is crucial for accurate diagnosis and future advances in this field.

The RNA-Binding Protein RBM3 Is Required for Cell Proliferation and Protects Against Serum Deprivation-Induced Cell Death

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 14C serine and 3H phenylalanine incorporation. Together, RBM3 is a critical factor providing cellular survival advantages in an adverse microenvironment presumably by restoring translation efficacy.

Temperature mapping of magnetic resonance-guided laser interstitial thermal therapy (LITT) in lymphangiomas of the head and neck.

Lymphangiomas of the tongue and neck are uncommon benign congenital lymphatic tumors. These vascular lesions are difficult to treat, frequently recur, and can cause patients significant morbidity. Treatment may also be complicated by adjacent vital anatomic structures. Magnetic resonance (MR)‐controlled laser‐induced interstitial thermotherapy (LITT) has been proven to be a noninvasive safe treatment. Real‐time monitoring of tissue temperature with thermosensitive sequences allows controlled coagulation necrosis.

The histopathology of gastrointestinal motility disorders in children

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.

Odontogenic myxoma: Diagnostic and therapeutic challenges in paediatric and adult patients – A case series and review of the literature

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.