These aggressive (high-grade) gliomas account for approximately 20 percent of all intracranial tumors, benign and malignant, and for more than 80 percent of gliomas of the cerebral hemispheres in adults. Although predominantly cerebral in location, they may also arise in the brainstem, cerebellum, or spinal cord. The peak incidence is in middle adult life (mean age for the occurrence of glioblastoma is approximately 60 years, and 46 years for anaplastic astrocytoma), but no age group is exempt. The incidence is higher in men (ratio of approximately 1.6:1). Almost all of the high-grade gliomas occur sporadically, without a familial predilection. Most arise in the deep white matter as a heterogenous mass and quickly infiltrate the brain extensively, sometimes attaining enormous size before attracting medical attention.
The fundamental change in classification and understanding of these tumors has been the recognition that glioblastoma is essentially defined by the presence of wild-type isocitrate dehydrogenase (IDH) and astrocytomas are characterized by mutant IDH, both somatic variants within the tumor. These characteristics to some extent eclipse the former histologic grading system and determine the clinical aggressiveness of a tumor. Epigenetic properties of these tumors, mainly methylation status of a promoter region, have been disclosed that influence tumor behavior and may relate to treatments. Some of these findings will be elaborated further on.
The imaging appearance is usually that of an inhomogeneous mass, often with a center that is hypointense and nonenhancing. An irregular rim of contrast enhancement surrounds the core lesion, and is surrounded by nonenhancing edematous brain tissue, consisting of a combination of infiltrating tumor cells and vasogenic edema (Figs. 30-2 and 30-3). It is not uncommon to see small nodular contrast enhancing lesions adjacent to, but distinct from, the primary lesion. Part of one lateral ventricle is often distorted, and both lateral and third ventricles may be displaced. Necrotic and sometimes cystic areas appear on imaging studies. An MRI series showed that 70 percent of patients show evidence of a small region of restricted diffusion immediately surrounding the tumor in the postoperative period (Ulmer and colleagues); it is likely that these regions may represent hypercellular tumor areas or ischemia that precedes necrosis.
Glioblastoma (IDH-wildtype). Contrast-enhanced T1-weighted MRI illustrates a large irregularly enhancing tumor with internal necrosis deep within the left cerebral hemisphere.
Astrocytoma (IDH-variant type) of the left frontal lobe; the T2-weighted MRI shows an infiltrating tumor with minimal mass effect and mild edema. The degree of contrast enhancement is variable but most often less than glioblastoma.
The CSF is no longer an essential part of the evaluation for brain tumor but it is often normal with glioma or it may show an increase in CSF protein (more than 100 mg/dL in some cases), as well as a pleocytosis of 10 to 100 cells or more, mostly lymphocytes, that may result from a tumor extending to the meningeal surface or the ventricular wall. Extraneural metastases involving bone and lymph nodes are rare; usually they occur only after a craniotomy has been performed but whether the surgery is causal is not known. Approximately 50 percent of glioblastomas occupy more than one lobe of a hemisphere; between 3 and 6 percent show multicentric foci of growth and thereby simulate metastatic cancer. A legitimate question is whether these tumors can have a multicentric origin or become multifocal as a result of spread via CSF pathways. We have the impression that the first configuration does exist but is not common.
In gross pathology, the tumor has a variegated appearance, being a mottled gray, red, orange, or brown, depending on the degree of necrosis and presence of hemorrhage, recent or old. The characteristic histologic findings of glioblastoma are hypercellularity with pleomorphism of cells and nuclear atypia; identifiable astrocytes with fibrils in combination with primitive forms in many cases; tumor giant cells and cells in mitosis; hyperplasia of endothelial cells of small vessels; and necrosis, hemorrhage, and thrombosis of vessels. This variegated appearance distinguishes glioblastoma from the anaplastic astrocytomas, which show frequent mitoses and atypical cytogenic features but not grossly necrotic or hemorrhagic areas. The histologic appearance of glioblastoma may vary from site to site within a tumor and it is common for sites of low-grade astrocytoma and glioblastoma to coexist; in some high-grade tumors there are even sites of well-differentiated astrocytoma. This relates to a problem that arises in interpreting single biopsy samples taken for diagnosis. It is worth emphasizing again that the IDH status of glioblastoma is now considered to be more informative than histologic grading with respect to prognosis.
Originally, glioblastoma was thought to be derived from and composed of primitive embryonal cells or, in the late decades of the twentieth century, to arise through anaplasia of maturing astrocytes. However, these views have been called into question because models of malignant transformation of neural stem cells or of glial progenitor cells explain many of the characteristics and behavior of gliomas. The location, cellular and genetic heterogeneity, and manner of growth and spread of these tumors are consistent with an origin in a primitive stem cell (Sanai and colleagues 2005), but this notion is not universally accepted and potential deficiencies in this theory have been noted (Reid and coworkers). The genetic or epigenetic events that lead to a malignant evolution of these progenitor cells not known but some aspects are discussed in the following text. Ironically, this is a reversion to the idea of the early last century that posited an embryonal origin of glioma. Furthermore, there are configurations of genetic markers that may promote the transformation of a lower-grade glioma into glioblastoma.
The natural history of untreated glioblastoma is poor. In the past, fewer than 20 percent of patients survived for 1 year after the onset of symptoms and only about 10 percent lived beyond 2 years (Shapiro) but these intervals have improved somewhat with gross total surgical resection, radiation, and chemotherapy. Age is a prognostic factor; fewer than 10 percent of patients older than age 60 years survive for 18 months, in comparison to two-thirds of patients younger than age 40 years. Survival with anaplastic astrocytoma is somewhat better, typically 3 to 5 years. Cerebral edema and increased ICP are usually the causes of death. Survival rates with treatment are discussed in the following text.
The diagnosis is confirmed by a stereotactic biopsy or by a craniotomy that aims to remove as much tumor as is feasible at the same time.
An expanded discussion of genetics that relates to glioblastoma and astrocytoma is useful here and the astrocytomas are further elaborated in the next section (Table 30-2). The current classification omits the term anaplastic astrocytoma and absorbs it into a group of astrocytomas defined by IDH status with prognostic significance, as elaborated in the following text. These are still graded 2, 3, or 4 but most are relatively high-grade gliomas, and the highest grade shares histologic and clinical features of what has traditionally been called glioblastoma but has a better prognosis than IDH-wild type tumors. The natural history for lower grades is generally to progress to glioblastoma associated with constellations of mutations that promote such transformations. The IDH-wild type glioblastoma, comprising about 80 percent of the adult glioma group in the new classification, is a separate category with poor prognosis in comparison to the 20 percent of astrocytomas with IDH variants that have a better outcome. The wild-type tumors are highly cellular, vascularized, and infiltrative, in keeping with the traditional conceptualization of glioblastoma but the high grade IDH-mutant astrocytomas with better prognosis can have many of the same characteristics.
Among the first detectable changes in glioblastoma are mutations acquired in the act of neoplastic cell division that inactivate the tumor suppressor gene p53 on chromosome 17p; over 50 percent of astrocytomas have deletions within this gene. Other early changes include overexpression of genes that control growth factors or their receptors, as noted below. After the tumor develops, progression to a more malignant grade of astrocytoma or to a glioblastoma may be triggered by defects causing overexpression of the epidermal growth factor gene. In fact, it is striking that analysis of the patterns of these defects in some tumors correlates with the staging and aggressive characteristics of these tumors. The events that lead to their accumulation are not clear, as noted below. As mentioned, mutations in the genes or the wild-type that code for isocitrate dehydrogenase (IDH1 and 2) are common in gliomas and oligodendrogliomas and their presence relates to tumor progression and generates the overarching classification of the astrocytoma group for WHO5. Mutations of IDH 1 and 2 cause gain of function in their respective enzymes that overproduce the oncometaolite, 2-hydroxyglutarae that influence epigenomic states (see below) and gene regulation.
Mutations in the paired 1p/19q region, EGFR, ATRX, TERT promoter, CDKN2, and other subsidiary genes influence the behavior of astrocytomas and, to some extent treatment response (see further on). Among other genetic changes, mutations in NFKBIA have been found that may be a change that is found exclusively with EGFR amplification and both presage poor outcome (Bredel et al).
As important are epigenetic characteristics, especially of MGMT methylation, involved in the response to antitumor agents and these figure into classification. These epigenetic changes interplay with the aforementioned gene variants as mentioned above and are not limited to IDH variants.
It is usually prudent to biopsy lesions that are considered on clinical and imaging grounds to be glioblastoma or astrocytoma. The tissue serves not only to provide potential information regarding grading, genetic changes, and prognosis and, to guide treatment but also to exclude the possibility of another neoplastic or nonneoplastic diagnosis such as lymphoma, brain abscess or other infection (see Chap. 31), tumefactive multiple sclerosis (see Chap. 35), infarction, encephalitis, and others.
Most lesions can be accessed with stereotactic techniques but limit the volume and quality of tissue obtained and obviate a direct visualization of the mass by the surgeon. In stereotactic biopsy, but also with open procedures, there is a risk of sampling error, meaning that parts of the tumor may show more malignant changes. The safety of biopsy or gross total resection is undertaken with the location and size of the lesion in mind, and consideration of the risks of causing irreversible neurologic deficits.
Treatment of glioblastoma
The basic outline of treatment consists of surgical maximal feasible resection followed by radiation and temozolomide. At operation, usually only part of the tumor can be removed; the multicentricity and diffusely infiltrative character of the more infiltrative tumors defy the scalpel. Partial resection of the tumor, however, seems to prolong survival, as noted below. Neurosurgeons have developed mapping and imaging techniques to facilitate maximal resection without injuring adjacent brain tissue.
For a limited period, glucocorticoids, usually dexamethasone in doses of 4 to 10 mg q6–12h, are helpful if there are symptoms of mass effect, such as headache or drowsiness; local signs and surrounding edema tend to improve as well. Antiepileptic medications are generally not required unless there have been seizures. Although some neurologists and neurosurgeons still administer them in order to preempt a convulsion, several series have found antiepileptic medications to be unnecessary for this purpose (Glantz et al). Skin reactions (erythema multiforme and Stevens-Johnson syndrome) may occur in patients receiving phenytoin at the same time as cranial radiation (Delattre et al).
Surgical resection is typically combined with subsequent radiation and chemotherapy. Cranial irradiation to a total dose of 6,000 cGy increases survival by 5 months on average (see further on). This is true even in the elderly who have had only a biopsy without resection according to one trial (Keime-Guibert and colleagues). In many centers, a fraction of this is delivered as a “boost” through focused or stereotactic radiation, particularly if the tumor is small enough to encompass in these fields. High-dose focused radiation (stereotactic radiosurgery) may improve survival but this has not been entirely clear and it continues to be studied. Brachytherapy (for example, implantation of iodine-125 or iridium-193 beads or needles) is not longer used, partly because they cause local radiation necrosis.
It had been considered that the addition of chemotherapeutic nitrosourea agents such as carmustine (BCNU) or lomustine (CCNU) increases survival slightly. Cisplatin and carboplatin have provided similar small improvements in survival beyond that obtained by debulking and radiation therapy. Several randomized trials, however, have failed to show substantial benefit of chemotherapy but the Glioma Meta-analysis Trialists (GMT) Group concluded that there was only a small benefit of chemotherapy.
Similarly, one trial demonstrated a 3-month benefit for progression-free survival, but not for overall survival, with the early use of the anti-VEGF compound bevacizumab with temozolomide and radiation (Gilbert et al); and the use of bevicizumab is largely restricted to clinical trials. This anti-angiogenic therapy improves the imaging appearance of tumors (less edema, smaller area of enhancement) but fails to inhibit tumor spread. In the field of novel therapeutics, adoptive T cells (chimeric antigen receptor–T-cell therapy, CAR-T), which had success with leukemia and lymphoma, has demonstrated efficacy in a few case series of metastatic glioblastoma (Brown et al).
The methylating agent temozolomide, given in the form of an orally administered prodrug, has lower toxicity and has been shown in several trials to produce superior results to placebo and to conventional chemotherapy. In a large and often cited trial (Stupp and colleagues), the median survival was 14.6 months with radiation and temozolomide, compared to 12.1 months with radiation alone, but 2-year survival was more than doubled from 10 to 27 percent. The drug is typically administered daily (75 mg/m2) concurrently with radiotherapy and, after a hiatus of 4 weeks, given for 5 days every 28 days for 6 cycles. Its main complications are thrombocytopenia or leukopenia in 5 to 10 percent of patients, and rare cases of Pneumocystis carinii pneumonia. Furthermore, high levels of a methyltransferase protein (MGMT) in some gliomas may lead to resistance to chemotherapy. Some investigators have found a relationship between the epigenetic silencing of the promoter of the gene that codes for this protein (“methylation status”) and the response to temozolomide (Hegi and colleagues) but this has not been a uniform finding. There is still activity of temozolomide in nonmethylated tumors and it is used in almost all cases. Additionally, there may be an interaction between MGMT methylation and mutations in other genes such as IDH1 as previously mentioned (Wick et al).
Tyrosine kinase inhibitors (erlotinib, gefitinib) have been developed in response to the upregulation of EGFR in some tumors. One study found that a deletion mutation of the gene for this protein and expression of the tumor suppression protein PTEN predicted responsiveness of recurrent gliomas to treatment with EGFR kinase inhibitors (Mellinghoff and coworkers). This represents one example in a growing field of prediction of treatment response in relation to tumor genetics; however, phase III studies of a tyrosine kinase inhibitor failed to improve outcome (Bode et al).
The treatment of recurrent glioblastoma or anaplastic astrocytoma after surgery and radiation, an almost inevitable occurrence varies and is guided by the location and pattern of tumor growth and the patient’s age and relative state of health. Almost all glioblastomas recur within 2 cm of their original site but approximately 10 percent develop additional lesions at distant locations. An aggressive approach—a second surgery and chemotherapy—can prove effective and has been generally used in patients younger than age 40 years whose original operation was many months earlier. If the PCV combination chemotherapy regimen discussed earlier has not already been used, some neurooncologists resort to it or temozolomide (which may be used if the PCV regimen was administered previously). These drugs may prolong the symptom-free interval but have little effect on survival. The newer cell therapies have already been mentioned and it is not clear if they will be applicable to tumor recurrences.
With aggressive surgical removal and radiotherapy, as described above, median survival for patients with glioblastoma has been approximately 12 months, compared to 7 to 9 months without such treatment.
In the WHO 2021 classification referred to earlier, glioblastoma wildtype and astrocytomas are included broadly with oligodendroglioma under “Adult-type diffuse gliomas.(Table 30-2)” Astrocytomas are considered with respect to genetic pathways as: (i) adult type IDH mutant (referring as above to the gene for isocitrate dehydrogenase), (ii) diffuse astrocytoma MYB- or MYBL1-altered (referring to an oncogene), (iii) pediatric diffuse gliomas of several types defined mainly by mutations, (iv) diffuse astrocytoma MYB- or MYBL1-altered, and v) circumscribed astrocytic tumors of several types including pilocytic astrocytoma that are classified separately. None of these is newly identified; they are, however, newly understood in terms of genetic variants. Details of the gene variants and in astrocytomas their biological functions can be found in the WHO 2021 classification. Most arise in the deep white matter as a heterogenous mass and quickly infiltrate the brain extensively, sometimes attaining enormous size before attracting medical attention.
In about two-thirds of patients with astrocytoma, the first symptom is a focal or generalized seizure, and between 60 and 75 percent of patients have recurrent seizures in the course of their illness. Other subtle cerebral symptoms follow after months, sometimes after years. Headaches and signs of increased ICP are relatively late occurrences.
On T1-weighted MRI, astrocytomas are isointense or hypointense; on T2 sequences, hyperintense, and there is variable enhancement of the solid portion of the tumor after gadolinium infusion (Figure 30-3). Cyst formation and small amounts of calcification are common, especially in cerebellar tumors. Other low-grade astrocytomas take the form of a more homogenous T1 hypointense and T2 hyperintense infiltrating mass with poorly defined borders and little or no contrast enhancement.
In children, astrocytic tumors usually arise in the cerebellum and declare themselves by some combination of gait unsteadiness, unilateral ataxia, and increased ICP (headaches, vomiting).
One of the more interesting developments in the treatment of low-grade cerebral tumors has been the comparison between the practices in two Norwegian centers prior to the inception of genetic classification, one which practiced an aggressive approach of removing accessible tumors when they are discovered, and another, of observing the patient by sequential imaging to determine if the tumor has transformed into a more aggressive mode (Jakola and colleagues). While a small and not a randomized trial, surgical excision resulted in longer survival. Excision of part of a cerebral astrocytoma can improve survival in a good functional state for many years. Modern techniques of brain mapping have allowed larger and probably safer resections of these tumors. An example of this has been offered by performing mapping of language areas in a large consecutive series of glioma patients (Sanai and colleagues 2008).
The pilocytic astrocytoma of the cerebellum in childhood is relatively benign in its overall behavior. A KIAA1549 BRAF fusion occurs in 80 to 90 percent of pilocytic astrocytomas, particularly those in the cerebellum, and may be associated with better overall survival. In such cases, resection of the tumor nodule may be of singular importance in delaying or preventing a recurrence. In clinical series, the rate of survival 5 years after successful surgery has been greater than 90 percent (Pencalet et al). The outcome is less assured when the tumor involves the brainstem and cannot be safely resected.
The natural history of the astocytomas is to grow slowly and eventually undergo malignant transformation. The duration of progression before this transformation occurs and the latency to recurrence with modern treatment may extend for many years. A survey of the outcome of these low-grade supratentorial tumors showed that 10-year survival after operation was from 11 to 40 percent provided that conformal radiation therapy (focused on the tumor, in contrast to whole brain radiation) 5,300 cGy was given postoperatively (Shaw et al). Repeated operations prolong life in some patients.
In younger patients, particularly if the neurologic examination is normal or nearly so, radiation can be delayed, and the status of the tumor is sometimes evaluated by serial imaging. A number of studies have come to the conclusion that delaying radiation in younger patients may avoid the consequences of dementia and hypopituitarism (Peterson and DeAngelis), but others have suggested that the tumor itself and antiepileptic drugs cause more difficulty than high-dose radiation. A randomized trial of early radiotherapy in adults demonstrated that median progression-free survival was extended to 5.3 years by early treatment in comparison to 3.4 years for observation only and radiation treatment that was initiated when signs of progression occurred, but that overall survival was unaffected, averaging just over 7 years in both groups (van den Bent et al). Lacking any clear benefit on survival, many clinicians consider that radiation may be withheld initially. An increase in seizures or worsening neurologic signs then presses one to turn to radiation or further surgery.
Although chemotherapy has an ambiguous place in the treatment of astrocytomas, tumors with an oligodendroglial component (see further on) respond well to combination chemotherapy used for the treatment of anaplastic oligodendroglioma. One randomized trial has shown a modest benefit in overall survival by adding chemotherapy (procarbazine, CCNU, vincristine; termed PCV) to radiation therapy of the brain (13.8 years median survival vs 7.8 years; Buckner et al). However, temozolomide has replaced PCV in most centers. Among the novel treatments being explored is direct injection into the tumor of oncolytic viruses that induce an inflammatory reaction in the tumor. They have produced responses that are promising in comparison to historical material, but controlled trials are awaited.
The special clinical and genetic features of astrocytomas of the pons, hypothalamus, optic nerves, and chiasm, which produce characteristic clinical syndromes and do not behave like a cerebral mass, are discussed further on in this chapter.
This interesting variant of high-grade glioma is no longer part of the WHO classification but is retained here for clinical and pedagogic purposes. It is probably subsumed in the new category of astrocytoma, IDH-mutant. Its behavior and appearance on imaging, as well as the property of diffuse infiltration of neoplastic glial cells, involving much of one or both cerebral hemispheres without a discrete tumor mass, make it a useful conceptualization for clinical purposes. Whether this type of “gliomatosis” represents neoplastic transformation of multicentric origin or, as is more likely, direct spread from one or more small neoplastic foci is not known. For these and other reasons, the tumor has been impossible to classify (or to grade) using the conventional brain tumor schemes. The genetic and molecular alterations found in high-grade gliomas, as described earlier, are seen in some cases of gliomatosis cerebri as well but mutations in TP53 are found throughout the tumor, supporting a monoclonal origin (Kros et al). Many have the same IDH mutations seen in other astrocytomas.
Small series of gliomatosis cerebri have been reported since Nevin introduced the term in 1938, but no truly distinctive clinical picture has emerged (Dunn and Kernohan). Impairment of intellect, headache, seizures, and papilledema are the major manifestations and do not set these cases apart on a clinical basis from the malignant astrocytoma, in which the tumor may also be more widespread than the macroscopic picture suggests. If there is a syndrome that can be associated early on with gliomatosis, in our experience it has been a nondescript frontal lobe behavioral syndrome sometimes mistaken for depression or a subacute dementia, or pseudobulbar palsy may be the first manifestation. The prognosis is variable but generally poor, measured in months to a few years from the time of diagnosis.
CT and MRI reveal small ventricles and one or more large confluent areas of signal change (Fig. 30–4). Imaging studies characteristically show the tumor crossing and thickening the corpus callosum (when in the frontal lobe, referred to as “butterfly glioma”). Contrast enhancement is scant, differentiating the tumor from cerebral lymphoma, which otherwise may have a similar appearance. As the tumor advances, enhancing nodules may appear, suggesting the emergence of foci of high-grade glioma.
Diffuse infiltrating astrocytoma, formerly called gliomatosis cerebri, invading both hemispheres. T2-weighted MRI shows a large confluent area of involvement in the frontal lobes with effacement of overlying cortical sulci. There is slight enhancement along the margins of the tumor after gadolinium infusion. The patient was mentally slow but had no other neurologic signs.
These tumors are too infrequent for categorical assessments of therapy, but the overall response to all antitumor treatments has been disappointing and the prognosis, as mentioned, is poor, with survival usually being measured in months. Glucocorticoids have little clinical effect, probably because of a paucity of vasogenic edema. Surgical resection has been recommended by some centers but seems almost pointless. Most trials suggest a benefit to radiation treatment, but the absolute prolongation of life has been only several weeks (Leibel et al). The addition of chemotherapy may confer a marginal further benefit when survival at 1 year is considered. Small series of patients treated with temozolomide suggest it may be a promising agent for this tumor but it will be difficult to conduct a randomized trial given its rarity and lack of clear categorization in modern schemes. When a large region is infiltrated, particularly in the temporal lobe, surgical debulking may prolong life, but otherwise surgery is futile except to obtain a diagnosis. Stereotactic biopsy is usually undertaken.
This tumor was first identified by Bailey and Cushing in 1926 and described more fully by Bailey and Bucy in 1929 (Table 30-2). It is derived from oligodendrocytes or their precursor cells and may occur at any age, most often in the third and fourth decades, with an earlier peak at 6 to 12 years. It is relatively infrequent, constituting approximately 5 to 7 percent of all intracranial gliomas. From the time of its original descriptions, it was recognized as being more benign than most other gliomas. The incidence in men is twice that in women. In some cases, the tumor may be recognized at surgery by its pink-gray color and multilobular form, its relative avascularity and firmness (slightly tougher than surrounding brain), and its tendency to encapsulate and form calcium and small cysts. Most oligodendrogliomas, however, are grossly indistinguishable from other gliomas, and a proportion—up to half in some series—are mixed oligoastrocytomas, suggesting that the precursor cell is pluripotential.
The neoplastic oligodendrocyte has a small round nucleus and a halo of unstained cytoplasm (“fried egg” appearance). The cell processes are few and stubby, visualized only with silver carbonate stains. Some of the oligodendrocytes have intense immunoreactivity to GFAP, similar to normal myelin-forming oligodendrocytes. Microscopic calcifications are observed frequently, both within the tumor and in immediately adjacent brain tissue.
A remarkable degree of progress has been made in understanding the genetic aberrations that occur as acquired somatic mutation within these tumors and the relationship of these changes to the prognosis and response to therapy. Specifically, loss of certain alleles on chromosome 1p has been somewhat predictive of responsiveness to the below-described PCV chemotherapy regimen, and a similar loss on chromosome 19q has been associated with longer survival. The current schemes for classification include mutations in the IDH gene family (see Yan et al) and a codeletion of 1p and 19q (1p/19q) but some tumors in childhood do not have these changes. The tumor does not lend itself easily to grading scales, but a distinction was in the past made between low grade (grade II) and anaplastic type with degeneration, evidenced by greater cellularity and by numerous and abnormal mitoses (grade III). Correspondingly, in the WHO classification “anaplastic” has been removed and the terminology is “Oligodendroglioma IDH-mutant, and 1p/19q codeleted.” Other variants appear in these tumors including in TERT promoter, FUBP1, and NOTCH1. (There is also classified a glioneuronal tumor with oligodendroglioma-like features).
The most common sites of this tumor are the frontal and temporal lobes (40 to 70 percent), often deep in the white matter, with one or more streaks of calcium but little or no surrounding edema. It is rarely found in other parts of the nervous system. By extending to the pial surface or ependymal wall, the tumor may metastasize distantly in ventricular and subarachnoid spaces, accounting for 11 percent of one series (Polmeteer and Kernohan) and (less frequent than medulloblastoma and glioblastoma (see also Yung et al).
The typical oligodendroglioma grows slowly. As with astrocytomas, the first symptom in more than half of patients is a focal or generalized seizure; seizures often persist for many years before other symptoms develop. Approximately 15 percent of patients have early symptoms and signs of increased ICP; an even smaller number have focal cerebral signs (hemiparesis). Much less frequent are unilateral extrapyramidal rigidity, cerebellar ataxia, Parinaud syndrome, intratumoral hemorrhage, and meningeal oligodendrogliosis (cranial–spinal nerve palsies, hydrocephalus, lymphocytes, and tumor cells in CSF).
The appearance of imaging studies is variable, but the most typical is a hypodense (on CT) or T2 hyperintense (on MRI) heterogenous mass near the cortical surface with relatively well-defined borders (Fig. 30–5). Intratumoral calcification can be seen in more than half the cases and is a helpful diagnostic sign, but in the context of seizures, this finding also raises the possibility of an arteriovenous malformation or a low-grade astrocytoma. Approximately half of oligodendrogliomas demonstrate some contrast enhancement, and leptomeningeal enhancement adjacent to the tumor can be seen but is rare.
A partially cystic oligodendroglioma of the right frontotemporal region showing calcification (dark) within the tumor.
Surgical excision followed by radiation therapy has been the conventional treatment for oligodendroglioma. However, because of uncertainty as to the histologic and genetic classification of many of the reported cases, it is not clear whether radiation therapy is attended by longer survival. Well-differentiated oligodendrogliomas should probably not receive radiation if seizures are well controlled and there are no neurologic deficits. As mentioned earlier the discovery by Cairncross and MacDonald is of considerable importance in that many oligodendrogliomas, especially anaplastic ones and those with IDH mutations and 1p/19q codeletion, respond to chemotherapeutic agents. This has been studied with the PCV regimen (procarbazine, cyclophosphamide, and vincristine) given in approximately 6 cycles, but also applies to the better-tolerated temozolomide, which has become the preferred treatment. However, temolzolomide has been recommended by some centers and is better tolerated than PCV.
Mixed oligodendrogliomas and astrocytomas are generally treated like astrocytomas, but temozolomide may suffice to treat both components. An adequate direct comparison between temozolomide and PCV is awaited.
Correctly identified by Virchow as early as 1863, the origin of this tumor from ependymal cells was first suggested by Mallory, who found the typical blepharoplasts (small, darkly staining cytoplasmic dots that are the basal bodies of the cilia as seen by electron microscopy) (Table 30-2) (See Also “Patients Who Present Primarily With Signs of Increased Intracranial Pressure” Further on). Two types were recognized by Bailey and Cushing: one was the ependymoma, and the other, with more malignant and invasive properties, the ependymoblastoma, now recognized as an anaplastic ependymoma. Fewer than 10 percent of all intracranial gliomas are ependymomas, with the percentage being slightly higher in children. Approximately 40 percent of the infratentorial ependymomas occur in the first decade of life, a few as early as the first year. The supratentorial ones are more evenly distributed among all age groups, but in general, the age incidence is lower than that of other malignant gliomas.
There is also a myxopapillomatous type of ependymoma, localized exclusively in the filum terminale of the spinal cord as discussed further on. The latter gives rise to a special syndrome that variably combines symptoms and signs of the conus medullaris and the cauda equina such as sciatica or femoral pain, bladder difficulty, saddle anesthesia, and spastic leg weakness.
A genetic aberration in which the RELA gene becomes fused to an open reading frame of chromosome 11 (RELA-fusion positive) occurs in the majority of supratentorial tumors in children. The WHO5 classification is otherwise discursive in listing ependymomas by their location (supratentorial, posterior fossa, and spinal) with note of ZFTA fusion-positive, YAP1 fusion positive and MYCN-amplified for the spinal type. However, conventional grading for the ependymal tumors have essentially been abrogated by the genetic characteristics.
Ependymomas are derived from ependymal cells, that is, the cells lining the ventricles of the brain and the central canal of the spinal cord; this is the most common glioma of the spinal cord. These cells have both glial and epithelial characteristics. As one might expect, the tumors grow either into the ventricle or adjacent brain tissue. The most common cerebral site is the fourth ventricle; less often they occur in the lateral or third ventricles. Grossly, those in the fourth ventricle are grayish pink, firm, cauliflower-like growths; those in the cerebrum, arising from the wall of the lateral ventricle, may be large (several centimeters in diameter), reddish gray, and softer and more clearly demarcated from adjacent tissue than astrocytomas, but they are not encapsulated. The tumor cells tend to form rosettes with central lumens or, more often, circular arrangements around blood vessels (pseudorosettes). Some ependymomas are densely cellular; others form papillae. Some of the well-differentiated fourth ventricular tumors are probably derived from subependymal astrocytes (see Ependymoma of the Fourth Ventricle).
The symptomatology depends on the location of the neoplasm. The clinical manifestations of fourth ventricular tumors are described further on; the point to be made here is the frequent occurrence of hydrocephalus and signs of raised ICP (manifest in children by lethargy, nausea, vomiting, and papilledema). Cerebral ependymomas otherwise resemble the other gliomas in their clinical expression in that seizures occur in approximately one-third of the cases.
The imaging characteristics are rather different from those of other tumors. With CT one observes a well-demarcated heterogeneous hyperdense mass with fairly uniform contrast enhancement. Calcification and some degree of cystic change are common in supratentorial tumors, but less so in infratentorial ones. There are mixed signal characteristics on MRI, generally hypointense on T1 sequences and hyperintense on T2. An intraventricular location supports the diagnosis of ependymoma, but meningioma and a number of other tumors may be found in this location. In keeping with the variability of anaplasia, the interval between the first symptom and the diagnosis ranges from 4 weeks in the most malignant types, to 7 to 8 years.
In a follow-up study of 101 cases in Norway, where ependymomas made up 1.2 percent of all primary intracranial tumors (and 32 percent of intraspinal tumors), the postoperative survival was poor. Within a year, 47 percent of the patients had died, although 13 percent were alive after 10 years. Doubtless the prognosis depends on the degree of anaplasia and genetic makeup of the tumor in each case (Mørk and Løken), the location of the tumor, and whether it is operable but the lack of certainty of these dicta have been alluded to earlier. Surgical removal is supplemented by radiation therapy, particularly to address the high rate of seeding of the ventricles and spinal axis. In the treatment of aggressive ependymomas, antineoplastic drugs are often used in combination with radiation therapy.
This tumor, first illustrated by Matthew Bailie in his Morbid Anatomy (1787) and identified properly by Bright, in 1831, originates from the dura mater or arachnoid (Table 30-3). It was analyzed from every point of view by Harvey Cushing and was the subject of one of his most important monographs (Cushing and Eisenhardt). The tumor is discussed again further on in relation to particular sites of origin.
Meningiomas represent approximately one-third of all primary intracranial tumors; they are more common in women than in men (2:1) and have their highest incidence in the sixth and seventh decades of life. Some are familial. There is evidence that persons who have undergone radiation therapy to the scalp or cranium are vulnerable to the development of meningiomas and that the tumors appear at an earlier age in such individuals (Rubinstein et al). Radiofrequency energy exposure from portable cellular devices has failed to be linked to elevated incidence of meningiomas (or gliomas) (Inskip et al). There are also a number of reports of a meningioma developing at the site of previous trauma, such as a cranial fracture line, but the association is uncertain.
In meningiomas of both the sporadic and neurofibromatosis type 2 (NF2)–associated types, somatic genetic defects are found including variants in NF2, AKT1, TRAF7, SMO, TERT promoter, and others. Merlin deletions probably also play a role in instances in which there is a loss of the long arm of chromosome 22. The conventional grading system has not been formally retained in WHO5 (Grades 1 to 4) but Grade 3 has been associated with variants in CDKN2 A/B.I (also found in gliomas).
Meningiomas also elaborate a variety of soluble proteins, some of which (VEGF) are angiogenic and probably relate to both the highly vascularized nature of these tumors and their prominent surrounding edema (see Lamszus for further details). Some meningiomas contain estrogen and progesterone receptors. These findings may relate to the increased incidence of the tumor in women, its tendency to enlarge during pregnancy, and an association with breast cancer.
The precise cellular origin of meningiomas is still not settled. According to Rubinstein, they may arise from dural fibroblasts, but it was the opinion of our colleague R.D. Adams that they are more clearly derived from arachnoidal (meningothelial) cells, in particular from those forming the arachnoid villi. Because the clusters of arachnoidal cells penetrate the dura in largest number in the vicinity of venous sinuses, these are the sites of predilection for the tumor. Grossly, the tumor is firm, gray, and sharply circumscribed, taking the shape of the space, in which it grows; thus, some tumors are flat and plaque-like, others round and lobulated. They may indent the brain and acquire a pia-arachnoid covering as part of their capsule, but they are clearly demarcated from the brain tissue (extraaxial) except in the unusual circumstance of a malignant invasive meningioma. Infrequently, they arise from arachnoidal cells within the choroid plexus, forming an intraventricular meningioma.
The cells of meningiomas are relatively uniform, with round or elongated nuclei, visible cytoplasmic membrane, and a characteristic tendency to encircle one another, forming whorls and psammoma bodies (laminated calcific concretions). A notable electron microscopic characteristic is the formation of very complex interdigitations between cells and the presence of desmosomes (Kepes). Cushing and Eisenhardt had divided meningiomas into many subtypes depending on their mesenchymal variations, the character of the stroma, and their relative vascularity, but the value of such classifications is debatable. Neuropathologists still recognize a meningothelial (syncytial) form as being the most common and it can be distinguished from other similar but nonmeningothelial tumors such as hemangiopericytomas, fibroblastomas, and chondrosarcomas.
Meningiomas occur at sites of dural folds, most commonly the frontoparietal parasagittal convexities, falx, tentorium cerebelli, sphenoid wings, olfactory groove, and tuberculum sellae. Ninety percent of meningiomas are supratentorial, and the majority of infratentorial meningiomas occur at the cerebellopontine angle. Some meningiomas—such as those of the olfactory groove, sphenoid wing, and tuberculum sellae—express themselves by highly distinctive syndromes that are almost diagnostic; these are described further on in this chapter. Rarely, the tumors are multiple. Inasmuch as the meningioma extends from the dural surface, it commonly incites hyperostosis of adjacent bone and can, in more malignant cases, invade and erode the cranial bones or excite an osteoblastic reaction, giving rise to an exostosis on the external surface of the skull. Most of the following remarks apply to meningiomas of the parasagittal, sylvian, and other surface areas of the cerebrum.
Small meningiomas, less than 2.0 cm in diameter, are often found at autopsy in middle-aged and elderly persons without having caused symptoms. Only when they exceed a certain size and indent the brain or cause a seizure do they alter function. The size that must be reached before symptoms appear varies with the size of the space in which the tumor grows and the surrounding anatomic arrangements. Focal seizures are an early sign of meningiomas that overlie the cerebrum. The parasagittal frontoparietal meningioma may cause a slowly progressive spastic weakness or numbness of one leg and later of both legs, and incontinence in the late stages. The larger sylvian tumors are manifest by a variety of motor, sensory, and aphasic disturbances in accord with their location, and by seizures.
Before brain imaging became widely available, a meningioma often gave rise to neurologic signs for many years before the diagnosis was established, attesting to its slow rate of growth. Even now some tumors reach enormous size, to the point of causing papilledema, before the patient comes to medical attention. Many are detected on imaging in individuals with unrelated neurologic diseases. In one study of 2000 MRI scans, 1 percent had incidentally found meningiomas (Vernooij et al). The diagnosis of meningioma is facilitated by their ready visualization with contrast-enhanced CT and MRI (Figs. 30-6 and 30-7), which demonstrates their tendency to calcify as well as their prominent vascularity. These changes are reflected by homogeneous contrast enhancement and by “tumor blush” on angiography. Typically, the tumor takes the form of a smoothly contoured mass sometimes lobulated, with one edge abutting the inner surface of the skull, along the dura. On CT performed without contrast they are isodense or slightly hyperdense; calcification at the outer surface or heterogeneously throughout the mass is common. The amount of edema surrounding the tumor is highly variable and may relate to the extent of local brain symptoms. The CSF protein is usually elevated.
A. Parafalcine meningioma; coronal image, MRI with gadolinium. Note the rightward displacement of an anterior cerebral artery (hypointense flow void) trapped between the right lateral margin of the mass and the right medial frontal lobe. B. Small and asymptomatic left olfactory groove meningioma, MRI with gadolinium.
Gadolinium-enhanced MRI of meningioma. Large subfrontal extraaxial mass with central calcification (dark stellate pattern) and surrounding vasogenic edema (bright white). Homogeneous enhancement is characteristic of the tumor.
Surgical excision affords long-term or permanent cure in most symptomatic and accessible tumors; however, many small asymptomatic tumors can be followed clinically and with imaging over time. Recurrence is likely if removal is incomplete, as is often the case, but for some the growth rate is so slow that there may be a latency of many years or decades. A few tumors show malignant qualities; that is, a high mitotic index, nuclear atypia, marked nuclear and cellular pleomorphism, and invasiveness of brain. Their regrowth is then rapid if they are not completely excised. Tumors that lie beneath the hypothalamus, along the medial part of the sphenoid bone and parasellar region, or anterior to the brainstem are the most difficult to remove surgically. By invading adjacent bone, they may become impossible to remove totally. Carefully planned radiation therapy, including various forms of stereotactic treatment, is beneficial in cases that are inoperable and when the tumor is incompletely removed or shows malignant characteristics.
Smaller tumors at the base of the skull can be obliterated or reduced in size by focused radiation, probably with similar or less risk than posed by surgery (see discussion by Chang and Alder). Conventional chemotherapy and hormonal therapy are probably ineffective, but the latter has been a subject of interest. Investigations are being undertaken with antiangiogenic antibodies for recurrent tumors.
Primary Central Nervous System Lymphoma
This tumor has assumed increasing significance because of its increased incidence in patients living with AIDS and other immunosuppressed states. There is a peak incidence in the fifth through seventh decades of life, or in the third and fourth decades in persons living with AIDS and the incidence is increasing independent of this form of immunosuppression. The current classification lists CNS lymphomas in a discursive way but includes intravascular lymphoma and the rare anaplastic large cell lymphoma that are ALK positive or negative in the brain, which are predictive of prognosis in systemic lymphoma.
For many years, the cell of origin of this tumor was attributed to the reticulum cell, a histiocytic component of the germinal center of lymph nodes that produces the reticulum stroma of the nodes, and the tumor was termed “reticulum cell sarcoma.” The meningeal histiocyte and microgliacytes are the equivalent cells in the brain to the reticulum cell and are considered then the origin of the tumor. Later, it was recognized that the malignant cells were lymphocytes and lymphoblasts, leading to its reclassification as a lymphoma (diffuse large cell type). It has been appreciated, on the basis of immunocytochemical studies, that the tumor cells are B lymphocytes. There is a fine reticulum reaction between the reticulum cells derived from fibroblasts and microglia or histiocytes. The disproportionate emphasis on this reticular stroma was the result of staining methods that brought it into relief with the lymphocytes. The B lymphocyte or lymphoblast is the tumor cell, whereas the fine reticulum and “microgliacytes” are secondary interstitial reactions.
In contrast, T-cell lymphomas of the nervous system are rare but do occur in both immunocompetent and immunosuppressed patients. Because the brain is devoid of lymphatic tissue, it is uncertain how this tumor arises; one theory holds that it represents a systemic lymphoma with a particular propensity to metastasize to the nervous system. This seems unlikely to the authors; systemic lymphomas of the usual kind rarely metastasize, as discussed further on, under “Involvement of the Nervous System in Systemic Lymphoma.”
Primary CNS lymphoma may arise in any part of the cerebrum, cerebellum, or brainstem, with 60 percent being in the cerebral hemispheres; they may be solitary or multifocal. A periventricular localization is common. Vitreous, uveal, and retinal (ocular) involvement occurs in 10 to 20 percent of cases; here vitreous biopsy may be diagnostic, but it is not often performed. (Two-thirds of patients with ocular lymphoma will have cerebral involvement within a year.) There is evidence that in advanced cases that were autopsied, microscopic deposits of tumor found their way to many regions of the brain and not solely in areas indicated by nodular enhancement on MRI (Lai and colleagues). Whether this indicates a widespread or multifocal origin of brain lymphoma is not clear.
The pia and arachnoid may be infiltrated, and a meningeal form of B-cell lymphoma that involves peripheral and cranial nerves is also known. Cases of what has been termed neurolymphomatosis may or may not arise from systemic lymphoma (hence, primary neurolymphomatosis) and present with variably painful, predominantly motor polyradiculopathies. Lymphomatous metastases to the same regions are probably more common than the isolated peripheral nerve and meningeal form but give rise to a similar syndrome of multiple radiculopathies. One such patient of ours had a flaccid paraparesis and back and sciatic pain; MRI showed tumor infiltrating the cauda equina nerve roots and contiguous meninges.
The tumor forms a pinkish gray, soft, ill-defined, infiltrative mass in the brain, difficult at times to distinguish from an astrocytoma. Perivascular and meningeal spread results in shedding of cells into the CSF, accounting perhaps for the multifocal appearance of the tumor in many cases. The neoplasm is highly cellular and grows around and into blood vessels (“angiocentric” pattern) but elicits no tendency to necrosis. The nuclei are oval or bean-shaped with scant cytoplasm, and mitotic figures are numerous. B-cell markers applied to fixed tissue define the lymphoblastic cell population as monoclonal and identify the tumor cell type. The stainability of reticulum and microglial cells also serves to distinguish this tumor microscopically. There is no tumor tissue outside the brain.
Several of our patients had meningeal and cranial nerve lymphoma with similar histologic characteristics to primary CNS lymphoma that were complications of chronic lymphatic leukemia, a type of so-called Richter transformation.
Primary lymphoma involving the cerebral hemispheres initially pursues a clinical course somewhat similar to that of the astrocytomas but with a vastly different response to treatment. Behavioral and personality changes, confusion, dizziness, and focal cerebral signs predominate over headache and other signs of increased ICP as presenting manifestations. Seizures may occur but are far less common, in our experience, than they are as the introductory feature of gliomas. Most cases occur in adult life, but some have been observed in children, in whom the tumor may simulate the cerebellar symptomatology of medulloblastoma.
The finding on CT and MRI of one or several dense (hypercellular), homogeneous, enhancing, infiltrating, nonnecrotic, nonhemorrhagic, and periventricular masses is characteristic (Fig. 30–8). However, rim enhancement also occurs, and any part of the brain may be involved. There is often restriction of diffusion on MRI because of the tumor’s dense cellularity. The radiologic appearance in the immunosuppressed patient is less predictable and may be difficult to distinguish from that of toxoplasmosis, progressive multifocal leukoencephalopathy (PML), or another process with which lymphoma may coexist.
Primary central nervous system lymphoma. Left: Axial T2-FLAIR MRI showing hyperintensity in the right periatrial white matter, without mass effect. Right: Contrast-enhanced MRI in the same patient demonstrates two foci of nodular parenchymal enhancement.
In some cases, a multitude of deep cerebral white matter lesions, some radially oriented and thereby simulating multiple sclerosis, are seen. Tumor enhancement with contrast agents tends to be more prominent and homogeneous than with the acute lesions of multiple sclerosis. A similar multinodular appearance occurs with intravascular lymphoma, discussed in a later section. Characteristic of primary CNS lymphoma is the disappearance on imaging of the lesions or complete but transient resolution of contrast enhancement in response to corticosteroids.
Lymphocytic and mononuclear pleocytosis of CSF is more frequent than with gliomas and metastatic tumors, occurring in up to half of cases. The immunohistochemical demonstration in CSF of monoclonal lymphocytes or an elevated beta-2 microglobulin points to leptomeningeal spread of the tumor (Li et al), but frequently the diagnosis is not possible from CSF cytologic examination. Gene rearrangements within the monoclonal cell populations, especially of the immunoglobulin heavy chain gene are used as a diagnostic test that is more sensitive than cytology of the spinal fluid. These findings occur in approximately one-quarter of patients with proved CNS lymphoma; as noted, it reflects the monoclonality of the lymphocytes.
People living with AIDS and less-common immunodeficiency states, such as the Wiskott-Aldrich syndrome and ataxia-telangiectasia, and those who are receiving immunosuppressive drugs for long periods, as for example, in renal transplantation, are particularly liable to develop this type of lymphoma. Many of the tumors in immunosuppressed patients contain the EBV genome, suggesting a pathogenetic role for the virus (Bashir et al); however, the EBV genome has also been found in the tumors of a few immunocompetent patients (Hochberg and Miller). Sometimes this tumor appears as a complication of an obscure medical condition such as salivary and lacrimal gland enlargement (Mikulicz syndrome) and the related Sjögren syndrome. Another disorder, lymphomatoid granulomatosis (called by several different names), is also driven by EBV virus and has similarities to CNS lymphoma, as outlined in a later section.
Stereotactic needle biopsy is the preferred method of establishing the histologic diagnosis in sporadic cases. In immunosuppressed patients, the differential diagnosis of a solitary brain nodule that is suspected to be lymphoma is aided by the response, or lack thereof, to treatment for toxoplasmosis, the main alternative diagnosis (see “Toxoplasmosis” in Chap. 31). Reduction in the size of the lesion with antimicrobial drugs makes biopsy unnecessary.
Because the tumors are deep and often multicentric, surgical resection is ineffective. Treatment with cranial irradiation and glucocorticoids often produces a partial or, transiently, a complete response, but the tumor recurs in greater than 90 percent of patients. At times, the response to corticosteroids can be striking, even eliminating imaging and histopathologic evidence of the tumor and making the diagnosis difficult. Paradoxically, clinicians use this dramatic disappearance as implicit evidence of the existence of CNS lymphoma, although other disorders such as demyelinating disease may do the same.
Until several decades ago, the median survival of patients had been 10 to 18 months, and less in those with AIDS and in individuals who were otherwise immunocompromised. The treatment of CNS lymphoma is different in patients with AIDS than in patients who are immunocompetent in that chemotherapy creates an additional risk for infection. Restoring immune competence is advisable but in contrast to the opportunistic infection that may be associated with immunosuppression, PML, there is little evidence that this restoration improves CNS lymphoma. While methotrexate, for example, had been eschewed, it has been tried in AIDS patients who also start antiretroviral treatment. Cranial irradiation is the predominant treatment.
There is currently only broad consensus on the optimal treatment of CNS lymphoma but methotrexate-based regimens are apparently most effective. Single high-dose intravenous therapy is widely used but multiple-dose regimens in combination with whole brain radiation are also employed. Cranial irradiation has been studied heterogeneously as part of the initial treatment. More recently, methotrexate plus rituximab and temozolomide has been assessed but not uniformly implemented. This may be followed by whole brain radiation or chemotherapy and autologous hematopoetic stem cell transplantation. Novel approaches include chimeric antigen receptor-T cell therapy (CAR-T cells). With these various regimens, despite high initial response rates, survival rates have been, at best near 50 percent. Survival in patients with AIDS is shorter but may be improved with the inception of aggressive antiretroviral treatment.
Ocular lymphoma is eradicated only by radiation therapy. Corticosteroids are added at any point to control neurologic symptoms. The median survival time with this approach in the non-AIDS patient is in the range of 3.5 years with intravenous methotrexate alone and 4 years or more if radiation is given subsequently. Some patients are alive at 10 years.
Intracranial Metastatic Cancer
These are far more common than are primary brain tumors. The presence of multiple intracranial lesions is also more suggestive of metastases compared to primary tumor. Among secondary intracranial tumors, only metastatic carcinoma occurs with high frequency. Lymphoma and leukemia are less frequent than carcinoma and they have less proclivity to spread to the brain or its coverings. Occasionally one encounters a rhabdomyosarcoma, Ewing tumor, carcinoid, and others that have metastasized, but these have such low incidence that cerebral metastases seldom become a matter of diagnostic concern. The interesting pathobiology of metastatic carcinoma—the complex biologic mechanisms that govern the detachment of tumor cells from the primary growth, their transport to distant tissues, and their implantation on the capillary endothelium of the particular organ in which they will eventually grow—is of research interest. Suffice it to say that tumor cell adhesion molecules, the vasculature, and a number of other cellular events participate in the implantation of what is essentially a neoplastic embolus.
Autopsy studies in the past disclosed intracranial metastases in approximately 25 percent of patients who die of cancer (Posner and Chernik 1978). Approximately 80 percent are in the cerebral hemispheres and 20 percent in posterior fossa structures, corresponding roughly to the relative size and weights of these portions of the brain and their blood flow. Intracranial metastases assume three main patterns— those to the brain itself, those to the skull and dura, and those spreading diffusely through the craniospinal meninges (leptomeningeal metastases, which include carcinomatous meningitis and lymphomatous meningitis). As common as intracranial metastases are, metastases to the vertebral column, which eventually cause compression of the spinal cord and nerve roots, are more frequent. This separate problem is discussed in Chap. 42. Metastatic deposits within the spinal cord itself are infrequent but are seen from time to time; they are more common, however, than another cancer-associated spinal cord lesion, paraneoplastic necrotic myelopathy (see the following text).
Metastases to the skull and dura occur with any tumor that metastasizes to bone, but they are particularly common with carcinoma of the breast and prostate and in the special case of multiple myeloma. Secondary deposits usually occur without metastases to the brain itself and reach the skull either via the systemic circulation (as in carcinoma of the breast) or via the Batson vertebral venous plexus—a valveless system of veins that runs the length of the vertebral column from the pelvic veins to the large venous sinuses of the skull, bypassing the systemic circulation (the route presumably taken by carcinoma of the prostate). Metastatic tumors of the convexity of the skull are usually asymptomatic but those at the base may implicate the cranial nerve roots or the pituitary gland. Bony metastases are readily recognized on various imaging techniques. Occasionally, a carcinoma metastasizes to the dura or subdural surface and compresses the brain, usually in a more focal manner than subdural hematoma. Many metastases in the skull and dura, perhaps most, are asymptomatic.
Apart from the above, most carcinomas reach the brain by hematogenous spread. Almost one-third of metastases to the brain originate in the lung and half this number in the breast; melanoma is the third most frequent source in most series, and the gastrointestinal tract (particularly the colon and rectum) and kidney are the next most common, in part reflecting the prevalence of each of these tumors but also because of a tropism for the nervous system, as noted below. Carcinomas of the gallbladder, liver, thyroid, testicle, uterus, ovary, pancreas, etc., account for the remainder. Tumors originating in the prostate, esophagus, oropharynx, and skin (except for melanoma) only rarely metastasize to the substance of the brain. From a different perspective, certain neoplasms are particularly prone to metastasize to the brain—75 percent of melanomas do so, 55 percent of testicular tumors, and 35 percent of bronchial carcinomas, of which 40 percent are small cell tumors. Up to half of metastases are solitary and are likely to come from kidney, breast, thyroid, and adenocarcinoma of the lung. Small cell carcinomas and melanoma metastases tend to be multiple, but exceptions abound.
Generally, the cerebral metastasis forms a circumscribed mass, usually solid but sometimes in the form of a ring (i.e., cystic), that excites little glial reaction but much regional vasogenic edema. Edema alone is often evident in imaging studies until the administration of contrast exposes small tumor nodules (Fig. 30–9). Metastases from melanoma and chorioepithelioma are often hemorrhagic, but it is not unusual for tumors originating in lung, thyroid, and kidney to exhibit this characteristic. In a number of these cases, one-quarter in some series, the first manifestation of the metastasis is an intratumoral hemorrhage. The relative frequency of lung cancer makes it the most common metastatic tumor to bleed, even though only a small proportion does so.
Contrast-enhanced MRI (left) showing multiple metastases from renal cell carcinoma. Note the extensive hypointense edema surrounding each lesion. The right image is a gradient echo MRI in which blood products appear hypointense (dark). This sequence can aid in detection of small or nonenhancing hemorrhagic metastases, such as the lesion in the left occipital lobe.
The usual clinical picture of metastatic carcinoma of the brain is of seizures, headache, focal weakness, mental or behavioral abnormalities, ataxia, aphasia, or signs of increased ICP—all progressive over a few weeks or months. In addition, a number of unusual syndromes may occur. One that presents particular difficulty in diagnosis is a diffuse cerebral disturbance with headache, nervousness, depressed mood, trembling, confusion, and forgetfulness, resembling a relatively rapid dementia from degenerative disease. Cerebellar metastasis, with headache, dizziness, and ataxia (the latter being brought out only by having the patient walk), is another condition that may be difficult to diagnose. Brainstem metastases, most often originating in the lung, are rare but distinctive, giving rise to diplopia, imbalance, and facial palsy, as in the characteristic case described by Weiss and Richardson.
The onset of symptoms from brain metastases may occasionally be abrupt or even “stroke-like” rather than insidious. Some cases of sudden onset can be explained by bleeding into the tumor and others perhaps by tumor embolism that occludes a cerebral vessel. In most cases, the explanation for this temporal profile is not known. However, non-bacterial thrombotic (marantic) endocarditis with cerebral embolism must be suspected when a stroke-like event occurs in a cancer patient. It is not unusual for either of these neurologic manifestations to precede the discovery of a pancreatic, bowel, gastric, breast, or lung carcinoma.
When any of the several clinical syndromes caused by metastatic tumor is fully developed, diagnosis is relatively easy. If only headache and vomiting are present, a common problem is to attribute them to migraine or tension headache. One should invoke such explanations only if the patient has the usual symptoms of one of these conditions. CT with contrast will detect practically all sizable (1 cm) metastases though MRI with gadolinium is probably more sensitive especially for small cerebellar lesions, and better exposes associated leptomeningeal disease. Multiple nodular deposits of tumor in the brain on imaging studies most clearly distinguish metastatic cancer from other tumors but this pattern may also occur with brain abscesses, brain lymphoma, and glioblastoma.
Solitary metastatic disease must be distinguished from a primary tumor of the brain, CNS lymphoma, tumefactive demyelination (see Chap. 35), and from infective abscess. Multiple brain metastases should not be confused with the syndromes associated with paraneoplastic neurologic syndromes that sometimes accompany carcinoma. The latter include limbic encephalitis. The paraneoplastic syndromes are discussed further on, under “Remote Effects of Neoplasia on the Nervous System (Paraneoplastic Disorders).”
In addition to the aforementioned conditions, there are patients with cancer who exhibit symptoms of an altered mental state without evidence of metastases or a recognizable paraneoplastic disorder. These symptoms usually have their basis in systemic metabolic disturbances (hypercalcemia in particular), drugs, and psychologic reactions, some of which have yet to be clearly delineated. Problems of this type were noted in a high percentage of cancer patients seen in consultation at the Memorial Sloan-Kettering Cancer Center (Clouston et al) and are seen almost daily on the wards of every general and cancer hospital. Once chemotherapy or brain radiation has been administered, the secondary effects of these treatments further cloud the picture.
The treatment of metastatic tumors of the nervous system has undergone frequent changes. Current programs utilize various combinations of glucocorticoids, radiation therapy (stereotactic, focal or whole brain), surgical removal, and chemotherapy and immune modulating treatment. Glucocorticoids often produce prompt improvement, probably on the basis of a reduction in the edema surrounding the lesion, but sustained use is restricted by side effects and eventual loss of efficacy. Most patients with multiple metastases also temporarily benefit from the use of whole-brain irradiation, usually administered over approximately a 2-week period, in multiple doses. High-dose and stereotactic radiotherapy (radiosurgery) is now considered the main alternative for single or several cerebral metastases.
One randomized trial comparing stereotactic radiotherapy alone compared to stereotactic combined with whole-brain radiation for 1 to 4 metastases, found no difference in survival but there was a reduction in the frequency of recurrence at other sites in the brain when whole-brain treatment was added (Aoyama et al). Several other studies have suggested that control of local symptoms related to a metastasis is better with focused radiotherapy. However, with the exception of a single lesion from small cell lung cancer, there does not seem to be a major advantage to either approach. If focused treatment has been used, whole-brain radiation can still be instituted at the time of a recurrence. Whether there is evidence to justify the routine implementation of this approach is not clear, especially as overall measures of the quality of life are not generally improved. Trials can be found that favor sterotactic treatment for one or a few lesions, but the effect size is small. An arbitrary limit of stereotactic treatment of four metastases arose as the field evolved but it appears that the results are similar with even greater numbers.
There remains a controversial issue of prophylactic radiation of the entire cranium in the case of certain tumors, particularly small cell lung cancer. Information from trials in patients with chemotherapy-responsive small cell lung cancer suggests that prophylactic radiation prolonged survival by 1.5 months and reduced the later emergence of metastasis to the brain (Slotman and colleagues and Aupérin and coworkers). Critics have noted that with recently improving survival rates the delayed cognitive effects of brain radiation may become evident.
In patients with a single parenchymatous metastasis (shown to be solitary by gadolinium-enhanced MRI), surgical extirpation may be undertaken provided that growth of the primary tumor and its systemic metastases is under good control and the metastasis is accessible to the surgeon and not located in a strategic motor or language area of the brain. Usually, excision is followed by radiation therapy to the entire brain. Survival and the interval between treatment and recurrence are longer and the quality of life was better in one often-cited study in patients treated in this way than in comparable patients treated with whole-brain radiation alone (Patchell et al). Single or dual metastases from renal cell cancer, melanoma, and adenocarcinoma of the gastrointestinal tract lend themselves best to surgical removal according to some matched cohort studies (Bindal and colleagues).
There is evidence that some metastatic brain tumors are sensitive to chemotherapeutic agents, especially if the primary tumor is similarly responsive. Intrathecal and intraventricular chemotherapy are not thought to be of value in the treatment of parenchymal metastases. Immunotherapy has not yet been widely employed for brain metastases but this is rapidly changing, for example, with CAR T-cell treatment of melanoma and lung cancer.
Prophylactic antiepileptic drugs are generally not employed as they do not appear to prevent a first seizure, as mentioned earlier. Several studies, some well controlled, corroborate this, as discussed in Chap. 15.
Despite all of these measures, survival is only moderately prolonged by treatment. The average period of survival in cases of brain metastases, even with therapy, is about 6 months, but it varies widely and is dominated by the extent of other systemic metastases. Between 15 and 30 percent of patients live for a year and 5 to 10 percent for 2 years, with certain radiosensitive tumors (lymphoma, testicular carcinoma, choriocarcinoma, some breast cancers); however, survival can be much longer. It has been stated, without strong corroboration, that patients with bone metastases tend to live longer than those with brain and meningeal metastases.
Carcinomatous and Lymphomatous Meningitis
Widespread dissemination of tumor cells throughout the meninges and ventricles, a special form of metastatic cancer, is the pattern in approximately 5 percent of cases of adenocarcinoma of breast, lung, and gastrointestinal tract, melanoma, childhood leukemia, and systemic lymphoma. This is among the most deceptive of neurologic diagnoses. With certain carcinomas, notably gastric, it may be the first manifestation of a neoplastic illness, although more often the primary tumor has been present and is under treatment.
Headache and backache, sometimes with sciatica, are common but not invariable. Polyradiculopathies (particularly of the cauda equina), multiple cranial nerve palsies, and a confusional state have been the principal manifestations, and many cases are restricted to one of these features. Only a small number have an uncomplicated meningeal syndrome of headache, nausea, and meningismus, but these features develop within weeks in many cases. Delirium, stupor, and coma follow. Focal neurologic signs and seizures may be associated, and somewhat fewer than half of the patients develop hydrocephalus. The combination of a cranial neuropathy, such as unilateral facial weakness, hearing loss (suggestive of lymphoma), or ocular motor palsy, with bilateral asymmetrical limb weakness, is particularly characteristic. The evolution in all these syndromes is generally subacute over weeks, with a more rapid phase as the illness progresses.
Neoplastic meningitis presents a characteristic pattern on imaging studies, particularly with gadolinium-enhanced MRI of the brain or spine. The leptomeninges are found to be thickened and variably enhancing, sometimes with nodular appearing lesions but as often with smooth contiguous areas of involvement. The basilar portions of the brain, around the cisternal segments of the cranial nerves and overlying the cerebellar folia are preferred regions for appearance of these findings (Fig. 30–10). There may be hydrocephalus, but it is surprisingly infrequent.
Leptomeningeal carcinomatosis from breast cancer showing infiltration of the cortical and cerebellar subarachnoid spaces on axial T1 post-gadolinium MRI. There is a small metastasis in the pontine tegmentum.
The diagnosis is established by identifying tumor cells in the CSF using cytology and flow cytometry techniques. We generally undertake an examination of the CSF with the exception of cases with noncommunicating hydrocephalus. In the latter instance, a ventricular drain may have been placed and CSF can be obtained from that source. More than one examination, using generous quantities of CSF, may be needed. Increased pressure in the subarachnoid space, elevation of CSF protein and low glucose levels, and lymphocytic pleocytosis (up to 100 cells but typically much fewer) are other common findings. Nevertheless, in a few patients, the CSF remains persistently normal. Measurement of certain biochemical markers of cancer in the CSF—such as lactate dehydrogenase (LDH), β-glucuronidase, β2-microglobulin, and carcinoembryonic antigen (CEA)—offers another means of making the diagnosis and following the response to therapy. These markers are most likely to be abnormal in hematologic malignancies but may also be altered in some cases of intracranial infection and parenchymal metastases (Kaplan et al). In many of the cases of meningeal carcinomatosis, there are also parenchymal brain metastases.
Also known is a rare primary malignant melanoma of the meninges that acts in a similar way to carcinomatous meningitis but has the striking feature of bloody CSF (1,000 to 10,000 red blood cells per mm3). The origin of the neoplasm is from native melanotic cells in the meninges. The prognosis is as bleak (Liubinas et al). The WHO5 classification also lists a diffuse leptomeningeal glioneuronal tumor.
Treatment and outcome of malignant meningitis
This consists mainly of radiation therapy to the symptomatic areas (cranium, posterior fossa, or spine) followed in selected cases by the intraventricular administration of methotrexate, but these measures rarely stabilize neurologic symptoms for more than a few weeks or months. The methotrexate is typically administered into the lateral ventricle via an Ommaya reservoir (12 mg diluted in preservative-free saline) or less often nowadays into the lumbar subarachnoid space through a lumbar puncture needle. Several regimens have been devised, including daily instillation for 3 to 4 days followed by radiation, or methotrexate doses on days 1, 4, 8, 11, and 15.
Involvement of the cranial nerves or an encephalopathy caused by widespread infiltration of the cranial meninges has been treated with whole-brain radiation, 3,000 cGy, given in fractions of 300 cGy per day for 10 days. Spinal root infiltration responds to spinal radiation, and regional treatments are helpful temporarily for local seeding of the lumbar roots. A study of CSF flow by the injection of a radionuclide agent may be useful to determine if there is impeded flow that prevents circulation of the methotrexate or exposes one region to excessive toxicity. In tumors that are sensitive to a specific chemotherapy, systemic administration may be effective depending on the permeability of the blood–brain barrier to these agents, for example, in some forms of breast cancer and melanoma, and the systemic use of check point (cell-cycle, e.g., PD-1) inhibitors is being investigated.
The median duration of survival after diagnosis of meningeal carcinomatosis is between 2 and 6 months, generally on the shorter end of this range. We have experience, however, with individuals who have survived with stable deficits for over a year with breast cancer metastatic to the meninges and lumbar roots. The encephalopathy caused by widespread tumor infiltration or hydrocephalus is a highly concerning and usually preterminal sign.
The leukoencephalopathy that follows the combined use of intrathecal methotrexate and radiation therapy is described later. Some patients do not survive long enough for the problem to be manifest. The best response to treatment occurs in patients with lymphoma and breast and small cell lung cancers; cases of meningeal infiltration by other lung cancers, and adenocarcinoma do less well.
Involvement of the Nervous System in Leukemia
Almost one-third of all leukemic patients, especially with childhood leukemia, have evidence of diffuse infiltration of the leptomeninges and cranial and spinal nerve roots at autopsy (Barcos et al). The incidence is greater in acute than in chronic leukemia and greater in lymphocytic than in myelocytic leukemia; it is also as mentioned far more frequent in children than in adults. The highest incidence is in children with acute lymphocytic (lymphoblastic) leukemia who relapse after treatment with combination chemotherapy (60 to 70 percent at the time of death). In those cases, the disease in the meninges may be fulminant. The clinical and CSF picture of meningeal leukemia has many similarities to that of meningeal carcinomatosis discussed earlier, with the qualification that leukemic cells are more likely to be found by cytologic examination of the spinal fluid. The treatment of the two disorders is also similar.
Studies have demonstrated that CNS leukemia is primarily a pial disease (Price and Johnson). The earliest evidence of leukemia is detected in the walls of pial veins, with or without cells lying freely in the CSF. The leukemic infiltrate in our pathologic material has extended to the deep perivascular spaces, where the pial-glial membrane often confines it; at this stage the CSF consistently contains leukemic cells. Depending on the severity of meningeal involvement, transgression of the pial-glial membrane eventually occurs, with varying degrees of superficial parenchymal infiltration by collections of leukemic cells. Hemorrhages of varying sizes are another common complication and are sometimes lethal. Chloroma, a solid green-colored mass of myelogenous leukemic cells, may infiltrate the dura or, less often, the brain, but it is distinctly uncommon.
Leukoencephalopathy following combined intrathecal methotrexate and cranial irradiation (see further on, under Radiation Toxicity)
Cranial radiation, combined with methotrexate given intrathecally or intravenously, has been effective in the prevention and treatment of meningeal involvement in childhood leukemia. However, in a significant number of patients this combination gives rise to a distinctive acute necrotizing leukoencephalopathy within several days to weeks after the last administration of methotrexate (Robain et al). This condition has been distinguished from the more conventional form of cerebral radiation necrosis discussed later. The leukoencephalopathy occurs most frequently and is most severe when all three modalities of treatment, that is, cranial irradiation and intrathecal and intravenous methotrexate, are used in children. The age differentiation may explain the infrequency of this condition in adults. The initial symptoms—consisting of apathy, drowsiness, depression of consciousness, and behavioral disorders—evolve over a few weeks to include cerebellar ataxia, spasticity, pseudobulbar palsy, extrapyramidal motor abnormalities, and akinetic mutism.
In the acute and fulminant form of the disorder, large hypodense areas of varying size appear on CT and there can be contrast enhancement and edema that may simulate a tumor. This is distinct from the common occurrence of regional radiation change surrounding a tumor or sometimes distant from it. On MRI these lesions appear T2 hyperintense and can have poorly demarcated borders. In a few patients this aggressive form of the condition stabilizes or improves, with corresponding resolution of enhancement and edema. (The concept of “pseudoprogression” of a brain tumor has been introduced to denote radiation change that simulates tumor growth). More often, the patient is left with severe persistent sequelae or rarely the edema may progress and lead to death.
In addition to radiation injury, important factors in the development of the fulminant syndrome are the age of the patient (many are younger than 5 years old). In an attempt to address the long-term cognitive sequela of cranial radiation in children with leukemia, a study found that it could be safely omitted if all other aspects of therapy have been optimized (Pui and coworkers).
Involvement of the Nervous System in Systemic Lymphoma
Extradural compression of the spinal cord or cauda equina is the most common neurologic complication of all types of lymphoma, the result of extension from vertebrae or paravertebral lymph nodes. Treatment is with radiation to the affected portion of the neuraxis or, if the compression is very acute and causing serious myelopathy, surgical decompression. Systemic lymphoma rarely metastasizes to the brain. In a review of more than 100 autopsies at the Mallory Institute of Pathology, our colleague R.D. Adams observed only a half-dozen instances where patients with lymphomas had deposits of tumor cells in the brain and in none of these cases were they from multiple myeloma (Sparling et al). In another series, comprising 592 patients with non-Hodgkin lymphoma, there were only 8 with intracerebral metastases (Levitt and associates).
The appearance of non-Hodgkin lymphoma in the meninges and adjacent roots or peripheral nerves (a form of the earlier mentioned neurolymphomatosis) is distinct from primary CNS lymphoma, in which there are parenchymal lesions and no systemic disease. The clinical and CSF pictures are similar to those of meningeal leukemia and carcinomatosis described earlier. In the rare cases of meningeal involvement with Hodgkin lymphoma, there may be an eosinophilic pleocytosis. Leptomeningeal dissemination occurs almost exclusively in high-grade lymphomas with diffuse (rather than nodular) changes in the lymph nodes. Cranial nerve palsies are common, with a predilection for the eighth nerve; the cauda equina is involved eventually in most cases. The optimal treatment has not yet been ascertained. Radiotherapy and systemic and intraventricular chemotherapy have all met with some degree of success in small series.
Intravascular Lymphoma and Related Disorders (Lymphomatoid Granulomatosis, Castleman Disease)
These conditions are presented here with other forms of lymphoma, although their clinical behavior is as much in keeping with a vasculitic or prelymphomatous process. Although considered rare, we encounter several new cases yearly in our service. The nomenclature is confusing and the original terms, lymphomatoid granulomatosis and Castleman disease, are not equivalent to the more recently elucidated process of intravascular lymphoma; it is more accurate to consider the first two as prelymphomatous processes. Lymphomatoid granulomatosis is a systemic disease with prominent nodular pulmonary lesions, dermal, and lymph node changes and, in approximately 30 percent of cases, involvement of the CNS (Liebow and colleagues). In a small proportion, the changes are confined to the nervous system. A systemic malignant lymphoma develops in approximately 12 percent of such patients (Katzenstein and associates). Castleman disease is precipitated by constituent HHV-8 virus infection in about half of cases and lymphomatoid granulomatosis has a similar viral origin, but mainly from EBV.
The intravascular lymphoma, on the other hand, is regarded as a multifocal neoplasm of large anaplastic monoclonal lymphocytes that infiltrate the walls of blood vessels and surrounding areas (Sheibani et al). The tumor cells grow intravascularly and cause occlusion of small and moderate-sized vessels and may cause small cerebral or spinal infarctions, as well as of other organs. The disease can be distinguished from primary CNS lymphoma, which is also typically “angiocentric,” meaning centered around vessels, but does not selectively invade and occlude vascular structures. In half of the cases, meningeal vessels are involved and in a few, the peripheral nerves, or more particularly the endoneurial vessels within spinal roots, have been involved by the neoplasm and we have seen two cases with a flaccid paraplegia on this basis.
The lymphoid origin of the intravascular anaplastic cells is clear, and the predominant species is of monoclonal B cells with a T-cell reactive component. As in some cases of primary CNS lymphoma, portions of the genome of EBV have occasionally been isolated from the malignant B cells. It has been proposed that the disorder in those cases represents an EBV-induced proliferation of B cells with a prominent inflammatory T-cell reaction (Guinee et al).
Because of the inconsistent location and size of the nervous system lesions there is no uniform clinical syndrome, but intravascular lymphoma should be suspected in patients with a subacute encephalopathy and indications of focal brain and spinal cord or nerve root lesions. Headache is a prominent early component in some cases. One of our patients had intermittent seizures 3 months before confusion and progressive encephalopathy. The variety of clinical presentations is emphasized in reviews (Beristain and Azzarelli; Glass and associates ). Some of our patients, as mentioned above, have also had a flaccid paraplegia as a result of infiltration of the cauda roots; this peripheral involvement has been commented on by other authors. Only a few patients will have nodular or multiple infiltrative pulmonary lesions, skin lesions, or adenopathy; almost all of our cases were restricted to the brain and spinal cord, but other reports suggest systemic disease in a high proportion, including infiltration of the adrenal glands.
MRI shows multiple nodular or variegated abnormalities on T2-weighted images throughout the white matter of the brain; most lesions are enhanced by gadolinium, and some demonstrate restricted diffusion resulting from microvascular occlusion and infarction. In one of the cases we studied there were numerous hemorrhagic lesions. Definitive diagnosis is possible through a biopsy of involved lung, skin, kidney, or nervous tissue that contains an adequate number of intrinsic blood vessels. A feature may be the presence of antibodies to nuclear cytoplasmic antigens (c-ANCA), in some cases, as they are in a number of other vasculitic and granulomatous processes. We are uncertain of the frequency of this finding. A small number of our patients have also had adrenal or renal enlargement, as mentioned earlier, presumably because of infiltration of the vessels of these organs by the neoplasm. The spinal fluid has a variable lymphocytic pleocytosis and protein elevation, but malignant cells are not found. The sedimentation rate and serum LDH are reported to be elevated in most patients, but this has not been consistently so in our experience.
Similar to demyelinating and lymphomatous lesions, these abnormalities in the brain may recede temporarily on imaging in response to treatment with glucocorticoids and there is corresponding clinical improvement. Furthermore, some lesions may follow the temporal course expected of small strokes. The course tends to be fluctuating over months, although one of our patients died within weeks despite treatment. In a few cases, whole-brain irradiation has been successful in prolonging survival, but the outlook in most instances is poor.
An uncertain number of these patients are infected with HIV, although we have not encountered this combination. The illness must be distinguished from multiple sclerosis, primary CNS lymphoma, gliomatosis cerebri, and a process that simulates it closely, sarcoidosis (which produces brain and lung lesions) as well as from the cerebral vasculitides and Behçet disease, but intravascular lymphoma is more rapidly progressive than most of these conditions.
Sarcomas of the Cranium and Brain
These tumors are composed of cells derived from connective tissue elements (fibroblasts, rhabdomyocytes, lipocytes, osteoblasts, smooth muscle cells). They take their names from their histogenetic derivation—namely, fibrosarcoma, rhabdomyosarcoma, osteogenic sarcoma, and chondrosarcoma—and sometimes from the tissue of which the cells are a part, such as adventitial sarcomas and hemangiopericytoma. In the newer WHO nomenclature these are denominate4d as CIC-rearranged sarcoma, primary intracranial sarcoma, DICER1-mutant and intracranial mesenchymal tumor, FET-CREB fusion positive and chondrosarcomas. However, they are all listed as of “Uncertain differentiation,” again emphasizing that these are not true disease categories and instead delineate markers of disease.
All these tumors are rare. They constitute from 1 to 3 percent of intracranial tumors, depending on how wide a range of neoplasms one chooses to include (see in the following text). Occasionally, cerebral deposits of these types of tumors will occur as a metastasis from a sarcoma in another organ. Almost all others are primary in the cranial cavity and exhibit as one of their unique properties a tendency to metastasize to nonneural tissues—a decidedly rare occurrence with primary glial tumors. It is a disturbing fact that a few sarcomas have developed 5 to 10 years after cranial irradiation or, in one instance among 3,000 patients related to us by R.D. Adams, after proton beam irradiation of the brain. Fibrosarcomas have occurred after radiation of pituitary adenomas and osteogenic sarcoma, after other types of radiation, all localized to bone or meninges. Our experience with hemangiopericytoma has included to three intracranial lesions that simulated meningiomas and two others that arose in the high cervical spinal cord and caused subacute quadriparesis, initially misdiagnosed as an acute polyneuropathy.
Patients Who Present Primarily With Signs of Increased Intracranial Pressure (Medulloblastoma, Ependymoma of the Fourth Ventricle, Hemangioblastoma of the Cerebellum, Pinealoma, Colloid Cyst of the Third Ventricle and Rare Related Tumors)
Upon first presentation, a number of patients with brain tumors show the characteristic symptoms and signs of increased ICP, namely periodic bifrontal and bioccipital headaches that awaken the patient during the night or are present upon awakening, projectile vomiting, mental torpor, unsteady gait, sphincteric incontinence, and papilledema. In the tumors listed above, most of the symptoms and the associated increase in ICP are the result of hydrocephalus rather than being attributable to the tumor mass.
The diagnostic problem is resolved by CT or MRI, which is obtained in patients with symptoms of increased ICP, with or without focal signs. In addition to the tumors listed above, others that may present in this way are craniopharyngioma, and a high spinal cord, cervicomedullary junction tumor. With some of the gliomas discussed in the preceding section, increased ICP may occasionally precede the first focal cerebral signs.
Medulloblastoma, Neuroblastoma, and Retinoblastoma
Medulloblastoma is an invasive and rapidly growing tumor, mainly of childhood, that arises in the posterior part of the cerebellar vermis and neuroepithelial roof of the fourth ventricle in children (Table 30-3). It accounts for 20 percent of childhood brain tumors. Rarely, it presents elsewhere in the cerebellum or other parts of the brain in adults (Peterson and Walker).
The origin of this tumor remained in doubt for a long time and is still not entirely settled, but some recent insights are notable. Bailey and Cushing introduced the name medulloblastoma, although medulloblasts have never been identified in the fetal or adult human brain; nevertheless the term has been retained for no reason other than its familiarity. The current view of the tumor is that it originates from pluripotential stem cells that can differentiate into neuronal or glial elements and have been prevented from maturing to their normal growth-arrested state. The classification of these tumors has undergone considerable change in WHO5 and they have been divided into two broad categories, one having four molecularly defined types (WNT-activated; SSH-activated and TP53-wildtype; SSH-activated and TP53-mutant; and non-WNT/non-SSH; SSH stands for sonic hedgehog and WNT for wingless/integrated). The remainder are considered histologically defined. In addition, cytogenic abnormalities, mainly in chromosome 17q, confer important differences in prognosis and radiosensitivity (summarized by Cohen). The tumor may differentiate uni- or pluripotentially, varying from case to case, and accounting for the recognized histologic variants, ranging from an undifferentiated medulloblastoma and extending to medulloblastoma with glial, neuronal, or even myoblastic components differences that have been largely overtaken by the molecular classification. Rosette formation, highly characteristic of the below-described neuroblastoma, is seen in half of medulloblastomas. Medulloblastomas are encountered in Gorlin syndrome, caused by mutations in the gene encoding “patched,” the receptor for sonic hedgehog ligand, and in Turcot syndrome, as a consequence of mutations in DNA repair genes (Louis et al). Among the non-WNT non-SSH tumors, amplification of MYCN and of CDK6 are associated with intermediate or poorer prognosis.
Most affected patients are children 4 to 8 years of age, and overall, males outnumber females 3:2 or 3:1 in most series, depending in part on molecular configuration. For example, SSH-activated tumors have equal sex distribution and most others are most often in males. As a rule, symptoms have been present for 1 to 5 months before the diagnosis is made. The clinical picture is fairly distinctive and derives from secondary hydrocephalus and raised ICP as a result of blockage of the fourth ventricle. Typically, the child becomes listless, vomits repeatedly, and has a morning headache. The first diagnosis that suggests itself may be gastrointestinal disease or abdominal migraine. Soon, however, a stumbling gait, frequent falls, and diplopia, as well as strabismus lead to a neurologic examination and the discovery of papilledema or sixth nerve palsies. However, when the tumor is located in the lateral cerebellum or in the cerebrum, as it usually is in adults, signs of raised ICP may be delayed. Dizziness (positional) and nystagmus are then frequent. A small proportion of children have a slight sensory loss on one side of the face and a mild facial weakness. Head tilt, the occiput being tilted back and away from the side of the tumor, indicates a developing cerebellar-foraminal herniation. Rarely, signs of spinal root and subarachnoid metastases precede cerebellar signs.
Extraneural metastases (cervical lymph nodes, lung, liver, and particularly bone) may occur, but usually only after craniotomy, which may allow tumor cells to reach scalp lymphatics. In rare instances the tumor cells may be spontaneously blood-borne and become metastatic to lung or liver. Decerebrate attacks (“cerebellar fits”) appear in the late stages of the disease.
The imaging appearance of this tumor is distinctive: high signal intensity on both T1-enhanced and T2-weighted MRIs, heterogeneous enhancement, and, of course, the typical location adjacent to and extending into the fourth ventricle. The tumor frequently fills the fourth ventricle and infiltrates its floor (Fig. 30–11). Seeding of the tumor may occur on the ependymal and meningeal surfaces of the cisterna magna and around the spinal cord. The tumor is solid, gray-pink in color, and fairly well demarcated from the adjacent brain tissue. It is very cellular, and the cells are small and closely packed with hyperchromatic nuclei, little cytoplasm, many mitoses, and a tendency to form clusters and pseudorosettes. The interstitial tissue is sparse.
Medulloblastoma. MRI in the sagittal (above) and axial (below) planes, illustrating the involvement of the cerebellar vermis and neoplastic obliteration of the fourth ventricle.
Maximal safe resection of the tumor is currently recommended. The addition of chemotherapy and radiotherapy of the entire neuraxis improves the rate and length of disease-free survival even for those children with the most extensive tumors at the time of diagnosis (Packer). The combination of surgery, radiation of the entire neuraxis, and chemotherapy permits a 5-year survival in more than 80 percent of cases. Molecularly targeted therapies are being explored (Rudin et al). Concerns about radiation-induced cognitive deficits in the young children most often affected by this tumor have led to exploration of postoperative chemotherapy without radiation as an alternative (Rutkowski and colleagues). Any of the features of brainstem invasion, spinal subarachnoid metastases, and very early age of onset (younger than 3 years) greatly reduce the period of survival.
This, the most common solid tumor of childhood, is a different entity from medulloblastoma but of nearly identical histologic appearance, arising in the adrenal medulla and sometimes metastasizing widely. Usually, it remains extradural even if it invades the cranial and spinal cavities. The main neurologic interest is a syndrome of polymyoclonus with opsoclonus and ataxia that occurs as a paraneoplastic complication, as discussed further on. A rare form of neuroblastic medulloblastoma in adults tends to be more benign (Rubinstein, 1985).
In keeping with the genetic determinants of prognosis in this broad class of tumors, a loss of heterozygosity of certain sites on chromosomes 1 and 11 has been associated with somewhat poorer outcomes (Attiyyich et al). MYCN amplification or overexpression is a poor prognostic factor, as it is in medulloblastoma. The WHO-5 classification is neuroblastoma FOXR2-activated.
Treatment is predicated on clinical staging, with the lowest risk category allowing observation because some lesions regress spontaneously. Those patients who are at intermediate risk are treated with chemotherapy and high-risk tumors have surgical resection and receive intensive chemotherapy, radiation, and in selected cases, hematopoietic stem cell transplantation. The two better-risk strata have survival rates exceeding 90 percent, but the highest-risk group has a 30 percent survival rate.
Another closely related tumor is retinoblastoma. This proves to be one of the most frequent extracranial malignant tumors of infancy and childhood. Eighty percent develop before the fifth year of life. It is a small cell tumor with neurofibrils and, like neuroblastoma, has a tendency to form rosettes. The tumor develops within the eye and the blindness that it induces may be overlooked in an infant or small child. It is easily seen ophthalmoscopically, because it arises from cells of the developing retina. An abnormal protein encoded by a growth-suppressor or antioncogenic gene (Rb), mentioned earlier in relation to the genetics of brain tumors, has been identified. It is postulated that an inherited mutation affects one allele of the normal gene, and only if this is accompanied by a mutation that eliminates the function of the second allele will the tumor develop. Early recognition and radiation or surgery effect cure.
Ependymoma of the Fourth Ventricle
Ependymomas arise from the lining cells in the walls of the ventricles (Table 30-2). Approximately 70 percent originate in the fourth ventricle (Fokes and Earle) (Fig. 30–12). Postmortem, some of these tumors, if small, are found protruding into the fourth ventricle, never having produced symptoms. Whereas the supratentorial ependymoma occurs at all ages, fourth ventricular ependymomas appear mostly in childhood. In a large series (83 cases), 33 developed in the first decade of life, 6 in the second decade, and 44 after the age of 20 years. Males have been affected almost twice as often as females (Fokes and Earle). There is also an important spinal ependymoma, some associated with a syrinx cavity, discussed in Chap. 42 on Diseases of the Spinal Cord. The important genetic delineations are ZFTA fusion positive, YAP1 fusion-positive, and two groups that appear in the posterior fossa, A, which occurs mainly in infants with relative loss of the epigenetic marker H3K27, and B in older children with a better prognosis than A. There is also a category of “not otherwise specified” if a molecular diagnosis cannot be made. The pathologist can still assign a WHO grade, typically 2 or 3 for ependymoma but the association with prognosis based on grade is not as firm as previously considered.
Ependymoma of the fourth ventricle. A. Coronal T2 MRI shows an ependymoma growing out of the fourth ventricle. B. Axial T2 FLAIR MRI shows that the mass completely obliterates the fourth ventricle.
Cerebral ependymomas of the floor of the fourth ventricle typically extend through the foramina of Luschka and Magendie. They may later invade the medulla. These tumors produce a clinical syndrome much like that of the medulloblastoma except for their more protracted course and lack of early cerebellar signs. The histologic features of this tumor were described earlier in this chapter. The degree of anaplastic change varies and has prognostic significance.
Symptoms may be present for 1 or 2 years before diagnosis. About two-thirds of the patients come to notice because of increased ICP; in the remainder, vomiting, difficulty in swallowing, paresthesia of the extremities, abdominal pain, vertigo, and neck flexion or head tilt are prominent manifestations. Some patients with impending cerebellar–tonsillar herniation are disinclined to sit and have vertical downbeating nystagmus. Surgical removal offers the only hope of survival. The addition of conformal radiation therapy and sometimes ventriculoperitoneal shunting of CSF may prolong life.
Papillomas of the choroid plexus are about one-fifth as frequent as ependymomas. They arise mainly in the lateral and fourth ventricles, occasionally in the third. Two studies (Laurence et al; Matson and Crofton) have given the ratio of lateral/third/fourth ventricular locations as 50:10:40. The tumor, which takes the form of a giant choroid plexus, has as its cellular element the cuboidal epithelium of the plexus, which is closely related embryologically to the ependyma. Essentially, these are tumors of childhood. Fully 50 percent cause symptoms in the first year of life and 75 percent in the first decade. In the younger patient, hydrocephalus is usually the presenting syndrome, sometimes aggravated acutely by hemorrhage; there may be papilledema, an unusual finding in a hydrocephalic infant with enlarging head. Headaches, lethargy, stupor, spastic weakness of the legs, unsteadiness of gait, and diplopia are more frequent in the older child. Tumors that arise from the choroid plexus and project into the lateral recess of the fourth ventricle may present with a syndrome of the cerebellopontine angle (see in the following text). One consequence of the tumor (rather uncertain or inconsistent) may be increased CSF formation, which contributes to the hydrocephalus. Some of the tumors acquire more malignant attributes (mitoses, atypia of nuclei) and invade surrounding brain. They have the appearance of a carcinoma and may be mistaken for an epithelial metastasis from an extracranial site.
Treatment by surgical excision is usually curative, but palliative ventricular shunting may be needed first if the patient’s condition does not permit surgery. The prognosis of the rare choroid plexus carcinomas is poor.
Primitive Neuroectodermal Tumors
This term, considered outdated but retained here for pedagogic purposes, was introduced by Hart and Earle in 1973 to describe tumors that have the histologic features of medulloblastoma but occur supratentorially (Table 30-2). Various poorly differentiated or embryonal tumors of infancy and childhood were in the past included in this group: medulloblastoma, neuroblastoma, retinoblastoma, ependymoblastoma, and pineoblastoma (described further on). Subsequent authors broadened the category of PNETs to include all CNS neoplasms of neuroectodermal origin. With the advent of genetic and immunohistochemical techniques, many of these poorly differentiated neoplasms of infancy came to be recognized as small cell gliomas (Friede et al); others, after ultrastructural study, could be classified as other types of primitive neoplasms but the term primitive neuroepithelial or neuroectodermal tumor (PNET) has been dropped from the WHO classification and they are called “CNS embryonal” tumors (along with medulloblastoma but hardly a useful advance) and characterized by their genetic drivers. In practical terms, the prognosis and treatment of all these tumors are much the same, regardless of what they are called (Duffner and Cohen). Certain patterns of gene expression are used to distinguish this group of tumors from histologically similar medulloblastomas.
Hemangioblastoma of the Cerebellum
This tumor is referred to most often in connection with von Hippel-Lindau disease, of which it is the essential element. Dizziness, ataxia of gait or of the limbs on one side, symptoms and signs of increased ICP from compression of the fourth ventricle, and in some instances an associated retinal angioma or hepatic and pancreatic cysts (disclosed by CT or MRI) constitute the von Hippel-Lindau syndrome. There is a tendency for the later development of malignant renal or adrenal tumors. Many patients have polycythemia as a result of elaboration of an erythropoietic factor by the tumor.
The age of onset is usually between 15 and 50 years. Blacks, whites, and Asians are equally affected. The dominant nature of the inheritance of von Hippel-Lindau disease is well known. Seizinger and coworkers, in cases associated with renal cell carcinoma and pheochromocytoma, localized a defect in a tumor suppressor gene (termed VHL; see Chap. 37).
The diagnosis can be deduced from the appearance on CT or MRI of a cerebellar cyst containing an enhancing nodular lesion on its wall. Often, the associated retinal hemangioma will be disclosed by the same imaging procedure. The angiographic picture is also characteristic: a cluster of small vessels forming a mass 1.0 to 2.0 cm in diameter (Fig. 30–13). Craniotomy with opening of the cerebellar cyst and excision of the mural hemangioblastomatous nodule is usually curative, but there is a high rate of recurrence if the entire tumor, including the nodule, is not completely removed. Endovascular embolization of the vascular nodule prior to surgery has been used, but it is not clear if this reduces the incidence of recurrence. Treatment with focused radiation is also sometimes undertaken for multifocal or surgically inaccessible lesions, and several case series have been reported with stereotactic radiosurgery.
Hemangioblastoma. Contrast-enhanced MRI in the axial plane (left) shows the vascular tumor in the left cerebellar hemisphere. Selective left vertebral angiogram (right) defines a hypervascular nodule with dilated draining veins.
Hemangioblastomas of the spinal cord are frequently associated with a syringomyelic lesion (greater than 70 percent of cases); such lesions may be multiple and are located mainly in the posterior columns. A retinal hemangioblastoma may be the initial finding and leads to blindness if not treated. New retinal lesions continue to be formed over a period of years while the patient is under observation. The children of a parent with a hemangioblastoma of the cerebellum should be examined regularly for an ocular lesion and renal cell carcinoma and genetic testing is appropriate in some instances.
There has been uncertainty as to the proper classification of pineal tumors (Table 30-3). Of the main groups of pineal tumors, approximately 50 percent are germinomas. The pinealomas, pineoblastomas, and gliomas are less frequent. Children, adolescents, and young adults—males more than females—are affected. Only rarely does one see a patient with a pineal tumor that has developed after the 30th year of life. Originally, they were all thought to be composed of pineal cells; hence they were classified as true pinealomas, a term suggested by Krabbe. Globus and Silbert believed that these originated from embryonic pineal cells but Russell later pointed out that some tumors in the pineal region are really atypical teratomas resembling the seminoma of the testicle. The WHO classification has not provided a major advance by listing germinoma with the larger group of germinomas and separately, pineocytoma, tumors of intermediate differentiation, pineoblastoma, papillary tumors and the rare desmoplastic myxoid tumor, each associated in some cases with genetic variants.
The pineal germinoma has its origin in germinal cells and as noted is classified separately from tumors that arise in pineal cells (pineocytoma and pineoblastoma). It is a firm, discrete mass that usually reaches 3 to 4 cm in greatest diameter. It compresses the superior colliculi and sometimes the superior surface of the cerebellum and narrows the aqueduct of Sylvius. Often it extends anteriorly into the third ventricle and may then compress the hypothalamus. A germinoma may also arise in the suprasellar area. Microscopically, these tumors are composed of large, spherical epithelial cells separated by a network of reticular connective tissue and containing many lymphocytes.
The pineocytoma, intermediate pineocytoma, and pineoblastoma reproduce the normal structure of the pineal gland. These tumors enlarge the gland, are locally invasive, and may extend into the third ventricle and seed along the neuraxis. Cytologically, the pineocytoma is a moderately cellular tumor with none of the histologic attributes of anaplasia. The tumor cells tend to form circular arrangements, so-called pineocytomatous rosettes. Pinealocytes may be impregnated by silver carbonate methods, and some contain the retinal S antigen of photoreceptor cells. Pineoblastomas are highly cellular and composed of small, undifferentiated cells bearing some resemblance to medulloblasts.
There are also teratomas and dermoid and epidermoid cysts of the pineal body that have no special features—some are quite benign. Gliomas of the pineal have the usual morphologic characteristics of an astrocytoma of varying degrees of malignancy.
In some cases, the clinical syndrome of the several types of pineal tumors are similar and consists solely of symptoms and signs of increased ICP. Beyond this, the most characteristic localizing signs are an inability to look upward and slightly dilated pupils that react on accommodation but not to light (Parinaud syndrome, See Chap. 13). Far less often ataxia of the limbs, choreic movements, or spastic weakness appears in the later stages of the illness. It is sometimes uncertain whether the ocular and motor signs are caused by neoplastic compression of the brachia conjunctivae and other tegmental structures of the upper midbrain or to hydrocephalus (dilatation of the posterior part of the third ventricle). Probably both mechanisms are operative.
Precocious puberty occurs in males who harbor a germinoma. Although the pineal gland is the source of melatonin, sleep is not affected to any important degree in patients with these tumors, as discussed in “The Pineal Gland and Melatonin” in Chap. 26. Measurement of CSF or serum melatonin is useful mainly in the detection of tumor recurrence after surgical extirpation. In patients with a germ cell tumor, the CSF or serum may show elevations of beta-human choriogonadotropin or alpha-fetoprotein. The diagnosis is made by neuroimaging (Fig. 30–14). The CSF may contain tumor cells and lymphocytes but may also be entirely normal.
Pineal tumor. T2-weighted MRI in the sagittal plane (above) demonstrates a tumor that compresses the tectum and the cerebral aqueduct. Axial T2 FLAIR MRI (below) shows the tumor and evidence of hydrocephalus and transependymal flow of CSF from the lateral ventricles, resulting from aqueductal compression.
Pineal lesions were formerly judged to be inoperable. However, the use of the operating microscope now makes it possible to excise them by a supracerebellar or transtentorial approach. Operation for purposes of excision and histologic diagnosis is advised because each type of pineal tumor must be managed differently. Moreover, one may occasionally find an arachnoidal cyst that needs only excision. The germ cell tumors are generally removed insofar as possible and the ventricular region radiated for germinomas, and the whole neuraxis is treated in the case of nongerminomatous lesions. The use of chemotherapy in addition to or instead of cranial irradiation is being evaluated. Several of our patients have survived more than 5 years after the removal of a pineal glioma.
Glioneurla and Neuronal Tumors (Germinomas, Gangliocytomas, Mixed Neuronal-Glial Tumors, and Lhermitte-Duclos Disease
Malignant germ cell tumors occurring in locations other than the pineal body are usually found in the suprasellar space and rarely in the roof of the third ventricle (Table 30-2). Germinoma, mentioned above, is the most common of this rare group of neoplasms, which also includes choriocarcinoma, embryonal cell carcinoma, endodermal sinus tumors, and malignant teratomas. Certain biochemical markers of these tumors are of interest and of clinical utility, because they may be detected in samples of the blood and CSF. The beta subunit of human chorionic gonadotropin (hCG) is elaborated by choriocarcinoma and alpha-fetoprotein, and by endodermal sinus tumors and immature teratomas. Typical germinomas have shown little elevation of either. Most often these markers indicate the presence of complex mixed germ cell tumors.
Gangliogliomas and mixed neuronal–glial tumors are special tumor types, more frequent in the young and of variable but usually low-grade malignancy. They are composed both of differentiated glial cells, usually astrocytes, and of neurons in various degrees of differentiation. The latter, which may resemble glial cells, can be identified by Nissl stains, silver stains, and immunochemical reactions for cytoskeletal proteins. Inflammation is common in the parenchyma and adjacent to these tumors; this has led to the erroneous diagnosis of a nonneoplastic inflammatory condition if only limited biopsy samples are taken. They are classified with other glioneuronal and neuronal tumors but not otherwise characterized as to genetic markers.
Some of these developmental tumors are difficult to separate from hamartomas or from the tubers of tuberous sclerosis. In the case of hamartomas, it may be difficult to determine if the tumor or the associated developmental abnormality is the cause of seizures. Some of these tumors take the form of large, slowly growing cystic lesions.
The best characterized, albeit rare, type in this group is the gangliocytoma, a tumor that occurs in the adrenal gland, retroperitoneal and thoracic sympathetic chain, internal auditory canal, and in the spinal cord. One form is the dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease). This is a slowly evolving lesion that forms a mass in the cerebellum; it is composed of granule, Purkinje, and glia cells. Reproduced therein, in a disorganized fashion, is the architecture of the cerebellum with no clear plane from normally structured cerebellar tissue. The importance of distinguishing this disease from other cerebellar tumors is its lack of growth potential and favorable prognosis. It is, however, excised if symptomatic. The appearance on imaging is highly characteristic; a cerebellar hemisphere is occupied with an indistinct mass of “tiger stripe” appearance as a result of alternating layers of dysmorphic cerebellar cells (Fig. 30–15). Interest in this entity derives from its association with a germ line mutation in the PTEN gene that relates the disease to other gangliocytomas and to Cowden syndrome of multiple skin hamartomas and cancers of the gynecologic, breast, and thyroid glands (and which may include Lhermitte-Duclos as a component). Mice with PTEN knocked-out have abnormal synaptic structure and dysplasia of the cerebellar granule cells.
Lhermitte-Duclos disease. T2-weighted MRI showing the characteristic “tiger stripe” appearance of this hamartomatous tumor in the right cerebellar hemisphere.
Other forms of gangliogliomas include the desmoplastic infantile ganglioglioma, some of the xanthoastrocytomas, and the dysembryoplastic neuroepithelioma tumor (DNET), not all of which are included in newer classifications.
This last of these tumors, dysembryoplastic neuroepithelial tumor, formerly called DNET, is worthy of comment as it often causes seizures that may be difficult to control in children. We have encountered them mostly in young adults after a single seizure or as an incidental finding on MRI. Although the tumors may be located in any part of the brain, there is a proclivity for the superficial (juxtacortical or intracortical) lateral or medial temporal lobe. The imaging appearance is usually of a nodule or small cyst, or more specific to this entity, a cluster of several adjacent small cystic lesions, generally not enhancing and hyperintense on T2-weighted MRI (Fig. 30–16). The lesion is very slow growing and, if appropriately situated, may remodel the bone of the orbital roof or calvarium. The tumors originate from dysplastic cells in the germinal matrix that become arrested during migration toward the cortex; they are often associated with an adjacent region of cortical heterotopia. The histologic appearance varies but has as its main element a collection of neuroepithelial cells and clusters of oligodendrocytes with multinodular architecture that create mucinous cysts in some cases. When the lesion is single and has a nonspecific radiologic appearance, a biopsy or resection is required to differentiate it from a low-grade glioma or oligodendroglioma. Biopsy alone may be misleading in showing only the adjacent inflammation, at times prominent enough to appear almost granulomatous. Resection is curative and often eliminates the seizures but it is not clear what the best course of action is for asymptomatic lesions.
Contrast-enhanced MRI of a cystic and nodular dysembryoplastic neuroepithelial tumor (DNET) of the left temporal lobe in an adult who had a single seizure. The nodule had an inflammatory component and the seizures ceased with resection.
Another tumor that may be considered in this group is the subependymal giant cell astrocytoma that is found in up to 20 percent of patients with tuberous sclerosis. It is classified with gliomas in WHO-5 rather than with neuroepithelial tumors. These are very slowly growing tumors that arise mostly near the foramen of Munro. Repeated resection is sometimes required to treat the hydrocephalus caused by the location of the tumor at the point of egress of CSF from the lateral ventricle. Everolimus, an inhibitor of the mTOR complex, which is disrupted in this phakomatosis, reduces the size of the tumor and ameliorates seizures (Krueger and colleagues). The remaining tumors mentioned earlier are rare and affect children mostly; therefore, they are not discussed further. Useful descriptions, particularly of histopathology, predating the new classification, are found in the monographs of Russell, of Rubinstein (1972), of Levine (both articles from 1993), and of Schmidek, and in the article by Zentner and coworkers.
Colloid Cyst and Other Tumors of the Third Ventricle
The most important of these is the colloid tumor (cyst), which is derived from ependymal cells of a vestigial third ventricular structure known as the paraphysis. The cysts formed in this structure are always situated in the anterior portion of the third ventricle between the interventricular foramina and are attached to the roof of the ventricle (Fig. 30–17). They vary from 1 to 4 cm in diameter, are oval or round with a smooth external surface, and are filled with a gelatinous material containing a variety of mucopolysaccharides. The wall is composed of a layer of epithelial cells, some ciliated, surrounded by a capsule of fibrous connective tissue. Although congenital, the cysts practically never declare themselves clinically until adult life, when they block CSF outflow through the foramen of Monro and produce an obstructive hydrocephalus.
Colloid cyst of the third ventricle. MRI in the axial and sagittal planes. Hydrocephalus due to obstruction at the foramen of Monro can occur, but is not apparent here.
Although many are found incidentally with cranial imaging, suspicion of this lesion in fullest manifestation is occasioned by intermittent, severe bifrontal–bioccipital headaches, sometimes modified by posture (“ball valve” obstruction) or with crises of headache and obtundation, incontinence, unsteadiness of gait, bilateral paresthesias, dim vision, and weakness of the legs, with sudden falls but no loss of consciousness (“drop attacks”). Stooping may result in an increase or onset of headache and loss of balance. However, this intermittent obstructive syndrome has been infrequent in our experience. More often the patient has no headache and presents with the symptoms comparable to those of normal-pressure hydrocephalus or, as frequently, the tumor is found incidentally on CT or MRI as mentioned. On CT and MRI, the lesion density depends on the hydration state of the mucopolysaccharides. These lesions do not restrict diffusion or enhance with contrast. Subtle behavioral changes have been common and a few patients (Lobosky and colleagues) have mild confusion and changes in personality that may reach the extreme of psychotic behavior. We have no experience with this behavioral constellation (aside from mental dullness from hydrocephalus) and find it difficult to understand from the location of the lesion, with chronic headache or gait difficulty being more common.
The treatment has been surgical excision, which carries some risk, far less than in the past, but satisfactory results have also been obtained by ventriculoperitoneal shunting of the CSF, leaving the cyst untouched. Decompression of the cyst by aspiration under stereotactic control has also become a popular procedure.
Other tumors found in the third ventricle and giving rise mainly to obstructive symptoms are craniopharyngiomas (see in the discussion on skull base tumors), papillomas of the choroid plexus, and ependymomas (discussed earlier).
This CSF-filled lesion, which is probably congenital and not representing a neoplasm but presented here for purposes of presentation, occurs at all ages but may become evident only in adult life, when it gives rise to symptoms of increased ICP and sometimes to focal cerebral or cerebellar signs, simulating an intracranial neoplasm. Seizures may occur but are not characteristic. In infants and young children, macrocrania and extensive unilateral transillumination are characteristic features. Usually, these cysts overlie the sylvian fissure or temporal pole; occasionally they are interhemispheric under the frontal lobes or lie in the pineal region or under the cerebellum. They may attain a large size, to the point of enlarging the middle cranial fossa and remodeling and elevating the lesser wing of the sphenoid, but they do not communicate with the ventricles. Rarely, one of these cysts may cover the entire surface of both cerebral hemispheres and create a so-called external hydrocephalus.
The cysts are readily recognized (often accidentally) on unenhanced CT or MRI, showing a circumscribed tissue defect filled with fluid that has the density of CSF (Gandy and Heier). If these cysts are completely asymptomatic, they are usually left alone; if symptomatic, imaging studies are indicated so as not to overlook a chronic subdural hematoma, which is often an associated disorder and may not be visualized on the unenhanced CT. Suprasellar arachnoid cysts are discussed further on, under “Empty Sella Syndrome.”
The treatment of enlarging and symptomatic cysts is marsupialization or, less preferably, by shunting from the cyst to the subarachnoid space.
Skull Base and Other Regional Intracranial Tumor Syndromes (Vestibular Schwannoma, Other Tumors of the Cerebellopontine Angle, Craniopharyngioma, Pituitary, Meningioma of the Sphenoid Ridge and Olfactory Groove, Glioma of the Optic Nerve, Pontine Glioma, Chordoma Chondrosarcoma, Glomus Jugulare and Carotid Body Tumors, Nasopharyngeal Carcinoma)
In this group of tumors, symptoms and signs of general cerebral impairment and increased pressure occur late or not at all. Instead, special syndromes referable to specific intracranial loci arise and progress slowly. One arrives at the correct diagnosis by localizing the lesion from the neurologic findings and by reasoning that the etiology must be neoplastic because of an afebrile and steadily progressive nature. Investigation by CT, MRI, and other special studies will usually confirm the clinical impression and many of these lesions are discovered incidentally when imaging is done for various purposes.
The tumors that most often produce these unique intracranial syndromes are the ones listed above as well as a number of other erosive tumors at the base of the skull. The aforementioned medulloblastoma, hemangioblastoma, and ependymoma of the fourth ventricle may have a similar regional clinical signature.
Vestibular Schwannoma (Acoustic Neuroma)
This tumor was first described as a pathologic entity by Sandifort in 1777, diagnosed clinically by Oppenheim in 1890, and recognized as a surgically treatable disease in the early 1900s. Cushing’s monograph (1917) was a milestone, and the papers of House and Hitselberger and of Ojemann and colleagues provide valuable descriptions of from the era before modern imaging. Many mutations have been detected in sporadic vestibular schwannoma, most often as mosaicism in the NF2 gene with loss of function, but none explains most sporadic cases.
Approximately 3,000 new cases of acoustic neuroma are diagnosed each year in the United States (incidence rate of 1 per 100,000 per year). The tumor occurs occasionally as part of von Recklinghausen neurofibromatosis, in which case it takes one of two forms. In classic von Recklinghausen disease (peripheral, or NF1 neurofibromatosis), a schwannoma may sporadically involve the eighth nerve, usually in adult life, but it may involve any other cranial (particularly trigeminal) or spinal nerve root. Rarely, if ever, do bilateral acoustic neuromas occur in this form of the disease. However, bilateral acoustic neuromas are the hallmark of the genetically distinct neurofibromatosis type 2 (NF2), which practically always occur before the age of 21 and show a strong autosomal dominant pattern (Fig. 30–18). Schwannomas are distinguished from neurofibromas (composed of both Schwann cells and fibroblasts) found in peripheral nerves of type 1 von Recklinghausen disease. A small percentage of neurofibromas become malignant, a phenomenon that is highly unusual in schwannomas.
Bilateral vestibular schwannomas in neurofibromatosis type 2. T1-weighted MRI in the axial plane before (left) and after (right) contrast administration.
Another rare form of familial schwannomatosis should be mentioned, characterized by multiple schwannomas without vestibular tumors, which maps genetically to chromosome 22 but is distinct from NF2. The primary gene defect in this familial schwannomatosis has not been defined (MacCollin et al), although mutations in the SMARCB1 gene on chromosome 22 locus has been implicated.
The typical vestibular schwannoma in adults presents as a solitary tumor. Being a schwannoma, it originates in nerve. The examination of small tumors reveals that they practically always arise from the vestibular rather than the cochlear division of the eighth nerve, just within the internal auditory canal (Fig. 30–18). As the eighth nerve schwannoma grows, it extends into the posterior fossa to occupy the angle between the cerebellum and pons (cerebellopontine angle). In this lateral position, it is so situated as to compress the seventh, fifth, and less often the ninth and tenth cranial nerves, which are implicated in various combinations. Later it displaces and compresses the pons and lateral medulla and obstructs the CSF circulation; very rarely, it is a source of subarachnoid hemorrhage.
Certain biologic and clinical data assume clinical importance. The highest incidence is in the fifth and sixth decades of life, and the sexes are equally affected. Familial occurrence is a mark, usually, of von Recklinghausen disease. The earliest symptom reported by the 46 patients in a decades-old but instructive series (Ojemann and coworkers) was loss of hearing in 33 of 46 patients; headache (4 patients); disturbed sense of balance (3 patients); unsteadiness of gait (3 patients); and facial pain, tinnitus, and facial weakness, each in a single case. Some patients sought medical advice soon after the appearance of the initial symptom, others sought treatment later, after other symptoms had occurred. One-third of the patients were troubled by vertigo associated with nausea, vomiting, and pressure in the ear. The vertiginous symptoms differed from those of Ménière disease in that discrete attacks separated by periods of normalcy were rare. The vertigo coincided more or less with hearing loss and tinnitus (most often a unilateral high-pitched ringing, sometimes a machinery-like roaring or hissing sound, like that of a steam kettle). Some of our patients ignored their deafness for many months or years; often the first indication of the tumor in such patients is a shift to the unaccustomed ear (usually right to left) in the use of the telephone. Others neglected these symptoms to a point where they presented with impaired mentation, imbalance, and sphincteric incontinence because of brainstem compression and secondary hydrocephalus.
The neurologic findings at the time of examination are of auditory and vestibular loss, facial weakness including disturbance of taste, sensory loss over the face, gait abnormality, and less often unilateral limb ataxia. Inequality of reflexes and 11th- and 12th-nerve palsies are present in only a few patients. Signs of increased ICP appear late and have been present in fewer than 25 percent of our patients. With the shift in recent years to fairly routine investigation of unilateral hearing loss by cerebral imaging, it is common to find these tumors at an earlier stage than in the past, or as an incidental finding on cerebral imaging, well before the tumor becomes symptomatic.
The contrast-enhanced CT will detect practically all vestibular schwannomas that are larger than 2.0 cm in diameter and project further than 1.5 cm into the cerebellopontine angle. Smaller intracanalicular tumors (i.e., restricted to within the internal acoustic canal) can be detected reliably by MRI with gadolinium (Fig. 30–19). Specialized and thin-slice MRI sequences such as steady-state free precession can accurately define anatomic relationships between the tumor and adjacent cranial nerves and vessels with high resolution.
A. MRI of a small vestibular schwannoma emanating from the left porus acusticus, showing typical homogenous gadolinium enhancement. B. A larger atypical vestibular schwannoma with rim enhancement, causing compression of the left middle cerebellar peduncle.
Audiologic and vestibular evaluation includes the various tests described in Chap. 14, the brainstem auditory evoked response probably being the most sensitive to the presence of acoustic schwannoma. In combination, they permit localization of the deafness and vestibular disturbance to the cochlear and vestibular nerves rather than to their end organs. The CSF protein is raised in two-thirds of the patients (greater than 100 mg/dL in one-third) although CSF examination is not usually performed; however, a clinically inevident acoustic schwannoma is one of the causes of an unexpectedly elevated CSF protein when a lumbar puncture is performed for other reasons.
The preferred treatments are surgical removal or focused radiation in most symptomatic cases. For smaller tumors, many of which are discovered incidentally with imaging, some clinicians wait to intervene and follow the patient clinically, with imaging and with audiograms to determine progression. Neurosurgeons who have had considerable experience with removing these tumors favor a microsurgical suboccipital transmeatal approach (Martuza and Ojemann). The facial nerve can usually be preserved by intraoperative monitoring of brainstem auditory responses and facial nerve electromyography (EMG); in experienced hands, hearing can be preserved in approximately one-third of patients with tumors smaller than 2.5 cm in diameter. If no attempt is to be made to save hearing, small tumors can be removed by a translabyrinthine approach.
An alternative to surgery is focused (sterotactic) radiosurgery, which controls the growth of many of the smaller tumors. In a series of patients treated with radiosurgery, facial motor and sensory functions were preserved in 75 percent of cases and, after 28 months of observation, no new neurologic deficits were detected (Kondziolka et al). This approach is favored in older patients with few symptoms but is being adopted increasingly for others. The rates of hearing loss and facial numbness and weakness are similar or lower than with surgery, especially if follow-up is restricted to only a few years (Flickinger et al). Focused radiation with Gamma Knife or proton beam appears to be preferable to surgery in cases of recurrent tumor. The antiangiogenic agent bevacizumab, in preliminary reports, has reduced the size of these tumors in patients with NF2 (Plotkin et al).
There is no consensus on the management of an incidentally identified tumor as mentioned above but it is reasonable to follow these with audiograms and serial imaging. Some authoritative sources suggest that half of lesions smaller than 2 cm in diameter will not progress or do so slowly enough that hearing and balance are not impaired. However, lesions larger than this size are associated with more surgical complications and make sparing of hearing less likely.
Other Tumors of the Cerebellopontine Angle
Neurinoma or schwannoma of the trigeminal (gasserian) ganglion or neighboring cranial nerves and meningioma of the cerebellopontine angle may, in some instances, be indistinguishable from a vestibular schwannoma. Fifth cranial nerve tumors should always be considered if deafness, tinnitus, and lack of response to caloric stimulation (“dead labyrinth”) are not the initial symptoms of a cerebellopontine angle syndrome. A true cholesteatoma (epidermoid cyst) is a relatively rare tumor that is most often located in the cerebellopontine angle, where it may simulate an acoustic neuroma but usually causes more severe facial weakness. Spillage of the contents of the cyst may produce intense chemical meningitis. Other disorders that enter into the differential diagnosis are glomus jugulare tumor (see later), metastatic cancer, neoplastic meningitis (especially lymphomatous), syphilitic meningitis, arachnoid cyst, and epidural plasmacytoma of the petrous bone. All these disorders may produce a cerebellopontine angle syndrome consisting of imbalance and unilateral hearing loss, but they are more likely to cause multiple lower cranial neuropathies and their temporal course differs from that of vestibular schwannoma. Occasionally, a tumor that originates in the pons or in the fourth ventricle (ependymoma, astrocytoma, papilloma, medulloblastoma) or a nasopharyngeal carcinoma may present as a cerebellopontine angle syndrome.
This is a histologically benign epithelioid tumor, generally assumed to originate from cell rests (remnants of the Rathke pouch [or adenohypophyseal diverticulum]) at the junction of the infundibular stem and pituitary gland (Suprasellar Epidermoid Cyst, Rathke Pouch or Hypophyseal Duct Tumor, Adamantinoma, Table 30-3). By the time the tumor has attained a diameter of 3 to 4 cm, it is almost always cystic and partly calcified. Usually, it lies above the sella turcica, compressing and elevating the optic chiasm and extending up into the third ventricle. Less often it is subdiaphragmatic, that is, within the sella, where it compresses the pituitary body and erodes one part of the wall of the sella or a clinoid process; seldom it balloons the sella like a pituitary adenoma. Large tumors may obstruct the flow of CSF.
The tumor is oval, round, or lobulated and has a smooth surface. The wall of the cyst and the solid parts of the tumor consist of cords and whorls of epithelial cells (often with intercellular bridges and keratohyalin) separated by a loose network of stellate cells. If there are bridges between tumor cells, which have an epithelial origin, the tumor had in the past been classed as an adamantinoma. The WHO classification points out two types: an adamantinomatous form that may contain elements of other epidermal tissues and often has variants in CTMMB1, and a papillary form associated in 95 percent with BRAF V600E variants.
The cyst contains dark albuminous fluid, cholesterol crystals, and calcium deposits; the calcium can be seen in plain films or CT of the suprasellar region in 70 to 80 percent of cases. The sella beneath the tumor tends to be flattened and enlarged. The majority of the patients are children, but the tumor is not infrequent in adults, and we have encountered patients up to 60 years of age.
The presenting syndrome may be one of increased ICP, but more often it takes the form of a combined pituitary-hypothalamic-chiasmal derangement. The symptoms are often subtle and long standing. In children, visual loss and diabetes insipidus are the most frequent findings, followed in a few cases by adiposity, delayed physical and mental development, headaches, and vomiting. The visual disorder takes the form of dim vision, chiasmal field defects, optic atrophy, or papilledema, as emphasized long ago by Kennedy and Smith. In adults, waning libido, amenorrhea, slight spastic weakness of one or both legs, headache without papilledema, failing vision, and mental dullness and confusion are the usual manifestations. One of the most remarkable cases in our experience was a middle-aged nurse who became distractible and ineffective at work and was thought for many months to be simply depressed. Often, drowsiness, ocular palsies, diabetes insipidus, and disturbance of temperature regulation (indicating hypothalamic involvement) occur later. Spontaneous rupture of the cystic lesion can incite severe aseptic meningitis, at times with depressed glucose in the CSF, a syndrome similar to that caused by rupture of the earlier described cholesteatoma.
In the differential diagnosis of the several craniopharyngioma syndromes, a careful clinical analysis is often more informative than laboratory procedures. Among the latter, MRI is likely to give the most useful information. Because of the cholesterol content, the tumor gives an increased signal on T1-weighted images. The cyst itself is usually isointense, like CSF, but occasionally it may give a decreased T2 signal.
Modern microsurgical techniques, reinforced by corticosteroid therapy before and after surgery and careful control of temperature and water balance postoperatively, permit successful excision of all or part of the tumor in most cases. Although smaller tumors can be removed by a transsphenoidal approach, attempts at total removal require craniotomy and remain a challenge because of frequent adherence of the mass to surrounding structures (Fahlbusch et al), as well as the potential for postoperative chemical meningitis from cyst contents. Partial removal practically ensures recurrence of the tumor, usually within 3 years, and the surgical risks of reoperation are considerable (10 percent mortality in older large series; less now). Stereotactic aspiration is sometimes a useful palliative procedure, as are focused radiation therapy and ventricular shunting in patients with solid, nonresectable tumors. Endocrine replacement is necessary for an indefinite time. We have several times seen a syndrome of prolonged but reversible delirium after tumor resection. Agents that inhibit BRAF (and MEK) are finding some success in reducing the size of papillary tumors that do not require immediate surgery or radiation.
This tumor is rare but of interest to neurologists. It is one of the paragangliomas, so classified because of their location in the paraganglia of the sympathetic nervous system, thereby relating it to the carotid body tumor discussed next. It is a purplish-red, highly vascular tumor composed of large epithelioid cells arranged in an alveolar pattern and possessing an abundant capillary network. The tumor is thought to be derived from minute clusters of nonchromaffin paraganglioma cells (glomus bodies) found mainly in the adventitia of the dome of the jugular bulb (glomus jugulare) immediately below the floor of the middle ear, as well as in multiple other sites in and around the temporal bone. These clusters of cells are part of the chemoreceptor system that also includes the carotid, vagal, ciliary, and aortic bodies. Individuals living at high altitudes have a higher incidence than those at sea level owing to stimulation of the chemoreceptors from hypoxia. About one-quarter are familial, with several genes having been identified.
The fully developed syndrome consists of partial deafness, facial palsy, dysphagia, and unilateral atrophy of the tongue combined with a vascular polyp in the external auditory meatus and a palpable mass below and anterior to the mastoid eminence, occasionally with a bruit that may be audible to the patient (“self-audible bruit”). Other neurologic manifestations are phrenic nerve palsy, numbness of the face, Horner syndrome, cerebellar ataxia, and temporal lobe epilepsy. As with vestibular schwannoma, the availability of MRI has led to the earlier discovery of these tumors.
The jugular foramen is eroded and CSF protein may be elevated. Women are affected more than men, and the peak incidence is during middle adult life. The tumor grows slowly over a period of many years, sometimes 10 to 20 or more. Treatment in the past has consisted of radical mastoidectomy and removal of as much tumor as possible, followed by radiation. The combined intracranial and extracranial two-stage operation has resulted in the cure of many cases (Gardner et al). Embolization prior to resection is now also employed.
This is a generally benign but potentially malignant tumor originating in a small aggregate of paraganglioma cells of neuroectodermal type. The normal carotid body is small (4 mm in greatest diameter and 10 mg in weight) and is located at the bifurcation of the common carotid artery. The cells are of uniform size, have an abundant cytoplasm, are rich in substance P, and are sensitive to changes in PO2, PCO2, and pH (i.e., they are chemoreceptors, not to be confused with baroreceptors). The tumors that arise from these cells are identical in appearance to tumors of other chemoreceptor organs such as the glomus jugulare neoplasm described in the preceding section (paragangliomas). Interestingly, they are many times more frequent in individuals living at high altitudes.
The usual presentation is of a painless mass at the side of the neck below the angle of the jaw; thus it must be differentiated from the branchial cleft cyst, mixed tumor of the salivary gland, and carcinomas and aneurysms in this region. As the tumor grows (at an estimated rate of 2.0 cm in diameter every 5 years) it may implicate the sympathetic, glossopharyngeal, vagus, spinal accessory, and hypoglossal nerves (syndrome of the retroparotid space; see Chap. 44). Hearing loss, tinnitus, and vertigo are present in some cases. Tumors of the carotid body have been a source of transient ischemic attacks in 5 to 15 percent of the 600 or more reported cases. One of the most interesting presentations has been with sleep apnea, particularly with bilateral tumors; respiratory depression as well as lability of blood pressure are common postoperative problems. Malignant transformation occurs in 5 percent of cases.
A similar paraganglioma of the vagus nerve has been reported; it occurs typically in the jugular or nodose ganglion but may arise anywhere along the course of the nerve. These tumors may also undergo malignant transformation in about 5 percent of cases, metastasize, or invade the base of the skull.
Carotid body tumor has been seen in combination with von Recklinghausen neurofibromatosis type 1 (NF1) and in von Hippel-Lindau disease. Familial cases are known, especially with bilateral carotid body tumors (about 5 percent of these tumors are bilateral). The treatment is surgical excision with or without prior intravascular embolization; radiation therapy has not been advised.
Tumors arising in the anterior pituitary are of considerable interest to neurologists because they often cause visual and other symptoms related to involvement of structures bordering upon the sella turcica, before an endocrine disorder becomes apparent (See Also “Pituitary Insufficiency” in Chap. 26). Pituitary tumors are age-linked; they become increasingly numerous with each decade. By the eightieth year, small adenomas are found in more than 20 percent of pituitary glands. In some cases, an apparent stimulus to adenoma formation is endocrine end-organ failure, as occurs, for example, with ovarian atrophy that induces a basophilic adenoma. Only a small proportion (6 to 8 percent) enlarge the sella; that is, most are “microadenomas,” as discussed below.
On the basis of conventional hematoxylin-eosin-staining methods, cells of the normal pituitary gland were for many years classified as chromophobe, acidophil, and basophil, these types being present in a ratio of 5:4:1. Adenomas of the pituitary are most often composed of chromophobe cells (4 to 20 times as common as acidophil cell adenomas); the incidence of basophil cell adenomas is uncertain. Histologic study is now based on immunoperoxidase-staining techniques that define the nature of the hormones within the pituitary cells—both of the normal gland and of pituitary adenomas. These methods have shown that either a chromophobe or an acidophil cell may produce prolactin, growth hormone (GH), and thyroid-stimulating hormone (TSH), whereas the basophil cells produce adrenocorticotropic hormone (ACTH), β-lipotropin, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). The WHO classification continues to divide the tumors by their cellular-endocrine makeup but has a new term, pituitary neuroendocrine tumor, and notes the rare pituitary blastoma, made up of primitive cells and found in infancy.
The development of sensitive methods for the measurement of pituitary hormones in the serum made possible the detection of adenomas at an early stage of their development and the designation of several types of pituitary adenomas on the basis of the endocrine disturbance. Tests for the detection of pituitary adenomas, preferably carried out in an endocrine clinic, are listed in Table 30-4. Between 60 and 70 percent of tumors in both men and women are prolactin secreting. About 10 to 15 percent secrete GH, and a smaller number secrete ACTH. Tumors that secrete gonadotropins and TSH are quite rare. These tumors may be monohormonal or plurihormonal and approximately one-third are composed of nonfunctional (null) cells.
Table 30-4HORMONAL TESTS FOR DETECTION OF PITUITARY ADENOMAS ||Download (.pdf) Table 30-4 HORMONAL TESTS FOR DETECTION OF PITUITARY ADENOMAS
|HORMONE ||TEST |
|Prolactin ||Serum prolactin level, chlorpromazine- or TRH-provocative tests, L-dopa suppression |
|Somatotropin (GH) ||Serum GH level, glucagon, L-dopa, glucose-GH suppression, somatometin C (IGF-1) |
|Adrenocorticotropin ||Serum cortisol, urinary steroids, metyrapone test, dexamethasone suppression |
|Gonadotropin ||Serum FSH, LH, estradiol, testosterone, GnRH stimulation |
|Thyrotropin ||TSH, T4, TRH |
|Vasopressin ||Urine and serum osmolality after water restriction for deficiency of hormone; without water restriction for excess of hormone |
Pituitary tumors usually arise as discrete nodules in the anterior part of the gland (adenohypophysis). They are reddish gray, soft (almost gelatinous), and often partly cystic, with a rim of calcium in some instances. The adenomatous cells are arranged diffusely or in various patterns, with little stroma and few blood vessels; less frequently the architecture is sinusoidal or papillary in type. Variability of nuclear structure, hyperchromatism, cellular pleomorphism, and mitotic figures are interpreted as signs of malignancy, which is rare. Tumors less than 1 cm in diameter are referred to as microadenomas and are at first confined to the sella. As the tumor grows, it first compresses the pituitary gland; then, as it extends upward and out of the sella, it compresses the optic chiasm; later, with continued growth, it may extend into the cavernous sinus, third ventricle, temporal lobes, or posterior fossa. Recognition of an adenoma when it is still confined to the sella is of considerable practical importance, since total removal of the tumor by transsphenoidal excision or some form of stereotactic radiosurgery is possible at this stage with prevention of further damage to normal glandular structure and the optic chiasm. Penetration of the diaphragm sellae by the tumor and invasion of the surrounding structures make treatment more difficult.
Pituitary adenomas come to medical attention because of endocrine or visual abnormalities. Headaches are reported by nearly half of patients with macroadenomas but are not clearly part of the syndrome. The visual disorder usually proves to be a complete or partial bitemporal hemianopia, which has developed gradually and may not be evident to the patient (see the description of the chiasmatic syndromes in “Neurologic Causes of Reduced Vision” in Chap. 12). Early on, the upper parts of the visual fields may be affected predominantly, as the fibers subserving those regions run along the inferior optic nerve and chiasm. A small number of patients will be almost blind in one eye and have a temporal hemianopia in the other. Bitemporal central hemianopic scotomata are a less-frequent finding. A postfixed (situated relatively posteriorly) chiasm may be compressed in such a way that there is an interruption of some of the nasal retinal fibers, which, as they decussate, project into the base of the opposite optic nerve (Wilbrand knee); the controversy regarding the validity of this projection in humans is mentioned in Chap. 12. This results in a central scotoma on one or both sides (junctional syndrome) in addition to the classic temporal field defect (see Fig. 12–2).
If the visual disorder is longstanding, the optic nerve heads are atrophic. In 5 to 10 percent of cases, the pituitary adenoma extends into the cavernous sinus, causing some combination of ocular motor palsies as well as potential compression of the cavernous segment of the internal carotid artery. Other neurologic abnormalities, rare to be sure, are seizures from indentation of the medial temporal lobe, CSF rhinorrhea from erosion of the sella, and diabetes insipidus, hypothermia, and somnolence from hypothalamic compression.
With regard to differential diagnosis, bitemporal hemianopia with a normal-size sella indicates that the causative lesion is probably a saccular aneurysm of the circle of Willis or a meningioma of the tuberculum sellae; multiple sclerosis may simulate this pattern and eventration of a hydrocephalic third ventricle is an uncertain cause (see Chap. 12). The idiopathic syndrome of an “empty sella” also can cause bitemporal hemianopia and is discussed further on.
The major endocrine syndromes associated with pituitary adenomas are described briefly in the following pages. Their functional classification can be found in the monograph edited by Kovacs and Asa. Worthy of emphasis is the catastrophic syndrome of pituitary apoplexy discussed further on.
As a rule, this syndrome becomes manifest during the childbearing years. The history usually discloses that menarche had occurred at the appropriate age; primary amenorrhea is rare. A common history is that the patient took birth control pills, only to find, when she stopped, that the menstrual cycle did not reestablish itself. On examination, there may be no abnormalities other than galactorrhea. Serum prolactin concentrations are increased (usually in excess of 100 ng/mL). In general, the longer the duration of amenorrhea and the higher the serum prolactin level, the larger the tumor (prolactinoma). The elevated prolactin levels distinguish this disorder from idiopathic galactorrhea, in which the serum prolactin concentration is normal.
Males with prolactin-secreting tumors rarely have galactorrhea and usually present with a larger tumor and complaints such as headache, impotence, and visual abnormalities. In normal persons, the serum prolactin rises markedly in response to the administration of chlorpromazine or thyrotropin-releasing hormone (TRH); patients with a prolactin-secreting tumor fail to show such a response. With large tumors that compress normal pituitary tissue, thyroid and adrenal function will also be impaired. It should be emphasized that large, nonfunctioning pituitary adenomas also cause modest hyperprolactinemia by distorting the pituitary stalk and reducing dopamine delivery to prolactin-producing cells.
This disorder consists of acral growth and prognathism in combination with visceromegaly, headache, and several endocrine disorders (hypermetabolism, diabetes mellitus). The highly characteristic facial and bodily appearance, well known to all physicians, is caused by an overproduction of GH after puberty; prior to puberty, an oversecretion of GH leads to gigantism. In a small number of acromegalic patients, there is an excess secretion of both GH and prolactin, derived apparently from two distinct populations of tumor cells. The diagnosis of this disorder, which is often long delayed, is made on the basis of the characteristic clinical changes, the finding of elevated serum GH values (0.10 ng/mL), and the failure of the serum GH concentration to decline in response to the administration of glucose or TRH. The new GH-receptor antagonist pegvisomant was introduced to reduce many of the manifestations of acromegaly (see the review by Melmed).
Described in 1932 by Cushing, this condition is only about one-fourth as frequent as acromegaly. A distinction is made between Cushing disease and Cushing syndrome, as indicated in Chap. 26. The former term is reserved for cases that are caused by the excessive secretion of pituitary ACTH, which, in turn, causes adrenal hyperplasia; the usual basis is a pituitary adenoma. Cushing syndrome refers to the effects of cortisol excess from any one of several sources—excessive administration of steroids (the most common cause), adenoma of the adrenal cortex, ACTH-producing bronchial carcinoma, and, very rarely, other carcinomas that produce ACTH. The clinical effects are the same in all of these disorders and include truncal obesity, hypertension, proximal muscle weakness, amenorrhea, hirsutism, abdominal striae, hyperglycemia, osteoporosis, and in some cases a characteristic mental disorder (see “Cushing Disease and Corticosteroid Psychoses” in Chap. 49).
Although Cushing originally referred to the disease as pituitary basophilism and attributed it to a basophil adenoma, the pathologic change may consist only of hyperplasia of basophilic cells or of a nonbasophilic microadenoma. Seldom is the sella turcica enlarged: Consequently, visual symptoms or signs as a result of involvement of the optic chiasm or nerves and extension to the cavernous sinus are rare. The diagnosis of Cushing disease is made by demonstrating increased concentration of plasma and urinary cortisol; these levels are not suppressed by the administration of relatively small doses of dexamethasone (0.5 mg qid), but they are suppressed by high doses (8 mg daily). A low level of ACTH and a high level of cortisol in the blood, increased free cortisol in the urine, and nonsuppression of adrenal function after administration of high doses of dexamethasone are evidence of an adrenal source of the Cushing syndrome—usually a tumor and less often a micronodular hyperplasia of the adrenal gland.
Diagnosis of pituitary adenoma
This is virtually certain when a chiasmal syndrome is combined with an endocrine syndrome of either hypopituitary or hyperpituitary type. Laboratory data that are confirmatory of an endocrine disorder, as described above, and sometimes a ballooned sella turcica on plain films of the skull are occasionally found. Patients who are suspected of having a pituitary adenoma should be examined by MRI with gadolinium; this procedure will visualize pituitary adenomas as small as 3 mm in diameter and show the relationship of the tumor to the optic chiasm (Fig. 30–20). This also provides the means of following the tumor’s response to therapy. It should be kept in mind that pituitary tissue normally enhances on CT and MRI, revealing small tumors as relatively hypoenhancing nodules.
Pituitary macroadenoma. Coronal T1 MRI before (left) and after (right) contrast administration. A homogenously enhancing mass originating in the sella protrudes into the suprasellar cistern and displaces the optic chiasm and inferior hypothalamus. The lesion also extends into the adjacent cavernous sinuses.
Tumors and lesions other than pituitary adenomas may sometimes expand the sella, as previously mentioned. Enlargement may be the result of an intrasellar craniopharyngioma, meningioma, carotid aneurysm, or cyst of the pituitary gland. Intrasellar epithelium-lined cysts are rare lesions. They originate from the apex of the Rathke pouch, which may persist as a cleft between the anterior and posterior lobes of the hypophysis. Rarer still are intrasellar cysts that have no epithelial lining and contain thick, dark brown fluid, the product of intermittent hemorrhages. Both types of intrasellar cysts may compress the pituitary gland and mimic the endocrine-suppressive effects of pituitary adenomas. Neoplasms originating in the nasopharynx or sinuses may invade the sella and pituitary gland, and sarcoid lesions at the base of the brain may do the same. Also, the pituitary gland and the infundibulum (and the chiasm) may be the site of metastases, most of them from the lung and breast (Morita et al); they give rise to diabetes insipidus, pituitary insufficiency, or orbital pain, and rarely may be the first indication of a systemic tumor.
More common than the aforementioned conditions is a nontumorous enlargement of the sella (“empty sella”). This results from a defect in the dural diaphragm, which may occur without obvious cause or with states of raised ICP, such as pseudotumor cerebri (see Chap. 29) or hydrocephalus, or may follow surgical excision of a pituitary adenoma or meningioma of the tuberculum sellae or pituitary apoplexy. The arachnoid covering the diaphragm sellae will bulge downward through the dural defect, and the sella then enlarges gradually, presumably because of the pressure and pulsations of the CSF acting on its walls. In the process, the pituitary gland becomes flattened, sometimes to an extreme degree; however, the functions of the gland are usually unimpaired. Flattening of the pituitary gland precedes bony expansion of the sella in many cases. Erosion or deshiscence of the sellar floor does not occur and the appearance of these changes implicates another type of lesion. Downward herniation of the optic chiasm occurs occasionally and may cause visual disturbances simulating those of a pituitary adenoma (Kaufman et al). As mentioned earlier, a bitemporal hemianopia with a normal-sized sella is usually caused by a primary suprasellar lesion (saccular aneurysm of the distal carotid artery, meningioma, or craniopharyngioma).
This varies with the type and size of the pituitary tumor, the status of the endocrine and visual systems, and the age and childbearing plans of the patient. The administration of the dopamine agonist cabergoline or bromocriptine (which inhibits prolactin; the former is more often used) may be the only therapy needed for small or even large prolactinomas and is a useful adjunct in the treatment of the amenorrhea–galactorrhea syndrome. The dose should be slowly increased by 2.5 mg or less every several days until a therapeutic response is obtained. Under the influence of bromocriptine, the tumor decreases in size within days, the prolactin level falls, and the visual field defect improves.
Some cases of acromegaly also respond to the administration of dopamine agonists but even better to octreotide or related compounds, all analogues of somatostatin. The initial dose of octreotide is 200 mg/d, increased in divided doses to 1,600 mg by increments of 200 mg weekly. Treatment with bromocriptine and octreotide must be continuous to prevent relapse. Newer slow-release somatostatin analogues and long-acting dopamine agonists such as cabergoline have been developed for use in patients who do not respond to the conventional agents (Colao and Lombardi).
If the tumor does not shrink with medical therapy or the patient is intolerant of medication, the treatment is surgical, using a transsphenoidal microsurgical approach, with an attempt at total removal of the tumor and preservation of normal pituitary function. Approximately 15 percent of GH-secreting tumors and prolactinomas will recur at 1 year. For this reason, incomplete removal or recurrence of the tumor (or tumors that are unresponsive to hormonal therapy) is usually followed by radiation therapy.
Alternative primary treatment for intrasellar tumors is forms of stereotactic radiosurgery, provided that vision is not being threatened and there is no other urgent need for surgery. These forms of radiation can be focused precisely on the tumor and will destroy it. In past decades proton beam radiation was used and in the more than 1,100 pituitary adenomas there were no fatalities and few complications (Kliman et al). An endocrine deficit will follow in most instances and must be corrected by hormone replacement therapy. Several more sophisticated methods of delivering radiation (Gamma Knife, Cyberknife) have become widely used. The advantage of these radiotherapeutic methods is that tumor recurrence is rare. A disadvantage is that the radiation effect is obtained only after several months. External beam-radiation therapy may also be employed after unsuccessful transsphenoidal surgery for Cushing disease (Estrada and colleagues). There are a few reports, however, of a decline in memory ability after radiation treatment of all types.
Large extrasellar extensions of a pituitary growth must be removed by craniotomy, usually with a transfrontal approach, followed by radiation therapy. Visual field defects often remain, but some improvement in vision can be anticipated.
This syndrome, described originally by Brougham and colleagues, occurs as a result of infarction of an adenoma that has outgrown its blood supply. It is characterized by the acute onset of severe headache that may be retro-orbital, frontal, bitemporal, or generalized ophthalmoplegia; bilateral visual loss; and in severe cases, drowsiness or coma, with either subarachnoid hemorrhage or pleocytosis and elevated protein in the CSF. The CT or MRI shows infarction of tumor, often with hemorrhage in and above an enlarged sella. Pituitary apoplexy may threaten life unless the acute addisonian state is treated by hydrocortisone. Blindness is the other dreaded complication. If there is no improvement after 24 to 48 h, or if vision is markedly affected, transsphenoidal decompression of the sella is indicated. Factors that may precipitate the necrosis or hemorrhage of a pituitary tumor are anticoagulation, pituitary function testing, radiation, bromocriptine treatment, and head trauma; most cases, however, occur spontaneously. Some pituitary adenomas have been cured by this accident.
Ischemic necrosis of the pituitary, without the presence of a tumor, followed by hypopituitarism, occurs under a variety of circumstances, the most common being in the partum or postpartum period (Sheehan syndrome).
Meningioma of the Sphenoid Ridge
This tumor, mentioned earlier in the chapter, is situated over the lesser wing of the sphenoid bone. As it grows, it may expand medially to involve structures in the wall of the cavernous sinus, anteriorly into the orbit, or laterally into the temporal bone. Fully 75 percent of such tumors occur in women, and the average age at onset is 50 years. Most prominent among the symptoms are a slowly developing unilateral exophthalmos, slight bulging of the bone in the temporal region, and radiologic evidence of thickening or erosion of the lesser wing of the sphenoid bone. Variants of the clinical syndrome include anosmia; oculomotor palsies; painful ophthalmoplegia (sphenoidal fissure and Tolosa-Hunt syndromes; see Table 44-2); blindness and optic atrophy in one eye, sometimes with papilledema of the other eye (Foster Kennedy syndrome); mental changes; seizures (“uncinate fits”); and increased ICP. Rarely, a skull bruit can be heard over a highly vascular tumor. Sarcomas arising from skull bones, metastatic carcinoma, orbitoethmoidal osteoma, benign giant cell bone cyst, tumors of the optic nerve, and angiomas of the orbit must be considered in the differential diagnosis. Neuroimaging with contrast provides the definitive diagnosis. The tumor is resectable without further injury to the optic nerve if the bone has not been invaded.
Meningioma of the Olfactory Groove
This tumor originates in arachnoidal cells along the cribriform plate. The diagnosis depends on the finding of ipsilateral or bilateral anosmia or ipsilateral or bilateral blindness—often with optic atrophy and mental changes. The tumors may reach enormous size before coming to the attention of the physician but as many are small and found incidentally with cerebral imaging (see Fig. 30–6B). If the anosmia is unilateral, it is rarely if ever reported by the patient. The unilateral visual disturbance may consist of a slowly developing central scotoma. Abulia, confusion, forgetfulness, and inappropriate jocularity (witzelsucht) are the usual psychic disturbances from compression of the inferior frontal lobes (see Chap. 21). The patient may be indifferent to or joke about his blindness. Usually there are radiographic changes along the cribriform plate. MRI with gadolinium is diagnostic. Except for the largest and most invasive tumors, surgical removal is possible.
Meningioma of the Tuberculum Sella
Cushing was the first to delineate the syndrome caused by this tumor. All of his 23 patients were female. The presenting symptoms were visual failure—a slowly advancing bitemporal hemianopia with a sella of normal size. Often the field defects are asymmetrical, indicating a combined chiasmal–optic nerve involvement. Usually there are no hypothalamic or pituitary deficits. If the tumor is not too large, complete excision is possible. If removal is incomplete or the tumor recurs or undergoes malignant changes, radiation therapy of one type or another is indicated. The outlook is then guarded; several of our patients succumbed within a few years.
Infiltrating astrocytomas of the brainstem have been discussed earlier in the chapter and no longer conventionally classified under this term but instead are attached to one or more genetic variants (Table 30-2). They are relatively slow-growing tumors that infiltrate tracts and nuclei. They produce a variable clinical picture depending on their location in the medulla, pons, or midbrain. Most often, this tumor begins in childhood (peak age of onset is 7 years), and 80 percent appear before the 21st year. Symptoms have usually been present for 3 to 5 months before coming to medical notice. In most patients the initial manifestation is a palsy of one or more cranial nerves, usually the sixth and seventh on one side, followed by long tract signs—hemiparesis, unilateral ataxia, ataxia of gait, paraparesis, and hemisensory and gaze disorders in addition to pseudobulbar dysarthria and palsy. In the remaining patients the symptoms occur in the reverse order—that is, long tract signs precede the cranial nerve abnormalities. Patients in the latter group survive longer than those whose illness begins with cranial nerve palsies. Headache, vomiting, and papilledema may occur, usually late in the illness. The course is slowly progressive over several years unless some part of the tumor becomes more malignant or, as rarely happens, spreads to the meninges (meningeal gliomatosis), in which instance the illness may terminate fatally within months.
The main problem in diagnosis is to differentiate this disease from a pontine form of multiple sclerosis, a vascular malformation of the pons (usually a cavernous hemangioma), or brainstem encephalitis, and to distinguish the focal from the diffuse type of glioma (see in the following text). The most helpful procedure in diagnosis and prognosis is contrast-enhanced MRI (Fig. 30–21).
Pontine glioma. Contrast-enhanced T1 MRI demonstrates a mass with prominent irregular peripheral gadolinium enhancement. The patient was a 3-year-old male with progressive cranial nerve and long tract deficits.
A study in the past had emphasized the importance of distinguishing between diffusely infiltrating and focal nodular tumors (Barkovich and coworkers) but this may be superceded by genetic analysis. In the more common diffuse type, there is mass effect with hypointense signal on T1-weighted MRI and heterogeneously increased T2 signal, which reflects edema and tumor infiltration. These diffusely infiltrating tumors, usually showing an asymmetrical enlargement of the pons, have a poorer prognosis than the focal or nodular tumors, which tend to occur in the dorsal brainstem and often protrude in an exophytic manner. Surgical exploration and biopsy may be necessary to establish the diagnosis. However, the general practice has been to avoid surgery unless the tumor exhibits unusual clinical behavior or does not conform to the typical MRI appearance of the diffuse type.
The treatment of the diffuse infiltrative type has generally been radiation, and if increased ICP develops as a result of hydrocephalus, ventricular shunting of CSF becomes necessary. Adjuvant chemotherapy has not been helpful. There have been preliminary series using oncolytic viruses that may prolong survival (Pérez-Larraya and colleagues) but further work is needed and, as with glioma in the cerebral hemispheres, it has not been clear if the inflammatory response to the virus or a direct oncolytic effect is the main factor. Gangliocytomas or mixed astrogangliocytomas are rare imitators of nodular glioma in the brainstem. The rarer cystic glioma of the brainstem (see Fig. 30–21), a pilocytic tumor like its counterpart in the cerebellum, is treated by resection of the mural nodule and, as mentioned earlier, has a better prognosis than the tumor in the brainstem.
Glioma of the Optic Nerves and Chiasm
This tumor, like the brainstem glioma, occurs most frequently during childhood and adolescence. In 85 percent of cases, it appears before the age of 15 years (average 3.5 years), and it is twice as frequent in girls as in boys (Cogan). The initial symptoms are dimness of vision with constricted fields, followed by bilateral field defects of homonymous, heteronymous, and sometimes bitemporal type and progressing to blindness and optic atrophy with or without papilledema. Ocular proptosis from the orbital mass is the other main feature. Hypothalamic signs (adiposity, polyuria, somnolence, and genital atrophy) occur occasionally as a result of proximal tumor extension. CT, MRI, and ultrasonography will usually reveal the tumor, and radiographs will show an enlargement of the optic foramen (greater than 7.0 mm). This finding and the lack of ballooning of the sella or of suprasellar calcification will exclude pituitary adenoma, craniopharyngioma, Hand-Schüller-Christian disease, and sarcoidosis. In adolescents and young adults, the medial sphenoid, olfactory groove, and intraorbital meningiomas (optic nerve sheath meningioma) are other tumors that cause monocular blindness and proptosis. If the entire tumor is prechiasmatic (the less-common configuration), surgical extirpation can be curative. For tumors that have infiltrated the chiasm or are causing regional symptoms and hydrocephalus, partial excision followed by radiation is all that can be offered. Both gliomas and nontumorous gliotic (hamartomatous) lesions of the optic nerves may occur in von Recklinghausen disease; the latter are sometimes impossible to distinguish from optic nerve gliomas and should be followed closely.
This is a soft, jelly-like, gray-pink growth that arises from remnants of the primitive notochord. It is located most often within the clivus (from dorsum sellae to foramen magnum) and in the sacrococcygeal region. It affects males more than females, usually in early or middle adult years, and is one of the rare causes of syndromes involving multiple cranial nerves or the cauda equina. Approximately 40 percent of chordomas occur at each of these two ends of the neuraxis; the rest are found at any point in the vertebral bodies in between. The tumor is made up of cords or masses of large cells with granules of glycogen in their cytoplasm and often with multiple nuclei and intracellular mucoid material. Chordomas are locally invasive, especially of surrounding bone, but they do not metastasize.
The cranial neurologic syndrome caused by this tumor is remarkable in that all or any combination of cranial nerves from the 2nd to 12th on one or both sides may be involved. Associated signs have been were facial pain, conductive deafness, and cerebellar ataxia, the result of pontomedullary and cerebellar compression (Kendall and Lee). A characteristic feature is neck pain radiating to the vertex of the skull on neck flexion. The tumors at the base of the skull may destroy the clivus and bulge into the nasopharynx, causing nasal obstruction and discharge and sometimes dysphagia. Extension to the cervical epidural space may result in cord compression. Thus, chordoma is one of the lesions that may present both as an intracranial and extracranial mass, the others being meningioma, neurofibroma, glomus jugulare tumor, and carcinoma of the sinuses or pharynx. CT of the skull base is useful for defining the bony margins of the tumor, and MRI can identify involved and adjacent neural and vascular structures. Midline (Wegener-granulomatous polyangiitis) other granulomas, histiocytosis, Erdheim-Chester disease, and sarcoidosis also figure in the differential diagnosis. Chondrosarcoma of the clivus produces a similar syndrome.
Treatment of the chordoma is surgical excision and radiation (focused radiation). This form of treatment has effected a 5-year survival without recurrence in approximately 80 percent of patients.
Nasopharyngeal Tumors at the Base of the Skull (Nasopharyngeal Transitional Cell Carcinoma, Schmincke Tumor)
These are seen from time to time in a general hospital; they arise from the mucous membrane of the paranasal sinuses or the nasopharynx near the eustachian tube, that is, the fossa of Rosenmüller. In addition to symptoms of nasopharyngeal or sinus disease, which may not be prominent, facial pain and numbness, abducens, and other cranial nerve palsies may occur. Diagnosis depends on inspection and biopsy of a nasopharyngeal mass or an involved cervical lymph node and radiologic evidence of erosion of the base of the skull. Bone scans and CT are helpful in diagnosis. The treatment is surgical resection and radiation but chemotherapy is increasingly being included. Carcinoma of the ethmoid or sphenoid sinuses and postradiation neuropathy, coming on years after the treatment of a nasopharyngeal tumor, may produce similar clinical pictures and are difficult to differentiate. The syndromes resulting from nasopharyngeal tumors are discussed in Chap. 44, under “Diseases of the Cranial Nerves.”
Other Tumors of the Base of the Skull
In addition to meningioma, nasopharyngeal tumors, and the other tumors enumerated earlier, there are a large variety of tumors, rare to be sure, that derive from tissues at the base of the skull and paranasal sinuses, ears, and other structures and give rise to distinctive syndromes. Included in this category are osteomas, chondromas, ossifying fibromas, giant cell tumors of bone, lipomas, epidermoids, teratomas, mixed tumors of the parotid gland, and hemangiomas and cylindromas (adenoid cystic carcinomas of salivary gland origin) of the sinuses and orbit; sarcoid granulomas may produce the same effect. Most of these tumors are benign, but some have a potential for malignant change. To the group must be added the esthesioneuroblastoma (of the nasal cavity) with anterior fossa extension and, perhaps most common of all of these, the systemic malignant tumors that metastasize to basal skull bones (prostate, lung, and breast being the most common sources), or involve them as part of a multicentric neoplastic process, for example, primary lymphoma, multiple myeloma, plasmacytoma, and lymphocytic leukemia.
Suprasellar arachnoid cysts also occur in this region. CSF flows upward from the interpeduncular cistern but is trapped above the sella by thickened arachnoid (membrane of Liliequist). As the CSF accumulates, it forms a cyst that invaginates the third ventricle; the dome of the cyst may intermittently block the foramina of Monro and cause hydrocephalus (Fox and Al-Mefty). Children with this condition exhibit a curious to-and-fro bobbing and nodding of the head, like a doll with a weighted head resting on a coiled spring. This has been referred to as the “bobble-head doll syndrome” (Benton and colleagues); it can be cured by emptying the cyst. Seesaw and other pendular and jerk types of nystagmus may also result from these suprasellar lesions.
Tables 30-5 and 44-1, adapted from Bingas’ large neurosurgical service in Berlin, summarize the facts about the focal syndromes of the skull base.
Table 30-5CLINICAL SYNDROMES CAUSED BY TUMORS AT THE BASE OF THE SKULL ||Download (.pdf) Table 30-5 CLINICAL SYNDROMES CAUSED BY TUMORS AT THE BASE OF THE SKULL
|SITE OF LESION ||EPONYM ||CLINICAL SYMPTOMS ||ETIOLOGYa |
|Anterior part of the base of the skull || ||Olfactory disturbances (uni- or bilateral anosmia), possibly psychiatric disturbances, seizures. ||Tumors that invade the anterior part of the base of the skull from the frontal sinus, nasal cavity, or the ethmoid bone, osteomas. Meningiomas of the olfactory groove. |
|Superior orbital fissure ||Rochon-Duvigneau; syndrome of the pterygopalatine fossa (Behr) and the base of the orbit (DeJean) commencing with a lesion of the maxillary and pterygoid rami and evolving into the superior orbital fissure syndrome. ||Lesions of the third, fourth, sixth, and first divisions of the fifth nerves with ophthalmoplegia, pain, and sensory disturbances in the area of V1; often exophthalmos, some vegetative disturbances. ||Tumors: meningiomas, osteomas, dermoid cysts, giant-cell tumors, tumors of the orbit, nasopharyngeal tumors; more rarely, optic nerve gliomas; eosinophilic granulomas, angiomas, local or neighboring infections, trauma. |
|Apex of the orbit ||Jacod-Rollet (often combined with the syndrome of the superior orbital fissure); infraclinoid syndrome of Dandy. ||Visual disturbances, central scotoma, papilledema, optic nerve atrophy; occasional exophthalmos, chemosis. ||Optic nerve glioma, infraclinoid aneurysm of the internal carotid artery, trauma, orbital tumors, Paget disease. |
|Cavernous sinus ||Foix-Jefferson; syndrome of the sphenopetrosal fissure (Bonnet and Bonnet) corresponding in part to the cavernous sinus syndrome of Raeder. ||Ophthalmoplegia caused by lesions of the third, fourth, sixth, and often fifth nerves; exophthalmos; vegetative disturbances. Jefferson distinguished three syndromes: (1) the anterior-superior, corresponding to the superior orbital fissure syndrome; (2) the middle, causing ophthalmoplegia and lesions of V1 and V2; (3) the caudal, in addition affecting the whole trigeminal nerve. ||Tumors of the sellar and parasellar area, infraclinoid aneurysms of the internal carotid artery, nasopharyngeal tumors, fistulas of the sinus cavernosus and the carotid artery (traumatic), tumors of the middle cranial fossa, e.g., chondromas, meningiomas, and neurinomas. |
|Apex of the petrous temporal bone ||Gradenigo-Lannois ||Lesions of the fifth and sixth nerves with neuralgia, sensory, and motor disturbances, diplopia. ||Inflammatory processes (otitis), tumors such as cholesteatomas, chondromas, meningiomas, neurinomas of the gasserian ganglion and trigeminal root, primary and secondary sarcomas at the base of the skull. |
|Sphenoid and petrosal bones (petrosphenoidal syndrome) ||Jacod ||Ophthalmoplegia caused by loss of function of the third, fourth, and sixth nerves; amaurosis; trigeminal neuralgia possibly with sensory signs. ||Tumors of the sphenoid and petrosal bones and middle cranial fossa, nasopharyngeal tumors, metastases. |
|Jugular foramen ||Vernet ||Lesions of ninth, tenth, and eleventh nerves with disturbance of deglutition; curtain phenomenon; sensory disturbances of the tongue, soft palate, pharynx, and larynx; hoarseness; weakness of the sternocleidomastoid and trapezius. ||Tumors of the glomus jugulare; neurinomas of eighth, ninth, tenth, and eleventh nerves; chondromas, cholesteatomas, meningiomas, nasopharyngeal and ear tumors; infections, angiomas, rarely trauma. |
|Anterior occipital condyles ||Collet-Sicard (Vernet-Sargnon) ||Loss of twelfth nerve function (loss of normal tongue mobility) in addition to the symptoms of the jugular foramen. ||Tumors of the base of the skull, ear, parotid; leukemic infiltrates; aneurysms, angiomas, and inflammations. |
|Retroparotid space (retropharyngeal syndrome) ||Villaret ||Lesions of the lower group of nerves (Collet-Sicard) and Bernard-Horner syndrome with ptosis and miosis. ||Tumors of the retroparotid space (carcinomas, sarcomas), trauma, inflammations. |
|Half of the base of the skull ||Garcin (Guillain- Alajouanine-Garcin); also described by Hartmann in 1904. ||Loss of function of all twelve cranial nerves of one side; in many cases, isolated cranial nerves spared; rarely signs of raised intracranial pressure or pyramidal tract symptoms. ||Nasopharyngeal tumors, primary tumors at the base of the skull, leukemic infiltrates of basal meninges, trauma, metastases. |
|Cerebellopontine angle || ||Loss of function of eighth nerve (hearing loss, vertigo, nystagmus); cerebellar disturbances; lesions of the fifth, seventh, and possibly ninth and tenth cranial nerves. Signs of raised intracranial pressure, brainstem symptoms. ||Acoustic neuromas (raised protein in CSF), meningiomas, cholesteatomas, metastases, cerebellar tumors, neurinomas of the caudal group of nerves and the trigeminal nerve, vascular processes such as angiomas, basilar aneurysms. |
Imaging techniques now serve to clarify many of the diagnostic problems posed by these tumors. MRI is particularly helpful in delineating structures at the base of the brain and in the upper cervical region. CT is also capable of determining the absorptive values of the tumor itself and the sites of bone erosion. When the lesion is analyzed in this way, an etiologic diagnosis often becomes possible. For example, the absorptive value of lipomatous tissue is different from that of brain tissue, glioma, blood, and calcium. Bone scans (technetium and gallium) display active destructive lesions with remarkable fidelity, but in some cases, even when the tumor is seen with various studies, it may be difficult to obtain a satisfactory biopsy.
Tumors of the Foramen Magnum
Tumors in the region of the foramen magnum are of particular importance because of the need to differentiate them from diseases such as multiple sclerosis, Chiari malformation, syringomyelia, and bony abnormalities of the craniocervical junction. Failure to recognize these tumors is a consequential matter because the majority are benign and extramedullary, that is, potentially resectable and curable. If unrecognized, they terminate fatally by causing medullary and high spinal cord compression.
Although these tumors are not common (approximately 1 percent of all intracranial and intraspinal tumors), sizable series have been collected by several clinicians (see Meyer et al for a complete bibliography). In all series, meningiomas, schwannomas, neurofibromas, and dermoid cysts are the most common types; others, all rare, are teratomas, dermoids, granulomas, cavernous hemangiomas, hemangioblastomas, hemangiopericytomas, lipomas, and epidural carcinomas.
Pain in the suboccipital or posterior cervical region, mostly on the side of the tumor, is usually the first and by far the most prominent complaint. In some instances, the pain may extend into the shoulder and even the arm. The latter distribution is more frequent with tumors arising in the spinal canal and extending intracranially than the reverse. For uncertain reasons, the pain may radiate down the back, even to the lower spine. Both spine and root pain can be recognized, the latter because of involvement of either the C2 or C3 root or both.
One pattern is weakness of a shoulder and arm progressing to the ipsilateral leg and then to the opposite leg and arm (“around-the-clock” paralysis), as discussed in Chap. 3. Another configuration is triplegia that is a characteristic but not invariable sequence of events, caused by the encroachment of tumor upon the decussating corticospinal tracts at the foramen magnum. Occasionally, both upper limbs are involved alone; surprisingly, there may be atrophic weakness of the hand or forearm or even intercostal muscles with diminished tendon reflexes well below the level of the tumor, an observation made originally by Oppenheim. Involvement of sensory tracts also occurs; more often it is posterior column sensibility that is impaired on one or both sides, with patterns of progression similar to those of the motor paralysis. Sensation of intense cold in the neck and shoulders has been another unexpected complaint, and also “bands” of hyperesthesia around the neck and back of the head. Segmental bibrachial sensory loss has been demonstrated in a few of the cases and a Lhermitte sign (really a symptom) of electric-like sensations down the spine and limbs upon flexing the neck has been reported frequently. The cranial nerve signs most frequently conjoined and indicative of intracranial extension of a foramen magnum tumor are dysphagia, dysphonia, dysarthria, and drooping shoulder (because of vagal, hypoglossal, and spinal accessory involvement); included less often are nystagmus and episodic diplopia, sensory loss over the face and unilateral or bilateral facial weakness, and a Horner syndrome.
The clinical course of such lesions often extends for years, with deceptive and unexplained fluctuations. The important diagnostic procedure is contrast-enhanced MRI (Fig. 30–22). With dermoid cysts of the upper cervical region, as in the case reported by Adams and Wegner, complete and prolonged remissions from quadriparesis may occur.
MRI demonstrating an epidermoid cyst in the left cerebellopontine angle just above the foramen magnum. The cyst is heterogenous and hyperintense on T2-weighted MRI (A) and demonstrates restricted diffusion (DWI sequence) (B), a characteristic feature.
Tumors of the foramen magnum, as mentioned, should be differentiated from spinal or brainstem-cerebellar multiple sclerosis, Chiari malformation with syrinx, and bony compression. Persistent occipital neuralgia with a foramen magnum syndrome is particularly suggestive of a tumor at that site. The early occipitonuchal pain must be differentiated from mundane cervical osteoarthritis. Treatment is surgical excision (Hakuba et al) followed by focused radiation if the resection is incomplete and the tumor is known to be radiosensitive.