Neurooncology

Tumour syndromes

Syndrome	Gene / product	Tumours
Neurofibromatosis type I	NF1 AD 17q11 (neurofibromin)	Optic glioma, other juvenile pilocytic astrocytomas, neurofibromas, malignant peripheral nerve sheath tumour (MPNST)
Neurofibromatosis type II	NF2 AD 22q11.2 (merlin)	Bilateral vestibular schwannomas, meningiomas, gliomas, ependymomas, neurofibromas, MPNST
Tuberous sclerosis	TSC1 AD chr9 (hamartin) TSC2 AD chr16 (tuberin)	Subependymal giant cell astrocytomas (SEGA), cortical tubers, hamartomas (hamartoblastomas), angiomyolipomas of kidney, lymphangioleiomyomatosis of lungs, rhabdomyomas, facial angiofibromas, ungal / subungal fibromas, astrocytic hamartomas of retina
Von Hippel Lindau	AD 3p VHL tumour suppressor gene	Angiomatosis in retina and other organs, hemangioblastomas in CNS, pheochromocytoma, renal cell carcinoma, tumours of the pancreas / neuroendocrine tumours
Li-Fraumeni syndrome	LFS1 AD 17p TP53 LFS2 AD 22q CHEK2 LFS3 1q	Breast cancer, osteosarcoma, soft tissue sarcoma, adrenocortical carcinoma, leukemia, astrocytoma, meningioma, others
Cowden disease (multiple hamartoma syndrome)	AD chr19q PTEN1	Multiple hamartomas of skin, mucosa, breast, thyroid. Lhermitte-Duclos disease.
Gorlin (basal cell nevus syndrome)	AD 9q PTCH (patched)	Basal cell nevoid cancer, medulloblastoma
Turcot syndrome	AD 5q APC	Familial adenomatous polyposis, medulloblastoma, glioblastoma multiforme

Neurofibromatosis type I (NIH criteria)

• An individual who has 2+ of these:
• 6+ café au lait macules >5mm (prepubertal) or >15mm (postpubertal)
• 2+ neurofibromas or 1 plexiform neurofibroma
• Axillary / inguinal freckling
• Optic glioma
• 2+ Lisch nodules (iris hamartomas)
• Distinctive osseus lesion (sphenoid dysplasia, tibial pseudarthrosis)
• 1^st degree relative with NF1 based of above criteria (parent, sib, offspring)

Neurofibromatosis type II

• An individual with 1+ of these:
• Bilateral vestibular schwannomas
• 1^st degree relative with NF2 and
• Unilateral vestibular schwannoma
• Two of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacity
• Unilateral vestibular schwannoma and two of above tumours or cataract
• Multiiple meningiomas and
• Unilateral vestibular schwannoma
• Two of above tumours or cataract

Tumours by age

Pediatric

Adult

Intracranial tumours Low grade gliomas (35-50%), including pilocytic astrocytomas (12-15%) Medulloblastoma (24%) Brainstem glioma / pontine glioma (10-20%) High-grade glioma (10-15%) Ependymoma Meningioma Craniopharyngioma Germ cell tumour Neuroblastoma Hemangioma Atypical teratoid / rhabdoid tumour Others (pinealoma, schwannoma, oligodendroglioma, etc.) Suratentorial tumours (30%) Low-grade astrocytoma (30-35%) High-grade astrocytoma (10-12%) PNET (3%) Ganglioglioma DNET Teratoma Infratentorial tumours (70%) Medulloblastoma (50-55%) Pilocytic astrocytoma (12-15%) Brainstem glioma Ependymoma Choroid plexus papilloma Suprasellar tumours Craniopharyngioma Pilocytic astrocytoma (optic pathway glioma) Germ cell tumour Langerhan’s cell histiocytosis Hypothalamic hamartoma Pituitary adenoma Nontumour – Rathke’s cleft cyst, arachnoid cyst, granuloma (TB/sarcoid) Infant (0-2y) – mostly supratentorial Teratoma (35%) Ependymoma (30%) Medulloblastoma PNET Choroid plexus papilloma / carcinoma Pilocytic astrocytoma (2%) Desmoplastic neuroepithelial tumour Meningeal sarcoma

Intracranial tumours Glioblastoma multiforme or anaplastic astrocytoma (50%) Meningioma (17%) Astrocytoma (10%) Pituitary adenoma Oligodendroglioma Ependymoma Nerve sheath tumours Medulloblastoma Others (craniopharyngioma, pinealoma, hemangioma, sarcoma, etc.) Primary CNS lymphoma Metastases (40% of all brain tumours) Supratentorial tumours (common) Glioblastoma multiforme Gliomas, grade II-III Lymphoma Metastases Infratentorial tumours (rare) Metastases Cerebellar hemangioblastoma Choroid plexus papilloma (4th ventricle) Medulloblastoma Suprasellar tumours Pituitary tumours (pituitary adenoma, met) Meningioma Craniopharyngioma Chordoma Nontumour – Rathke’s cleft cyst, granuloma (TB/sarcoid)

Tumours by location and special features

Cerebellopontine angle tumours Vestibular schwannoma Meningioma Epidermoid Facial nerve schwannoma Others (brainstem glioma, arachnoid cyst, cholesteatoma, paraganglioma, metastases) 4^th ventricle tumours Ependymoma Medulloblastoma Meningioma Choroid plexus papilloma Metastases Pineal region tumours Germ cell tumour (children) Pineocytoma Pineoblastoma Pineal cyst Dermoid / epidermoid Nonneoplastic – vein of Galen varices Lateral ventricle tumours SEGA (TS) Choroid plexus papilloma (children) Subependymoma Meningioma (adult) Central neurocytoma (adult) Corpus callosum lesions Glioblastoma multiforme Lymphoma Metastases Nontumour: WM lesions (MS, PML, ALD, Marchiafava-Bignami, PRES), trauma (shear injury), stroke, lipoma Brainstem tumours Diffuse astrocytoma (children) Pilocytic astrocytoma Glioblastoma multiforme (adults) Spinal cord (intramedullary) Ependymoma Astrocytoma Oligodendroglioma Paraganglioma

Spinal cord (extramedullary) Neurofibroma Dysembryoplastic (dermoid, epidermoid, teratoma, lipoma) Meningioma Arachnoid cyst Metastatic Spinal cord (extraaxial) Neuroblastoma Sarcoma Osteochondroma Metastatic Temporal lobe tumours (with seizures) Dysembryoplastic neuroectodermal (DNET) Pilocytic xanthoastrocytoma (PXA) Ganglioglioma Tumours that scallop skull inner table PXA Ganglioglioma DNET Meningioma Tumours that bleed Melanoma Renal cell carcinoma (mets) Thyroid (mets) Breast (mets) Choriocarcinoma (mets) Tumours that seed GBM Lymphoma Ependymoma Medulloblastoma Choroid plexus papilloma / carcinoma Germinoma PNETs Small blue cell tumours SCC lung / prostate Medulloblastoma / PNETs Esthesioneuroblastoma Adrenal neuroblastoma Spinal cord neuroblastoma Retinoblastoma Merkel cell tumour

Metastases

Primary tumour	Skull base	Dura	Brain parenchyma
Melanoma (48%)			2
Lung (32%)	3		1
Breast (21%)	1	1	3
Renal cell ca (11%)
GI (6%)
Prostate	2	2
Lymphoma		3
Bladder
Gynecological

Tumour markers

• Glioblastoma multiforme
• Primary – EGFR, MDM2
• Secondary – TP53, PDGF, RB
• Pediatric – TP53
• Oligodendroglioma -LOH 1p, 19q (good response to PCV)
• Meningioma - Deletion chr22
• Medulloblatoma - TrkC (good), cMyc (bad)
• Neuroblastoma
• Homovanillic acid (HVA), vanillylmandelic acid (VMA) in urine
• N-myc (bad if >10 copies)
• Ependymoma - LOH 22q, monosomy 17q
• Atypical teratoid/rhabdoid tumour (ATRT) - INI-1 on chr22, BAF47, vimentin, cytokeratin
• Germ cell tumours
• Germinoma – alkaline phosphatase
• Choriocarcinoma – beta-HCG
• Yolk sac tumour – alpha-fetoprotein

Pediatric brain tumours (points of interest)

• CNS germ cell tumours (sensitive to cisplatin and radiation)
• Germinoma, esp. pineal (high alk phos)
• Non-germinoma
• Teratoma
• Yolk sac tumour (high AFP)
• Choriocarcinoma (high beta-HCG)
• Primitive neuroectodermal tumours (PNETs)
• Medulloblastoma
• Pineoblastoma
• Ependymoblastoma
• Retinoblastoma
• Flexner-Winterstreiner rosettes
• Prognosis less if tumour crosses the lamina cribrosa to the optic nerve
• Neuroblastoma
• Esthesioneuroblastoma
• Desmoplastic neuroepithelial tumours
• Presents in infancy with macrocephaly and seizures
• Large hemispheric tumour with cystic and enhancing solid components
• Resection is curative – looks bad but does well
• Chordoma
• Originates from notochord
• Clivus in children, sacrum in adults
• Causes multiple cranial neuropathies

WHO classification of brain tumours

Tumours of neuroepithelial tissue Astrocytic tumours Diffuse astrocytoma Fibrillary (supratent, low grade) Protoplasmic Gemistocytic Anaplastic astrocytoma (grade III) Glioblastoma (grade IV) Giant cell Gliosarcoma Pilocytic astrocytoma (grade I) Optic pathway / hypothalamic glioma Tectal glioma Pleomorphic xanthoastrocytoma (PXA) Subependymal giant cell astrocytoma (SEGA) Oligodendroglial tumours Oligodendroglioma Anaplastic oligodendroglioma Mixed gliomas Oligoastrocytoma Anaplastic oligoastrocytoma Ependymal tumours Ependymoma (grade II) Cellular Papillary Clear cell Tanocytic Anaplastic ependymoma Myxopapillary ependymoma Subependymoma (grade II) Choroid plexus tumours Choroid plexus papilloma Choroid plexus carcinoma Neuronal and mixed neuronal-glial tumours Gangliocytoma (grade I/II) Dysplastic gangliocytoma of cerebellum Desmoplastic infantile astrocytoma / ganglioglioma Dysembryoplastic neuroepithelial tumour (DNET, gr I) Ganglioglioma (grade I/II) Anaplastic ganglioglioma Central neurocytoma (grade II) Cerebellar liponeurocytoma Paraganglioma of the filum terminale Neuroblastic tumours Olfactory neuroblastoma Olfactory neuroepithelioma Neuroblastomas of adrenal gland and sympathetic NS

Pineal parenchymal tumours Pineocytoma Pineoblastoma Pineal parenchymal tumour of intermed. Differentiation Embyronal tumours Medulloepithelioma (grade IV) Ependymoblastoma Medulloblastoma Desmoplastic medulloblastoma Large cell medulloblastoma Medullomyoblastoma Melanocytic medulloblastoma Supratentorial primitive neuroectodermal tumour Neuroblastoma Ganglioneuroblastoma Atypical teratoid/rhabdoid tumour Tumours of the peripheral nerve Schwannoma (grade I) Neurofibroma (grade I) Perineuroma Malignant peripheral nerve sheath tumour (MPNST) Tumours of the meninges Tumours of meningothelial cells Meningioma Mesenchymal, non-meningothelial tumours Primary melanocytic lesions Lymphomas and hematopoietic neoplasms Germ cell tumours Germinoma Embryonal carcinoma Yolk sac tumour Choroicarcinoma Teratoma Mature Immature With malignant transformation Mixed germ cell tumour Tumours of the sellar region Craniopharyngioma (grade I) Adamantinomatous Papillary Granular cell tumour Metastatic tumours

Paraneoplastic disorders

• Affects 0.1% cancer patients
• High-risk situations:
• Lambert-Eaton Myasthenic Syndrome – 3% of small cell lung cancer
• Myasthenia gravis – 15% of thymoma
• Demyelinating polyneuropathy – 50% of POEMS syndrome

Syndrome	Features	Associated neoplasms	Antibodies
Limbic encephalitis	§ Memory disturbance § Seizures § Acute confusion § Hallucination, depression § Brainstem symptoms	§ SCC Lung (Hu) § Testicular (Ta/Ma2) § Breast	§ Anti-Hu (ANNA-1) § Anti-Ta/Ma2
Opsoclonus myoclonus	§ Dancing eyes, limbs § Treat with IVIG	§ Neuroblastoma	§ Anti-Hu § Anti-Ri (ANNA-2)
Brainstem encephalitis	§ Gaze palsies, diplopia § Sleep apnea	§ Testicular § Lung	§ Anti-Hu § Anti-Ma2 § Anti-Ri
Cerebellar degeneration	§ Cerebellar signs § Downbeat nystagmus	§ Ovary, breast (Yo) § Hodgkin lymphoma (Tr) § Lung	§ Anti-Yo (anti-purkinje) § Anti-Tr (anti-purkinje) § Anti-Hu § Anti-Ta/Ma2
Peripheral neuropathy	§ Asymmetric, painful § Sensory ataxia § Autonomic § Sensorimotor § Mononeuropathy (ulnar or CN8)	§ SCC Lung § Lymphoma (CIDP-like) § Waldenstrom macroglobulinemia (MAG)	§ Anti-Hu § Anti-MAG
Motor neuron disease	§ ALS/PLS-like	§ Breast cancer	§ Anti-Hu
Lambert-Eaton MS	§ Proximal weakness, dry mouth, areflexia, LE>UE § Cranial n, autonomic	§ Small cell lung cancer	§ Anti-P/Q type VGCC
Mysathenia gravis	§ Ocular paresis, preserved reflexes	§ Thymoma (AChR)	§ Anti-AChR § Anti-MusK
Myositis	§ Polymyositis (15%) § Dermatomyositis (30%)	§ Ovarian § Lung § Pancreas § Colon (dermatomyositis) § Non-Hodgkin lymphoma § Lung (polymyositis)	N/A
Neuromyotonia	§ Hyperexcitable motor neurons à stiff, cramp, sweaty	§	§ Anti-VGKC
Stiff person syndrome	§ Rigidity, spasms	§ SCC lung (amphiphysin) § Breast (amphiphysin)	§ Anti-GAD (Glu DH) § Anti-amphiphysin

Common chemotherapy side effects

• Nitosoureas (BCNU, CCNU, carmustine, lomustine) – myelosuppression, pulmonary toxicity
• Procarbazine – MAOI action, myelosuppression
• Cisplatin
• Large fiber sensory neuropathy
• Ototoxicity
• L’Hermitte’s sign
• PRES
• Methotrexate
• Arachnoiditis
• PRES
• Leukoencephalopathy
• 5-fluorouracil
• Pancerebellar syndrome
• Encephalopathy
• Cytarabine
• Pancerebellar syndrome
• Encephalopathy
• Fludarabine
• Posterior leukoencephalopathy
• Vinca alkaloids (vincristine, vinblastine)
• Symmetric sensorimotor polyneuropathy
• Autonomic neuropathy
• Cranial neuropathies, retinal damage
• Taxanes (Paclitaxel)
• Large and small fiber sensory neuropathy
• Myalgias, arthralgias
• L-asparaginase
• Prothrombotic (low ATIII, plasminogen, fibrogen, factor IX, protein C, protein S)
• Especially CSVT

Updated: December 29, 2007

Disclaimer: These are personal study notes. No promises for accuracy or originality.