An Overview of Neuro-Oncology

An Overview of Neuro-Oncology Nicholas G. Avgeropoulos, M.D. Medical Director, Neuro-Oncology Center WDMCI at Florida Hospital Ass‟t Consulting Prof, Duke Univ Med Cntr Generalizations • Most common tumors are metastatic tumors > gliomas > meningiomas > pituitary adenomas • In the case of primary tumors, visceral metastases are very rare – Neuroectodermal tumors do not invade the vessels as compared with visceral tumors such as carcinomas – The most likely tumor types to metastasize are PNET, hemangiopericytoma • Neuroectodermal tumors are not encapsulated ... they grow diffusely into the surrounding brain tissue and spread along tracts and myelinated fibers Generalizations • In adults, 2/3 tumors occur supratentorially • In children, 2/3 tumors are infratentorial • The most common neoplasms along the spinal cord are schwannomas and meningiomas • The most common glioma found in the spinal cord is the ependymoma • The brain and its coverings are primarily or secondarily involved by neoplasm in about 30% of all cases of systemic cancer Clinical Presentation • Symptomatology is protean – Headache is the presenting symptom in approx 1/3 patients with brain tumors and about 2/3 will experience headache through their clinical course – Cognitive disturbances are the initial symptom of brain tumor in 1/3 of patients with glioma and occur eventually in 1/2 of these patients – Quite common are weakness and AMS – 8% of patients with a brain tumor have papilledema – Seizures and „prognosis‟ R esp on se criteria for p h ase II stu d ies of su p raten torial m align an t gliom a. R esp o n se C o m p lete R esp o n se (C R ) P artial R esp o n se (P R ) P ro g ressiv e D isease (P D ) S tab le D isease (S D ) E n h a n cin g T u m o r A rea  9 5 % d ecrease 5 0 -9 4 % d ecrease  2 5 % in crease A ll o th er situ atio n s N eu ro lo g ica l S ta tu s Im p ro v ed o r stab le Im p ro v ed o r stab le W o rsen ed A ll o th er situ atio n s S tero id s O ff S tab le o r d ecreased d o se S tab le o r in creased d o se A ll o th er situ atio n s Astrocytoma - Neuropathology • Histologic diagnosis - 4 main parameters – – – – Nuclear atypia Mitoses Endothelial proliferation Necrosis • WHO – II - 1; III - 2; IV - 3 or 4 Pilocytic (Cerebellar) Astrocytoma • Most common in children / young adults - ‘juvenile type’ • Of cerebellar tumors, 1/3 are pilocytic astrocytomas (another 1/3 medulloblastomas, and 1/3 other types) • Solid tumors or mural nodules within a large cyst • Grossly, the mural nodule is discrete; the tumor is usually reddish-brown and moderately bloody • Microscopically, solid portions of the tumor consist of elongated, thin and tapering cells. Prone to undergo microcystic degeneration and exhibit areas of rarified cellularity Pilocytic (Cerebellar) Astrocytoma • Conspicuous pleomorphism, vascular proliferation, breakthrough to leptomeninges, and multinucleated giant cells should not be interpreted as prognostically significant. Key features include Rosenthal fibers and / or eosinophilic hyaline granules • Treatment is surgery when feasible • Prognosis is excellent with total removal with 10 year survival rates approaching 100%. Regrowth with subtotal resection is quite slow • WHO Grade I Fibrillary Astrocytoma • Diffuse form usually in cerebral hemisphere of adults but can also occur in brainstem and cerebellum of children and adolescents • Circumscribed forms usually in cerebellum and diencephalon of young patients • Grossly firm, rubbery and frequently with poorly defined borders. Infiltration is frequently present • Microscopically, round to oval shaped nuclei with both fine and coarse neuroglial fibrils; micro and macrocysts are relatively common in these „low grade‟ (WHO Grade II) astrocytomas Fibrillary Astrocytoma • Therapy usually consists of surgery and radiation ... Radiation is generally contraindicated in children < 3-5 years of age. In these cases, chemotherapy may be substituted. • Prognosis - in general, the younger the patient and the smaller the post-op tumor burden, the better the prognosis. 5 year survival - 36%, 10 year survival 25%, 15 year survival - 16%. • At least 50% of astrocytomas transform to anaplastic lesions Anaplastic Astrocytoma • Grossly, friable, granular, and gray. Prone to hemorrhage • Microscopically, neoplastic cells can be variably small, large, stellate, pilocytic, etc. Key feature is usually mitotic figures to make WHO Grade III • Survival is favorably affected by younger age, maximal resection, and by less involved anaplastic features • Median survival is 2-3 years with maximal combination modality therapy (reviewed later) Gemistocytic Astrocytoma • Rare. Usually restricted to the cerebral hemispheres • Gross - gray, granular, homogeneous, soft and well circumscribed • Microscopic - cells are large, globoid, and packed with a hyaline cytoplasm. Eccentric nuclei with coarse chromatin and conspicuous nucleoli. GFAP+ • The presence of >20% gemistocytes in a glial neoplasm is a poor prognostic sign as 80% gemistocytic astrocytomas convert into GBM Malignant Glioma - Statistics • 5-8 / 100,000 malignant gliomas • 35,000 primary CNS neoplasms / year • 15-20% of all primary intracranial tumors (1/2 of gliomas). Occurs in 40‟s - 50‟s with a M:F of about 2:1 • Disproportionate disability and mortality – 3rd leading cause of cancer related death among men 15-54 years – 4th leading cause in women 15-34 years Glioblastoma Multiforme • Grossly, spherical to irregular or „butterfly‟ shaped in larger centrally located tumors. More superficial tumors penetrate cortex and invade adjacent leptomeninges to attach to dura. Mottled appearance with frequent hemorrhage and necrosis. Multiplicity in 10% of cases • Microscopically, features of anaplastic astrocytoma with key presence of endothelial proliferation and necrosis Malignant Glioma - Survival • Surgery : 20 weeks • Surgery + RT : 36 weeks • Surgery + RT + chemotherapy : 40-50 weeks Benefits of Surgery • Removes heterogeneously resistant cells • Tumor burden diminished - increase in ratio of immune to neoplastic cells • Increases proliferative fraction suscept (decr G0) • Improves oxygenation and vulnerability to RT • Reduces tumor cell density / paracrine factors • Diminishes pool of potential mutants Benefits of Surgery • Diagnostic (sampling) • Neurologic (improved QOL, relief of neurologic deficit / ICP, reduction of steroid requirement) • Oncologic (extension of survival, reduce tumor burden, allow or enhance adjuvant therapy) • More complete surgical resection tends to result in longer survival Radiation Therapy - Principles • Many techniques for delivering RT - linac, proton beam, gamma knife, interstitial brachytherapy, etc • LINAC - high freq EM waves / microwave accelerator. • Usual total dose is 60 Gy in 2 Gy Fx‟s. Treatment area by MRI includes contrast enh. + T2 + 2 cm (46 Gy) with cone down to contrast enh. + 2cm (14 Gy) Chemotherapy • Marginal effectiveness for malignant gliomas but works best in patients with better prognostic factors including WHO Grade III, age <40 at diagnosis, and high KPS • „Standard‟ chemotherapy has been a nitrosourea based regimen or platinum drug • „Newer‟ promising chemotherapy includes Temozolomide and CPT-11 • Experimental approaches are also evaluating brachytherapy, delivery systems, biological therapies... Oligodendroglioma • 5-6% of all gliomas (perhaps much higher percentage) • Generally occurs from 30‟s to 50‟s - also a peak from 612 year olds • Grossly involve cerebral cortex and subcortical white matter. Solid with some foci of necrosis, cystic degeneration, and calcification. Propensity to bleed • Microscopically, tumor cells are composed of uniform, small, round nuclei that may exhibit a ‘fried egg’ appearance. Frequently infiltrate the cortical gray matter. Also, ‘chicken wire’ vascular changes and calcification can be seen Oligodendroglioma • Surgery is the usual initial treatment. • Anaplastic oligodendrogliomas tend to be chemosensitive (this is the exception to the rule). The regimen that has been used is PCV. • Combined loss of 1p and 19q may be a positive predictor of overall survival in oligo‟s • 75% 5 year survival. 6-10 year median survival. 3-4 year life expectancy in anaplastic oligo‟s Ependymoma • 2-6% of all gliomas. Occur mostly in 4th ventricle / ventricular system. Most ependymomas are found below the tentorium and in children < 10 y.o. Account for 60% of gliomas in the adult spinal cord • Usually fleshy, gray, and discrete ... associated with syrinx in spinal cord Ependymoma • Microscopically, cells with round to oval nuclei lie close to each other separated by areas of diminished cellularity or nuclear free zones (perivascular pseudorosettes); blepharoplasts and calcification may be seen as well • Treatment is usually with surgery and radiation therapy. Chemotherapy efficacy is questionable • 30-50% 5 year survival • Spinal ependymomas generally have a more favorable prognosis Medulloblastoma • 7-8% of all intracranial tumors of neuroepithelial origin • 25% of intracranial tumors in children - most of these occur in 1st decade; 2nd peak in adults from 20-24 y.o. • Associated with nevoid basal cell carcinoma syndrome, Turcot‟s syndrome (glioma polyposis), atax-telang, and XP Medulloblastoma • Microscopically, extreme cellularity is characteristic. Small, round to oval nuclei, very blue secondary to coarse chromatin and dusky nucleoplasm. Scanty cytoplasm with frequent mitoses. Neuroblastic differentiation manifest as H-W rosettes (cells at periphery extend cytoplasm centrally). Spongioblastic differentiation is expressed by a rhythmic palisading and interlacing bundles of bipolar cells Medulloblastoma • Treatment - attempt total surgical resection with craniospinal irradiation as an adjunct. Overall >50% survival and diminished spread of disease with radiation but tradeoff is intellectual decline. • Adjuvant treatment with chemotherapy is felt to be useful (esp high risk). Regimens vary and may include CDDP, CCNU, VP-16, VCR, CPA. • Neoadjuvant chemo in patients less than 3 y.o. Meningioma • 13-19% of all primary brain tumors. 12% of meningiomas found in spinal cord area • Occur in 5th decade with a clear predominance in women • Proposed etiologic factors include genetic, head injury, irritation from a chronic SDH, long standing infection, ionizing radiation Meningioma • In cerebral convexities, about 50% of meningiomas are found along the sagittal sinus (middle 1/3 > frontal > occipital). • In spinal cord, thoracic > other regions • Grossly hemispheric, globular growths that are firmly attached to the dura. Thin investing capsule from the soft meninges. Hyperostosis in about 5% of cases Meningioma • Histologic patterns as per the WHO category scheme include meningotheliomatous, fibrous, transitional, psammomatous, hemangioblastic, hemangiopericytic, papillary, and anaplastic / malignant variants • Only papillary meningiomas as a specific meningeal tumor morphology other than “anaplastic” or “malignant” types is associated with a somewhat worse prognosis Meningioma • Anaplastic - high mitotic rate, microscopic necrosis, cellular atypia with multi-nucleation and nuclear hyperchromasia, change in morphology. Malignant is with brain invasion • Treatment is gross total resection when possible / feasable. Radiation treatment has been proved a useful adjunct to greatly slow tumor progression • Survival after total resection of a benign tumor is 93%, 80%, and 68% at 5, 10, and 15 years • Survival after subtotal resection is 63%, 45%, and 9% at 5, 10, and 15 years Primary CNS lymphoma • Arise sporadically in otherwise healthy people (1%) but most frequently in AIDS patients (2%) • The incidence of sporadic PCNSL has nearly tripled in the past two decades • Usually deep supratentorial parenchymal mass occuring as solitary (mostly immunocompetent) or multiple (AIDS) lesions • Primary CNS lymphoma usually manifests in the brain (30-50%), leptomeninges (10-25%), eye (10-20%), or spinal cord Primary CNS lymphoma • Microscopically, most PCNSL cells are large with round nuclei and prominent nucleoli. Infiltrates are patchy, poorly demarcated, and angiocentric. • Immuno - >90% of cells are B-cell + LCA+ • High dose methotrexate has been the focus of treatment. WBRT is usually reserved for nonresponders after MTX to prevent side effects from radiation and leukoencephalopathy. Schwannoma • 8% of primary tumors in skull cavity and 80-90% of tumors in CPA • Female to male ratio is 2:1. Occur mostly in middle decades of life • Sensory nerves are selectively affected. Tumor arises on the nerve root after pial penetration Schwannoma • Grossly firm, circumscribed, encapsulated. Usually elastic and milky white although cystic changes may occur • Microscopically divided into „Antoni type A‟ and „Antoni type B‟ morphology. • Total resection is considered curative. Radiation therapy may be useful Neurofibroma • NF-1 occurs in 1:3,500. AD. Clinical manifestations include cafe au lait spots, axillary freckles, Lisch nodules in iris, and multiple peripheral nerve tumors • NF-2 occurs in 1:50,000. AD. Clinically, bilateral vestibular schwannomas, family history (50%), or two of following - neurofibroma, meningioma, glioma, schwannoma, lenticular opacity Neurofibroma • Plexiform - Characteristic of NF. Grossly soft, elastic and whitish. Microscopically with scanty cell content, loose texture, and fusiform or wavy nuclei • Dermal - Grossly soft, homogeneous, and not encapsulated. Demarcated from epidermis and merges with subcutaneous tissues. Microscopically interwoven bundles of fusiform cells, collagen fibrils, and scanty mucoid matrix • Immuno - S100 + • Surgery is considered curative of that lesion Craniopharyngioma • 3% of all intracranial neoplasms • Adamantinomatous subtype most frequent. Usually present in childhood and adolescence • Probably arise from Rathke‟s pouch and thereby found in suprasellar area • Grossly, cystic and filled with „machinery oil‟ fluid composed of cholesterol crystals Craniopharyngioma • Microscopically, prominent epithelial lobules, stellate myxoid areas, cystic spaces filled with amorphous debris. Also, wet keratin and calcium deposits. Extensive fibrosis, chronic inflammation, and cholesterol clefts. Periphery of tumor usually shows Rosenthal fiber-rich gliosis • Treatment is usually surgical with adjunct radiation therapy for incomplete resection. Good results with surgically resectable tumors Pituitary adenoma • 10-20% of all intracranial tumors • Usually benign lesions found in sella turcica but about 75% of cases are accompanied by a hypersecretory syndrome; other neurologic sy‟s and sx‟s from compression of optic nerve, optic chiasm, cavernous sinus, oculomotor nerve, etc • Therapy is aimed at restoring hormonal balance and preserving neurologic function. Surgery can be curative; medical and radiation therapy as adjuncts Neurologic Complications of Cancer • Occur in 10-15% of patients with systemic cancers • Lung carcinoma (especially small cell and adenocarcinoma) most common source of metastases followed by breast carcinoma, malignant melanoma, renal cell carcinoma, and colorectal cancer • 50% occur as solitary / 50% as multiple lesions • Frequently found in gray-white junction Neurologic Complications of Cancer • Neurologic complications are seen in about 30% of cancer patients – Metabolic encephalopathy – Metastatic disease – Paraneoplastic syndromes • Lambert-Eaton, dermatomyositis, carcinomatous neuromyopathy, polyradiculopathy, retinal degeneration, opsoclonus-myoclonus, myelitis – Complications related to cancer therapy • Radiation encephalopathy, radiation necrosis, neuropathy, psychosis, cerebellar dysfunction, leukoencephalopathy Paraneoplastic Abs • Anti-Yo - Cerebellar degeneration (anti-pkje) Gynecologic malignancies (although others as well) • Anti-Hu - Sensory neuropathy or encephalomyelitis - Oat cell carcinoma • Anti-Ri - Retinal degeneration - Oat cell carcinoma Epidural Cord Compression • Acute or subacute radicular or „band-like‟ back pain occurs in >90% of patients • Look for sensory levels, paraparesis, bowel and bladder incontinence • MRI of spine or CT myelogram is needed urgently • DXM 100 mg over 1 hour and then 4 mg IV q 6 • Usually, RT is treatment of choice unless RT has already been given or radioresistant tumor