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RadioGraphics
Computed Tomography
The computed tomographic (CT) appearance of primary CNS lymphoma has been well described in the literature (20,51,53,54,55,56,57,58). Lesions typically have high attenuation on plain CT scans and virtually all show enhancement after administration of contrast material (Figure 3, Figure 4, Figure 5, Figure 6). However, negative findings from a CT examination do not exclude the diagnosis of CNS lymphoma (29,59). Remick et al (8) demonstrated a 38% false-negative rate from initial CT studies performed on 21 patients with biopsy-proved CNS lymphoma, and 13% of these patients never had positive CT findings at any time during the course of the disease. For this reason, MR imaging is currently considered the imaging modality of choice in the evaluation of patients with CNS lymphoma.
MR Imaging
MR imaging is superior to CT in the radiologic evaluation of CNS lymphomas. The lesions manifest as well-demarcated round, oval, or rarely gyral-shaped masses (60). On T1-weighted images, the lesions are typically slightly hypointense to isointense relative to gray matter and produce relatively little mass effect for their size (Figure 7, Figure 8). In the early literature, lesions were described as being almost uniformly hyperintense on T2-weighted images. More recently-and likely because of better MR imaging software that has led to greater appreciation of subtle details—the lesions are now known to be more commonly hypointense to isointense relative to gray matter on T2-weighted images (Figure 9, Figure 10). This appearance likely reflects the increased nuclear-cytoplasmic ratio in these densely packed and highly cellular tumors (50,61,62). Less commonly, the lesions may show T2 hyperintensity relative to gray matter. T2 hypointensity, when seen, helps differentiate CNS lymphoma from gliomas and demyelinating disease, which are more commonly hyperintense on T2-weighted images. A ring pattern is typical in immunocompromised patients with CNS lymphoma and is caused by a T2 hypointense, densely cellular rim in a hyperintense "sea of edema" about the lesion. The central portion of this ring correlates with necrosis (8,50). On T1-weighted images, this same rim appears slightly hyperintense relative to the surrounding hypointense edema and exhibits intense ring-shaped contrast enhancement, which may be smooth or irregular and may have associated enhancing mural nodules (58). Findings of irregular, sinuous, or even gyral-like contrast enhancement suggest CNS lymphoma rather than toxoplasmosis, which typically has smooth, peripheral ring enhancement (62). The distinction is of prime importance in affected AIDS patients. Homogeneous enhancement may also occur and is more common in lesions that are isointense on unenhanced T1-weighted images (50).
Angiography
CNS lymphoma has a variety of appearances on angiograms, including an avascular mass, a focal blush in the late arterial-to-capillary phase that persists well into the venous phase, arterial encasement, dilated deep medullary veins, and tumor neovascularity (16,55,63,64,65). Dural supply to CNS lymphomas is a rare feature that may be seen in lesions involving the dura mater or leptomeninges (Figure 6) (56).
General Neuroimaging Features
With all imaging modalities, enhancement of CNS lymphomas tends to be solid and homogeneous in immunocompetent patients (Figure 11) as opposed to irregular and heterogeneous, often with a ring pattern, in the immunocompromised group (Figure 12, Figure 13, Figure 14). It is generally reported that the deep gray matter is a classic location for CNS lymphoma (Figure 3). This belief has most likely been engendered by the fact that few other lesions produce this appearance. However, only 33% of CNS lymphomas occur in this location, and most of these lesions occur in the cerebral white matter. In study by Hobson et al (47), 55% of lesions occurred either in the cerebral white matter or near or within the corpus callosum; 17% in the deep central gray matter of the basal ganglia, thalamus, or hypothalamus; 11% in the posterior fossa; and 1% in the spinal cord. Radiologic studies revealed multiple lesions in 16% of cases, but the true prevalence of multiple lesions proved at pathologic examination is 20%-44% (47). The cerebral white matter of the frontal lobe is the most common site for CNS lymphoma, followed in decreasing order of frequency by the temporal, parietal, and occipital lobes (4,66,67).
One of the more characteristic features of CNS lymphoma is its tendency to abut the ependyma, the meninges, or both (Figure 6, Figure 8, Figure 10, Figure 14, Figure 15, Figure 16). This feature supports the theory that the lesion originated in the periadventitial cells of penetrating arterioles in the perivascular Virchow-Robin spaces in this area (16,27,68).
When lesions involve the frontal lobes and the genua of the corpus callosum, a "butterfly" pattern of involvement is demonstrated (66). Cerebellar lesions account for about 10% of CNS lymphomas and are more common in the white matter. Regardless of its location, pretherapy CNS lymphoma does not show calcification and rarely demonstrates hemorrhage at imaging studies (16,29,62). In rare cases, calcification may occur after radiation therapy or chemotherapy.
The finding of periventricular enhancement on CT and MR images of AIDS patients is highly specific for CNS lymphoma, and immediate biopsy is warranted in such cases (69). This appearance may be mimicked by cytomegaloviral ependymitis (70). Periventricular involvement is best seen on contrast-enhanced T1-weighted images. The CT and MR imaging findings of primary CNS lymphoma in pediatric patients are similar to those seen in adults (71).
Dural involvement by primary CNS lymphoma is rare and may mimic meningioma because of its extraaxial location and appearance on CT and MR images (hyperattenuated on CT scans and usually hypointense relative to gray matter on T2-weighted images, typically enhancing intensely with contrast material) (Figure 9) (9). Hyperostosis of the skull may be noted (Figure 17), and extension across the skull into the scalp has also been reported (Figure 18). Rarely, primary CNS lymphoma arising from the skull may invade adjacent dura mater and scalp, producing an appearance identical to that of a primary dural lesion (48).
The differential radiologic diagnosis of CNS lymphoma includes glioma, abscess and other infections, demyelinating disease, and, in the pediatric population, primitive neuroectodermal tumor (Table 1). Any disease that can spread perivascularly, including brain-to-brain metastasis from primary glioblastoma multiforme, sarcoidosis, tuberculosis, or other granulomatous diseases, may have an imaging appearance similar to that of primary CNS lymphoma (Table 2). Although T2 hyperintensity of gliomas and demyelinating disease may allow them to be distinguished from CNS lymphoma, it is more difficult to exclude abscess because of its tendency to produce ringlike T2 hypointensity that enhances intensely on contrast-enhanced T1-weighted images. The moderate to severe edema that typically surrounds parenchymal abscesses in the brain contrasts with the comparatively little to mild edema seen in CNS lymphoma. However, in the clinical setting of an immunocompromised patient, differentiation between CNS lymphoma and toxoplasmosis abscess is not always possible on the basis of imaging findings alone (72). The problem is compounded by the increased prevalence of multicentric CNS lymphoma in this group of patients, because multicentricity is also a common feature of infectious lesions. To help resolve this issue, an empiric trial of antitoxoplasmosis drug therapy may be employed. If the lesions resolve or decrease in size after 2 weeks of drug therapy, they are presumed to be toxoplasmosis and therapy is continued until they completely resolve. However, if the lesions remain the same or increase in size, a diagnosis of CNS lymphoma is favored and biopsy is recommended. Immunocompromised patients with only a single enhancing lesion are four times as likely to have CNS lymphoma, and early biopsy of such a lesion is recommended in that setting (59). These issues are important because patients with CNS lymphoma have an increased chance of prolonged survival if they receive prompt radiation therapy (24).
Multiple lesions occur in about 11%-47% cases of CNS lymphoma, with their prevalence being lower in immunocompetent patients and higher in immunocompromised patients (Figure 3) (16,27,50,73). Immunocompromised patients with CNS lymphoma tend to have smaller lesions, and the temporal lobe is more frequently affected. Because of the low risk of extraneural spread from primary CNS lymphoma, routine radiologic evaluation of the rest of the body is not recommended but rather should be performed on the basis of clinical suspicion, signs, or symptoms (7).
No difference in the CT and MR imaging appearances of primary versus secondary CNS lymphoma has been observed, with the exception that secondary lymphoma tends to involve the dura mater and leptomeninges (29). With the prolonged survival of patients with primary systemic (nodal) lymphoma, there is greater likelihood that the radiologist may find secondary lymphomatous involvement of the CNS. In these patients, leptomeningeal disease is the most common type and palsies of the cranial nerves, especially III, VI, and VII, are the most common presenting clinical sign (Figure 16) (74).
The imaging appearance of CNS lymphoma in immunocompetent patients differs somewhat from that in immunocompromised patients. CNS lymphoma in immunocompromised patients tends to be multicentric, hypoattenuated at unenhanced CT, and characterized by ring enhancement at contrast-enhanced CT (21,50,58).
Other Radiologic Methods under Investigation
Except in rare circumstances, neither CT nor MR imaging provide adequate specificity for making the preoperative diagnosis of CNS lymphoma in immunocompromised patients. The ability to differentiate between CNS lymphoma and toxoplasmosis accurately and noninvasively would reduce biopsy-related morbidity and expedite appropriate therapy.
In 1982, Di Chiro et al (75) demonstrated the usefulness of performing positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose in the detection of cerebral gliomas. Because of their increased glucose metabolism, gliomas demonstrate hypermetabolic areas of increased uptake at PET. The usefulness of PET for identifying CNS lymphoma, also a highly metabolic tumor, was shown in 1988 by Kuwabara et al (76). Numerous studies since then have confirmed the utility of PET in the initial diagnosis of CNS lymphoma, even in patients undergoing steroid therapy (77,78,79,80,81). The increased metabolism of the tumor causes rapid uptake of the radiotracer carbon-11 methionine, which is seen on PET images in areas that extend beyond the areas of enhancement seen on CT or MR images; these areas of uptake have histologically been proved to represent the tumor margins. C-11 methionine PET has also been useful in monitoring the effects of therapy (78).
Single-photon emission computed tomography (SPECT) performed with thallium-201 has also been shown to have high sensitivity and specificity in differentiating malignant intracranial neoplasms such as primary CNS lymphoma (hypermetabolic) from other nonneoplastic entities (iso- to hypometabolic) (Figure 19) (82,83). The utility of Tl-201 SPECT appears to be directly related to regional blood flow, blood-brain barrier permeability, and cellular uptake, possibly through an adenosine triphosphate pump transport mechanism (82).
However, despite the high accuracy of these preliminary studies of using PET and SPECT in the detection of CNS lymphoma, false-positive and false-negative results do occur with both PET and SPECT, usually related to errors in interpretation (83) but occasionally because the tumor may not demonstrate increased uptake (84) or because nonmalignant lesions such as bacterial abscess (85) or progressive multifocal leukoencephalopathy (80) may show hypermetabolism. In addition, the limited availability and increased cost of PET studies preclude the use of this modality in the mainstream of community radiology practice.
Radiologic Features