Box 16.1 shows WHO classification of brain tumours. WHO grading system (Box 16.2) is important in deciding management and prognosis. Molecular features can be incorporated in this grading system to yield important prognostic information. Clinico-pathological features of individual tumours are discussed later.

Box 16.1
WHO classification of brain tumours

Choroid plexus tumours

• Papilloma and carcinoma

Embryonal tumours

• Medulloblastoma and its variants (grade 4)

• Supratentorial primitive neuroectodermal tumour (PNET) (grade 4)

Pineal tumours

Neuronal tumours

• Ganglioglioma

• Anaplastic ganglioglioma

• Neurocytoma

Tumours of cranial/spinal nerves

Tumours of the meninges

• Meningioma (grade 1–3)

Tumours of uncertain histogenesis

Haematopoietic neoplasms

Germ cell tumours

Tumours of sellar region

• Pituitary adenoma and carcinoma

• Craniopharyngioma

Metastatic tumours

Box 16.2
WHO grading of primary CNS tumours

Grade 1 – tumours with low proliferative potential and tumour growth by expansion. Generally curable by surgery alone.

Grade 2 – tumours with low proliferative potential but exhibit infiltration. Surgery alone is rarely curative and these tumours can progress to grade 3–4 tumours.

Grade 3 – tumours with cytological evidence of malignancy such as nuclear atypia, endothelial proliferation and mitotic activity. These are rarely curable.

Grade 4 – highly malignant tumours often with necrosis. These are aggressive.

Presentation

Brain tumour can present with non-specific as well as specific features. Non-specific features are headache (50%) and vomiting due to raised intracranial pressure. Specific features are due to location of the tumour. Lateralizing signs (50%) include hemiparesis, aphasia and visual field defects. Seizure, generalized, partial or focal, can be the presenting symptom in 50% of high-grade and 25% of low-grade gliomas. Stroke-like presentations occur mainly due to bleeding associated with the tumour. It can occur in 5–8% of high-grade and 7–14% of low-grade tumours. Altered mental status can be a presenting feature of primary brain tumour, but is more commonly a presentation of multiple brain metastases.

Investigations

Imaging

CT scan

Contrast enhanced CT scan is usually the initial investigation in patients suspected to have a brain lesion. CT scan is not an ideal investigation for low-grade tumours or tumours in the posterior fossa. CT scan may also show features of oedema, hydrocephalus, haemorrhage and calcification depending on the histological variant of brain tumour. Table 16.1 shows radiological appearance of common tumours.

Table 16.1 Radiological appearance of common brain tumours

Type of tumour	Imaging characteristic
Pilocystic astrocytoma	Well-circumscribed, contrast enhancing tumour with a cystic or enhancing mural nodule.
Grade II astrocytoma	Isodense or hypodense on CT. Hypointense on T1W image and hyperintense on T2W and FLAIR images. No contrast enhancement and if present suggest malignant transformation. No associated cerebral oedema.
Oligodendroglioma	Same CT/MRI as grade II astrocytoma; but can be associated with areas of contrast enhancement, calcification and haemorrhage.
Anaplastic astrocytoma and GBM	CT – irregular hypodense lesions with varying degree of contrast enhancement and associated oedema and pressure effect. Ring-like enhancement surrounding an irregular shaped necrosis suggests GBM. Some of the high-grade tumours can be non-enhancing particularly in the elderly. MRI – irregular hypointense on T1W and irregular contrast enhancement and hyperintense on T2W and FLAIR, representing tumour and oedema.

Anaplastic oligodendroglioma Contrast enhancing heterogeneous mass with frequent cystic components, calcifications and necrosis. Medulloblastoma

CT – hyperdense midline mass with associated hydrocephalus. Marked contrast enhancement. Sometimes show calcification cysts, haemorrhage and nodular seedling.

MRI – heterogeneous hypo or isointense on T1W with slightly heterogeneous contrast enhancement. Iso-hyperintense on T2W.

Ependymoma Heterogeneously enhancing lesion with cystic component. There may be associated calcification and haemorrhage. Primary CNS lymphoma Solitary or multiple periventricular homogenously enhancing diffuse lesions (‘cotton wool’ appearance). Ring enhancement common in immunocompromised patients. Meningioma Homogenously contrast enhancing lesion arising from the dura. There is little associated brain oedema. There will be enhancement of dura (’dural tail’ sign). Craniopharyngioma Solid and cystic lesion on CT scan. MRI appearance depends on the composition of tumour. T1W can be hypo, iso or hyperintense with variable contrast enhancement. T2W can also be hypo, iso or hyperintense. Pituitary Contrast enhancing seller/suprasellar lesion on CT. T1W iso-hypointense and T2W hyperintense. Metastasis Solitary or multiple irregularly contrast enhancing lesion which may be solid or cystic at the junction of grey and white matter. Location and characteristic depends on type of tumour.

Evaluation of the craniospinal axis

MRI of the craniospinal axis and CSF evaluation is needed for tumours with a high risk of CSF dissemination such as medulloblastoma, germ cell tumours, CNS lymphoma, PNET and ependymoma (Figure 16.2). CSF evaluation includes CSF biochemistry (typically elevated protein >40 mg/dL and reduced glucose <50 mg/mL), cytology and in cases of suspected germ cell tumours, the estimation of tumour markers (AFP and beta hCG) in CSF and serum. Evaluation of the craniospinal axis is best done prior to surgery or >3 weeks after surgery to avoid false positive results.

Figure 16.2 Multiple contrast-enhancing tumour nodules in ependymoma suggesting leptomeningeal disease.

Tissue diagnosis

Histologic confirmation is necessary in all patients prior to definite treatment. Biopsy is obtained by either stereotactic guided techniques or open biopsy. In intrinsic brainstem tumours, biopsy may cause neurologic damage and hence may be avoided. Biopsy is avoided in patients with multiple brain metastases from a known primary, optic meningioma and CNS lymphoma in HIV positive patients showing typical radiological findings.

Prognostic factors

The outcome of brain tumours depends on the following factors:

1 Pathology – outcome depends on pathologic type and grade. High-grade tumours have poor prognosis. Recently molecular factors are shown to be important in certain tumour types.

2 Age – increased age is associated with poorer outcome.

3 Performance status – is an important factor in outcome and guiding treatment.

4 Extent of surgical resection – based on observational studies, patients with less residual disease after surgery have a better prognosis.

Principles of management

General medical management

Steroids

Steroids may improve symptoms by reducing intracranial pressure. The most commonly used agent is dexamethasone which is started at a dose of 2–16 mg daily (low doses given once daily and higher doses as 2–4 equally divided doses) and titrated against the patient’s symptoms. The optimal dose is just above that at which symptomatic deterioration occurs. If there is no symptomatic improvement, steroids should be stopped.

Anti-epileptics

All patients who have had a seizure should be treated with an anti-epileptic drug (AED); prophylactic use of anti-epileptics is not recommended. Many anti-epileptics are enzyme-inducers, and hence should be carefully monitored when they need to be used concurrently with drugs metabolized by cytochrome p450 enzyme system.

Analgesics

Patients requiring pain control are managed according to the WHO analgesic ladder (p. 66).

Surgical management

Surgery in brain tumours helps in pathological diagnosis, symptom control and definite treatment.

Biopsy can be either stereotactic guided or an open biopsy. Surgery is useful in relieving pressure symptoms as well as decreasing the frequency and intensity of seizures. Surgical resection is constantly evolving in brain tumours. It is common practice to confirm the diagnosis with an intraoperative frozen section or smear prior to attempting a full resection. Complete or maximal resection with minimal injury to neighbouring critical structures is the aim of surgery. The importance of surgical resection in specific tumours is discussed later. The various resection techniques are:

1 Image guided stereotactic resection – is useful in technically challenging locations such as the peri-thalamic region, to minimize critical structure injury.

2 Neuronavigation guided resection – distortion of brain anatomy by tumour and oedema makes surgical resection according to conventional landmarks difficult. Neuronavigation systems allow registration of stored imaging data which can be incorporated with real time intra-operative imaging using intra-operative ultrasound or MRI. This helps surgeons to guide resection based on real time shift of structures during operation.

3 Cortical mapping awake craniotomy – is useful in resection of tumours inside or adjacent to functional brain areas. Intraoperative cortical or subcortical stimulation helps to map functional areas. Initial craniotomy and preliminary stimulation are done with the patient asleep. After arousal, under sedative/hypnotic anaesthesia, the patient responds to motor or language commands but with subsequent amnesia.

4 Fluorescent guided surgery – an evolving technique for malignant gliomas.

Radiotherapy in brain tumours

Radiotherapy has a major role in the management of CNS tumours. Radiotherapy is proven to improve local control and/or survival in grade 3–4 tumours whereas its role in grade 2 tumours is doubtful and has limited role for grade 1 tumours. Radiotherapy is delivered by the following methods:

1 External beam radiotherapy is commonest mode of delivery of radiotherapy to the brain. Immobilization and proper localization is important in the delivery of EBRT. Target volume depends on the type of tumour and intention of treatment.

2 Stereotactic technique – this technique involves improved localization of tumour and precision. Treatment is delivered either as multiple fractions using linear accelerator (called stereotactic radiotherapy) or as single fraction (called radiosurgery) using gamma knife, a special machine for cranial radiosurgery.

3 Charged particle radiotherapy – mainly protons, which deposit the energy only at a depth and hence useful in skull base tumours.

A summary of radiotherapy details for common tumours are given in Table 16.2.

Table 16.2 Radiotherapy for common brain tumours

Radiation tolerance and reactions

Radiation to the brain can cause structural damage to critical structures if attention is not paid not to exceed the tolerance dose of individual structures.

Acute radiation reactions may manifest up to 6 weeks following completion of irradiation. These reactions are generally those of raised intracranial pressure, fatigue and worsening of neurology. Vomiting is particularly common in patients receiving radiotherapy to the brainstem region.

Early delayed (intermediate) side effects usually appear from 6 weeks to 6 months following radiotherapy and are due to changes in capillary permeability and transient demyelination. Symptoms include headache, somnolence syndrome, lethargy and frequently recurrence of the original presenting features. Recovery is spontaneous but can be accelerated by steroids.

Delayed radiation reaction develops 6 months after radiotherapy. This is thought to be due to white matter injury secondary to vascular injury, demyelination and necrosis. The most serious form of this is radiation necrosis which peaks at 3 years. Conventional imaging fails to distinguish this from recurrent tumour and special imaging is therefore needed (p. 265). Treatment is with steroids and debulking. Other late effects include, depending on the area irradiated, memory problems, pituitary failure, hearing loss, visual changes and second malignancies.

Chemotherapy in brain tumours

Chemotherapy has an established role in paediatric brain tumours mainly as a substitute for radiotherapy. The role of chemotherapy in adult brain tumours is increasing. The active agents are nitrosoureas (carmustine and lomustine), procarbazine, temozolomide, platinum and vincristine. The role of chemotherapy in specific brain tumours is discussed later in this chapter and the commonly used chemotherapy regimens are given in Box 16.3.

Box 16.3
Chemotherapy regimes in brain tumour

PCV (glioma)

• Procarbazine 100 mg/m² (max 200 mg) oral Day 1–10

• CCNU 100 mg/m² (max 200 mg) oral Day 1

• Vincristine 1.5 mg/m² (max 2 mg) IV Day 1

Cycles repeated every 6 weeks for 6 cycles

Temozolomide (glioma)

• Concomitant – 75 mg/m² D1–D42 oral, 1 hour prior to radiotherapy & morning dose on weekends

• Adjuvant and palliative – 150 mg/m² D1–5 oral for first cycle, then 200 mg/m² D1–D5 total 6 cycles (adjuvant starting 4 weeks after radiotherapy)

Packer regime (medulloblastoma and PNET)

• Concurrent with radiotherapy – vincristine 1.5 mg/m² (max 2 mg) weekly with radiotherapy, then 6 weeks of rest followed by:

• A combination of:

• CCNU 75 mg/m² every 6 weeks and cisplatin 68 mg/m² every 6 weeks and vincristine 1.5 mg/m² (max 2 mg) for 3 consecutive weeks. Cycle repeated every 6 weeks for total of 8 cycles

New agents in brain tumours

A number of biological agents have been tried recently in the management of brain tumours, particularly in gliomas. Since gliomas exhibit marked neovascularization, anti-angiogenesis inhibitors are an attractive option. Bevacizumab has been studied alone and in combination with chemotherapy in recurrent GBM.

Since EGFR are frequently amplified and overexpressed in GBM, agents such as cetuximab and tarceva seem to be attractive agents. Other target molecules under investigation include PDGF antagonists (e.g. imatinib) and farnesyltransferase inhibitors (e.g. tipifarnib).

Follow-up

Follow-up consists of clinical evaluation with attention to neurological examination and assessment of seizure control. MRI is the image of choice whenever imaging follow-up is indicated. Visual field and hormonal function assessments are important in sellar tumours.

Clinico-pathological features and management of specific tumours

Glioma

Astrocytomas diffusely infiltrate surrounding brain. Pilocytic astrocytoma (grade 1) occurs in children and young adults and are located in the optic tract, hypothalamus, basal ganglia and posterior fossa. These tumours grow slowly and stabilize spontaneously. Diffuse astrocytoma (grade 2) is a low-grade tumour. Anaplastic astrocytoma (grade 3) and glioblastoma multiforme (grade 4-GBM) are high grade tumours. Anaplastic astrocytoma is distinguished from low-grade tumours by greater cellular differentiation and hyperchromasia, more frequent mitoses and prominent small vessels lined by epithelioid endothelial cells. Glioblastoma is distinguished by increased cellularity, pleomorphism, giant cells, abnormal mitotic figures and endothelial cell proliferation. Necrosis surrounded by nuclei aligned in pseudopalisading pattern is characteristic. Astrocytomas stain for glial fibrillary acidic protein (GAFP).

Oligodendroglial tumours have typical histological appearance of evenly distributed cells with uniform and rounded nuclei with perinuclear halo. Mixed tumours are composed usually of an oligodendroglial component and an astrocytic component. Their overall prognosis and treatment is dictated by the most aggressive component.

Treatment of pilocytic astrocytoma

Complete surgical resection alone is adequate which results in a 20-year survival of 80%. In patients for whom a complete resection is not possible, maximal safe resection should be attempted followed by observation. In the majority of these patients the tumour does not progress. A second surgery may be attempted during progression, if feasible, followed by non-surgical management. Patients with unresectable tumours with progressive neurological deficit are treated with radiotherapy and carboplatin-based chemotherapy.

Treatment of low grade glioma (WHO grade 2)

Diffuse astrocytoma, oligodendroglioma (Figure 16.3) and mixed oligoastrocytoma are grouped together as low-grade glioma. These tumours mainly affect the young adults (mean age of 35 years for astrocytoma and 45 years for oligodendroglioma). Patients generally present with seizures and in the majority adequate seizure control with serial MRI monitoring will be sufficient. Many of these patients have slow growing tumours. There are two main patterns of progression – secondary gliomatosis cerebri and malignant transformation. Secondary gliomatosis cerebri is characterized by diffuse extension of the tumour sometimes to the opposite hemisphere and it often remains low-grade. Malignant transformation involves progression to a high-grade tumour with characteristics of anaplastic astrocytoma, anaplastic oligodendroglioma or glioblastoma. Imaging shows new areas of irregular contrast enhancement in a previously non-contrast enhancing tumour.

Figure 16.3 MRI scan of oligodendroglioma in right temporal area. MRI scan of oligodendroglioma will exhibit the same features of astrocytoma (A); however oligodendroglioma can have subtle contrast enhancement (arrows on B) and calcification.

Surgery

The role of surgery in grade 2 tumours is unclear. When safe complete or near complete resection is feasible, it may be attempted. A recent retrospective study showed that gross total resection (complete resection of preoperative FLAIR abnormality) improved survival (10-year OS 76%) compared with near total resection (<3 mm thin residual FLAIR abnormality around resection cavity) (10-year OS 57%) and subtotal resection (residual nodular FLAIR abnormality) (10-year OS 49%; p = 0.017). Incomplete resection is only indicated to control specific symptoms such as seizures or intracranial pressure which may be relieved with removal of the appropriate region of tumour. The majority of patients are followed up or treated with non-surgical treatment after biopsy.

Radiotherapy

Immediate radiotherapy is as effective as delayed radiotherapy (i.e. delayed until progressive symptoms). In a symptomatic patient, radiotherapy reduces the tumour size and leads to symptomatic improvement in 50–75%. However, in patients with well-controlled seizures early radiotherapy does not improve overall survival compared with radiotherapy deferred until clinical progression, but improves the progression-free interval. A randomized study of early vs. delayed radiotherapy showed a 5-year overall survival of 63% with early radiotherapy compared with 66% with delayed radiotherapy. The 5-year disease free survival was better (44% vs. 37% p = 0.02) with early radiotherapy. There is no clinical benefit beyond a radiotherapy dose of 45–50 Gy, and higher doses cause significant side effects of fatigue and poor emotional functioning.

Chemotherapy

Chemotherapy can improve symptoms and lead to a radiologic response. The role of chemotherapy in newly diagnosed disease is however undefined. Chemotherapy is used in malignant transformation. Oligodendroglioma with allelic loss of chromosome 1p/19q usually responds to chemotherapy with alkylating agents (Box 16.3).

Outcome

The median survival of low-grade glioma is 5–8 years. Oligodendroglioma has a better prognosis of 12–16 years.

Management of recurrence or progression after first definitive treatment

Management of recurrence or progression depends on previous treatment. Radiotherapy can be considered for those who have not previously received radiation treatment. Chemotherapy is the option in patients who progress after previous radiotherapy.

Gliomatosis cerebri

Gliomatosis is characterized by diffuse infiltration of the brain with malignant glial cells. It usually presents with headaches, personality changes or seizure. MRI with FLAIR is more sensitive in detecting the lesion which shows diffuse isointense to hypointense lesions on T1W and hyperintense lesions involving at least two lobes of the brain on T2W & FLAIR. Surgery is of little benefit but radiotherapy (principles same as low grade glioma) can stabilize or improve the disease. Chemotherapy can be attempted when radiotherapy is technically difficult. Median survival is around 12 months.

Treatment of high-grade (malignant) glioma (WHO grade 3 and 4)

High-grade gliomas account for around 50% of brain tumours. These can be either anaplastic glioma (grade 3) or GBM. These tumours are highly aggressive and the aim of treatment is to improve neurological deficit, quality of life and to increase survival. Optimal medical management includes steroids to improve oedema, anti-convulsants in patients who have had seizures and rehabilitation.

GBM

GBM accounts for 75% of malignant gliomas. The median survival is around 1 year. There is no randomized data showing superior survival with surgical resection compared with biopsy alone. Maximal resection will improve time to progression as well as tolerability to subsequent radiotherapy and hence, maximal safe resection is recommended.

Adjuvant radiotherapy improves median survival of GBM from 14 weeks to 40 weeks and is given as a dose of 58–60 Gy in 1.8 to 2 Gy per fraction. Hence patients aged <70 years with good performance status (0–1) are considered for radical radiotherapy, whereas patients aged >70 years and performance status of 0–2 may be considered for short course radiotherapy. Patients with poor PS and significant neurological deficit are treated with supportive measures (Box 16.4).

Box 16.4
Treatment of glioma

• Surgical resection alone is the treatment option for pilocytic astrocytoma

• Low-grade glioma is treated with active surveillance, complete resection or biopsy followed by delayed radiotherapy

• High-grade glioma is treated with:

• Radical radiotherapy (with concomitant and adjuvant temozolomide for GBM) for <70 years, PS0–1 and no significant neurological deficit

• Palliative radiotherapy for >70 years and PS0–2, or <70 years with significant neurological deficit or midline tumours

• Supportive care for PS>2 or severe residual deficit (e.g. hemiplegia, confusion)

A meta-analysis of adjuvant chemotherapy trials showed a slight improvement in median survival of 2 months. Recently a randomized study reported a significant survival benefit with concurrent and adjuvant temozolomide. In this study of newly diagnosed GBM patients, temozolomide (75 mg/m²) given concurrently with radiation followed by adjuvant monthly treatment (200 mg/m² days 1–5) up to 6 months produced a survival advantage at 2 years of 16% which was sustained at 4 years compared to radiation alone (10–26%). Hence this is the treatment of choice for GBM. However, the benefit of temozolomide is only seen in patients with methylation of the O⁶-methylguanine-DNA methyltransferase (MGMT) gene promoter. The overall survival was increased in patients with methylated MGMT promoter regions compared to those with unmethylated MGMT promoter regions (18.2 months and 12.2 months, p < 0.001). However test for methylation of the MGMT gene promoter is not routinely used, to select patients for concurrent chemoradiotherapy.

Anaplastic glioma (AG)

AG constitutes 25% of high-grade glioma. Patients with anaplastic astrocytoma have a median survival of 3 years and those with anaplastic oligodendroglioma have a better prognosis, particularly those with loss of heterozygosity of 1p and 19q (median survival 5–7 years). Current standard treatment of AG is maximal cytoreduction with postoperative radiotherapy.

The value of temozolomide in grade 3 astrocytoma and oligodendroglioma is not proven. Patients with anaplastic oligodendroglioma demonstrating LOH on 1p/19q have 60–80% response rates with alkylating chemotherapy. Despite that, early administration of adjuvant chemotherapy before or after radiotherapy does not impact on overall survival and there is no difference in efficacy between PCV and temozolomide chemotherapy.

Management of recurrence and progression

In the majority of patients (>80%) with high-grade glioma, tumours recur within a 2–3 margin of the original tumour (Figure 16.4). Repeat surgery is an option for those with favourable prognostic features such as age <50 years, good performance status, progression free survival of >6 months and well circumscribed tumour, which offers a median survival of 6–8 months with 20% 1-year survival. In this group of patients polymer-based carmustine chemotherapy in a wafer (Gliadel) is proven to be useful. A randomized study showed an increased 6-month survival from 44% to 64% (p = 0.02) and median survival from 23 to 31 weeks with Gliadel wafers.

Figure 16.4 GBM recurrence. GBM can spread along the white matter track and manifest with recurrence away from the original lesion. This patient, who had left temporal lobectomy (B-long arrow) for GBM (A), presents with a non-homogenous contrast enhancing recurrent lesion (B-arrow head), which indicates spread along the white matter track.

An alternative treatment option is radiosurgery if the recurrent tumour is small. In patients who are not suitable for the above options palliative chemotherapy should be considered. PCV results in 20–50% response with 4–8 months survival.

Brainstem glioma

Brainstem gliomas are rare in adults. Diffuse intrinsic pontine gliomas are generally high grade whereas exophytic tumours are low grade. These tumours usually present as multiple cranial nerve paralysis, ataxia and hemiparesis. MRI shows diffuse enlargement of the pons on T1W images and enhancement is seen in high-grade glioma. Surgery is an appropriate treatment for exophytic low-grade lesions whereas inoperable low-grade lesions and intrinsic lesions are treated with involved field radiotherapy. The median survival of non-enhancing lesions is in the region of 7 years and of enhancing lesions is approximately 11 months.

Ependymoma

Ependymomas (grade 2) are slow growing tumours arising from the ependymal or subependymal cells surrounding the ventricles, spinal canal or filum terminale. These are typically low-grade but exhibit a high risk of recurrence and can spread through the CSF. They are rarely infiltrative and seldom metastasize outside CNS. Subependymoma, which occur in the cerebral ventricles and myxopapillary ependymoma, which occurs in the filum terminale are grade 1 variants of ependymoma. Histologically these tumours consist of uniform round cells with widespread pseudorosette formation. Maximal surgical resection followed by postoperative radiotherapy is the treatment of choice in adults (Table 16.2). Local radiotherapy is recommended if spinal MRI and CSF cytology are clear. Craniospinal RT is recommended only in cases of neuraxis spread. There is no recommended role for chemotherapy, except in recurrence after radiotherapy. Postoperative radiotherapy increases 5-year survival from 18% to 68%.

Choroid plexus tumour

Choroid plexus papilloma (grade 1) usually presents as an intraventricular mass in children. These are cured with excision. Choroid plexus carcinomas (grade 3) are also common in children and behave aggressively with extensive ventricular and subarachnoid space spread. Choroid plexus carcinoma is treated with a combination of surgery and radiotherapy, with or without chemotherapy.

Medulloblastoma and PNET

Medulloblastoma (grade 4) commonly occurs in children, but can also occur in adolescents and adults. It usually affects the cerebellum and can spread locally, through CSF and outside the CNS. Histologically the tumour consists of small primitive round or spindle cells which might express neuron specific enolase, synaptophysin, Leu-7 and protein gene product 9.5.

PNET (grade 4) are aggressive supratentorial tumours in children and young adults. Histology shows highly cellular diffuse sheets of cell with extensive necrosis. The prognosis is worse than medulloblastoma.

Treatment of medulloblastoma and PNET

In medulloblastoma, the extent of surgical resection correlates with survival and hence, maximal surgical resection is attempted in localized disease. All patients are treated with postoperative craniospinal radiotherapy followed by additional radiotherapy to the posterior cranial fossa. Radiotherapy with concurrent vincristine followed by adjuvant chemotherapy with cisplatin, CCNU and vincristine (Packer regime) is an effective regime (Box 16.3); but it is very toxic in adults (especially neurotoxicity) and hence sometimes radiotherapy alone may be used.

Acoustic neuroma (vestibular schwannoma)

Acoustic neuromas are tumours arising from the Schwann cell of the myelin sheath of the eight cranial nerves. These can occur sporadically (4–5th decade of life) or as part of NF2 (2nd–3rd decade of life). These are expansile slow growing tumours. Clinical presentation is usually with progressive sensorineural hearing loss (up to 95%). Large cerebello-pontine angle tumours can lead to trigeminal involvement and pressure effect on the cerebellum and brainstem can give rise to ataxia and lower cranial nerve (IX–XII) involvement.

Imaging shows a homogenously enhancing lesion close to internal auditory canal. Follow-up with regular imaging may be adequate for some patients. When treatment is indicated, for progressive tumours or large tumours with pressure symptoms, the treatment options are surgery and radiotherapy (either radiosurgery or fractionated radiotherapy). Surgery achieves a complete excision of 97% at the expense of complete hearing loss and transient facial palsy. Radiosurgery is appropriate for lesions of <3 cm size. Fractionated radiotherapy may preserve hearing in patients with good control rates; but long-term follow-up is needed.

Pineal tumours

Pineal tumours are common in children. Pineocytoma (grade 2) are slow growing tumours which are treated with surgery and radiotherapy. Pineoblastomas (grade 4) are aggressive tumours treated with surgery, radiotherapy and chemotherapy. Pineal parenchymal tumours of intermediate differentiation have an unpredictable clinical behaviour. Treatment recommendation varies from surgery alone to surgery followed by craniospinal radiotherapy. Management of pineal germ cell tumours is discussed below.

Germ cell tumours

Germ cell tumours occur in the midline structures, pineal, sellar, hypothalamic and third ventricular regions. The majority of patients are diagnosed between 11–20 years. Histological appearance is similar to their gonadal counterpart. Immunohistochemically germinomas may stain for placental alkaline phosphatase (PLAP) and hCG and non-germinoma may stain for hCG and AFP.

Presentation depends on the tumour type and location. These tumours usually arise from the pineal region and present with features of CSF obstruction and Parinaud’s syndrome (dorsal midbrain compression leading to failure of up gaze, nystagmus and light-near dissociation of pupil). Suprasellar tumours present with neuroendocrine deficits.

On imaging germinomas appear as a homogenously enhancing mass and non-germinomas as a heterogeneous mass with cysts, calcification and/or haemorrhage. Spinal imaging with MRI may show leptomeningeal disease in 10–15% of cases.

The role of surgery is mainly to obtain a tissue biopsy. In tumour marker positive disease (AFP above 25 IU/L or serum or CSF hCG of >50 IU/L in Europe and >100 IU/L in USA), imaging alone is sufficient prior to non-surgical treatment. Surgery may have a role in symptomatic residual masses after non-surgical management.

Germinoma is treated with craniospinal radiotherapy, which results in a 5-year survival of 90–95% and 10-year survival of 91%. Chemotherapy is being evaluated to avoid the need for craniospinal radiotherapy and to reduce the dose of radiotherapy in paediatric germinoma. Non-germinoma is treated with platinum based chemotherapy followed by radiotherapy. In non-germinoma, with radiotherapy alone the overall survival is only 10–30%, whereas combined modality treatment results in a 5-year survival of 45%.

Meningeal tumours

Meningiomas (Figure 16.5) account for 30% of primary intracranial neoplasms and occur predominantly in women. Grade 1 meningiomas (90% of meningiomas) are benign with a low risk of recurrence, atypical (grade 2) meningiomas (5–7%) have a high risk of local recurrence after complete excision and grade 3 meningiomas (3–5%) are aggressive. Papillary meningioma (grade 3) is seen in young patients, shows aggressive behaviour with frequent recurrences, brain invasion and metastasis. Anaplastic (malignant) meningioma is also aggressive.

Figure 16.5 CT scan of meningioma. A, A homogenously contrast enhancing lesion arising from the dura. B, Bone window showing increase in thickness of skull bone (hyperostosis) at the site of the tumour (arrows), a feature of meningioma.

An incidental finding on CT/MRI is one of the common modes of diagnosis. Presentation depends on the location of tumour. Base of skull tumours usually present with cranial nerve involvement whereas tumours over the convexity of the cerebrum present with headache or seizure.

Treatment of meningioma

Meningiomas can be observed if they are small and asymptomatic. Treatments of choice for progressive or symptomatic meningioma are either complete surgical resection if in an operable location or radical radiotherapy or radiosurgery, if in an inoperable site. Complete resection is usually difficult for skull base (Figure 16.6A), cavernous sinus and cerebellopontine angle meningiomas. After incomplete resection, either a policy of imaging surveillance with delayed radiotherapy on progression or immediate postoperative radiotherapy is adopted. The policy of image surveillance with delayed radiotherapy depends on:

1 Location of tumour – tumour near critical structures may cause neurological damage when it progresses and hence early radiotherapy is indicated (e.g. tumour near optic chiasma).

2 Grade of tumour – grade 2 and 3 tumours have a 5-year recurrence rate of 40–100% even after complete resection whereas that of grade I tumour is 7–12%. Hence all patients with grade 2/3 tumours are treated with immediate postoperative radiotherapy.

Figure 16.6 Tumours of the base of the brain. A, Homogeneously enhancing meningioma. B, Heterogeneously enhancing craniopharyngioma. C, Cystic enhancing pituitary adenoma.

Data suggest that postoperative radiotherapy improves local control compared with no radiotherapy after subtotal resection (15-year local control 81% vs. 49%; p = 0.0001).

Primary CNS lymphoma (PCNSL)

PCNSL has a higher incidence in immunocompromised individuals than in the normal population. It commonly presents in the third and fourth decades in immunocompromised individuals whereas it occurs three decades later in those who have a competent immune system. The usual presentations include focal symptoms, raised intracranial pressure, behaviour and personality changes and confusion. Biopsy shows diffuse large cell B cell lymphoma in 80–90%. Up to 20–40% patients have CSF involvement. Less than 5% people have systemic involvement. Tissue diagnosis is made from an open or stereotactic biopsy. Staging investigations include HIV testing, chest X-ray, CSF examination and slit lamp examination (10–20% have uveitis). Systemic staging is only indicated if B symptoms are present (see p. 306).

The role of surgery is limited to biopsy. Steroids may cause complete disappearance of tumour (ghost tumours) and hence should be avoided until tissue diagnosis. Current standard treatment is high-dose intravenous methotrexate with whole brain radiotherapy (40–50 Gy) which results in a 2-year survival of 43–73%. However this treatment is extremely toxic particularly in the elderly when 60–80% patients older than 60 years develop progressive leucoencephalopathy and cognitive dysfunction. Hence in the elderly chemotherapy alone with delayed radiotherapy is an alternative. In immunocompromised patients reduction of radiotherapy dose may be necessary to reduce toxicity.

Craniopharyngioma

Craniopharyngioma (Figure 16.6B) arises from the epithelial remnants of Rathke’s pouch. These are slow growing tumours often with a solid and cystic component, the latter filled with a fluid having a ‘motor oil’ appearance.

The clinical presentation is with pituitary hormonal abnormalities, pressure symptoms on the optic pathway (visual field defects) and neurological symptoms.

Surgical resection is the recommended treatment if feasible. Following incomplete resection or cyst decompression and biopsy, postoperative radiotherapy is indicated which results in a 5-year survival of 89% and 10-year survival of 77%.

Pituitary adenoma and carcinoma

Pituitary adenoma

Pituitary adenoma (Figure 16.6C) usually presents between the ages of 30–50 years. These are slow growing tumours with an insidious onset of symptoms. The usual presentation is hormonal dysfunction or symptoms resulting from pressure effects such as visual field defects.

Medical management is important in secretory tumours. Transphenoidal surgery is the standard surgery for secretory tumours other than prolactinoma and macroadenoma producing pressure symptoms. The indication for radiotherapy is relative and usually indicated in tumour progression after surgery, uncontrolled hormone production, extensive residual tumour and invasion of the cavernous sinus. Radiotherapy is usually given as stereotactic fractionated radiotherapy or radiosurgery. Radiotherapy controls hypersecretion in 80% patients with acromegaly, 50–80% with Cushing’s disease and 33% with hyperprolactinaemia. In non-secretory tumours, surgery followed by radiotherapy results in a 20-year progression free interval of >90%. The long-term side effects of radiotherapy are hypopituitarism, increased risk of a second cancer (20-year risk of 2.4%), and increased risk of cerebrovascular death (relative risk 4.1).

Pituitary carcinoma

Pituitary carcinomas are rare (0.2% of pituitary tumours). They often present with secretory features (Cushing’s or hyperprolactinaemia). There is limited literature, but the prognosis is poor with multiple local recurrences and metastatic spread.

Metastatic tumours of brain

Metastatic brain tumours are four times commoner than primary brain tumours and one quarter of all cancer patients develop brain metastases during their illness. The incidence of brain metastases is increasing because of the improved systemic control of many cancers. The commonest primaries are lung in whom 30–80% develop brain metastases, breast (20–30%) and gastrointestinal cancer. Other cancers include renal cell carcinoma (5–10%) and malignant melanoma (10–20%).

Presentation

Eighty percent of brain metastases are diagnosed after development of the primary cancer and 20% present with brain metastases prior to and simultaneously with the diagnosis of primary. Headache is the commonest symptom. Up to 20% can have seizures and lateralizing signs. 5–10% can present with an acute neurological deficit due to bleeding into the tumour or cerebral infarction.

Diagnosis

Contrast enhanced CT scan is usually diagnostic with more than half of the patients showing multiple metastases (Figure 16.7). The lesions are typically contrast enhancing and located in the junction between grey and white matter. MRI scan is useful in lesions in the posterior fossa, those with negative CT scans, those with suspected leptomeningeal disease and to confirm a solitary lesion if planning for surgical resection.

Figure 16.7 Various appearances of brain metastases. A, Bleeding metastasis (melanoma). B, Single cystic metastasis (mucinous carcinoma, breast). C, Multiple metastasis (lung cancer). D, Predominant posterior fossa metastases (HER2+ breast cancer).

Prognosis

Untreated symptomatic patients have a median survival of 4–8 weeks. With steroids the survival is 8–12 weeks. A prognostic classification is shown in Table 16.3.

Table 16.3 Prognostic groups in brain metastases

Prognostic group*	Definition	Median survival (months)
Class 1	Age less than 65 years, KPS ≥70, controlled primary disease and no extracranial metastases.	7.1
Class 2	Neither class 1 nor 2	4.2
Class 3	KPS <70	2.3