BRAIN TUMORS IN ADULTS Clark C. Chen, M.D., Ph.D.

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1 BRAIN TUMORS IN ADULTS Clark C. Chen, M.D., Ph.D. INTRODUCTION BRAIN TUMORS IN ADULT Brain tumors may be characterized as either primary or secondary. Primary brain tumors are those which arise initially in the central nervous system (CNS) or its adjacent structures. In contrast, secondary tumors arise outside of the CNS and secondarily metastasize to the brain or its adjacent structures. Relative to cancer of other anatomic sites, primary brain tumor is a fairly rare entity. A national survey from the National Institute of Health reported the occurrence of 15,000 primary intracranial tumors yearly in the U S. This translates into an incidence of primary brain tumors of 5-6 per 100,000 population. Secondary neoplasms have become increasingly common with an incidence of 8-9 per 100,000. The prognosis for CNS tumors varies dramatically depending on the histologic grade and anatomic location. The anatomic location dictates the spectrum of peri-operative morbidities. The outcome with more malignant tumors depends not only upon histologic grade and anatomic location, but also upon other factors such as age of patient, functional status, and extent of tumor spread. It is rare for CNS tumors to metastasize to other parts of the body. Intracranial tumors, such as infiltrating gliomas, may spread along white matter tracts. Other modes of spread within the CNS include cerebrospinal fluid (CSF) spaces. Intracranial metastatic disease involving the CSF is known as meningeal carcinomatosis and often carries a poor prognosis. A classification of brain tumors is listed below. Table 1. Incidence of Primary Brain Tumors GLIOMAS Primary Brain Tumors % Glioma 50 Meningioma 20 Pituitary tumor 10 Craniopharyngioma 2 Lymphoma 2 Gliomas: Introduction Importance. Among adult CNS malignancies, gliomas are the most common and cause the vast majority of morbidity and mortality. For these reasons, malignant gliomas have been the targets of a considerable amount of research, and for these tumors the data concerning the molecular details of pathogenesis are the most abundant.

2 Definition. Glioma refers to tumor derived from neoplastic transformation of glial cells and constitutes the most common form of primary CNS cancer ( Glia is derived from the Greek term for glue. The term is meant to describe the non-neuronal cells in the nervous system that are found dispersed amongst neurons, gluing the distinct neurons into a cohesive system. In addition, glial cells perform critical functions to maintain the CNS. These functions include: modulation of neurotransmission, axon insulation (via formation of myelin), regulation of metabolic and nutritional microenvironment, cerebrospinal fluid secretion and circulation, formation of the blood brain barrier, immune response to pathogens, and tissue remodeling following injury. While glial cells are initially thought to serve primarily supportive roles to facilitate the function of the more important neurons, recent studies suggest that some glial cells actively regulate neuronal transmission in ways that critically impact cognition, memory, and learning. Intriguingly, histological analysis of Albert Einstein s brain revealed an increase in the number of glial cells as well as altered glial morphology in select locations thought to mediate complex cognition without changes in neuronal number or morphology. Types of glial cells. CNS glial cells consist of distinct histologic cellular subtypes. In the adult CNS, the four most abundant types of glial cells are: astrocytes, oligodendrocytes, ependymal cells, and microglial cells. Astrocytes derive their name from their star-like appearance ( astro is from the Greek word for star ) and are the most abundant form of glial cells. They are widely interspersed in the CNS and serve a number of critical functions. Astrocytes regulate metabolic/nutritional microenvironment and neuro-transmission by uptake of extracellular ions and neurotransmitters. Astrocytes also form tight junctions with the basal lamina of the cerebral endothelial cells. In doing so, they contribute to the maintenance of the blood brain barrier and the regulation of cerebral blood flow. Additionally, upon injury to the CNS, astrocytes become phagocytic to ingest the injured neurons and facilitate remodeling. Finally, astrocytes secrete cytokines to regulate the function of other types of glial cells. Oligodendrocytes are the second most abundant form of glial cells. They send out long cellular process to coat neuronal axons. These processes consist of specialized membranes, termed myelin, that provide insulation. This insulation allows efficient transmission of electric signal through the coated axon. Ependymal cells line the walls of the ventricles and harbor beating cilia that facilitate the circulation of the CerebroSpinal Fluid (CSF). Specialized ependymal cells in the choroid plexus are responsible for the production of CSF. Microglia are specialized macrophages derived from hematopoietic precursors that are capable of phagocytosis. These cells mediate immune response to foreign pathogens and CNS remodeling after injury. Types of glial tumors. One common feature of glial cells is that they retain the ability to undergo cell division in the adult CNS whereas most neurons cannot. Since carcinogenesis is a process that requires sequential accumulation of genetic aberrations through cell division, it is not surprising that gliomas constitute the most common form of primary brain cancer ( The incidences of the various forms of gliomas (astrocytomas, oligodendrogliomas, and ependymomas) parallel their relative prevalence in the CNS. It is important to note that a subset of gliomas exhibit histologic features reminiscent of both astrocytic and oligodendrocytic lineage. These mixed gliomas are classified into a distinct category termed oligoastrocytomas. WHO classification. Astrocytic tumors are classified histologically using the World Health Organization (WHO) grades of I to IV (Figure 2). Grade I tumors are characterized by lack of

3 tumor extension beyond the tumor capsule. These tumors are biologically benign. Patients afflicted with grade I tumors are essentially cured by complete surgical excision. Grade II tumors are histologically characterized by hypercellularity with diffuse infiltration into the surrounding cerebral parenchyma. Complete surgical excision of grade II tumors cannot generally be achieved. These tumors are considered low-grade and typically follow a long clinical course. The median survival for patients afflicted with grade II tumors ranges from 5 to 8 years. Any tumor graded III or IV is considered malignant. In addition to hyper-cellularity, grade III astrocytomas exhibit features of nuclear atypia and notable increase in mitotic figures. The average median survival for patients afflicted with grade III tumor is approximately 3 years. Grade IV astrocytomas are the most frequently encountered form of astrocytoma, consisting of >50% of all astrocytomas. The tumors are histologically characterized by evidence of angiogenesis, necrosis, and significant heterogeneity in aberrant cytology. Because of this morphologic heterogeneity, it is thought that these tumors either originate from or revert to less differentiated immature cells. Accordingly, WHO grade IV astrocytomas are also termed glioblastoma ( blast in reference to immature cells as the putative cell of origin). Grade IV tumors are extremely aggressive in behavior and are associated with a median survival of month. Table 2. Grading system for astrocytoma (WHO system) Grade I Grade II Grade III Grade IV Juvenile pilocystic astrocytoma Diffuse growth of well-differentiated astrocytes pleomorphism, increased mitosis, vascular proliferation Undifferentiated or primitive-appearing cells predominant Table 3. Prognosis - Astrocytomas WHO GRADE MEDIAN SURVIVAL (YEARS) II 6-8 III 2-3 IV 1 Primary and secondary glioblastomas. Based on clinical presentation, glioblastomas have been further subdivided into two subtypes: primary and secondary. Clinically, primary glioblastomas are defined as those tumors that present without a prior history of lower grade astrocytomas. Secondary glioblastomas are defined as those that arose by progressive transformation from lower grade astrocytomas. Of these subtypes, the primary glioblastoma constitutes the majority of all cases and typically afflict patients age > 50 ( Secondary glioblastoma occur less frequently and are found predominantly in younger (age <50) patients. It can be argued that such classification is inherently problematic as it is difficult to unambiguously verify that a primary glioblastoma did not arise from an asymptomatic lower grade tumor. Nevertheless, these clinically defined glioblastoma subtypes comprise distinct genomic profiles with strikingly different gene transcription patterns. CLINICAL FEATURES. Gliomas present with many different symptoms depending on their location in the brain. Presenting symptoms include headaches, seizures, visual symptoms,

4 personality change, nausea and vomiting, unsteadiness, weakness, numbness, visual changes, cognitive deterioration, speech difficulties, and compromise of speech comprehension. Neurological examination findings also depend on the location of the tumor in the brain. These findings indicate mental status alterations, papilledema, dysphasia, hyperreflexia, hemiparesis, ataxia, and cranial nerve abnormalities. Neuro-imaging studies. Magnetic resonance imaging is the most sensitive study to detect neoplasms in the CNS. They can often demonstrate sub-centimeter abnormalities. Computer tomography (CT) scans with contrast are also very sensitive in detecting brain tumors. CT scans may miss lesions less than 1 cm in diameter, near major venous sinuses, or near bone. Skull x-rays are not sensitive in detecting most brain tumors. Cerebral angiography is helpful in assessing the vascularity of a tumor (e. g. "tumor blush") or displacement of vessels. It is not as sensitive as CT or MR scans and is not a routine diagnostic test for work-up of brain tumors. Neuro-imaging studies may suggest a differential diagnosis, but definitive diagnosis is dependent upon examination of tissue histology. Definitive diagnosis requires a surgical procedure to obtain tissue. This can be accomplished with either a closed CT or MR directed stereotactic needle biopsy or via an open crainiotomy to biopsy and/or debulk the tumor. Management of patients with gliomas CNS lesions. Dexamethasone decreases cerebral edema associated with brain tumors. Anticonvulsants are often started prophylactically to prevent seizures. Surgical treatment. Craniotomy is generally performed in an attempt to debulk as much tissue as safely possible (cyto-reduction), to obtain a representative tissue biopsy, relieve mass effect, and/or to initiate chemotherapy treatment e. g. placement of local chemotherapy wafers. There is good clinical evidence to suggest that the extent of resection correlate with clinical outcome in terms of patient survival. Stereotactic needle biopsy is generally performed to obtain a tissue diagnosis in patients that are not good candidates for extensive resection of the gross tumor, or for tumors located in or near eloquent areas of the brain that are critical for neurologic functions e. g. speech, motor, sensory function. Radiation treatment. After definitive diagnosis, patients with III/IV or IV/IV gliomas are treated with standard radiation therapy. Typically, conventional external beam irradiation therapy ( cgy) is delivered to a region that includes a 2-3 cm perimeter around the margin of the enhancing lesion noted on neuro-imaging studies in fractionated treatments over a six week period. Side effects include alopecia, scalp dermatitis, and radionecrosis. Chemotherapy. For glioblastomas, temozolomide, a DNA alkylating agent, is the current standard of care in the U.S. Other DNA alkylating agents, including BCNU, Procarbazine, CCNU, and ACNU are also used in the setting of tumors that recurred after standard Temozolomide treatment. It is important to note that a subset of glioblastoma patients attain significant benefit from temozolomide. Approximately 20% of patients undergoing concurrent temozolomide/radiation therapy are attain 5-year survival. METASTATIC BRAIN TUMORS

5 Cerebral metastases constitute an ongoing therapeutic challenge in neuro-oncology. It is estimated that approximately 20-40% of patients afflicted with cancer will eventually develop cerebral metastases. In the U.S., this estimate translates into roughly 170,000 new cases of cerebral metastases each year. Because of the aging population, improved treatment for systemic diseases, and failure of many therapeutic cancer agents to cross the blood-brain barrier, the incidence of cerebral metastases is expected to rise. The prognosis of patients afflicted with cerebral metastases is poor. The median overall survival for untreated and treated patients is approximately one month and four months, respectively. The mainstay treatment for cerebral metastases involves radiation (whole brain or focal radiation) with or without preceding surgery. Prognostic factors conferring a more favorable prognosis have been identified and include: younger age, absence of significant neuro-cognitive dysfunction, and systemic disease status. The Radiation Therapy Oncology Group (RTOG) integrated these variables into an ordinal scale termed Recursive Partitioning Analysis (RPA) class. RPA class I is defined by age <65 and absence of significant neurocognitive function (as assessed by Karnofsky Performance Score (KPS)>70), controlled systemic disease, and no extracerebral metastasis; RPA class III is defined by KPS<70; all other patients are defined as RPA class II. The respective median survival for RPA class I, II, and III are 7.1, 4.2, and 2.3 months, respectively. In recent series, longer-term survivors have been noted in a subset of RPA class I patients. Given the inherent poor prognosis associated with cerebral metastases, management from a surgical perspective requires judicious considerations factoring the potential benefit, efficacy of competing and less invasive modalities (such as radiosurgery), time required for functional recovery, and anticipated patient survival. With the exception of patients with a single cerebral metastasis, surgical excision generally does not significantly contribute to an improvement in overall patient survival. For patients with multiple cerebral metastases, poor RPA class, or medical condition prohibitive of general anesthesia, the major goal for surgical intervention is palliation. Table 4. Secondary Brain Tumors Primary Cancer Incidence Brain Metastasis (%) Lung 58 Breast 11 Genitourinary 9 Melanoma 6 Gastrointestinal 2 Unknown 10 Other 4 Patient management metastatic lesions. Clinical management: Dexamethasone is effective in decreasing cerebral edema associated with cerebral metastases. Anticonvulsants may be given prophylactively to lessen the threat of seizures, particularly in lesions located in cortical locations.

6 Treatment options. There are four general treatment options considered in patients with metastatic brain. These include supportive care only, standard fractionated radiation therapy, surgical resection ± whole brain radiation/radiosurgery, or radiosurgery ± whole brain radiation. In patients with advanced systemic disease and poor functional status one may decide on supportive care only Patients with advanced disease, poor functional status, and/or diffuse CNS disease may be treated with standard fractionated radiation therapy to the whole brain. Treatment paradigms typically consist of relatively short courses (10-14 fractions) delivered in dose tractions in the range 2-3Gy/day with total whole brain dosages in the cgy range. While thorn are reports of long term control of CNS metastatic lesions with conventional whole brain radiation, the treatment generally provides palliation there is a significant recurrence rate after several months. Surgical resection is usually reserved for patients with fewer than 3 metastatic lesions with anticipated low surgical morbidity. Patients also should be good surgical candidates with consideration of factors such as the age of patient, extent of systemic disease, type of tumor, associated medical conditions, and overall prognosis for survival. It is important to note that the local control rate after surgical resection is only about 50%. This is, in large part, due to the presence of micro-metastatic foci. This local control rate may be increased to 90% when either whole brain radiation is performed after surgical resection or radiation is delivered to the resection cavity via radiosurgery (see below). Stereotactic radiosurgery. In contrast to radiation therapy where low doses of radiation are given daily over a finite span of time, radiosurgery refers to the delivery of a single, high dose radiation to a well-defined lesion. As initially proposed by Dr. Lars Leksell, this is achieved by converging multiple, non-parallel radiation beam sources on the target lesion, thereby minimizing radiation received in each individual beam path. Thus, while the cumulative dose of radiotherapy is fractionated in the temporal axis, the cumulative dose of radiosurgery is fractionated on the spatial axis. Typically, the marginal dose delivered in a single session ranges from 11 Gy (for the treatment of benign lesions) to 70 Gy (for thalamotomy in the treatment of movement disorders) Radiosurgery constitutes an option in patients with lesions located in surgical inaccessible locations or with multiple lesions. The primary benefit of radiosurgery is thought to relate to the preservation of cognitive function as it minimizes radiation to the unaffected regions of the cerebrum. The risks associated with radiosurgery increases with the size of the lesion. Meningeal carcinomatosis is diffuse spread of neoplastic cells in the CSF in the subarachnoid space. This condition may be treated with cranio-spinal radiation and/or chemotherapy. Chemotherapy may be delivered directly in the ventricles via a ventricular catheter and Ommaya reservoir (subcutaneous silicone bubble reservoir). Prognosis is generally poor with this condition. MENINGIOMAS Meningiomas are usually benign neoplasm that develop from arachnoid cell rests and typically arise from the meninges (dura mater and arachnoid membrane). Thus they are nearly always

7 based along the dura. The only exceptions are intraventricular development (3% of intracranial meningiomas). Meningiomas demonstrate identified genetic alterations in 60% of cases. The most common abnormality involves chromosome 22. They occur twice as often in females and have been associated with hormonal receptors. The term meningioma was coined by Cushing and Eisenhardt in their classic description. There have been many descriptive terms describing subtypes of meningiomas. The most useful categorization includes the common typical meningioma (WHO I); less common atypical meningioma (WHO II); and rare anaplastic or malignant meningioma (WHO III). Clinical presentation. Meningiomas are usually slow-growing lesions that occur more commonly in the fifth, sixth, and seventh decades. They are distinctly rare in children. Meningiomas may grow to large sizes prior to causing symptoms. They are frequently an incidental finding on neuro-imaging studies done for other reasons. Generally, meningiomas are named in accordance with their anatomic location. Clinical presentations are directly related to the tumor locations as outlined below. Table 5. Clinical Presentation of Meningiomas Location Convexity Cavernous Sinus Medial Sphenoid Wing Tentorial Petro-Clival Spinal Optic Sheath Symptoms Seizures Diplopia 3 rd Nerve Palsy; Loss of Vision Ataxia Cranial Nerve Palsies Paraparesis Loss of Vision Treatment Options. Small meningiomas that are found incidentally and are not correlated with neurologic symptoms may be observed. Large meningioma or those causing symptoms will require treatment either by surgical resection or radiation. The primary treatment of meningiomas is surgical resection. Meningiomas may be cured if grossly resected. Recurrences occur with various rates depending on the completeness of resection, pathological characterization, and length of follow-up. Recurrence rates after complete resection have been reported at 10% at 5-years, 22% at 10 years, 55% at 20 years. Atypical meningiomas recur at high frequencies even after gross resection with rates as high as 40% at 5 years. Surgical resection may be limited by several factors such as age, associated medical problems, and invasion of tumor into the adjacent cerebrum. The location of the meningioma with involvement of critical blood vessels, cranial nerves, or the brain stem often limits the extent of tumor resection, particularly with tumors along the skull base. Stereotactic radiosurgery may be used to treat residual tumors (less than 3 cm), particularly those involving the skull base. Radiosurgery confers a greater than 80% local control rate in most series. Non-resectable tumors that are too large for radiosurgery may also be treated with 3-D conformation fractionated radiation, again with approximately 80% growth control. Postoperative patients with malignant meningiomas are recommended to have radiation, even following gross tumor resection. Chemotherapy is not routinely used in treatment of meningiomas.

8 PITUITARY TUMORS Pituitary tumors are generally benign neoplastic growths involving the sella and parasellar region. These tumors may present with a variety of manifestations. Clinically, these lesions present with either evidence of pituitary dysfunction or secondary to localized pressure from the tumor on the normal gland. Pituitary marcro-adenomas with growth into the supra-sellar space often involve the nearby optic structures. Classically, midline lesions may present with bitemporal hemianopsia secondary to compression of the crossing fibers in the optic chiasm. Table 7. Clinical Features of Pituitary Adenomas/Dysfunction Syndrome Hormone Clinical Features Acromegaly GH Over-Growth Face/Extremities; Facial Pain; Diabetes; Cardiomyopathy; Hypertension; Reduced Life Expectancy Cushing s Disease ACTH Diabetes; Hypertension; Central Obesity; Reduced Life Expectancy Amenorrhea- PRL Infertility; Dysmenorrhea, Impotency; Galactorrhea Galactorrhea Nelson s Syndrome ACTH S/P Bilateral Adrenalectomy; Hyperpigmentation Hypo-Pituitarism NULL Loss of Libido; Hypothyroidism; Fatigue; Adrenal Insufficiency TSH Secreting TSH Hyperthyroidism LH/FSH Secreting LH, FSH None Pituitary apoplexy. Acute or catastrophic neurologic syndrome resulting from hemorrhage and/or infarction of a pituitary adenoma. Clinical features include sudden severe headache, decreased level of consciousness, decrease or loss of vision, diplopia, and acute adrenal insufficiency. Pituitary apoplexy is a surgical and medical emergency with expedient diagnosis and treatment indicated. Treatment of pituitary tumors. Various treatment options are available for pituitary adenomas including medical treatment, surgical treatment and stereotactic radiosurgery/conformal fractionated radiation therapy. Prolactinomas may be treated with the dopamine agonist bromocryptine. GH secreting tumors (acromegaly) may be treated with the somatostatin analogue octreotide. Unfortunately, octreotide must be injected and is quite expensive. These drugs usually must be continued indefinitely. Transphenoidal surgery is a quick and efficient way to decompress the optic chiasm with midline tumors. Large tumors that grow off the midline may be approached via a craniotomy. Surgery is often indicated for patients with acromegaly and Cushing s disease. In some cases, surgery may be effective for treatment of an infertile female with microprolactinoma. Alternatively, bromocryptine may be effective in the latter situation. Radiation therapy has been used as a treatment option for patients with pituitary adenoma for a number of years. Stereotactic radiosurgery is now used with increasing frequency as an adjunctive treatment after partial transphenoidal resection or recurrent adenomas. CRANIOPHARYNGIOMAS.

9 These suprasellar tumors occur in a bimodal age distribution with about half occurring in patients less than 20 years of age. It is the most common non-glial tumor of childhood. A second peak occurs in adults in the fifth through seventh decades. These are benign tumors that arise from squamous epithelial cell rests persisting from Rathke s pouch during embryogenesis. Common presenting symptoms include visual problems, endocrine dysfunction, hydrocephalus secondary to obstruction of CSF pathways at the foramen of Monro, somnolence, or hypothalmic dysfunction. Treatment includes surgery and/or radiation therapy. Frequently, emergency CSF diversion through ventriculostomy are required in patients who present with acute hydrocephalus. While surgical excision is possible, gross total resection is typically unattainable due to adherence of the tumor cell to critical anatomic structures such as the optic nerve or hypothalamus. Tumor recurrence is frequent and often treated with either re-resection, radiation, or both. PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA. Primary Central Nervous System Lymphoma (PCNSL) is an extranodal form of non-hodgkin s lymphoma that is confined to the cranial spinal axis. It accounts for 4% of all primary brain tumors and 2% of all non-hodgkin s lymphoma. However, the incidence of PCNSL has been increasing steadily over the last three decades, paralleling an increase in systemic Non- Hodgkin s lymphoma, the extensive use of immunosuppressive therapy in organ transplantation/autoimmune diseases, and prolonged survival of AIDS patients. Though the appearance of PCNSL on neuro-imaging typically involves discrete contrast enhancing lesion(s), surgical resection of these lesions does not significantly improve survival. When left untreated, median survival ranges 3-5 months. Surgical resection of the contrast enhancing lesion(s) prolongs median survival by 1-2 months. These observations suggest that PCNSL is aggressively infiltrative in nature. As such, the role for surgery in the management of PCNSL remains diagnostic. The limited efficacy of surgical resection in the management of PCNSL led to investigations on the use of whole brain radiotherapy (WBRT) and chemotherapy. While WBRT frequently produces immediate tumor response and symptomatic relief as treatment for PCNSL, these responses are often short-lived. Ultimately, most patients suffer rapid disease relapse. A prospective trial of cranial irradiation by the Radiation Therapy Oncology Group (RTOG ) reveals a median survival of months after WBRT. Dose escalation does not achieve improved disease control or survival. First generation chemotherapy for PCNSL is based on regimens used to successfully treat systemic non-hodgkin s lymphoma. However, these regimens are ineffective against PCNSL, in large part due to the blood-brain barrier. Thus, second generation chemotherapeutic regimens have been built around the agents with good penetration of the blood-brain barrier. Amongst these agents, high dose Methotrexate (MTX) has emerged as the single most effective chemotherapeutic agent for PCNSL. The use of high-dose MTX based therapy in newly diagnosed PCNSL has improved median survival to approximately 35 months, exceeding that achieved by WBRT. The addition of WBRT to MTX chemotherapy, either as an upfront therapy or as a salvage modality, has been shown to enhance therapeutic efficacy. DeAngelis et al. reported that the combination of up-front WBRT and MTX based therapy improved the median survival of

10 PCNSL patients beyond that achieved by MTX therapy alone. Similarly, two retrospective series document that WBRT as salvage therapy for PCNSL improved patient survival. Despite this enhanced efficacy, the combination of MTX and WBRT is associated with significant neurotoxicity, especially in patients over the age of 60. On MR imaging, the toxicity is manifested in the form of diffuse periventricular leukoencephalopathy and ventriculomegaly. Clinically, the patients suffer symptoms that significantly hamper their quality of life, including urinary incontinence, ataxia, and dementia. It is estimated that >90% of patients over age 60 suffered these symptoms within two years of combined MXT-WBRT therapy. The clinical importance of this neurotoxicity is underscored by the fact that PCNSL typically affect patients in their fifth or sixth decade of life. The current treatment strategies for PCNSL vary, pending on the treating physician. Most treatment strategies are based on high dose MTX. Radiosurgery is occasionally performed for focal recurrence after MTX. COLLOID CYSTS. These are rare but extremely important lesions to diagnose and treat appropriately. This is a histologically benign lesion that arises in the anterior superior aspect of the third ventricle immediately posterior to the foramen of Monro. It typically has a sessile base attached to the choroid plexus of the hydrocephalus. Patients may acutely deteriorate from the hydrocephalus over a matter of hours. Patients with these symptoms or lesion > 1 cm in size should be emergently admitted to the hospital for neurosurgical treatment. Treatment is usually craniotomy or endoscopy for resection of the cyst. BRAIN TUMORS IN CHILDREN Central nervous system (CNS) tumors are the second most common tumors of childhood, with an incidence of 2-5/100,000. The types of tumors are similar to those seen in adults but with different frequencies. Pathologies more common in children are: medulloblastoma, cerebellar astrocytoma, craniopharyngioma, germ cell tumor, and choroid plexus tumor. Posterior fossa tumors are much more frequent in children. In children, 54% of tumors are supratentorial, 41% are infratentorial and 5% occur in the spinal region. Imaging: Modalities are as described in the adult section. However, special attention needs to be paid in terms of radiation exposure as they relate to CT. The pediatric population is particularly prone to the long-term effects of radiation in terms of malignancy. Another consideration is that pediatric patients may not be able to hold still during MR imaging. It is not infrequent that general anesthesia and intubation are needed for completion of MR imaging. Treatment Strategies Surgery: Many of the tumors encountered in children are potentially curable with gross total resection. Others require aggressive adjunctive therapy to achieve even moderate five year survivals. Radiation therapy has proven effective in many CNS tumors. There are significant sequelae when used on the developing brain of infants and children and unacceptable cerebral injury and retardation when used on children less than three or four years of age. Whole brain irradiation causes known decline in intellectual function in children 3 to 12 years of age and recently has been shown to lead to hormonal deficiencies in most children (growth hormone,

11 thyroid function). Cranio-spinal axis irradiation (used for some tumors that can disseminate in the cerebrospinal fluid spaces) can lead to short stature and growth retardation. Typically, radiation is delayed until the patient is >3 years in age. This is achieved by upfront chemotherapy. Chemotherapy has the usual toxic side effects (bone marrow suppression, sterility) but has a definite role in temporizing during infancy (0-3 years) before beginning radiation. It is being combined with standard surgical and radiation therapy to prolong survival or to attempt to reduce radiation dose. Posterior fossa tumors (except brainstem) Types Astrocytomas Medulloblastoma/primitive neuorectodermal tumor (PNET) Ependymoma Astrocytoma: Astrocytomas represent 12% - 28% of all pediatric brain tumors. The mean age at presentation is nine years. The majority are low grade. However, when found in pontine, the lesions typically represent a high grade tumor. Outside of the brainstem, surgical excision is the first line treatment, and gross total resection is usually possible. There is no clear role for adjunctive therapy in partial resection. Radiographic lesions that are classic for pontine glioma does not require tissue diagnosis. Most oncologists will proceed with treatment when the radiographic findings are unequivocal. Medulloblastoma: Medulloblastomas represent 15% to 20% of pediatric central nervous system tumors, with the peak incidence between three and eight years of age. The duration of symptoms is usually shorter due to faster tumor growth. It is often considered the same as similar supratentorial tumors (primitive neuroectodermal tumor {PNET}). It tends to invade or infiltrate adjacent structures, including the brainstem and the floor of the fourth ventricle, precluding total removal. It is capable of CSF dissemination. Staging is required postoperatively to rule out CSF spread, includes CSF cytology and imaging of the spinal canal with a CT myelogram or MR scan. Extra neural metastasis is rare but can occur to the peritoneum, bone marrow, and cervical lymph nodes. Standard treatment is surgery followed by craniospinal irradiation and ongoing evaluation of adjunctive chemotherapy to reduce radiation and/or prolong survival. Survival ranges from 40% to 80% at five years. Factors affecting survival adversely are: young age and greater extent of disease (CSF spread or >75% residual tumor). Survival increases with a greater initial resection of the tumor. Ependymoma: These represent 10% to 12% of all childhood CNS tumors, with 50% occurring before age five years and one-third by two years. They arise from the roof, floor or lateral recesses of the fourth ventricle, making it difficult to completely resect these tumors. Surgical resection has a higher morbidity due to brainstem involvement. Suprasellar tumors: The types of suprasellar tumors are: craniopharyngioma, optic glioma, hamartoma/hypothalamic glioma, dermoid and arachnoid cyst. Craniopharyngioma is as described in the adult section. Optic glioma is discussed below. Other lesions are sufficiently rare as not to warrant further discussion here.

12 Optic nerve glioma Thirty percent to fifty percent of these tumors are associated with neurofibromatosis. They can cause progressive visual loss. Loss of visual acuity in the infant may manifest itself by strabismus or nystagmus. Tumors extending posteriorly from the chiasm may present with diabetes insipidus, obesity, or anorexia, hypersomnia, precocious puberty or the diencephalic syndrome. Treatment varies due to the indolent course of these tumors. Tumors confined to one optic nerve with no visual function can be resected. When visual acuity persists, tumors generally followed by serial clinical and radiographic examinations. Posterior third ventricle/pineal region The types of these tumors are pineal parenchyma (pineocytoma, pineoblastoma) 28%; glial 26% and germ cell (germinoma, teratoma, choriocarcinoma) 37%. These lesions tend to present with acute hydrocephalus from obstruction of the posterior third ventricle or aqueduct or compression of the tectum and midbrain causes ocular motility dysfunction and Parinaud s syndrome. MR scanning remains the best imaging method. Germ cell tumors may give off markers detectable in blood or CSF. These include alpha-fetoproein and beta human chorionic gonadotropin. If elevated prior to treatment, these markers can be used for follow up of tumor recurrence. The germ cell tumors can be diagnosed based on CSF studies. Further, these lesions are radiation sensitive and may be treated with radiation with or without chemotherapy. Thus, CSF studies constitute the first line work-up. Other lesions are not radiosensitive, and biopsy should be undertaken for tissue diagnosis when CSF work up is not revealing. Total resection can be curative. Residual tumors are typically treated with radiation and chemotherapy. Choroid plexus papilloma Choroid plexus papillomas are rare intraventricular neoplasms, constituting approximately 0.4% of brain tumors in adults. Interestingly, this tumor is frequently observed within the first year of life, making up 13% of pediatric tumors that occur within the first year of life. The cell of origin is thought to involve cells that give rise to the cuboidal choroid epithelial cells. The neoplastic process may be related to choroid plexus cyst formation sometimes found in utero. The presence of choroid plexus papilloma is often marked by hydrocephalus due to obstruction of CSF flow, malabsorption of CSF or over-production of CSF (21). While hydrocephalus secondary to CPP are mostly related to non-communicating hydrocephalus, cases of communicating hydrophalus have also been reported in CPP patients. Thus careful follow-up of non-shunted patients warrant consideration. Rare cases of spontaneous hemorrhage or symptoms related to neural element compression have also been reported. Histologically, the lesion consists of delicate papilla formed by delicate fibrovascular connective tissue fronds covered by a single layer of uniform cuboidal or columnar epithelial cells. The nuclei are typically monomorphic and basally located. The presence of occasional mitotic figure, microscopic infiltration, ependymal differentiation, or mild cellular atypia does not portend poor prognosis or tendency for recurrence. The classic radiologic description of choroid plexus papilloma is an intensely, homogenous enhancing, cauliflower-like interventricular lesion. However, heterogeneous appearances secondary to cystic formation and calcification have also been reported. As with most mass lesions, choroid plexus papillomas are hypo- to iso-intense on T1 and hyperintense on T2 weighted MR imaging. Associated vascular hypertrophy is evidenced as flow voids and choroidal artery enlargement. The typical locations, in order of descending frequencies are: fourth ventricle, lateral ventricle, and third ventricle. Choroid plexus papillomas can occasionally be bilateral or multiple. Interventricular extension is an ancillary diagnostic sign that are not typically seen with other ventricular lesions.

13 There have been four retrospective studies examining the natural history of choroid plexus papillomas. For the most part, choroid plexus papillomas are benign entities that lend itself to surgical cure. However, up to 10% of the patients suffer tumor recurrence or progression after initial gross total resection. Thus, long-term follow-up of the patients is needed. Radiation and chemotherapy are considered only in cases of surgically inaccessible lesions. Radiation therapy involves delivery of Gy in 1.8 to 2.0 Gy fractions (reference here). Chemotherapeutic regimens generally include nitrosourea or cisplatin based therapy. Combination of Bevacizumab and Lapatnib are undergoing clinical trial.