Neuro-oncology and Neurocutaneous Syndromes



Neuro-oncology and Neurocutaneous Syndromes


Jahannaz Dastgir

Gabriel Dabscheck

Nicole J. Ullrich



NEURO-ONCOLOGY


Brain Tumors

DEFINITION: Brain tumors are a diverse group of primary tumors arising from one of many different cell types within the central nervous system. Diagnosis, treatment, and prognosis depend on the tumor cell of origin and pattern of growth. See overview in Table 12.1.

EPIDEMIOLOGY: Brain tumors constitute 20% to 25% of all pediatric malignancies and are the most common solid tumors in children as well as the most common cause of cancer death in children <15 y1 Most cases of brain tumors in children are sporadic, although 5% are associated with hereditary syndromes that predispose to neoplasia (Table 12.2). Environmental exposures such as ionizing radiation have been implicated in meningiomas, gliomas, and nerve sheath tumors. No convincing evidence has demonstrated a link with trauma, occupation, diet, or electromagnetic fields.

CLINICAL PRESENTATION: Clinical presentation is often influenced by the age of onset, tumor location (supratentorial often present in # 3 yo and >10 yo; infratentorial often in 4 to 10 yo), tumor histology, and rate of growth. Additionally, the chronicity of symptoms may provide an indirect correlate of tumor biology and prognosis.2 Symptoms can be grossly divided into focal neurologic signs and symptoms that are directly referable to the tumor location and diffuse symptoms that indicate either larger regional involvement or symptoms suggestive of increased intracranial pressure (ICP; Table 12.3).

HEADACHES: The most common presenting symptom of children with brain tumors. It is estimated that 41% of children will experience headaches at the time of presentation, often due to increased ICP, and % of patients will experience headaches over the course of the illness.2 Headaches are typically described as a pain that awakens the patient from sleep, occurs in the early morning, and/or can be worsened with coughing or Valsalva maneuver, is often bilateral, and is described as a pressure-like feeling. Patients should be evaluated for communicating or noncommunicating/obstructive hydrocephalus since cerebrospinal fluid volume may be increased due to impaired reabsorption (secondary to blood from subarachnoid hemorrhage, increased protein from meningitis, or overpopulation with malignant cells) or overproduction. Indirect causes of headache in children with brain tumors include surgery (hemorrhage, vascular injury, perioperative stroke, CSF leak), chemotherapy (retinoids, antibiotics, cytokines, leukoencephalopathy, venous sinus thrombosis), supportive therapy (steroids, antihistamines, antiemetics), radiotherapy (acute edema, radionecrosis, secondary tumor, vascular changes), and other causes (infarction, fever, infection, post lumbar puncture).2

















TABLE 12.1 Pediatric Neuro-oncology
















































































































































































Tumor Type


Incidence


Location


Diagnostic Features


Treatment


Prognosis


Astrocytic


Grade I/Pilocytic astrocytoma


20% of astrocytomas


Male = Female Peak, 5-14 yo Increased in NF1


Cerebellum (most) Brainstem


Optic pathway


Hypothalamus


CT/MRI: 50% well circumscribed


Cyst with mural nodule Contrast enhancing


Solid parts with low attenuation relative to cerebellar parenchyma


Path: Rosenthal fibers


Maximal surgical resection


± Chemotherapy


± RT


Total surgical resection is curative in 95%-100%


May stabilize for long periods


Grade II/ Diffuse astrocytoma


15% of astrocytomas


Peak, 2-4 yo and early adolescence


Frontal and temporal lobes > brainstem and spinal cord


MRI: heterogeneous


CT: solid parts are low density


Path: ft cellularity, diffuse infiltration of neighboring brain structures


Maximal surgical resection


± Chemotherapy


± RT


With gross total resection, 80%-100% survival


With partial resection, 50%-95% survival


Worse prognosis if tumor is midline


High-grade astrocytoma


Anaplastic astrocytoma/


Grade III Glioblastoma/Grade IV


10% of pediatric tumors


Peak, 9-10 yo


Most are supratentorial


CT/MRI: often with mass effect, variable contrast enhancement, areas of necrosis (if grade IV), restricted diffusion


MRS: low choline, high citrate


Path: increased cellularity, atypia; grade IV with vascular proliferation and necrosis


Maximal surgical resection


± Chemotherapy and RT


5-y survival rate is 15%-30% for supratentorial lesions, <10% for pontine


Pleomorphic xanthoastrocytoma


<1% of all astrocytomas; typically develops in children and adolescents


Cortical/hemispheric predominance


Most common origin = temporal lobe


MRI: peripheral hemispheric mass w/heterogeneous enhancement post contrast


Solid parts show signal intensity similar to gray matter


Maximal surgical resection


Seizure management


Recurrence-free survival rates of 72% at 5 y and 61% at 10 y


Subependymal giant cell astrocytoma


Almost exclusive to TSC patients


Peak, 1st decade


Most in lateral ventricle, near foramen of Monro


MRI: circumscribed, homogenously enhancing mass characteristically located within the lateral ventricle


Maximal surgical resection


Seizure management CSF diversion mTOR inhibitors


Survival ˜95% at 5 y


Oligodendroglioma


Well-differentiated/WHO grade II)


Anaplastic/WHO grade III)


1% of childhood brain tumors


Supratentorial


CT: presence of dense nodular calcification suggests diagnosis; osseous remodeling of skull inner table to the skull is common, mineralization frequent


MRI: predominantly solid mass centered peripherally in the cerebral hemispheres


Histology: honeycomb/ground glass appearance


Maximal surgical resection


± Chemotherapy and RT if recurrence


10-y survival rate up to 80%


Ependymoma


8%-10% of childhood brain tumors


Peak, 0-5 yo; 30% < 3 yo


Posterior fossa (60%)


Supratentorial tend to occur in a periventricular location


May have drop metastases at presentation (10%) or at recurrence


MRI: usually heterogeneously enhancing, along the ventricular lining; cerebellopontine predilection; tend to extend through the outlet foramina of the 4th ventricle; mineralization, necrosis, and hemorrhage common, isointense to gray matter


LP: check for leptomeningeal spread


Maximal surgical resection ± RT


Chemotherapy may delay RT


Prognosis depends on extent of resection, age, and tumor location


Choroid plexus


Choroid plexus papilloma (CPP)


Choroid plexus carcinoma (CPC)


2%-4%


If <1 yo, 10%-20% (80% CPP, 20% CPC)


Peak, 0-5 yo


Lateral ventricle (50%); 4th ventricle (40%)


Associated with Li-Fraumeni


MRI: markedly lobulated, often frondlike, solid mass within ventricle


CPC is more heterogeneous ± necrosis and parenchymal invasion ± CSF dissemination


Both will enhance post administration of IV contrast


MRS: CPP marked inc of myoinositol; CPC marked inc choline


Maximal surgical resection


Multiagent chemotherapy for CPC


CPP: 10-y survival, 85% if gross total resection


CPC: 5-y survival, 26% (most deaths occurring within 7 mo of surgery)


May metastasize if associated with Li-Fraumeni


Neuronal and mixed neuronal-glial


Dysembryoplastic neuroepithelial tumor (DNET)


Overall incidence of ˜1%. In one study, 18%-19% of patients undergoing temporal lobe resection for refractory epilepsy had a DNET


Often presents with seizures


Always centered in cerebral cortex (temporal > frontal lobes)


CT: peripherally located, low density mass


MRI: circumscribed mass centered within the cerebral cortex; involvement of subcortical WM is not uncommon and tends to show a centripetal tapering


Cystic components are common (soap bubble appearance)


MRS: normal


Pathology: may have surrounding areas of dysplasia


Maximal surgical resection


Have potential for recurrence following complete surgical resection


Seizure control may be challenging


Ganglioglioma


3% of brain tumors; 6% of all supratentorial tumors in children


Peak, adolescence


Often presents with seizures


Cerebral cortex, most commonly the temporal lobe


CT: mineralization common


MRI: peripherally located, intra-axial, wholly solid or partly cystic


Maximal surgical resection


Potential for recurrence following complete surgical resection


Seizure control may be challenging


Germ cell tumors


Germinoma nongerminomatous germ cell tumor (NGGCT)


1%-2% of childhood brain tumors


Mean age at diagnosis, 10-12 y


M:F = 2-3:1


Suprasellar more common in females; pineal more common in males


Can have synchronous or consecutive tumors


MRI: predominantly solid, suprasellar mass with signal characteristics approximating that of gray matter


If suprasellar, often pituitary bright spot is absent


Labs: for germinoma, markers negative; for NGGCT, elevated α-fetoprotein and βHCG


Diagnostic biopsy if markers negative


RT for germinoma


RT+ chemotherapy for NGGCT


May require CSF diversion


Germinoma: most localized germinomas can be cured with RT therapy alone, survival is 65%-95% @ 5 y


NGGCT survival, 40%-70% @ 5 y. High-dose chemotherapy and stem cell rescue at relapse


Teratoma


2nd most common germ cell tumor of the pineal region


Most common neonatal tumor


Usually pineal


MRI:


Benign form—marked heterogeneity; coexistence of cystic, solid enhancing, fatty, and mineralized components


Malignant form—a predominantly solid, enhancing mass without associated fat or mineralization


Diagnostic biopsy if markers negative


May require surgical resection


May require CSF diversion


Survival is dependent upon location and the patient’s ability to tolerate gross total resections


Parenchymal tumors of pineal gland


Pineoblastoma


Pineocytoma


Each account for up to 45% of all tumors in the pineal region


Peak, 1st decade (pineocytoma are most common in 25-35 yo)


Pineal


MRI:


Pineoblastoma—heterogeneous enhancement post contrast administration; leptomeningeal dissemination may occur, and/or necrosis and hemorrhage


Pineocytoma—partially cystic mass, commonly associated with mineralization


Pathology: pineoblastoma; (small round cell tumor; histology similar to PNET)


Diagnostic biopsy with resection if possible


May require CSF diversion


May consider markers to exclude NGGCT


Pineoblastomarelated RT + chemotherapy


Operative morbidity high


Pineocytoma often has metastases at diagnosis, prognosis is poor, survival is 86% @ 5 y


Pineoblastoma survival is 58% @ 5 y after treatment with various modalities


Primitive neuroectodermal tumors (PNET)


Supratentorial PNET


5% of all supratentorial tumors in children


Peak, 0-5 yo


Hemispheric


CT: calcification and osseous erosion


MRI: large, heterogeneous, often with necrosis, cystic degeneration, and hemorrhage; heterogeneous enhancement; isodense to gray matter


MRS: markedly elevated choline peak


Maximal surgical resection


Chemotherapy + RT


Prognosis is dependent upon risk category


Local relapse is a more significant failure pattern in supratentorial PNET than in medulloblastoma


Primitive neuroectodermal tumors (PNET)


Medulloblastoma


15%-20%


Peak, 5-9 yo


M:F = 2.4:1


Posterior fossa


MRI heterogeneous; enhancing mass; 30%—40% disseminated at diagnosis


MRS: elevated choline peak


LP: check for leptomeningeal spread


Maximal surgical resection


Multiagent chemotherapy


If >3 yo, craniospinal RT with focal boost


Standard risk, 85% survival High risk, 65% survival Poorer prognosis in infants, large cell/anaplastic variant


Molecular stratification will guide future therapies


Atypical teratoid rhabdoid


1.5-2.1% of childhood CNS tumors


Peak, <2 yo


Posterior fossa Can be supratentorial


MRI: signal intensity similar to gray matter; heterogeneous secondary to frequent necrosis and sometimes hemorrhage


Path: loss of INI1 staining on immunohistochemistry


Maximal surgical resection


Multiagent (+ intrathecal) hemotherapy


If >3 yo, craniospinal RT with focal boost


5-y survival 35%


Meningeal


Meningioma (wide range of histopathologic appearances that classify them as WHO grade I/II/III)


Rare in children and adolescence


May be associated with NF2 or prior history of RT


Most commonly vertex or orbital in children


CT/MRI: homogeneous enhancement is the rule with dural tail


Hyperostosis of adjacent osseous structures is suggestive


Maximal surgical resection if symptomatic


Seizure control


After surgical resection, WHO grade I recur in 7%-20%; grade II in 29%-40%; grade III in 50%-78%


Malignant histologic features correlate with shorter survival times


Sellar/Suprasellar


Pituitary adenoma


Increased incidence with improved detection


17% of all pituitary neoplasms (and only a minority are symptomatic)


Prolactinoma type is the most common


Hormonally active > inactive


macroadenoma >1 cm; microadenoma >1 cm


MRI: relative hypoenhancement compared with normal surrounding pituitary glandular tissue


A significant fraction of macroadenomas are hemorrhagic


Hormonal therapy


If surgical intervention required, trans-sphenoidal surgery is treatment of choice


Initial remission rate of 83%


Craniopharyngioma (WHO grade I)


7%-10% of all childhood brain tumors


Peak, 2nd decade and 4th-5th decades


Originate within the sellar or suprasellar region


MRI: large multilobulated heterogeneous masses with cystic and solid component; may be T1 hyperintense secondary to high cholesterol or protein content


CT: may show calcification


Path: most with adamantinomatous histology


Maximal surgical resection


RT if incomplete resection or recurrence


Chemotherapy not helpful


Postoperatively often with panhypopituitarism


May need stress-dose steroids


10-y progression-free survival rate 60%-93% in a large series, the most significant prognostic factor associated with tumor recurrence is the extent of surgical resection


Hypothalamic hamartoma


Rare and most occur sporadically; may be associated with TSC or Pallister—Hall syndrome (10%)


Hypothalamus


CT: appears as a gray matter density, suprasellar mass


MRI: round or ovoid mass centered at, or pedunculated from, the tuber cinereum. Does not enhance with contrast


Endoscopic disconnection if possible


Seizure control


Dependent upon ability to treat seizures (manifesting as several types, including gelastic) in addition to endocrinological and behavioral side effects


Spinal cord


2%-4% of all primary CNS tumors, 1/3 in the intramedullary compartment


Extradural


Metastases (neuroblastoma, sarcoma, medulloblastoma, ependymoma)


Intradural—extramedullar


Meningiomas, nerve sheath tumors (schwannoma, neurofibroma)


Intradural—Intramedullary


Astrocytoma, ependymoma, myxopapillary ependymoma


MRI: mass; appearance depends on tumor type


Surgical resection is the mainstay of treatment


Observation for low-grade tumors postresection


Systemic therapy for relapse after maximal surgery and/or radiation


Consideration for radiation therapy depending on histology


Metastases have added increased risk for spinal cord compression


Depends on tumor histology


AA, anaplastic astrocytoma; ADC, apparent diffusion coefficient; AT ataxia; CPC, choroid plexus carcinoma; CPP, choroid plexus papilloma; CSF, cerebrospinal fluid; CT, computed tomography; DFA, diffuse fibrillary astrocytoma; DIPG, diffuse intrinsic pontine glioma; DNET, dysembryoplastic neuroepithelial tumor; FLAIR, fluid-attenuated inversion recovery; GBM, glioblastoma multiforme; JPA, juvenile pilocytic astrocytoma; LCH, Langerhans cell histiocytosis; MRI/S, magnetic resonance imaging/spectroscopy; NF-1, neurofibromatosis type 1; NGGCT, nongerminomatous germ cell tumor; OAC, oligoastrocytoma; ODG, oligodendroglioma; PBL, pineoblastoma; PCY, pineocytoma; PNET, primitive neuroectodermal tumor; PXA, pleomorphic xanthoastrocytoma; RT, radiation therapy; TSC, tuberous sclerosis complex; VHL, von Hippel—Lindau; WM, white matter.


From Louis DN, Ohgaki H, Wiestler OD, et al. WHO Classification of Tumors of the Nervous System. Lyon, France: IARC; 2007 and Paldino, Faerber EN, Poussaint TY. Imaging tumors of the pediatric central nervous system. Radiol Clin North Am. 2011:49:589-616, with permission.










TABLE 12.2 Hereditary Cancer Syndromes Associated with Brain Tumors in Children




































































































Cancer Syndrome


Gene


Classification


Tumors


Li-Fraumeni


TP53


Tumor suppressor


Soft tissue and bone sarcoma, leukemia, breast carcinoma, brain tumor, adrenocortical carcinoma


Familial retinoblastoma


Rb


Tumor suppressor


Retinoblastoma, osteosarcoma, Dineal tumors


Wilms tumor syndromes


WT-1


Tumor suppressor


Wilms tumor


WAGR syndrome


Denys-Drash syndrome


Frasier syndrome





Neurofibromatosis type 1


NF1


Tumor suppressor


Neurofibromas, optic pathway tumors, other brain tumors, leukemia, malignant peripheral nerve sheath tumors


Neurofibromatosis type 2


NF2


Tumor suppressor


Vestibular schwannoma, schwannoma, meningioma


Von Hippel—Lindau


VHL


Tumor suppressor


Renal cell carcinoma, vascular tumors, retinal and central nervous system hemangioblastoma, pheochromocytoma


Tuberous sclerosis


TSC1, TSC2


Tumor suppressor


Subependymal giant cell astrocytomas, cortical tubers, hamartomas, renal and extrarenal angiomyolipoma, renal cell carcinoma, cardiac rhabdomyomas


Familial breast and ovarian cancer syndrome


BRCA-1


Tumor suppressor


Breast carcinoma, ovarian carcinoma1


Familial breast cancer syndrome


BRCA-2


Tumor suppressor


Breast carcinoma, Fanconi anemia, brain tumor1


Familial adenomatous polyposis


APC


Tumor suppressor


Colorectal carcinoma, hepatoblastoma, brain tumors (typically medulloblastoma)1


Familial melanoma


P16


Tumor suppressor


Melanoma1


Nevoid basal cell carcinoma/Gorlin syndrome


PTCH


Tumor suppressor


Basal cell carcinoma, medulloblastoma, cardiac and ovarian fibroma


Cowden syndrome


PTEN1


Tumor suppressor


Breast cancer, hamartoma


Multiple endocrine neoplasia type 2 (MEN)


RET


Oncogene


Thyroid and parathyroid carcinomas, pheochromocytoma1


Ataxia telangiectasia


ATM


DNA repair


Leukemia, lymphoma


Nijmegen breakage syndrome


NBS1


DNA repair


Lymphoma, medulloblastoma, glioma, rhabdomyosarcoma


Rhabdoid predisposition syndrome


SNF5, INI1


Growth arrest, DNA repair


Rhabdoid tumors of kidney and brain, choroid plexus tumor


1No primary involvement of peripheral or central nervous system.







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Jun 20, 2016 | Posted by in NEUROLOGY | Comments Off on Neuro-oncology and Neurocutaneous Syndromes

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TABLE 12.3 Brain Tumors in Children: Presenting Signs and Symptoms