CNS embryonal tumours: WHO 2016 and beyond.

Embryonal tumours of the central nervous system (CNS) present a significant clinical challenge. Many of these neoplasms affect young children, have a very high mortality and therapeutic strategies are often aggressive with poor long-term outcomes. There is a great need to accurately diagnose embryonal tumours, predict their outcome and adapt therapy to the individual patient's risk. For the first time in 2016, the WHO classification took into account molecular characteristics for the diagnosis of CNS tumours. This integration of histological features with genetic information has significantly changed the diagnostic work-up and reporting of tumours of the CNS. However, this remains challenging in embryonal tumours due to their previously unaccounted tumour heterogeneity. We describe the recent revisions made to the 4th edition of the WHO classification of CNS tumours and review the main changes, while highlighting some of the more common diagnostic testing strategies.

Carcinogen-specific mutational and epigenetic alterations in INK4A, INK4B and p53 tumour-suppressor genes drive induced senescence bypass in normal diploid mammalian cells.

Immortalization (senescence bypass) is a critical rate-limiting step in the malignant transformation of mammalian somatic cells. Human cells must breach at least two distinct senescence barriers to permit unfettered clonal evolution during cancer development: (1) stress- or oncogene-induced premature senescence (SIPS/OIS), mediated via the p16-Rb and/or ARF-p53-p21 tumour-suppressive pathways, and (2) replicative senescence triggered by telomere shortening. In contrast, because their telomerase is constitutively active, cells from small rodents possess only the SIPS/OIS barrier, and are therefore useful for studying SIPS/OIS bypass in isolation. Dermal fibroblasts from the Syrian hamster (SHD cells) are exceptionally resistant to spontaneous SIPS bypass, but it can be readily induced following exposure to a wide range of chemical and physical carcinogens. Here we show that a spectrum of carcinogen-specific mutational and epigenetic alterations involving the INK4A (p16), p53 and INK4B (p15) genes are associated with induced SIPS bypass. With ionizing radiation, immortalization is invariably accompanied by efficient biallelic deletion of the complete INK4/CDKN2 locus. In comparison, SHD cells immortalized by the powerful polycyclic hydrocarbon carcinogen benzo(a)pyrene display transversion point mutations in the DNA-binding domain of p53 coupled with INK4 alterations such as loss of expression of p15. Epimutational silencing of p16 is the primary event associated with immortalization by nickel, a human non-genotoxic carcinogen. As SIPS/OIS bypass is a prerequisite for the immortalization of normal diploid human epithelial cells, our results with the SHD model will provide a basis for delineating combinations of key molecular changes underpinning this important event in human carcinogenesis.

Internal jugular vein thrombosis secondary to a permanent cardiac pacemaker: an unusual case of lateral neck swelling.

OBJECTIVE: To describe an unusual case of lateral neck swelling in a patient with a permanent cardiac pacemaker. CASE REPORT: We describe a patient who presented with a painful, lateral neck swelling due to an internal jugular vein thrombus. This thrombus originated from around pacemaker wires in the subclavian vein. This case is unusual, as the vast majority of thromboses in patients with cardiac pacemakers are found in the subclavian vein alone. We also review the literature on the relationship between cardiac pacemakers and internal jugular vein thrombosis, and on the management of the latter. CONCLUSION: Our patient illustrates a rare cause of a painful, lateral neck swelling: an internal jugular vein thrombus secondary to a cardiac pacemaker. Clinicians should be wary of such pathology in similar patients, in order to ensure early treatment and avoidance of complications.

Severe laryngitis following chronic anabolic steroid abuse.

The effects of anabolic steroids on the quality of voice have been well documented; however, no study has established significant structural changes in the larynx as a direct result of anabolic steroid use. We report a unique case of a 47-year-old male smoker and professional body builder who presented with progressive stridor and hoarseness following abuse of anabolic steroids over a period of two years. Conservative management failed to resolve his symptoms and a planned tracheostomy was performed to secure his airway. Subsequently he was treated with multiple laser resections and eventually decannulated. No case of severe laryngitis in association with anabolic steroid usage has been reported previously in the literature.

Intranasal myopericytoma. A tumour with perivascular myoid differentiation: the changing nomenclature for haemangiopericytoma.

We present a case report of a patient who developed a sinonasal myopericytoma treated by surgical excision through a lateral rhinotomy. Some aggressive features on pre-operative computed tomography scanning and the complexity of recent changes in the histological nomenclature for these tumours led to consideration of adjuvant therapy. The close histological relationship between myopericytoma, myofibromatosis, solitary myofibroma and infantile haemangiopericytoma is discussed. This group of lesions constitute a single morphological spectrum with differentiation towards perivascular myoid cells (pericytes). Currently myopericytoma is the most appropriate and accepted term embracing all these entities. A review of the literature has been reassuring in identifying these tumours as benign but with a reasonably high rate of local recurrence (17 per cent). The treatment of choice is surgical excision with further excisions for local recurrence.

Synchronous bilateral tonsillar carcinoma: role of fluoro-deoxyglucose positron emission tomography scanning in detecting occult primary tumours in metastatic nodal disease of the head and neck.

We present the second case of primary synchronous bilateral tonsillar squamous cell carcinoma reported in the English literature and evaluate the role of fluoro-deoxyglucose positron emission tomography scanning in the search for the occult primary tumour in a patient presenting with metastatic nodal disease in the head and neck.

Airway emergency in tuberculosis.

We report a case of acute fatal stridor in a patient newly diagnosed with pulmonary tuberculosis and human immunodeficiency virus (HIV) infection. No evidence of direct airway encroachment was identified at autopsy. We review mechanisms by which tuberculosis may cause stridor and discuss the implications of co-existent HIV infection with reference to the recent literature. The report highlights the need for recognition of acute or evolving airway compromise as an uncommon manifestation of tuberculosis.

Is preparation for bronchoscopy optimal?

The results of a questionnaire survey, of the current preparation for and practice of diagnostic bronchoscopy in England and Wales, are reported in this paper. The British Thoracic Society (BTS) has recently published guidelines on bronchoscopy and these provide a consensus statement on the current evidence base. There is no specific guidance on drugs or techniques, although it is recommended that all patients should be offered sedation, except where there are contraindications. In the present survey, there was a response rate of 76%, (344 responses to 452 questionnaires) and the median number of bronchoscopies performed per session was 5 (interquartile range 4-6). Most operators use lignocaine gel to the nose (65%), spray to the throat (70%), followed by the "spray as you go" method (84%), recommended by the BTS. Atropine is routinely used by 13% contrary to the guidelines and despite concerns about its side-effects. Most operators use sedation with midazolam (85%) or a wide variety of combinations of sedative, analgesic, and anaesthetic agents (27%), and 27% perform unsedated bronchoscopies, with only 0.1% routinely performing unsedated bronchoscopies. A total 251 (77%) responders stated they assessed adequacy of sedation, with most using patient observation alone (149 (46%)). Only three operators assessed sedation using a formal sedation score. Thus, most centres routinely perform sedated bronchoscopies and the systematic level of monitoring is poor. The current controversies about sedation and safe sedation practice are discussed. There is a need for more evidence to allow more specific guidance to be produced in this difficult area.

The expression of fibroblast growth factors and their receptors in the embryonic and neonatal mouse inner ear.

Four different fibroblast growth factor receptors (FGFR) are known, three of which have splice variants (known as the b and c variants) in the FGF-binding domain, to give different patterns of sensitivity to the different FGFs. The expression of the b and c variants of the FGF receptors, together with the expression of the ligands FGF1, FGF2, FGF3, FGF7, FGF8b and FGF8c, was determined by quantitative reverse transcription-polymerase chain reaction in developing whole mouse inner ears, and in dissected components of the postnatal mouse inner ear. At embryonic age (E)10.5 days, when the otocyst is a simple closed sac, the receptor most heavily expressed was FGFR2b, relative to the postnatal day 0 level. Over the period E10.5-E12.5, during which the structures of the inner ear start to form, the expression of the different FGF receptors increased 10(2)-10(4) fold per unit of tissue, and there was a gradual switch towards expression of the 'c' splice variants of FGFR2 and FGFR3 rather than the 'b' variants. At E10.5, the ligands most heavily expressed, relative to the postnatal day 0 level, were FGF3, FGF8b and FGF8c. In the postnatal inner ear, the patterns of expression of receptors and ligands tended to be correlated, such that receptor variants were expressed in the same regions as the ligands that are known to activate them effectively. The neural/sensory region expressed high levels of FGFR3c, and high levels of the ligand FGF8b. The same area also expressed high levels of FGFR1b and FGFR2b, and high levels of FGF3. The lateral wall of the cochlea (including the stria vascularis and the spiral ligament) expressed high levels of FGFR1c and FGF2. It is suggested that the different FGF receptors and ligands are expressed in a spatially coordinated pattern, to selectively program cochlear development.

Basic fibroblast growth factor and fibroblast growth factor receptors in adult olfactory epithelium.

Basic fibroblast growth factor (FGF2) stimulates proliferation of the globose basal cells, the neuronal precursor in the olfactory epithelium. The present study investigates the expression of basic fibroblast growth factor and fibroblast growth factor receptors in the adult olfactory epithelium. FGF2 immunoreactivity was expressed widely in the olfactory epithelium, with the highest density of immunoreactivity in the supporting cells. In contrast, most cells in the epithelium expressed FGF2 mRNA. Fibroblast growth factor receptor-1 (FGFr1) immunoreactivity was densest in the basal cell and neuronal layers of the olfactory epithelium and on the apical surface of supporting cells. In the lamina propria FGF2 immunoreactivity and mRNA were densest in cells close to the olfactory nerve bundles. FGFr1 immunoreactivity was heaviest on the olfactory ensheathing cells. Using reverse transcriptase-polymerase chain reaction analysis, the olfactory epithelium was shown to express only three receptor splice variants, including one (FGFr1c) with which basic fibroblast growth factor has high affinity. Other receptor splice variants were present in the lamina propria. Taken together, these observations indicate endogenous sources of FGF2 within the olfactory epithelium and lamina propria and suggest autocrine and paracrine pathways via which FGF2 might regulate olfactory neurogenesis. The observation of only three receptor splice variants in the olfactory epithelium limits the members of the fibroblast growth factor family which could act in the olfactory epithelium. The widespread distribution of receptors suggests that fibroblast growth factors may have roles other than proliferation of globose basal cells.

Lateral interactions account for the pattern of the hair cell array in the chick basilar papilla.

It has been suggested that lateral interactions set up the array of hair cells and supporting cells in the chick basilar papilla. The presence of a hair cell would inhibit adjacent cells from becoming hair cells, and promote the formation of supporting cells. Models of cell specification were tested, starting with a closely packed array of multipotent progenitor cells. Lateral interactions, in which emerging hair cells promoted a supporting cell phenotype in adjacent cells, and in which emerging supporting cells promoted a hair cell phenotype in adjacent cells, produced an array of cells similar to that observed experimentally in the distal and central parts of the basilar papilla. In these areas, the ratio of supporting cells to hair cells is very close to 2:1, each hair cell on average being surrounded by six supporting cells, and each supporting cell being surrounded by three hair cells and three supporting cells. Identical patterns of hair and supporting cells could be produced by models in which either of the lateral inhibitory factors was replaced by a diffusive factor, i.e. a factor which acts on all cells in the model irrespective of position. The agreement of the model with observed cell ratios supports the view that the fate of both hair cells and supporting cells in the chick basilar papilla is a product of cell interactions within the papilla. It is possible that one factor, that provides contact lateral inhibition and promotes the formation of supporting cells, is the Notch/Delta system. It is possible that the other factor is retinoic acid, a diffusive factor that promotes the formation of hair cells.

Expression of EphA4 in developing inner ears of the mouse and guinea pig.

The expression of EphA4, an Eph-class receptor tyrosine kinase, was determined by immunohistochemistry in developing inner ears of the mouse and the guinea pig. In the mouse, EphA4 expression was visible in the fibroblasts of the spiral ligament and in the structures that were to become the osseous spiral lamina. Cochlear nerve ganglion cells expressed ephrin-B2, and the modiolus expressed mRNA coding for ephrin-B3, both transmembrane ligands for EphA4. In contrast, in the guinea pig, cells of the cochlear nerve ganglion expressed EphA4, as did supporting cells of the organ of Corti (Hensen's cells and inner pillar cells). There was also some expression in fibroblasts of the spiral ligament but none in the structures that were to become the osseous spiral lamina. It is suggested that in the mouse, EphA4 may help direct the cochlear innervation towards the organ of Corti by a repulsive interaction, but that this is highly species dependent.

Pleomorphic adenoma and myotonic dystrophy: an association?

To date there are only two recorded cases of patients with coexistent pleomorphic adenoma and myotonic dystrophy in the literature. We present two further cases, describe the general features of myotonic dystrophy and discuss the theory of a direct association between these two conditions.

A tyrosine kinase screen of mouse vestibular maculae.

Receptor tyrosine kinases allow extracellular signals to influence intracellular events, while other tyrosine kinases are involved in intracellular signalling. They may therefore be involved in the development, maintenance and repair of the sensory epithelia of the inner ear, since these are believed to be affected by inter- and intracellular signalling. In order to analyse possible tyrosine kinases expressed in sensory areas of the inner ear, a reverse transcription polymerase chain reaction screen of microdissected sensory epithelia was undertaken, using primers targeted at conserved sequences in tyrosine kinase domains. Tissue was taken from the maculae of the mouse vestibular organs, and consisted mainly of hair cells and their supporting cells. Of 80 clones sequenced, 49 coded for tyrosine kinases, and 11 for other known molecules. Further analysis of one of the sequences, for FGF receptor 4, showed a novel variant, expressed in the inner ear and elsewhere, with a variation in the intracellular domain which suggests differential activation of known signalling pathways. Other clones coded for tyrosine kinases expected to be involved in cell surface and intracellular signalling. The technique forms a powerful tool for analysing a range of the tyrosine kinases expressed, and provides a starting point for the analysis of cell-cell signalling in the inner ear.

Fibroblast growth factor receptor-4 splice variants cause deletion of a critical tyrosine.

We have identified two novel isoforms of fibroblast growth factor receptor-4 (FGFR4). They result from alternative splicing of intron 17. Two transcripts, both slightly larger than the one coding for the known mouse FGFR4, are generated. The shortest (FGFR4-17a) includes the 31-most 3'-nucleotides of intron 17; the longest (FGFR4-17b) includes all 114 nucleotides of intron 17. Translation of the FGFR4-17a and FGFR4-17b splice variants predicts that both novel putative FGFR4 isoforms have a truncated C-terminal intracellular tail. The first amino acid residue affected by the insertions in both novel isoforms is Tyr-760, a residue that may play a crucial role in intracellular signaling through stimulation of the phosphatidylinositol-biphosphate pathway.

Traumatic laryngocoele.

This is the first reported case of a laryngocoele developing after laryngeal trauma. A 26-year-old man sustained a shotgun injury to his larynx. A large number of shotgun pellets was removed from his left vestibular fold. He subsequently developed a left-sided laryngocoele, probably due to fibrosis around the neck of the saccule. The laryngocoele was removed by an external approach.