Gliomatosis cerebri

Gliomatosis cerebri is an unusual manifestation of glioma characterized by extensive involvement of at least three lobes of the brain by glial cell neoplastic proliferation (Figure 14.4). It is most common in middle age, often with delayed presentation due to variable features and lack of localizing neurological signs. It may be low or high grade, and a biopsy is required for diagnosis. It is usually too extensive for surgical treatment, and is managed by large radiation fields and temozolomide chemotherapy.




Ependymoma



Ependymomas (Figure 14.5) are found anywhere along the ventricular system and occur at any age. There are three grades - Gd1 (myxopapillary and



Figure 14.4 Gliomatosis cerebri. A 67-year-old man presenting with cognitive decline and seizures. Axial T2W MRI showing diffusely infiltrating high signal change in both cerebral hemispheres compressing the right posterior horn. Biopsy showed gliomatosis cerebri.



Figure 14.5 Intramedullary spinal cord tumour. Sagittal MRI showing a well-demarcated tumour in the lumbar region. Histology showed a WHO grade II ependymoma.



Primary spinal tumours may be intramedullary (ependymomas and astrocytomas) or more frequently extramedullary. Extramedullary tumours are either intradural (schwannomas, meningiomas) or extradural (e. g. metastases).



Between Gd2 and Gd3 astrocytomas. They are more common in children, with two-thirds in the posterior fossa, presenting with focal neurology and obstructive hydrocephalus. Spinal ependymomas are more common than intracranial ependymomas in adults, usually in the cervical spine or the conus medullaris. Adult ependymomas have better survival rates than other gliomas (over 50 per cent are curable), with survival related to age, performance status, extent of resection and grade.



Craniospinal dissemination can occur, so imaging of the entire craniospinal axis is required at diagnosis and on follow up. Ependymoma is primarily managed surgically, with the extent of resection determining prognosis, and the natural history being a prolonged one characterized by local recurrence, usually after incomplete resection.



Adjuvant radiotherapy is indicated after subtotal resection of Gd2 tumours (and should always be discussed after complete resection) and in all Gd3 tumours. Historically, craniospinal radiotherapy was used for posterior fossa lesions, but has been replaced by focal radiotherapy after studies demonstrated only a 3 per cent relapse rate outside the primary site. Ependymomas are not chemosensitive, with vincristine-based regimes being used with only modest benefit for inoperable relapses following radiotherapy.



Spinal tumours



Spinal ependymomas present in middle age and have a better prognosis than when intracranial, but there is the risk of significant neurological morbidity with complete surgical resection. The diagnosis is often made after months or years of slowly progressing symptoms. MRI demonstrates a well-defined, brightly enhancing lesion. Recurrence rates are around 5-10 per cent in low grade, fully resected tumours. As with intracranial ependymomas, adjuvant radiotherapy should be considered after incompletely resected Gd1, and for all Gd2 and Gd3 tumours. Localized radiotherapy is used except when lumbosacral. Tumours at this site may spread with a ‘sugar coating’ of ependymoma along the nerve roots below the primary site, thought to be secondary to gravity. Standard practice is therefore to encompass the whole thecal sac within the radiation field.



Spinal astrocytomas are usually the fibrillary, low-grade subtypes, presenting in a similar manner to ependymomas. Prognosis is less good than for ependymoma. The median survival of spinal high-grade gliomas is about 20 months. Surgery is the mainstay of treatment but needs to be carefully considered in high-grade lesions or in patients with significant neurological deficit. Radiotherapy is indicated as for the low - and high-grade intracranial astrocytomas.



Meningiomas_



There are two main predictors of increased rate of recurrence: atypical and malignant histology, and residual disease following surgery. Adjuvant radiotherapy has been shown to reduce local recurrence, but without a survival advantage. There is also the issue of the long-term side-effects of radiation,



Meningiomas (Figure 14.6) account for about 20 per cent of all intracranial tumours, peak in the sixth decade and are more common in women. Many are asymptomatic when they are discovered as an incidental finding. They are slow growing and only rarely invade brain. They can involve bone and cause hyperostosis (best demonstrated on the CT bone windows). They often have a dural tail visible on MRI. Common intracranial sites are parasagittal, olfactory groove, tuberculum sellae and the sphenoid wing. Most are benign, but up to 5 per cent will be histologically atypical (WHO grade II) and 2-3 per cent anaplastic (malignant, WHO grade III). Treatment is surgical, with recurrence rates less than 10 per cent in the benign lesions.



Especially pertinent when treating younger patients with a long life expectancy. Radiotherapy is usually given after the first relapse, unless the neurological cost of local progression is high, or as primary treatment in inoperable cases (with local control rates over 90 per cent in Gd1 tumours).



Primitive neuroectodermal tumours



PNETs are generally childhood tumours, responsible for only 1 per cent of CNS tumours in adults (mainly younger adults). Most PNETs are medulloblastomas (the most common childhood CNS tumour at 20 per cent) arising in the cerebellum. PNETs arising in the cerebral hemispheres are called supratentorial primitive neuroectodermal tumours (sPNET), and in the pineal area called pineoblastoma. The sPNET have a significantly worse outcome than medulloblastoma, possibly due to complete surgical resection being more difficult and to biological differences.



PNETs are all histologically similar with small round cells with larger hyperchromatic nuclei clustered into rosettes. There are distinct subtypes of medulloblastoma, all highly malignant WHO grade IV tumours with a propensity for spread via the CSF. A third will have radiological evidence of leptomeningeal disease at presentation. About 5 per cent disseminate outside the CNS (most commonly to bone), a phenomenon not seen with other primary CNS tumours.



Staging requires preoperative MRI of the brain and whole spine. In children, they appear as well-defined, enhancing midline tumours whereas in adults they are poorly defined masses in the cerebellar hemispheres. Residual postoperative disease, an important prognostic factor, is best demonstrated by comparing the preoperative MRI with one obtained within 24 hours of surgery. When the residual exceeds 1.5 cm2 (maximum cross-sectional area), further ‘second look’ surgery should be considered. Unless there is evidence of meningeal/ metastatic disease on the preoperative imaging, a lumbar puncture for CSF cytology is necessary. This must be performed at least 15 days following surgery to avoid false positives due to contamination.



Poor prognostic factors are metastatic disease, postoperative residual greater than 1.5 cm2, anaplastic or large cell pathology, age (children under 36 months and adults). These divide patients into two treatment groups: standard risk, medulloblastoma, no metastases, residual less than 1.5 cm2,



Figure 14.6 Meningioma. MRI showing skull base meningiomas in three patients. (a) Right cavernous sinus. (b) Bilateral posterior fossa. (c) Left lateral sphenoid and middle cranial fossa with intra-orbital extension causing visual loss in left eye.



Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin’s lymphoma (NHL), accounting for only 5 per cent of all primary brain tumours (Figure 14.7). It arises in, and is confined to, the brain, spinal cord and leptomeninges, with 20 per cent of patients having intra-ocular involvement at diagnosis. Over the last three decades survival has improved, mainly because of the introduction of methotrexate-based combination chemotherapy. Long-term treatment-related neurological toxicity remains a major problem.



Children; and high risk, sPNET (including pin-eoblastoma), M1-4, anaplastic/large cell, residual greater than 1.5 cm2, adults.



Surgical resection of a medulloblastoma may result in cerebellar mutism syndrome. This occurs in up to 8 per cent of all posterior fossa craniotomies but most commonly after resection of a medulloblastoma extending into the brainstem, thought to be caused by damage to the dentate nuclei.



Following maximal resection, craniospinal axis radiation (CSA) must be given and has been the standard management for decades. This is complex and the technical quality of radiotherapy is closely related to outcome in PNET. It should therefore only be delivered in designated paediatric and young adult radiotherapy centres. An 85 per cent 5YS is now seen in standard risk patients given 35 Gy to the whole CSA, followed by a boost to 55 Gy to the primary tumour.



There is now an increasing focus on quality of survival, in addition to cure. CSA radiotherapy leads to significant endocrine, growth and cognitive deficits in children. Multimodality treatment has been introduced for standard risk children, which enables the dose of CSA radiotherapy to be safely reduced, with the addition of a ‘Packer’ chemotherapy regimen (weekly vincristine during radiotherapy, followed by eight cycles of CCNU, cisplatin and vincristine). However, chemotherapy brings its own adverse effects including peripheral neuropathy, hearing loss, renal failure and myelosupression.



In the high risk group of children, the priority is still to improve survival. The 5YS rates are still 30-50 per cent despite the addition of chemotherapy to CSART. The optimal chemotherapy regimen has yet to be defined, with new high-dose regimens promising improved survival.



However, there are few clinical data to help define treatment strategies in adults and young people, and this patient group does not have the same issues with the harmful late effects of CSA radiotherapy. Chemotherapy should not be used routinely outside the context of a clinical trial.



Primary CNS lymphoma_



Most patients are over 60 years with a male predominance. Immunosupressed patients, mostly HIV positive, are at far greater risk (up to 1000 times) than the general population. It is usually an aggressive high-grade malignant lymphoma, mainly B-cell, and patients typically present with focal neurological symptoms developing over a few weeks. Behavioural changes and seizures are also common.



Characteristic brain imaging features are of solidly enhancing mass lesions; typically in the periventricular regions, deep grey matter structures and corpus callosum. Lesions are more frequently frontal and multifocal.



Corticosteroid treatment usually results in marked initial reduction in mass effect and contrast enhancement, and can confound radiological diagnosis and localization of targets for stereotactic biopsy. Wherever possible, corticosteroid therapy should be avoided prior to biopsy.



A neuropsychological baseline evaluation should be carried out before treatment and repeated during and after treatment. Cognitive dysfunction is present in 83 per cent of patients at the time of diagnosis, but improvement is seen in up to 60 per cent of patients who achieve clinical remission after primary chemotherapy. However, radiotherapy and chemotherapeutic agents are neurotoxic and the neurocognitive risk is increased when these treatment modalities are combined. The aim is to achieve the right balance between long-term disease control and neurotoxicity. This is a particular issue with older patients.



Treatment options include steroid therapy, whole brain radiotherapy (WBRT) and chemotherapy. Surgery has no role apart from diagnostic biopsy.



WBRT has limited long-term efficacy and causes delayed neurotoxicity (at around 1-2 years). Neurotoxicity presents as dementia, ataxia and urinary incontinence. WBRT is not recommended as



Figure 14.7 Primary CNS lymphoma. A 56-year-old woman presenting with visuospatial disorientation and headache. Contrast enhanced MRI (axial and coronal slices) show a homogeneously enhancing periventricular lesion; biopsy revealed a high-grade B cell lymphoma. There was no evidence of systemic lymphoma.



First-line treatment except as palliation in patients unfit to receive chemotherapy. All good performance status patients should be offered high-dose methotrexate chemotherapy regimes. For patients who achieve a complete response, consolidation WBRT can increase 5YS to 65 per cent. However, in patients over 60 years, neurocognitive adverse effects are more likely to outweigh potential benefits Relapsed or refractory disease should be treated with salvage radiotherapy. Dexamethasone should be considered for short-term palliation.



Pineal tumours, of a variety of different histological types, make up 1-2 per cent of all CNS tumours. There are around 50 cases per year in the UK. The majority are germinomas (45 per cent), then astrocytomas (17 per cent), non-germinomatous germ cell tumours (NGGCTs) (16 per cent) and pineal parenchymal tumours (pineocytoma and pineoblastoma) (15 per cent). Meningiomas, pineal cysts and metastases are also seen.



Pineal tumours (including GCTs)



GCTs (Figure 14.8) are derived from pluripotential primordial germ cells, most commonly seen as gonadal (ovary/testis), mediastinal and intracranial tumours. They arise in the midline structures of the brain: pineal, third ventricle, suprasellar region and basal ganglia. Two-thirds are germinomas, one-third are NGGCTs made up of secreting GCTs (embryonal, yolk sac tumours and choriocarcinoma), teratomas (mature and immature) and mixed GCTs.



Intracranial germinomas are histologically identical to testicular seminoma, do not usually have raised CSF and/or serum tumour markers and are extremely radiosensitive. The secreting GCTs are characterized by significant secretion of alpha-fetoprotein (AFP) or human choriogonadotropin (b-HCG) detectable in the CSF and blood.



Since they are more frequent in children (up to



Diagnosis, immediate management and staging requires craniospinal MRI, relief of hydrocephalus, CSF sampling for tumour markers and cytology. High levels of AFP/b-HCG are pathognomic of secreting NGGCTs, replace the need for biopsy and can be used to monitor response to chemotherapy or remission status on surveillance. Biopsy and endocrine assessment are indicated for all other cases.




Figure 14.8 Germ cell tumour. An eight-year-old boy presenting with diabetes insipidus. Tumour markers revealed elevated beta-human chorionic gonadotrophin. Axial, coronal and sagittal MRI shows a contrast-enhancing midline suprasellar tumour typical of a germ cell tumour.



A



8 per cent of childhood CNS tumours), many of the principles of adult management have been adapted from current childhood guidelines.



Treatment and prognosis are diagnosis-dependent. Germinomas have a 90 per cent cure rate with craniospinal radiotherapy alone. NGGCTs have a worse prognosis and require multi-modality therapy with platinum-based chemotherapy, resection of any residual tumour and then focal radiotherapy. Teratomas require surgery only. Pineocytomas are treated with maximum tumour resection and adjuvant radiotherapy. Pineoblastomas are managed as all other supratentorial PNETs. Astrocytic tumours are managed as astrocytomas elsewhere.



Pituitary tumours_



Pituitary adenomas (Figure 14.9) arise from the anterior pituitary and account for 10 per cent of intracranial tumours. Most are benign, but atypical tumours occur. Pituitary carcinoma is exceedingly rare, diagnosed by the presence of craniospinal or systemic metastases rather than local invasion, with a poor prognosis. It is thought to arise from a benign adenoma rather than de novo, and there is no obvious link between previous radiotherapy and



Figure 14.9 Pituitary adenoma.



A 70-year-old man presenting with bitemporal hemianopia. Coronal and sagittal MRI show a large peripherally enhancing pituitary macroadenoma invading the left cavernous sinus. Histology revealed a silent corticotroph.



They present with hormonal effects, either over - or underproduction, or mass effect on the pituitary stalk with visual defects, typically a bitemporal hemianopia due to optic chiasm compression. Rarely, there may be cranial nerve palsies from cavernous sinus involvement (III, IV, V1 and V1,2) causing ptosis and double vision, or visual loss due to direct compression of the optic nerve. Temporal lobe epilepsy occasionally occurs due to direct extension. Hypothalamic disturbances including diabetes insipidus (DI) and (rarely) pituitary apoplexy also occur. They are sometimes seen as incidental findings on MRI.



Pituitary apoplexy occurs when there is acute infarction or haemorrhage into the pituitary, and causes abrupt onset of headache, diplopia, visual loss and impaired consciousness, followed by panhypopituarism. It is more common in pregnancy and following trauma and diabetic ketoacidosis. Management requires steroids and occasionally decompressive surgery.



Malignant transformation. Rarely, metastases and lymphoma are found in the pituitary fossa.



Pituitary adenomas are classified according to:



1  Size: microadenomas (more common) or macroadenomas depending on whether the tumour is less than or greater than 10 mm in diameter.



2  Histology: acidophilic, basophilic or chromophobic derivation and hormonal staining.



3  Hormonal function: functional (hormone-secreting) or non-functional (30 per cent).



Prolactinomas are the most common secreting adenomas (70 per cent), 15 per cent secrete GH causing acromegaly and 5 per cent secrete adrenocorticotropic hormone (ACTH) causing primary Cushing syndrome. Thyroid-stimulating hormone (TSH) or gonadotroph hypersecretion is rare.



Initial investigation includes MRI of the pituitary region, full endocrine assessment (many patients will require life-long hormonal replacement, which may start at presentation, or years later) and careful charting of the visual fields. The



Majority will undergo surgery. However, medical therapy alone with dopamine agonists may be sufficient in prolactinomas, and, in tumours found as incidental findings which are non-functioning and not causing mass effect, no therapy may be necessary.



The role of surgery is to obtain the histological diagnosis, to achieve decompression of the optic chiasm and to produce an early reduction in hormone levels if required. Surgery is usually via the trans-sphenoidal route (which is well tolerated and allows visualization of the gland and tumour). More extensive tumours may require a frontal craniotomy.



Radiotherapy is given following surgery to reduce the risk of recurrence, and contributes to control rates of around 95 per cent at ten years. The broad indications for radiotherapy are for non-functioning tumours with incomplete removal (especially around the cavernous sinus), a large mass at diagnosis (the large silent corticotroph especially prone to early recurrence), recurrence after surgery alone, and failure of surgery to produce a hormonal ‘cure’ in functional tumours.



Radiotherapy carries an increased risk of hypopituitarism and the need for full hormonal replacement. This tends to develop many years after radiotherapy, but this will depend on the ‘reserve’ left by the tumour and the extent of surgical excision. The risk of recurrence (which may well be managed by further surgery) needs to be balanced against the risk of pituitary hypofunction. In young patients, radiotherapy can be delayed to maintain reproductive capabilities. Similarly, it can be avoided in older patients with normal pituitary function as they may die from other causes before recurrent tumour develops. The risk to visual function from conventionally fractionated radiotherapy is very low.



Surgery will cure 60-80 per cent of acromegalics. Radiotherapy is necessary in the surgical failures but produces a slow fall in GH levels, which may continue over many years. About 80 per cent are cured at ten years, particularly those with lower GH levels at presentation. Symptomatic patients will require medical therapy with somatostatin analogues in the meantime.



Surgery will cure 80 per cent of Cushing's, and again radiotherapy is indicated for the surgical failures. The fall in ACTH occurs over many months with radiotherapy. Excess ACTH can be acutely life-threatening and patients with significant hypersecretion after surgery should be considered for adrenalectomy.



Up to 90 per cent of prolactinomas will respond to cabergoline, which produces a fall in prolactin and a reduction in tumour mass. The clinical picture, with a markedly raised prolactin and subsequent response to cabergoline, is diagnostic, and biopsy is not indicated for small tumours confined to the pituitary fossa. However, macroadenomas threatening vision require surgery and radiotherapy. It is important to be aware that any pituitary tumour may cause a moderate rise in prolactin due to pituitary stalk compression.



Craniopharyngiomas_ than subtotal resection (60-90 versus 30-50 per cent), but may cause increased neuroendocrine, neurocognitive and visual deficits. Adjuvant radiotherapy will improve performance-free survival after a subtotal resection. The tumour capsule may be difficult to resect as it is usually adherent to the adjacent brain tissue. Cyst rupture may cause a chemical meningitis.



Currently, adjuvant radiotherapy is recommended in all adults. In children, radiotherapy is only given routinely to older children after subtotal resection in an attempt to balance the neurocognitive and neuroendocrine morbidity of radiotherapy.



Chordomas and chondrosarcomas



Craniopharyngiomas are slow growing, benign tumours but can cause significant morbidity, especially in younger patients with hypothalamic involvement. They account for 2 per cent of all adult CNS tumours, but 8 per cent of those in childhood (median age of eight years at presentation).



Chordomas are thought to arise from the remnants of the primitive notochord, and may arise anywhere within the axial skeleton. However, the base of skull, clivus and the sacrococcygeal regions are the most frequent sites. Childhood chordomas are more aggressive than in adults, and may metastasize to bone, lung and skin. The overall 5YS is around 65 per cent.



Adults usually present with headaches and visual field defects (typically a bitemporal hemi-anopia due to chiasmal compression), while children present with diabetes insipidus, endocrin-opathies, behavioural disturbances and visual failure. Involvement of the hypothalamus can lead to hyperphagia and obesity. Compression of the third ventricle causes hydrocephalus and raised ICP.



They present with symptoms related to local invasion. A chordoma arising in the clivus will produce lower cranial nerve palsies, dysphagia, dysarthria and motor weakness. A chordoma arising in the sacrum will involve the sacral nerve roots, causing pain and sphincter disturbance.



They originate from the remnants of Rathke’s pouch and most are suprasellar, though they may occur within the sella or adjacent to it. Over half are entirely cystic (containing cholesterol-laden fluid), 15 per cent are solid, and the rest are mixed.



Preoperative opthalmological and endocrine work-up is essential. Imaging is usually diagnostic: calcification is seen on CT; MRI will distinguish the solid and cystic components.



Surgery is the mainstay of treatment, usually via a transphenoidal route. Progression-free survival is greatly improved with complete rather



Surgery via ‘open door maxillotomy’ is the mainstay of treatment, but the location and invasive nature often prevents complete resection necessitating adjuvant radiotherapy. Chordomas are radioresistant, requiring doses up to 70 Gy, which is not possible, even with IMRT, due to the proximity of critical structures (the brainstem for clival lesions, the bowel for sacrococcygeal lesions). There is now an established role for proton therapy for base of skull chordoma.



Base of skull chondrosarcomas present clinically like chordomas but, despite their name, behave in a more benign fashion. Treatment is also radical surgery followed by adjuvant radiotherapy, again preferably with protons due to radioresistance.



Benign tumours of Schwann cells are called schwannomas, and may involve any cranial nerve, spinal root or peripheral nerve. Most commonly, they occur on the vestibulocochlear, trigeminal and facial cranial nerves. Bilateral acoustic neuromas are seen in neurofibromatosis type 2.



Nerve sheath tumours



Vestibulocochlear schwannomas (Figure 14.10) present with progessive unilateral hearing loss, tinnitus and vertigo. Facial sensory loss and facial weakness, due to compression of the trigeminal and facial nerves, develop when the tumour extends beyond the internal auditory meatus. Eventually, with neglected tumours, brainstem compression and obstructive hydrocephalus develop.



Treatment is required for progressive tumours, either surgery or radiotherapy. Complete excision of small tumours, with microsurgical dissection techniques, is curative with low morbidity although there is now a greater trend to treating these tumours with stereotactic radiosurgery. However, only surgery can relieve brain stem compression. Large acoustic neuromas lead to severe or complete sensorineural deafness, and this is inevitable following surgical excision. Salvage surgery is used for recurrence following radiotherapy.



Radiotherapy for these tumours is either conventionally fractionated (as stereotactic radiotherapy or IMRT) for larger lesions or single fraction gamma knife or linear accelerator based radiosurgery for smaller lesions. Control rates for all types of radiotherapy are consistently above 90 per cent, with hearing preservation at 75 per cent with radiosurgery and 85 per cent with fractionated regimes.



Malignant peripheral nerve sheath tumour (MPNST) originates from peripheral nerve sheaths, with up to 20 per cent associated with neurofibromatosis type 1. The most common sites are the trunk and extremities, but, extremely rarely, they may be seen in association with a cranial nerve (YIII, V and VIIth) and the spinal column. Despite surgery and radiotherapy, the overall survival is only around 66 per cent.

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