Epidemiology

The chance of developing a primary malignant brain tumor in the United States is small relative to the chance of developing a tumor of the lung, breast, colon, or prostate. The majority of these are gliomas. Data collected by the Central Brain Tumor Registry of the U.S. (CBTRUS) and Surveillance, Epidemiology, and End Results consortia demonstrates an adult incidence of 5.1 gliomas per 100,000 person-years; almost 50% of these are glioblastoma. Brain cancer incidence rises with age, peaking at 65–70 years. For glioblastoma alone, the highest incidence is at age 62 years. Men are significantly more likely to develop a glioma (M : F = 1.8). Brain cancer incidence also varies regionally; the incidence in Hawaii is roughly half that of New England, and globally the incidence of brain tumors in Israel is roughly eight times that of Japan. Although some studies suggest that Caucasians are more predisposed to gliomas than African or Asian populations, diminished health care availability in non-Westernized socioeconomic settings may be the primary mechanism explaining this discrepancy rather than genetic susceptibility differences. Gliomas, like most cancers, are usually a random event and rarely have a familial predisposition. However, having a first-degree relative with a glioma doubles a patient’s risk but this risk is still small. Rarely, gliomas occur as part of an inherited disorder such as neurofibromatosis types 1 and 2 and tuberous sclerosis. There are no well-defined environmental toxins, with the exception of previous brain irradiation, that predispose patients to glioma.

Pathology

Gliomas typically exhibit features of astrocytes, or oligodendrocytes, or both (mixed glioma) (Fig. 52-1). Microscopically, gliomas appear as diffusely infiltrating cancers of three types: astrocytic, oligodendroglial, and oligoastrocytic (combining the morphologic features of both oligodendroglioma and astrocytoma).

Figure 52-1 Gliomas.

The World Health Organization uses a three-tiered classification system based on histologic criteria that divides these tumors into low-grade glioma, anaplastic glioma, and glioblastoma multiforme (Table 52-1). Low-grade tumors may contain a high density of almost normal-appearing cells. Here the percentage of cells that are dividing (as determined by mib-1 or KI-67 staining) is often 2% or less. Anaplastic gliomas exhibit more atypical cells, with pleomorphic nuclei having growth rates in the 5–10% range but no evidence of necrosis. Gliomas with high growth rates (>10% mitotic figures) and necrosis are classified as glioblastoma multiforme (GBM). The less common pilocytic astrocytomas are a separate category of glioma that are histologically characterized by Rosenthal’s fibers, usually occur in children, and often have a good prognosis if surgical resection can be achieved. Tumor grade is the most reliable predictor of prognosis. Even if the lesion cannot be safely excised, a needle biopsy is often indicated. Gliomas are not staged as other cancers are because they rarely metastasize outside the CNS. Analysis of tumor samples for genetic abnormalities can help predict response to therapy and will likely lead to a better classification system for gliomas. This classification is valuable prognostically; low-grade gliomas have median survivals of 5–15 years, anaplastic gliomas 2–5 years, and GBM 12–18 months.

Diagnosis, Treatment, and Prognosis

MRI is the most specific diagnostic modality (Fig. 52-2). On most occasions, one sees focal heterogeneous irregular-margined cystic mass lesions with perilesion edema, gadolinium rim enhancement, and often enough mass effect to produce a transtentorial herniation. In contrast, the occasional patients with gliomatosis cerebri have a characteristic diffusely abnormal MRI picture characterized by multiple areas of subtle white matter enhancement with extension into the cortical mantle, extending far beyond what their clinical presentation usually dictates (Fig. 52-3).

Figure 52-2 Glioma MRI and Pathology.

Figure 52-3 Gliomatosis Cerebri.

Even with early diagnosis, the prognosis remains grim and most patients will fail therapy within 12 months of diagnosis. The first treatment step is to perform as wide a surgical resection as is functionally tolerable. Younger patients with a normal examination who have had a gross total resection have the best prognosis. Postoperative radiation therapy (RT) clearly benefits many patients as those GBM patients who receive RT have a median survival twice that of those who did not.

Combining RT with concomitant and adjuvant chemotherapy is now the standard of care for patients with GBM. RT plus temozolomide leads to a modest benefit in overall survival (14.6 vs. 12.1 months). However, more importantly, there is a significant increase in the percentage of those surviving 2 or more years (26.5% vs. 10.4%). Bevacizumab, an antagonist of vascular endothelial growth factor, has recently proven safe and effective in patients with recurrent GBM. Recent reports indicate a 6-month progression-free survival of 46%. It is now an urgent priority to determine how best to use this new tool and what agents might work synergistically with it.

When patients have failed these Food and Drug Administration (FDA)–approved treatments, a clinical trial should be considered. Molecular research is defining a number of potential glioma cell targets. These are mostly second messenger molecules involved in pathways that enhance cell proliferation or inhibit programmed cell death. The goal is to treat a selected group of patients whose tumors overexpress the specific target of the treatment drug.

Clinical Vignette

This 34-year-old right-handed woman presented with generalized seizures. Several months earlier, she noted episodes of an unusual smell but these did not cause her immediate concern. Brain MRI demonstrated a right temporal lobe lesion, bright on T2 and FLAIR imaging but hypointense on T1, with no evidence of enhancement after gadolinium (Fig. 52-4). The patient was treated with oxcarbazepine and admitted to the hospital. Open biopsy was nondiagnostic but subsequent temporal lobectomy revealed an oligodendroglioma with a Ki-67 index of 3.8%. Postoperatively, the patient was treated with monthly temozolomide for 1 year. She is now receiving no treatment and has been clinically and radiographically stable for 2 years.

Figure 52-4 Oligodendroglioma.

Clinical Presentation/Pathology

Low-grade gliomas (LGGs) are slow growing with a symptom history that can extend from months to years. Although easily defined by MRI (see Fig. 52-4), LGGs often do not enhance with gadolinium. Their course is usually relatively stable for several years before eventually progressing. At time of diagnosis, LGGs have a much better prognosis than GBM. However, eventually LGGs progress to become glioblastomas with their inherent poor prognosis. Histologically, low-grade gliomas are classified as astrocytomas, oligodendrogliomas, or oligoastrocytomas (mixed glioma). A low mitotic index, younger patient age, and a supratentorial nonelegant locus (i.e., not affecting language function) that is amenable to resection predict a longer progression-free survival.

Treatment and Prognosis

The choice of therapeutic modalities is always an issue. Retrospective studies suggest that gross total resection, for gliomas that can be safely removed, provides longer progression-free survival. However, the surgeon can never remove all tumor tissue when dealing with infiltrative gliomas. These lesions always harbor an innate, almost serpiginous invasion of what appears to be grossly normal brain tissue to the surgeon’s eye. At the time of resection, these characteristics prevent appreciation of the full microscopic extent of the entire tumor mass. Therefore, gliomas eventually will demonstrate progression even after what appears initially to be a gross “total resection.” In this setting, so-called disabling resections in patients with astrocytomas or oligodendrogliomas are neither wise nor helpful. This is especially true when dealing with tumors in eloquent cerebral cortical areas, including language and memory, function, as well as those portions essential to use of extremities, particularly motor structures within the dominant hemisphere where preservation of functional mobility is particularly important.

Subtotal resection is indicated in most gliomas remediable to decompression without leaving a significant disability (such as aphasia) and especially when the tumor’s mass effect is causing disability. In patients with pilocytic astrocytoma, surgical indications differ slightly; a complete resection may provide a cure, and a more aggressive surgical approach is often indicated.

The next therapeutic decision is whether to recommend external beam RT. Although RT does not prolong overall survival, there is a significant increase in progression-free survival in the treated group. Unfortunately, this benefit may be offset by a higher incidence of long-term cognitive impairment in the RT-treated group. Survival is not the only factor when considering RT. There are some clinical predictors suggesting which patients will benefit from RT. If more than two answers to the five questions listed below are yes, the patient is likely to benefit from RT: (1) Is the patient older than age 40 years? (2) Is the tumor symptomatic (other than seizures)? (3) Does the tumor cross the midline? (4) Is the tumor an astrocytoma (as opposed to an oligodendroglioma)? (5) Is the tumor larger than 5 cm?

The dose of RT for LG is usually 54 Gy given in 30 fractions. Higher doses resulted have not shown a clear benefit and should not be used.

Until recently chemotherapy has not been employed for treatment of LGG. However the recent widespread use of temozolomide, an oral alkylating agent for GBM, raises the question of whether there are a selected group of patients with LGG who potentially may also benefit from this therapy. Temozolomide is currently used in patients who do not meet criteria for RT, as listed above, but whose tumor has a mitotic index of greater than 3%. Although patients with low-grade tumors have a much better prognosis than those with anaplastic glioma and GBM, low-grade gliomas are still usually fatal. The median survival is 5–7 years for astrocytoma and 7–10 years for oligodendroglioma.

Clinical Vignette

A 49-year-old right-handed man presented with 5 weeks of numbness and weakness in the left leg. Examination revealed decreased strength and slowed rapid movements of his left foot. There was extinction to touch and loss of joint position sense. Brain MRI revealed a 3 × 4-cm cystic mass centered in the medial aspect of the right parietal lobe and heterogeneous enhancement with gadolinium (Fig. 52-5).

Figure 52-5 Glioma, Anaplastic Astrocytoma.

Lesion resection revealed an anaplastic astrocytoma (Fig. 52-5). Postoperatively, he was treated with a combination of RT and concomitant temozolomide. He was treated monthly for 1 year and is now receiving the same dose at 8-week intervals. He is neurologically intact and radiographically stable 3 years after diagnosis.

Pathology

Anaplastic gliomas are intermediate-grade tumors with a higher mitotic index than low-grade gliomas but lacking the necrosis and endothelial proliferation of glioblastomas. They commonly affect patients in the 35–50-year age range, who often present with symptoms dating back just a few weeks or months. As in low-grade gliomas, anaplastic gliomas can be composed of astrocytes (anaplastic astrocytoma [AA]), oligodendrocytes (anaplastic oligodendroglioma [AO]), or a mixture of the two (anaplastic oligoastrocytoma [AOA]). The presence of an oligodendroglial component confers a better prognosis.

Treatment and Prognosis

Theoretically complete surgical resection is the best initial intervention; however, a heroic but neurologically disabling procedure is not indicated as noted in the LGG section. Most patients with anaplastic gliomas should be treated with radiation. It is not clear whether adding a chemotherapy drug such as temozolomide at the time of diagnosis is beneficial. Previous studies have shown a high rate of response to temozolomide in patients with recurrent anaplastic astrocytoma. Anaplastic astrocytoma has median survival of approximately 3 years.

Ependymoma

These are unusual tumors of glial origin that can arise anywhere within the neuraxis. The floor of the fourth ventricle is the most common intracranial site for an ependymoma to develop. Histologically, ependymomas often have a cellular appearance characterized by a pseudo-rosette perivascular pattern. There is also a more malignant version with an anaplastic appearance; although unlike gliomas, anaplasia may not confer poor prognosis. Myxopapillary ependymoma is a variant that occurs within the filum terminale at the end of the spinal cord.

MRI is the study of choice (Fig. 52-7). Surgical resection is the primary treatment; however, tumor location determines whether a complete resection is achievable. The extent of tumor resection is the most important indicator of the eventual clinical course. Surgical resection of a myxopapillary ependymoma frequently results in a cure. Indicators of poor prognosis include incomplete resection and CSF spread. Such patients require either local or craniospinal RT. Chemotherapy is seldom used at the time of diagnosis.

Figure 52-7 Ependymoma.

Medulloblastoma

These are a class of uncommon primitive neuroectodermal tumors that usually occur in the posterior fossa, often in the midline. Typically, these patients present with double vision, ataxia, hydrocephalus, nausea, and vomiting (Fig. 52-8). These tumors comprise 3% of all primary brain tumors and are significantly more prominent in children. Brain MRI usually reveals a homogeneously enhancing mass situated in the roof of the fourth ventricle, often with some degree of hydrocephalus. Pathologically, medulloblastomas are characterized by sheets of small, poorly differentiated cells with minimal cytoplasm.

Figure 52-8 Medulloblastoma.

Medulloblastomas require both surgical and radiation therapy. When one is able to surgically remove more than 90% of the tumor mass, there is usually an improved survival. Because of this tumor’s propensity to spread along the leptomeninges and throughout the CSF, patients need to undergo evaluation of the entire craniospinal axis to establish the extent of disease. If such has occurred, additional treatment is usually required. External beam RT is directed at the areas identified, often the entire brain and spine. Chemotherapy is then given. This combination therapy is associated with improved survival.

Cerebellar Astrocytoma

Most childhood primary brain tumors are in the glioma family, and many of these occur within the cerebellum (Fig. 52-9). Pilocytic astrocytomas are the most common posterior fossa variant. These tend to arise within the cerebellar hemisphere. A second form of cerebellar astrocytoma, the diffuse or fibrillary form, often arises in the midline and produces obstruction of the fourth ventricle and hydrocephalus. Cerebellar astrocytomas are often cystic in appearance, with an enhancing mural nodule.

Figure 52-9 Cystic Astrocytoma of Cerebellum.

Surgical resection can sometimes be curative, particularly with pilocytic astrocytomas. Incompletely resected tumors often require postsurgical irradiation. The survival rate of patients with cerebellar astrocytomas is often very significantly better than those with supratentorial glial tumors.

Pontine Glioma

These serious tumors primarily occur in childhood but are on rare occasions found in adults. They tend to be higher grade tumors that expand the pons and infiltrate into the surrounding tissue (Fig. 52-10). Presenting symptoms are consistent with their location, namely, hydrocephalus from fourth ventricle obstruction, or long tract signs from impairment of corticospinal axonal pathways. Isolated cranial neuropathies, particularly sixth and seventh nerve lesions, may also occur from compression of brainstem nuclei. The infiltrative nature of these tumors often precludes any degree of significant surgical resection. Unfortunately RT is usually ineffective at achieving long-term growth control.

Figure 52-10 Brainstem Glioma.

Clinical Vignette

A 52-year-old right-handed woman physician had a 2-week history of clumsiness using her right hand, particularly noticeable while performing electromyographies. Neurologic evaluation revealed moderate weakness and clumsiness of her right hand and a hint of a right central facial weakness. She had a 30 pack-year history of tobacco abuse but had discontinued this habit 8 years earlier.

Gadolinium-enhanced brain MRI demonstrated multiple, round ring-enhancing lesions consistent with metastases. As she had no known primary lesion identified during this evaluation, a stereotactic biopsy of a lesion close to the surface demonstrated small cell carcinoma consistent with lung cancer. It took another 4 months before the presumed primary lung lesion was identified with chest CT. She was treated with whole brain RT followed by systemic chemotherapy. Although she had initial symptomatic improvement, her difficulties returned, focal motor seizures developed followed by a dense hemiparesis. She died within 18 months despite three extensive and heroic attempts to achieve remission with focused beam radiosurgery.

For the medical oncologist and internist, metastatic brain tumors are the most common neuro-oncologic challenge. Of all cancer patients, 25% develop CNS metastases, usually after the primary tumor has been diagnosed, but occasionally as the initial sign as noted in this vignette. Typically CNS metastases are either a single or multiple solid tumors compressing the brain and spinal cord, or more diffusely with leptomeningeal infiltration of cancer cells throughout the CSF and neuraxis, especially involving spinal and cranial nerve roots.

Lung cancer is the most common primary tumor that metastasizes to the CNS (50%), followed by breast (33%), colon (9%), and melanoma (7%) (Fig. 52-11). The interval between the primary diagnosis and presentation of a CNS metastasis depends on the tumor type. For lung cancer, the median interval is 4 months; for breast cancer, 3 years. CNS metastasis is an indicator of poor prognosis and portends a survival of <6 months for most patients.

Figure 52-11 Tumors Metastatic to Brain.

Clinical Presentation and Diagnosis

As with primary CNS malignancies, clinical presentation depends on the tumor site. The onset can be almost precipitous, mimicking a stroke, or can be indolent, with gradual development of focal neurologic deficit: motor, sensory, language, visual, gait, or coordination. In other instances, patients may have focal or generalized seizures or present with nonspecific symptoms, perhaps suggesting increased intracranial pressure, such as positional headaches, cranial neuropathies, and rarely nausea, vomiting, or both.

Gadolinium-enhanced MRI typically demonstrates the presence of focal metastases. When there is a hemorrhagic component, an underlying melanoma is most often responsible. Typically, a number of melanoma patients have forgotten their seemingly innocuous and remote skin lesion or thought it irrelevant as there is often a major delay in the eventual presentation of the metastasis in comparison to the time of its initial removal.

Meningeal gadolinium enhancement portends the presence of carcinomatous leptomeningeal invasion with the important exception of the low pressure syndrome (see below). The malignant enhancement usually has a very irregular character in contrast to the very smooth enhancement seen with the very benign low pressure syndrome (see Fig. 52-23). CSF cytologic analysis, in most instances of leptomeningeal cancer, demonstrates an increased number of malignant cells, thus confirming the diagnosis. Sometimes the initial CSF in this setting is negative. Here, if there is a high clinical suspicion, one must make repeated spinal taps. On one occasion we had a patient who required six different CSF cytologic examinations before a specific diagnosis could be made.

Treatment

Although treatment is clearly palliative, most metastatic brain cancer patients benefit some from CNS-directed therapy. Whole brain RT is indicated for most of these individuals. The patient with an isolated, single brain lesion, who has no evidence of systemic recurrence, is a candidate for surgical resection. On occasion, the pathology is totally unexpected in that some resected solitary lesions, initially thought to be a metastasis prove to have an entirely different pathology, including benign tumors such as a meningioma. Focal radiation is helpful only in patients with one to two lesions who are otherwise stable. In the occasional patient having a solitary brain metastasis and who has received surgery or focal RT, it is reasonable to withhold whole brain RT until there is evidence of tumor progression in the brain. Rarely there is a symptom-free interlude of a number of years after the initial resection of an isolated metastasis.

Treatment of carcinomatous meningitis involves direct infusion of chemotherapeutic agents, either methotrexate or cytarabine, directly into the CSF via lumbar puncture or preferably a ventricular reservoir. This is a palliative treatment at best; the overall prognosis is usually just a matter of months once malignant leptomeningeal invasion is confirmed.

Therapy and Future Directions

Treatment of malignant brain tumors remains challenging and often unsuccessful. Advances in therapy are being made in the field of imaging, where PET and MR spectroscopy are often able to distinguish recurrent tumors from necrotic, posttreatment change. Image guidance in the operating room allows for smaller, more precisely located incisions and provides real-time information on the extent of tumor resection.

Radiotherapy remains the mainstay for treating malignant brain neoplasms. Stereotactic radiosurgery is being used more frequently to provide additional doses to previously irradiated tissue, improving the control of tumor growth.

Perhaps the greatest improvements in treating gliomas are the novel chemotherapy treatments, such as temozolomide, that are showing promise in controlling tumor growth. Gene therapy and other targeted, biochemically based treatments are also showing promise.

Clinical Vignette

A 48-year-old healthy woman, mother of two young adult children and a respected school teacher, had a history of chronic intermittent low-grade generalized headaches with a family history of migraine. Recently she noted that her headaches were occurring more frequently. These were not responding to the modest simple analgesics that she had previously used. She was unaware of any precipitating factors. Her family physician evaluated her; she also reported that recently her marriage had fallen apart when it became widely acknowledged in her small local community that her husband was having multiple affairs. She was very embarrassed and had become socially withdrawn. Her practitioner requested a neurologic consultation. Subsequently this neurologic consultant determined that her examination was normal. A diagnosis of tension stress headache was made. Amitriptyline was prescribed prophylactically. She was referred to a marriage counselor.

The headaches became increasingly bothersome, at times awakening her from her sleep; she had periods of helplessness and spells of crying. She was switched to a selective serotonin reuptake inhibitor for presumed increasing depression. However, she was not convinced of the diagnosis and sought another neurologic opinion. Her history remained unchanged. The only possible abnormal finding on neurologic examination was a subtle suggestion of a left central facial weakness. When this was called to her attention as to whether this finding was new or just a normal asymmetry, neither she nor her accompanying sister had previously noted this, suggesting that this was a significant observation. Contrast-enhanced brain CT demonstrated a homogeneously enhancing mass overlying the right frontal cortex. Brain MRI confirmed its superficial location. There was concomitant dura mater enhancement within the area immediately adjacent to the tumor. A meningioma was identified at surgery; a complete surgical resection was successfully performed. Postoperatively, her headaches ceased.

Demographics

Meningiomas typically occur in middle-aged and older individuals, especially women, but do occur at any age. Approximately 15–20% of intracranial tumors are meningiomas. These tumors may present at any level of the neuraxis; they are primarily located intracranially, typically found at the parasagittal falx cerebri separating the two hemispheres, the meninges covering the hemispheres, along the sphenoid ridge medial skull base, and the olfactory groove along the anterior skull base. Meningioma is typically a benign lesion arising from arachnoid meningeal cells.

Classically, these are slow-growing tumors attaining large size before becoming symptomatic; however, occasionally they seem to grow much more rapidly, especially during pregnancy. Meningiomas arising adjacent to the frontal lobe are particularly prone to being clinically silent because of the disproportionately large size of this part of the brain where there is much more tissue to be “forgiving.” Such a slowly enlarging lesion can gradually compress brain tissue without producing definitive symptoms in this “clinically silent” part of the brain. A good example occurs when a meningioma affects the prefrontal cortex. Subtle personality changes gradually develop that are only appreciated in retrospect. However, if the tumor lies adjacent to overtly functional brain tissue, such as the motor cortex, symptoms may present relatively early (Fig. 52-12).

Figure 52-12 Meningiomas.

Clinical Presentation

Meningiomas usually have an ingravescent course, presenting with a variety of symptoms such as long-standing headache, personality change, particularly disinhibition when involving the prefrontal cortex, various types of focal seizures, gait difficulties, or varied cranial nerve palsies as simple as unilateral loss of smell with olfactory groove lesions. On rare occasions, meningiomas may have a precipitous onset mimicking a stroke or even a brief transient ischemic attack. Today many relatively small and clinically silent meningiomas are first identified incidentally on CT and MRI during evaluation of unrelated events, such as for evaluation of posttraumatic injury. Presumed meningiomas located at the base of the skull near blood vessels need to be differentiated from cerebral aneurysms. These lesions are best evaluated with magnetic resonance angiography (MRA) to distinguish these disorders prior to consideration for possible neurosurgery.

Treatment

A decision to treat meningiomas rests on several factors. Because many are initially asymptomatic, it is important to determine that subsequently appearing neurologic symptoms arise from the lesion per se. Given the typical slow growth of these benign tumors when the patient continues to be asymptomatic, radiographic follow-up is recommended on an annual to biannual basis. No treatment is necessary for those individuals who remain asymptomatic when follow-up CT and MRI demonstrate no change in tumor size or configuration. When the patient develops progressive symptoms or follow-up imaging indicates increasing size of the tumor, surgical resection is in order.

The surgical complexity is directly related to tumor site; those on the brain convexity or along the falx cerebri are often easily resected. Skull base tumors located near blood vessels and cranial nerves often present a surgical challenge when the meningioma becomes entwined with these structures. Radiation therapy, chemotherapy, or both are rarely used to treat typical benign meningiomas. Antiprogesterone agents to slow the growth of the meningiomas are being investigated.

Clinical Vignette

Bilateral galactorrhea developed in a 32-year-old woman. Her menses had stopped a few months earlier and she thought she was pregnant; however, pregnancy testing was negative. Otherwise, she was in excellent health. Three years earlier, she gave birth to a healthy child. Her neurologic examination was normal.

Endocrinologic evaluation demonstrated a significantly elevated serum prolactin with decreased follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels in her blood. A mass was evident with MRI imaging of her sella turcica. This was consistent with a primary pituitary adenoma.

Demographics

Benign pituitary adenomas are the second most common of the various benign brain tumors. Intrinsic pituitary lesions represent approximately 10% of all intracranial tumors; these are classified according to whether they are endocrinologically active. The majority of pituitary adenomas arise from the anterior portion of the pituitary gland (adenohypophysis).

Clinical Presentation

Endocrinologically active tumors secrete hormones, often resulting in symptoms appropriate to the target glands to which the specific active cell type is directed. The clinical picture characteristic of a pituitary tumor depends on its primary cell type of origin (Fig. 52-13). For example, in the preceding vignette, abnormal galactorrhea was directly related to the production of increased amounts of prolactin-secreting tumor cells. These are one of the most common endocrinologically active pituitary tumors. Pituitary acidophil adenomas that primarily secrete growth hormone lead to the clinical syndrome of acromegaly with gigantism and/or enlarged bony features in the face, skull, and hands. Cushing disease with truncal obesity, cervical buffalo hump, moon-like flushed facies, proximal muscle weakness, hypokalemia, and glucose intolerance occurs when pituitary adenomas primarily secrete adrenocorticotropic hormone, leading to increased circulating serum cortisol (Fig. 52-14).

Figure 52-13 Pituitary Adenoma Clinical Manifestations.

Figure 52-14 Basophilic Adenoma Cushing Disease.

Chromophobe adenomas are not endocrinologically productive; however when an adenoma develops here initially these tumors may be clinically silent. Although histologically benign, pituitary adenomas may have serious consequences when undiagnosed early on because their proximity to the optic nerves, the optic tracts, the cavernous sinus, and the temporal lobe tip may lead to significant neurologic consequences. The nonendocrinologically active tumors frequently reach a large size before symptoms develop (Fig. 52-15). Typically, their diagnosis depends on the presentation of mass effect symptoms. Bitemporal visual field cuts result when pituitary macroadenomas extend above the sella and compress the overlying optic chiasm.

Figure 52-15 Pituitary Macroadenoma.

Pituitary apoplexy is a relatively rare clinical presentation for pituitary adenomas. Classically, this is an acute-onset severe headache associated with significant visual impairment and decreased mental status. Sometimes this may well mimic a ruptured intracranial aneurysm. The cause is often a hemorrhage into a preexisting pituitary adenoma (Fig. 52-16).

Figure 52-16 Pituitary Adenoma Gradation vis-à-vis Sella Enlargement.

Diagnostic Approach

Patients with suspected pituitary adenomas are evaluated with a combination of imaging and endocrinologic studies. Brain MRI is the best radiographic modality to identify pituitary tumors. Sella expansion, diminished enhancement within the sella, and shifting of the pituitary stalk to one side are all clues for a possible pituitary microadenoma In contrast, macroadenomas (measuring >25 mm) extend above the sella or into the cavernous sinus on either side of the sella and are easily identified with MRI (see Fig. 52-16). A thorough endocrine evaluation includes serum levels of prolactin, follicle-stimulating hormone and luteinizing hormone, cortisol, and growth hormone and thyroid function parameters.

Treatment

Initially many pituitary adenoma patients primarily require medical therapy. Prolactin secreting tumors are often successfully controlled with bromocriptine, a dopamine agonist that suppresses prolactin production and concomitantly decreases tumor volume. Growth hormone–secreting tumors are often controlled with octreotide, a somatostatin analog. Small, nonsecreting pituitary tumors may often be observed for endocrine dysfunction or signs of growth with combined clinical and MRI modalities.

Endocrinologically active tumors that cannot be controlled with medication are a prime indication for surgical treatment as are patients harboring a macroadenoma producing mass effect. The surgery is primarily performed using a transsphenoidal approach through the nasal cavity and the sphenoid sinus, wherein the contents of the sella can be visualized and the tumor can be removed, often sparing the pituitary gland.

Postoperatively, these patients require follow-up for signs of hypopituitarism. This is particularly important for those individuals presenting with Cushing disease. Subsequent to surgery, their adrenocorticotropic hormone secretion is diminished. These patients usually require postoperative and sometimes lifelong steroid replacement. Pituitary adenoma surgery is associated with concomitant sodium balance and fluid intake problems leading to hyponatremia with polydipsia and polyuria. This necessitates careful follow-up and sometimes treatment with desmopressin acetate (DDAVP) to replace the naturally occurring antidiuretic hormone (ADH). This is a synthetic analogue of the natural pituitary hormone 8-arginine vasopressin, an ADH affecting renal water conservation.

Clinical Vignette

A previously healthy 42-year-old Army chaplain noted that he could no longer hear well on the telephone using his left ear or understand a colleague when there was much ambient noise particularly from other conversations. In retrospect, he had experienced mild progressive ringing in this ear. Initially this was attributed to chronic loud noise exposure while assigned to an artillery brigade. Although this gradually worsened over several years, it was not until his telephone difficulties led him to test himself that he found he could no longer appreciate the sound of a watch ticking. He was otherwise totally well. His only abnormal finding on neurologic examination was grossly diminished hearing in his left ear.

Audiometric examination revealed markedly decreased high-frequency appreciation and diminished speech discrimination in his left ear. Gadolinium MRI demonstrated a homogeneously enhancing 2 × 1.5-cm mass within the left cerebellar pontine angle. This emanated from his internal auditory canal and was associated with mild pontine distortion.

Demographics

Acoustic neuromas are the second most common of the benign brain tumors. These comprise approximately 6–8% of all primary intracranial neoplasms. There is a 2% incidence within the general population. Most commonly, acoustic neuromas present between ages 40 and 60 years. With the exception of patients who have genetically determined neurofibromatosis type II, it is unusual to see a patient have an acoustic neuroma become clinically recognized before age 20 years. The non–genetically determined acoustic neuromas predominantly develop unilaterally. In contrast, those occasional patients with type II neurofibromatosis often have bilateral acoustic neuromas. These benign tumors arise from the Schwann cells of the vestibular nerve within the eighth cranial nerve complex (Fig. 52-18).

Figure 52-18 Acoustic Neuroma.

Clinical Presentation

The classic history is illustrated in the above clinical vignette. Patients typically report a slowly progressive, unilateral hearing loss associated with tinnitus. This is consistent with the innate slow growth of a benign acoustic neuroma (also referred to as a vestibular schwannoma).

Although acoustic neuromas arise from the vestibular portion of cranial nerve (CN) VIII, hearing loss is usually the most prominent symptom. Anatomically, CN-VII (facial) is closely related to CN-VIII; however, it is almost unheard of for an acute facial nerve palsy to be the initial presenting symptom of an acoustic neuroma. Because of the eighth nerve’s relation to the vestibular nerve within the cerebellopontine angle, adjacent to the brainstem and cerebellum, patients with very large acoustic neuromas may also have gait instability and sometimes associated headaches, but these individuals do not present with acute vertigo. Later on an acoustic neuroma may sometimes lead to pressure on either the trigeminal (fifth) cranial nerve or its adjacent brainstem, affecting CN-V function with a resultant ipsilateral facial sensory loss and a diminished corneal reflex. Occasionally very large tumors may impair the CSF circulation near the fourth ventricle, leading to hydrocephalus.

During clinical examination, cranial nerve evaluation is the key to this diagnosis and of utmost importance. Hearing loss from CN-VIII involvement is the hallmark finding for acoustic neuromas. Lateral gaze nystagmus is occasionally noted when testing extraocular movements. Larger tumors may cause CN-VII and CN-V impairment as previously summarized. It is most unusual to have any lower cranial nerve involvement or clinically significant enough brainstem compression to lead to either a hemiparesis or hemisensory loss.

Diagnostic Studies

MRI is the primary diagnostic modality. Its clarity, resolution, and ability to scan in multiple planes allow for three-dimensional assessment. Because lesion size and its relation to adjacent neurologic structures, such as the pons and various cranial nerves, often determine treatment, MRI is also a therapeutically very crucial investigational modality. Typically, these well-demarcated, homogeneously enhancing tumors arise within the cerebellar pontine angle and extend into the internal auditory canal (see Fig. 52-18).

Treatment

Surgery is the traditional and primary therapeutic modality; stereotactic radiosurgery is occasionally used. Acoustic neuromas often grow slowly. It is reasonable to observe some tumors temporally, if clinically warranted, particularly with elderly patients presenting with unilateral hearing loss who also have multiple other medical issues. Often the better part of valor here is to just follow the patient with serial imaging. When MRI evidence demonstrates significant tumor growth or patients have progressively worsening symptoms, especially in addition to hearing loss, surgical intervention is indicated.

Surgical resection of acoustic neuromas is often performed concomitantly using both neurosurgery and otorhinolaryngology specialists. The surgical goal is tumor resection and preservation of CN-VII and CN-VIII function when at all possible. This approach is particularly important with large-volume tumors exhibiting brainstem compression. Hearing preservation in patients with these large acoustic neuromas is often impossible because the cochlear nerve becomes indistinguishable from the tumor. Success rates for hearing preservation vary directly with tumor volume. When CN-VII is densely adherent to the tumor capsule, a subtotal resection is often indicated, because facial nerve preservation is more important than complete surgical removal.

Stereotactic radiosurgery involves a single nonsurgical treatment using high-dose radiation to a precisely localized three-dimensional volume. This modality can control approximately 80–85% of acoustic tumors. It retains many of the same risks as conventional surgery but is an excellent option for patients with small tumors (2–3 cm) who have no useful hearing. Control of tumor growth is achieved and operative risks are avoided. With improved imaging, acoustic neuromas are being detected earlier; therefore, greater potential exists to achieve a complete cure early on in the natural history of the acoustic neuroma.

Chordoma

These are very rare usually benign tumors that have embryologic elements similar to intervertebral disks. Typically, chordomas develop either on the clivus of the skull base or the sacrum (Fig. 52-19). Intracranial chordomas arise from within the skull bone and cause local destruction. Concomitantly these tumors enter the intradural space, where they sometimes affect the brainstem and cranial nerves.

Figure 52-19 Chordomas.

The histology of typical chordomas is characterized by, large, mucus-filled cells called physaliferous cells. Very uncommonly, a few chordomas demonstrate features of frank malignancy. Additionally their aggressive local invasion of bone mimics a locally malignant process. The tumors that lead to significant bony destruction often recur locally at a high rate, thus making a surgical cure difficult to achieve. Nevertheless, surgical resection is often used initially, but complete resection is often impossible because of local anatomic constraints. Although radiation therapy is generally used, the role of this modality for treatment of residual tumor is unclear. Radiosurgery and proton beam irradiation have been proposed, but their benefit is also uncertain. Chemotherapy is not of value for treatment of chordomas.

Pineal Region Tumors

Tumors occurring in the region of the pineal gland are uncommon, comprising approximately 1% of intracranial tumors. These neoplasms, having a histologically mixed benignancy, include germ cell tumors, glial neoplasms, and pineal parenchyma tumors (Fig. 52-20). Germ cell origin tumors are the most common, usually occurring in younger patients. Gliomas can arise from within the pineal gland itself or from the glial cells in the surrounding tissue. In this region, glial tumors tend to be of lower grade. Tumors arising from the pineal parenchyma comprise approximately 20% of pineal region tumors.

Figure 52-20 Pineal Region Tumors.

These neoplasms are further classified into pineoblastomas and pineocytomas. Pineoblastomas are poorly differentiated tumors that can spread throughout the cerebrospinal fluid pathways or directly into adjacent brain parenchyma. Pineocytomas are usually well-encapsulated cellular tumors that do not invade surrounding tissue. A mixed form of pineal parenchymal tumor contains features of both pineocytoma and pineoblastoma. Teratomas, embryonal carcinomas, endodermal sinus tumors, and choriocarcinomas are also found in the pineal region.

With the increasing use of MRI, asymptomatic pineal region cysts are identified more commonly. These cysts are usually incidental findings and rarely require any treatment. Serial MRI scans are used to track any growth over time.

Colloid Cysts

These are histologically benign third ventricle tumors that arise from embryologic development remnants. The cells lining the walls of the cyst are ciliated. Third ventricular lesions of this type typically do become symptomatic during adulthood but can be seen in children. Posturally precipitated headaches, with concomitant symptoms and signs of hydrocephalus are the most common clinical presentations for colloid cysts. Because of their inherent intraventricular location, these cysts lead to CSF obstruction at the foramina of Monro (Fig. 52-21).

Figure 52-21 Intraventricular Tumors.

Colloid cysts occasionally are associated with sudden death presumably from an acute hydrocephalus; however, most patients present with a more gradual temporal profile. Although the diagnosis is typically suggested by recurrent posturally triggered headaches, MRI or CT is ideal for confirming the presence of a cystic-appearing intraventricular mass.

Treatment of symptomatic colloid cysts is usually surgical, and complete resection is often possible. Care must be exercised during surgical resection because the fornix, adjacent to the tumor, can be injured, resulting in severe memory impairment. If surgery for resection is not possible, CSF diversion through shunting can often relieve the symptoms of hydrocephalus.

With the increased use of MRI, many more cystic tumors within the third ventricle are being described. These asymptomatic lesions are followed with serial scans; treatment is reserved for those patients whose cysts increase in size.

Pseudotumor Cerebri/Idiopathic Intracranial Hypotension, Intracranial Hypotension, and Other Brain Lesions

Clinical Vignette

An obese 42-year-old woman presented with a 2-month history of increasingly severe headaches and intermittent double vision. Her headaches were exacerbated by postural changes, particularly bending forward or jarring in the car. Bilateral limitation of adduction of her eyes compatible with sixth cranial nerve paresis and modest papilledema (Fig. 52-22) were noted on neurologic examination. Brain imaging demonstrated diminished size of her lateral ventricles. Cerebrospinal fluid (CSF) pressure was 350 mm CSF (normal < 180 mm CSF); it was otherwise normal.

Figure 52-22 Pseudotumor Cerebri.

This case is representative of a rather uncommon syndrome known as idiopathic intracranial hypertension, i.e., pseudotumor cerebri (PTC). This usually occurs in obese young women who are otherwise healthy. Clinically PTC is primarily characterized by progressively severe, poorly defined headaches, often with diplopia. Transient visual obscurations and pulsatile tinnitus may also occur. On neurologic examination these patients are typically awake, alert, have papilledema, sometimes a lateral rectus muscle weakness, but no focal neurologic deficits. By definition MRI is normal or demonstrates small lateral ventricles. PTC by definition is associated with increased CSF pressure (250–500 mm CSF).

Although idiopathic PTC has no identifiable etiology, certain predisposing factors need to be considered, including oral contraceptives, corticosteroids, estrogens and progestational therapies, NSAIDs, hypervitaminosis A, various antibiotics (tetracycline, minocycline, nitrofurantoin, ampicillin, or nalidixic acid), anesthetic agents (ketamine and nitrous oxide), amiodarone, and perhexiline.

Other neurologic disorders may occasionally present with a PTC clinical picture. These include leptomeningeal diseases such as chronic infectious or granulomatous processes, that is, tuberculosis, metastatic cancer or lymphoma seeding, cerebral venous sinus obstruction, and various endocrinologic disorders, for example, myxedema, hypoparathyroidism, and Addison and Cushing diseases. There are very rare reports of a PTC picture presumed to be related to extremely elevated CSF protein levels, particularly with Guillain–Barré syndrome or primary spinal cord malignancies.

Treatment

Discontinuation of an offending medication will reverse the PTC syndrome on the rare occasion such is identified. Most importantly one needs to be concerned by the fact that chronic increased intracranial pressure leads to loss of visual acuity. This is secondary to swelling of the optic nerve head, that is, papilledema. It is measured by frequent and formal visual field testing to identify increasing size of the blind spots. This is essential to prevent permanent visual loss with PTC. Potential treatments include weight loss, low-salt diet, diuretics, and symptomatic headache control. When PTC continues to evolve with progressive visual compromise, more aggressive therapy is indicated, including optic nerve sheath fenestration or one of the various CSF shunting procedures.

Intracranial Hypotension (Low-CSF-Pressure Syndrome)

Clinical Vignette

A vigorous previously healthy 60-year-old physician, who had recently developed severe depression, requiring both a serotonin reuptake inhibitor as well as unilateral electric shock therapy (EST), developed increasingly severe posturally exacerbated headaches. When these were greatly exacerbated while he was a passenger in a small float plane as it landed bouncing over the water, he went to a neurologist. His examination was normal. Postgadolinium MRI demonstrated leptomeningeal enhancement but no mass lesions. CSF pressure was too low to measure. No known relation with the EST was identified. He then recalled having a relatively severe closed head injury 3 weeks earlier when he forcefully struck his forehead on an unexpectedly low-set barn door frame. A 20-mL extradural blood patch was empirically injected at his mid-lumbar spine. The headaches gradually and totally cleared within 2 weeks.

Classic low-CSF-pressure headaches are severe, exacerbated by postural factors, and often mimic the ball valve effect seen in some intraventricular brain tumors. Most commonly, these occur subsequent to a diagnostic lumbar puncture, spinal anesthesia, or a seemingly benign closed head injury. MRI with gadolinium is essential to the diagnosis (Fig. 52-23). When there is no history of a spinal tap or significant head trauma, this clinical setting, as well as the MRI, somewhat mimics various leptomeningeal neoplastic or inflammatory lesions. The MRI imaging with low pressure headache syndrome has a smooth enhancement in contrast to serpiginous irregular enhancement seen with neoplastic infiltration. The CSF analysis primarily helps make this differentiation. Occasionally introduction of a radioisotope into the CSF will identify a source of CSF leak that may require surgical repair. In many of these instances, no site of potential spinal fluid leak is identified. As in the above vignette, a spinal blood patch can provide relief and a therapeutic diagnosis; however, it is not universally successful and in rare instances the patient may have permanent incapacitation not being able to raise his/her head, preventing one from pursuing an occupation or even many routine activities of daily living.

Figure 52-23 Intracranial Hypotension.

Other Intracranial Lesions

Subdural hematomas, herpes encephalitis, brain abscess, and arteriovenous malformations may all have a clinical presentation similar to a brain tumor. There are other rare disorders both of demyelinating nature that require consideration in the differential diagnosis of brain tumors. Occasional patients have MRI findings mimicking a malignant glioma, but stereotactic biopsy demonstrates a primary monofocal acute inflammatory demyelination (see Chapter 46). These lesions usually are self-limited and occur in the setting where there is no prior clinical or MRI evidence of multiple sclerosis. Fortunately these are often responsive to corticosteroids. Subsequently, new lesions may appear in different portions of the cerebral cortex. An acute disseminated encephalomyelitis (ADEM) and acute hemorrhagic leukoencephalopathy (AHL) are two acute postinfectious demyelinating disorders; the former is more likely to respond to corticosteroids and the latter frequently has a fulminate course (see Chapter 47).

Progressive multifocal leukoencephalopathy (PML) may also present in a fashion similar to a brain tumor in immunocompromised hosts receiving long-term immunosuppressive therapy or in patients with HIV (see Chapter 51).