Turcot syndrome

Primary brain tumors are a diverse group of neoplasms that develop after transformation of cells within the brain, cerebral vasculature or meninges. These tumors affect both adults and children, but the presenting symptoms and signs often differ by age group. Because of their intracranial location and proximity to delicate brain structures, even slowly growing benign brain tumors may cause severe neurologic sequelae if the diagnosis is delayed. An awareness of the common types of primary brain tumors and their typical presentations allows prompt diagnosis and referral for therapy, thus minimizing morbidity and mortality.

Epidemiology

Each year in the United States, primary brain tumors comprise approximately 2 percent of newly diagnosed malignancies. The most common and clinically important tumors are listed in Table 1,[1] separated into two groups by their malignant potential. The annual incidence across all age groups is six to nine cases per 100,000 population, which corresponds to about 15,000 new cases each year (Table 2).[2] The most common types of primary brain tumors are gliomas, meningiomas and pituitary adenomas.

Primary brain tumors occur at all ages, with two distinct peaks of incidence: adults 55 to 65 years of age and children three to 12 years of age. In general, primary brain tumors are much more common in adults over 45 years of age than in children or young adults. However, brain tumors are still the most common solid neoplasms diagnosed in young patients, second only to leukemia in overall cancer incidence. The annual mortality rate in adults is higher for primary brain tumors than for Hodgkin's disease or multiple sclerosis.[1]

The location and histology of common primary brain tumors in adults are distinctly different from those in children (Table 3). In young patients, more than 60 percent of tumors develop in the infratentorial cavity within the cerebellum, pons and brainstem. In contrast, most brain tumors in adults develop supratentorially within the cortical, subcortical and basal ganglia regions.

Etiology

The etiology of primary brain tumors remains obscure. Many of the factors associated with an increased risk in other tumor types, such as smoking, diet or excessive alcohol intake, have not been found to correlate with primary brain tumors. Other medical diseases and their treatments do not appear to predispose patients to primary brain tumors.[3] No correlation has been found with a prior history of head injury, which had been previously reported to increase the risk of primary brain tumors.[3]

Cranial radiation increases the risk of a primary brain tumor, usually many years after the exposure.[4,5] Most radiation-induced tumors are meningiomas, astrocytomas or glioblastoma multiformes.

Genetic factors appear to play a strong role in the development of primary brain tumors and other types of neoplasia. A family history of cancer is present in up to 19 percent of patients with primary brain tumors.[2] In patients with glioblastoma multiforme, the familial history of cancer increases to 30 percent. Several genetically transmitted diseases are commonly associated with an increased risk for primary brain tumors, including neurofibromatosis, tuberous sclerosis, Turcot syndrome, Li-Fraumeni cancer syndrome and von Hippel-Lindau disease.

Pathogenesis

Modern molecular biology techniques have caused a revolution in thinking about the pathogenesis of neoplasia, including primary brain tumors. At the level of the cell nucleus, both positive and negative regulators of growth are necessary for normal control of cell proliferation. The positive regulators are called proto-oncogenes; their products function as growth factors, growth factor receptors and intracytoplasmic signaling enzymes. Excessive production or activity of proto-oncogenes may occur because of chromosomal abnormalities or mutations within the gene, converting proto-oncogenes into oncogenes. The presence of oncogenes within a cell results in a growth advantage and is part of the neoplastic transformation process.[1,6,7]

Negative regulators of cell growth are called tumor suppressor genes. Suppressor genes inhibit cellular proliferation at the level of the nucleus, often functioning as transcription factors. The loss of tumor suppressor gene function by mutation, deletion or reduced expression is also involved in the transformation of cells to the malignant phenotype.

In most solid tumors such as primary brain tumors, transformation requires abnormalities affecting the function of both proto-oncogenes and tumor suppressor genes. The excessive stimulation and lack of inhibition confer a malignant growth advantage and lead ultimately to neoplastic proliferation.

Clinical Presentation

The most important feature of the clinical presentation in patients with primary brain tumors is the progressive nature of their symptoms. The rate of progression can range from an extremely indolent time course to an acute hemorrhagic event within a tumor.

The evolving presentation is variable, influenced by many factors, including the type of tumor and its method of expansion (infiltrative within the brain versus encapsulated mass), the location, the rapidity of growth, and the degree of associated edema and mass effect. Table 4[8] lists Common symptoms noted at presentation in a large series of adult patients with supratentorial gliomas.

While individually none of the symptoms listed in Table 4 is pathognomonic for primary brain tumor, the degree of suspicion for a primary brain tumor should increase if several of these symptoms occur together in the context of a progressive neurologic illness.

The symptoms and signs associated with a primary brain tumor can be divided into two groups: generalized signs and symptoms, which are produced by disturbances of intracranial pressure regulation, and focal signs and symptoms, which are produced by alteration of function of specialized regions of the brain due to tissue destruction and/or compression.

GENERALIZED SYMPTOMS AND SIGNS

The most common generalized symptoms of primary brain tumor are headache, generalized seizure activity, cognitive and personality changes, nausea and emesis, diplopia and alteration of consciousness. These symptoms occur as the expanding tumor and associated edema raise intracranial pressure and compress localized nervous structures. Tumor compression of ventricular pathways and associated edema may cause hydrocephalus, which further augments elevated intracranial pressure.

Headache. The most common symptom of primary brain tumor is headache, which is present in 65 to 70 percent of patients.[8] Headaches are probably caused by a combination of elevated intracranial pressure and traction on sensitive structures such as blood vessels and overlying dura mater.

In most patients, the headache occurs in the frontal or vertex region, but it may be diffuse. Pain may awaken the patient during sleep but more commonly is present on awakening in the morning. It may be more severe in the morning as a result of elevated [PCO.sub.2] during the hypoventilation of sleep, which in turn increases cerebral blood volume and exacerbates peritumoral edema; another factor may be the reduced cerebrospinal fluid drainage that occurs in the recumbent position.

The pain is usually of moderate to severe intensity and often lasts for hours at a time. In contrast to typical migraine headache, the headache pain of a primary brain tumor is not always pounding or throbbing, nor is it as consistently associated with nausea, emesis or photophobia.

The headaches of primary brain tumor differ from cluster headaches; there is no associated unilateral scleral injection, tearing, rhinorrhea or sinus congestion. The intensity of the pain may be increased by coughing, sneezing, straining or other maneuvers that increase intrathoracic (and consequently intracranial) pressure.

Differentiating the headaches of primary brain tumor from other common headaches by history may be very difficult. A patient in whom headache is a new development should be evaluated carefully, especially if the patient is older. Patients with stable headache disorders and a well-described pain pattern who complain of a new type of headache or a progressive worsening of their usual headaches should receive close observation. In most patients with primary brain tumors, the headaches are progressive in frequency and intensity, and are more resistant to analgesics than headaches not related to tumor.

Nausea and Emesis. These symptoms are present in one-third of patients with primary brain tumors and do not always correlate with headaches. Nausea and emesis are caused by elevation of intracranial pressure and are often most severe in the morning. The nausea and emesis may become progressively worse and often may lead to an extensive gastrointestinal evaluation, especially in children with posterior fossa tumors. Such an evaluation can significantly delay proper diagnosis.

Generalized Seizure Activity. Generalized seizures occur in the form of tonic-clonic or absence seizures in approximately 22 percent of patients with primary brain tumors.[2] The growing tumor causes irritation and compression of neural tissues, producing epileptogenic activity that generalizes to the whole brain.

Seizures are commonly the initial symptom in patients with primary brain tumors. Primary brain tumor should always be included in the differential diagnosis of a patient with a first seizure, especially if the patient is more than 20 to 25 years of age. In patients with a well-established seizure disorder, a progressive worsening of control or a change in the character of a typical seizure may be an indication of an underlying primary brain tumor.

Cognitive and Personality Changes. Elevation of intracranial pressure, mass effect and disruption of central pathways may produce changes in cognition and personality. These changes are more pronounced with large tumors, but they may also occur with small lesions. Mild alterations of memory, concentration and reasoning are commonly noticed by family members. Dulling of affect or loss of energy and initiative may also develop.

Alteration of Consciousness. Elevation of intracranial pressure due to tumor mass and edema may result in lethargy, drowsiness, irritability or coma. The most common alteration is excessive daytime sleepiness or lethargy, which is typically noted by a spouse or parent.

Diplopia. Complaints of double vision and other general visual disturbances develop in fewer than 10 percent of patients with primary brain tumor. Diplopia is caused by dysfunction of the sixth cranial nerve, secondary to elevated intracranial pressure, as the nerve courses from the brainstem to the orbit. Diplopia is often apparent to the patient before dysconjugation is noted by the physician. The onset of diplopia, especially in a patient with other progressive symptoms, should alert the physician to the possibility of a primary brain tumor.

FOCAL SYMPTOMS

Focal symptoms, which are helpful for localization of the tumor, result from destruction, compression or irritation of specialized regions of the brain. Tumors near the cerebral cortex can induce focal motor or sensory seizures, which in some studies are the most common seizure type reported.

Any area of the body may be affected, but the face and arm are most often involved. Todd's postictal paralysis (prolonged weakness of the limbs after seizure activity) is more common with primary brain tumors than with other conditions.

Focal symptoms such as personality or cognitive changes (e.g., apathy, dulling of affect, jocularity, forgetfulness), limb weakness or loss of sensation, aphasic speech disturbances, hemianopic visual field changes, gait disturbances (e.g., ataxia, imbalance) and limb incoordination are frequent in patients with primary brain tumors and are commonly progressive. Recognition and evaluation of such symptoms are very important for early diagnosis.

Neurologic Examination

Neurologic examination is an important tool in analyzing the signs that accompany the many symptoms of patients with primary brain tumors. Common neurologic signs in a series of adults with supratentorial gliomas are listed in Table 5.[8] Hemiparesis, cranial nerve palsies and papilledema are each found in more than 50 percent of patients. Early in the course of the illness, these findings may be subtle.

Hemiparetic weakness involves the arm more often than the leg and may be accompanied by an ipsilateral increase in tendon reflexes and a Babinski sign. Arm weakness is usually more severe in extensor muscles than in flexor muscles. It is caused by dysfunction of the corticospinal pathways as they descend to the spinal cord to innervate the limbs.

The most common cranial nerve deficits are lower facial weakness (ipsilateral to the hemiparesis), caused by seventh nerve palsy, and incomplete eye abduction, secondary to sixth nerve palsy. Maneuvers that demonstrate the abnormal eye abduction may elicit complaints of diplopia from the patient.

Papilledema is seen on ophthalmoscopic examination as swelling of the optic nerve head with blurring of the disk margin; in more severe stages, retinal venous engorgement and hemorrhage may occur, caused by increased intracranial pressure that is transmitted down the optic nerve, with subsequent disturbance of axoplasmic flow and swelling of axons. Severe papilledema may produce central visual field defects because of enlargement of the blind spot.

Hemianopic visual field defects are found on examination in more than 25 percent of patients with primary brain tumors. If the defect develops slowly, the patient may remain unaware until it is discovered on visual field examination.

Speech disturbances can manifest as difficulty with articulation (dysarthria), commonly seen in children with infratentorial tumors affecting the brainstem or cerebellum, or as a language deficit (dysphasia), with an impaired ability to express thoughts ("I can't get my words out") or to understand speech.

By the time of diagnosis, primary brain tumors are often large enough to produce symptoms and signs that enable localization to specific lobes or regions of the brain. Focal manifestations and corresponding regions of the brain are listed in Table 6. An awareness of these syndromes, especially in the context of a progressive illness, is invaluable for early recognition and diagnosis.

In children, the symptoms and signs commonly caused by primary brain tumors (Table 7) are somewhat different from those in adults, because of the predilection of these tumors for the posterior fossa. Symptoms such as poor appetite, change in school performance, weight loss, ataxia, dizziness, posterior neck pain, dysphagia and head tilt (caused by vertical misalignment of the eyes) are more common in children than in adults. Neurologic findings, such as truncal or limb ataxia, nystagmus, bulbar weakness (weakness of palatal and pharyngeal muscles), gaze palsy (difficulty with horizontal conjugate gaze to one side due to damage or compression of pontine gaze centers) and opisthotonos (severe extension of the neck and spine, often due to plateau waves of elevated intracranial pressure) are more common in children because of the frequency of brainstem and cerebellar tumors in this age group.

Infants with unfused sutures may not develop typical signs of elevated intra-cranial pressure, but they may have accelerated head growth, irritability and episodes of opisthotonos or extremity stiffening. Other general symptoms and focal signs, such as headache, nausea and emesis, diplopia, papilledema, facial weakness and corticospinal tract weakness, are similar to those in adults and have the same pathophysiology. However, despite the similarities of many of the symptoms and signs in adults and children with primary brain tumors, they may be more significant indicators in pediatric patients. For example, the triad of headache, nausea and emesis and papilledema is estimated to occur in 75 to 80 percent of children with medulloblastoma.

Neuroimaging

In a patient with a history and neurologic examination suspicious for a primary brain tumor, neuroimaging is an invaluable tool for diagnosis. Magnetic resonance imaging (MRI) in combination with the paramagnetic contrast agent gadolinium-DTPA has become the modality of choice for diagnosing primary brain tumors in adults[1] and children.[9] A brain tumor appears as a region of altered signal with surrounding edema and mass effect (Figures 1a and 1b). Most malignant tumors enhance with contrast, because of an alteration of the blood-brain barrier within tumor vasculature. In addition, MRI clearly demonstrates low-grade tumors and allows the differentiation of vascular masses from tumors.

Because there is no bone artifact, MRI is more sensitive than computed tomography (CT) for detecting tumors in the posterior fossa involving the brainstem and cerebellum (Figures 2a, 2b, 3a and 3b). Despite the overall superiority of MRI for the diagnosis of primary brain tumors, CT remains an excellent diagnostic technique and is less costly. With the addition of a contrast agent, CT can readily demonstrate the enhancing mass, surrounding edema and mass effect of most tumors, especially if they are supratentorial (Figure 4).

Contrast enhancement should always be ordered for CT or MRI scans when the possibility of a primary brain tumor is being investigated. Contrast enhancement increases the sensitivity for discovering a tumor and helps in differentiating it from other lesions that may have a similar appearance (Table 8).

Cerebral abscess is the only entity characterized by a progressive course and ring-enhancing appearance on contrast-enhanced CT or MRI, similar to that of a primary brain tumor. Biopsy is usually necessary to differentiate between primary brain tumor and abscess and, on occasion, the other disease processes listed in Table 8.

Principles of Treatment

CONTROL OF SEIZURES AND EDEMA

Once the diagnosis of primary brain tumor has been confirmed, a few general treatment issues should be addressed. When the patient has seizures, anticonvulsant therapy must be instituted and followed carefully. Phenytoin (Dilantin) and carbamazepine (Tegretol) are both excellent agents for control of generalized seizure activity.

For patients with partial complex or focal motor/sensory seizures, carbamazepine may have slightly more efficacy than other anticonvulsants. Valproic acid (Depakote) is an excellent second-line anticonvulsant for patients who cannot tolerate, or whose seizures are not well controlled by, phenytoin and carbamazepine.

Monotherapy with one of these three drugs is always the initial management approach. A second drug should be added only if excessive seizure activity continues despite high therapeutic levels of the first anticonvulsant. Serum levels must be monitored carefully.

Many patients with primary brain tumors receive high-potency corticosteroids, usually dexamethasone (Decadron), to reduce symptoms caused by peritumoral edema. These agents are helpful for symptom control but should be used sparingly because of the wide range of side effects, which include hyperglycemia, peripheral edema, proximal myopathy, gastritis and infection.[10,11] The lowest possible dose of steroid that can control the patient's pressure-related symptoms should be used.

SURGICAL THERAPY

Surgical intervention is an important aspect of initial therapy in most patients with a primary brain tumor. Surgical extirpation, the most rapid method for cytoreduction of tumor burden, often prolongs life, allowing further treatment. It also provides tissue for a definitive pathologic diagnosis, which is critical as a foundation for decisions about which therapy to implement.

The immediate removal of tumor tissue relieves mass effect and lowers intracranial pressure, often with rapid improvement of symptoms and signs. It is theorized that reduction of tumor bulk can induce residual nondividing cells to enter an active phase, thus making them more susceptible to radiation therapy and chemotherapy.

Complete removal of benign tumors, such as meningioma, pilocytic astrocytoma and schwannoma, can be curative. For malignant tumors, such as glioblastoma multiforme, medulloblastoma and anaplastic astrocytoma, complete surgical resection is not curative but may prolong survival when compared with partial resection or biopsy.[1,12] Further research is necessary to clarify the survival benefit of aggressive surgery.

For patients with deep tumors or tumors located in specialized regions of the brain, CT- or MRI-guided stereotactic biopsy is a safe and accurate way to obtain tissue for diagnosis.

RADIATION THERAPY

After surgical resection or biopsy, all malignant tumors and, in specific circumtances, certain benign tumors require radiation therapy.[1,13] Radiation therapy has been shown to prolong survival for many malignant tumor types, including glioblastoma multiforme, anaplastic astrocytoma, medulloblastoma and ependymoma.

The most common treatment method is fractionated external beam radiotherapy, in which the daily dose, 180 to 200 centigray (cGy), is divided and administered to the cranium using parallel opposed ports.

The use of whole-brain ports plus a boost to the tumor bed is a frequent strategy, although limited-field dosing, which is under study, may be as effective and is potentially less toxic.[1,13,14] For most malignant tumors (and selected low-grade tumors) treatment consists of a total dosage of 5,000 to 6,000 cGy, delivered in 30 fractions over five to six weeks.

In addition to the cranial dosage, spinalaxis radiation therapy is required for tumors that often seed the meninges, such as medulloblastoma, pineoblastoma and anaplastic ependymoma.

New developments include using radiosensitizers to improve the efficacy of radiation therapy, hyperfractionated radiation therapy, brachytherapy (stereotactic placement of radioactive seeds within tumors),[15] radiosurgery (stereotactic delivery of single, high doses of radiation into tumors)[16] and the application of radiation therapy to carefully selected benign primary brain tumors.

CHEMOTHERAPY

Chemotherapy is used as adjunctive treatment for malignant primary brain tumors and for certain benign tumors that progress despite resection and radiation therapy. The addition of chemotherapy has resulted in only modest improvement in survival in adults with tumors[17,11] but has proved more efficacious for primary brain tumors in children.[19,20]

In adults, it is malignant astrocytomas that most commonly require chemotherapy Nitrosoureas, in particular carmustine (BCNU; BiCNU), are the most effective drugs for these tumors.[17,18] Other agents with activity include procarbazine (Matulane), administered alone[21] or in combination with lomustine (CCNU; CeeNU) and vincristine (Oncovin)[22]; cisplatin (Platinol); etoposide (VePesid), and cyclophosphamide (Cytoxan). Methotrexate has activity against primary brain lymphoma.

For children, agents with efficacy against the common tumors (e.g., medulloblastoma, anaplastic astrocytoma) include lomustine, vincristine, cisplatin, carboplatin (Paraplatin), procarbazine, methotrexate, etoposide and cyclophosphamide.

The cause of tumor progression in patients receiving chemotherapy is usually de novo or acquired chemoresistance.

Final Comment

Family physicians are often the first medical professionals in contact with patients who have primary brain tumors. An awareness of the common symptoms and signs and the natural history of these neoplasms expedites diagnosis and treatment. Because the management and treatment of patients with primary brain tumors is often complex, these patients should, if possible, be referred to a comprehensive facility that utilizes a multidisciplinary team of neuro-oncologists, neurosurgeons, radiation oncologists, neuropathologists and oncology researchers.

REFERENCES

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HERBERT B. NEWTOWN, MD. is assistant professor of neurology and director of the Division of Neuro-Oncology at the Ohio State University Hospitals and the Arthur James Cancer Hospital and Research Institute, Columbus, Ohio. A graduate of the State University of new York at Buffalo School of Medicine, Dr. Newton served a neurology residency at the University of Michigan Medical Center, Ann Arbor, and completed a fellowship in neuro-oncology at Memorial Sloan-Kettering Cancer Center, New York City.

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