Case 1-2005 — A 35-Year-Old Woman with Difficulty Walking, Headache, and Nausea
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《新英格兰医药杂志》
Presentation of Case
A 35-year-old woman was admitted to the emergency department because of difficulty walking, headache, and nausea.
Two weeks before admission, the patient had noticed that her gait had become increasingly unbalanced, so that she described herself as walking "like a drunk person." Bifrontal and occipital headache and neck pain developed over the next several days. These symptoms worsened, and nausea developed when she bent forward to put on her shoes. She did not experience dizziness or vomiting. Over the next week, her balance deteriorated and on one occasion she fell in the shower. Other people noticed that she tended to neglect her left side. She came to the emergency department of this hospital.
The patient had emigrated from Brazil to the United States nine years earlier. She had had no previous illnesses and had undergone bilateral breast-reduction surgery 10 years before admission. She was allergic to morphine and oxycodone and was taking no medications. She lived with her boyfriend of four years and had no children. She did not smoke or use illicit drugs and drank approximately one beer every six months. She was a self-employed housekeeper.
On physical examination, she appeared well. The blood pressure was 120/84 mm Hg, the pulse 80 beats per minute, and the temperature 37.2°C. Her neck was supple, the lungs were clear on auscultation, and the heart rate and rhythm showed no abnormalities. Her abdomen was soft and nontender.
On neurologic examination, the patient was awake, alert, and oriented to time, place, and person. Her naming, repetition, reading, and calculation abilities were all good. An examination of the cranial nerves showed no abnormalities. There was normal muscle bulk and tone, with full strength in both arms and legs. There was a left pronator drift when she held her arms out in front of her. Proprioception and sensation of light touch and vibration were normal. She tended to ignore her left side. There was ataxia of the left arm on finger-to-nose testing. She was unable to keep her balance while sitting unsupported, and she was unable to stand on her own. She had mild clumsiness in her left arm and leg when performing finger tapping and on heel-to-shin testing. Deep-tendon reflexes were 2+ in both arms and 3+ at both knees, and there were several beats of clonus at both ankles. Plantar responses were flexor bilaterally.
Computed tomographic (CT) scanning of the brain followed by magnetic resonance imaging (MRI) showed two enhancing brain masses. The dominant mass expanded and infiltrated the splenium of the corpus callosum and spread into the parietal white matter bilaterally. A smaller mass within the right temporal and parietal lobes appeared to connect with the main mass. Imaging of the orbits, paranasal sinuses, and skull showed no abnormalities. The levels of blood glucose, electrolytes, calcium, phosphorus, magnesium, protein, amylase, lipase, and lactic dehydrogenase were normal, as were the results of renal- and liver-function tests.
The patient was admitted to the hospital and a diagnostic procedure was performed.
Differential Diagnosis
Dr. Tracy T. Batchelor: May we review the neuroradiologic studies?
Dr. Bradley R. Buchbinder: On CT and MRI scans of the brain (Figure 1), a mass is seen that expands and infiltrates the splenium of the corpus callosum, extending into the parietal white matter bilaterally. Before the administration of intravenous contrast material, the mass is isodense on CT and isointense on T2-weighted MRI, as compared with gray matter. After the administration of contrast material, the mass is intensely and uniformly enhanced on T1-weighted MRI. Feathery, linear enhancing structures emanate from the margins of the lesion, indicating that the mass has spread through the Virchow–Robin perivascular spaces. A satellite mass is present in the right parietal and temporal lobes. Surrounding areas are hypodense on the CT scan and hyperintense on the T2-weighted MRI scan — findings that are consistent with edema. There is no sign of calcification or hemorrhage.
Figure 1. Initial CT and MRI Scans of the Brain.
Axial CT scans without and with contrast material (Panel A and Panel B, respectively) show an infiltrative mass that expands from the splenium of the corpus callosum (asterisk) and spreads into the right parietal lobe (arrow). The mass appears isodense with respect to the gray matter. After the administration of contrast material, the two masses show homogeneous enhancement. Mild, low-attenuation edema surrounds the lesions (arrowheads). An axial T2-weighted MRI scan (Panel C) shows that the splenial lesion (asterisk) and the right parietal lesion (arrow) are isointense with respect to the gray matter. Edema in the right parietal lobe is hyperintense (arrowheads). An axial T1-weighted MRI scan obtained after the administration of contrast material (Panel D) shows that the splenial lesion (asterisk) and right parietal lesion (arrow) enhance intensely. Linear enhancing structures that emanate from the corpus callosum indicate spread through the Virchow–Robin perivascular spaces (thin arrows). The edema is hypointense on the T1-weighted image (arrowheads).
The differential diagnosis of an expansile, infiltrative mass within the corpus callosum includes astrocytoma, primary central nervous system (CNS) lymphoma, and demyelinating disorders. Although these entities are sometimes difficult to distinguish on radiologic imaging, in this case a highly specific feature is present: enhancement along the Virchow–Robin spaces. This finding is common only in primary CNS lymphoma and neurosarcoidosis.1 Identification of primary CNS lymphoma on imaging studies is important, since the approach to the diagnosis differs from that used with glial tumors and other lesions involving the brain.
The radiologic patterns of primary CNS lymphoma differ between patients who are immunocompetent and those who are immunodeficient.2,3,4,5,6,7,8,9 In immunocompetent patients, primary CNS lymphoma most often appears as a solitary mass, but it may also take the form of multiple masses or a diffuse, infiltrative lesion. The most common location is the cerebral hemispheres. Less frequent but characteristic locations are the deep gray-matter nuclei and the corpus callosum.
Primary CNS lymphoma has an appearance that can be readily identified on CT and MRI. Although a majority of pathologic processes in the brain, including neoplasms, are hypodense on CT scans and hyperintense on T2-weighted MRI as compared with normal gray matter, primary CNS lymphoma is often isodense to hyperdense on CT scans and isointense to hypointense on T2-weighted MRI. The former pattern is attributed to increased water content, whereas the latter is usually attributed to high cell density and scant cytoplasm. Whereas other pathologic processes may have this pattern, only gliomas and primary CNS lymphoma have a predilection for involvement of the corpus callosum. Edema may surround the lymphoma, producing mass effect. Primary CNS lymphoma almost always shows enhancement with the administration of contrast material. When central necrosis is present, irregular ring enhancement is seen. In immunocompromised patients, multiple lesions, necrosis, ring enhancement, and surrounding edema are all more common than in immunocompetent patients. Enhancement of the Virchow–Robin spaces, although not constant, is a highly specific feature.1
In this case, the involvement of the corpus callosum by a lesion that is isodense on CT scans and isointense on T2-weighted MRI relative to normal gray matter, with intense homogeneous enhancement, and that has spread through the Virchow–Robin spaces, strongly favors a diagnosis of primary CNS lymphoma.
Pathological Discussion
Dr. Nancy Lee Harris: The diagnostic procedure was a stereotactic biopsy of the lesion. Intraoperative analysis of a frozen section confirmed the presence of tumor and suggested that it was lymphoma. Frozen sections were cut for immunohistochemical analysis and the remainder of the tissue was fixed for permanent sections. The tumor cells were about three times the size of normal lymphocytes, with round or multilobated nuclei, inconspicuous nucleoli, and scant cytoplasm (Figure 2). The morphologic features were typical of lymphoma, but a poorly differentiated nonlymphoid neoplasm needed to be ruled out. Immunohistochemical studies on frozen sections showed that the tumor cells expressed the common leukocyte antigen CD45 and the B-cell antigen CD20 and lacked the T-cell antigen CD3. The staining test did not reveal immunoglobulin kappa or lambda light chains. Together with the morphologic features, these results confirmed the diagnosis of diffuse large-B-cell lymphoma.
Figure 2. Stereotactic Brain-Biopsy Specimen.
The brain tissue (hematoxylin and eosin) is entirely replaced by an infiltrate of cells that are about three times the size of normal lymphocytes and have large nuclei (some with a multilobated appearance), inconspicuous nucleoli, and scant cytoplasm. In other stains the cells expressed CD45 (a pan-leukocyte antigen) and CD20 (a pan-B-cell antigen) and were Bcl-6–positive, confirming the diagnosis of diffuse large-B-cell lymphoma.
Diffuse large-B-cell lymphoma is the most common type of lymphoma worldwide, making up 30 percent of all non-Hodgkin's lymphomas,10 and approximately 90 percent of primary CNS lymphomas.11 It is clinically heterogeneous, both in terms of sites of involvement and in behavior. For this reason, both pathologists and oncologists are actively seeking features that will permit stratification of these tumors in a clinically useful way.
Two types of large B cells are recognized in normal tissues: centroblasts, the proliferating cells of the germinal center, and immunoblasts, cells that are found outside germinal centers, which are assumed to be post–germinal-center cells. Normal centroblasts and immunoblasts can be distinguished to some extent by morphologic,12 immunophenotypic, and genetic features.13,14,15,16,17,18 The neoplastic cells in most large B cells resemble either centroblasts or immunoblasts morphologically; the associations among morphologic appearance, gene-expression profile, and prognosis are controversial.16,17,19,20 At this hospital, in a study of 33 patients who had diffuse large B-cell lymphoma of the brain and who had been treated with high-dose methotrexate, patients whose tumors expressed the nuclear protein Bcl-6, a marker for cells that have been exposed to the germinal center, had a better overall survival than did patients whose tumors did not express Bcl-6 protein (Figure 3).21 The patient under discussion was one of the cases studied, and her tumor cells expressed the Bcl-6 marker.
Figure 3. Overall Actuarial Probability of Survival among Patients with Primary CNS Lymphoma Treated with Methotrexate.
Patients who received treatment with high-dose methotrexate and whose tumors expressed Bcl-6 protein had better overall survival than those whose tumors lacked the protein (adapted from Braaten et al.,21 with permission).
Discussion of Management
Dr. Batchelor: This patient has a rare form of extranodal non-Hodgkin's lymphoma that is confined to the CNS. The most common form of lymphoma involving the nervous system occurs when a systemic lymphoma invades the leptomeninges. Less commonly, as in the present case, the nervous system may be the only site of disease, a condition known as primary CNS lymphoma.22 This rare neoplasm accounted for 2.7 percent of all primary brain tumors diagnosed in the United States from 1995 through 1999.23 The incidence of brain lymphoma increased from 2.7 cases per 10 million population in the period from 1973 through 1975 to 7.5 cases per 10 million in the period from 1982 through 198424; the increase was influenced by the human immunodeficiency virus (HIV) epidemic. Persons infected with HIV have a risk of primary CNS lymphoma that is 3600 times as high as the risk of persons in the general population.25 Although the incidence continued to increase after 1984, recent data suggest that the rates are stabilizing or decreasing slightly.26 Congenital or acquired immunodeficiency is the only established risk factor for primary CNS lymphoma. There was no evidence of congenital immunodeficiency in this patient, and no history of exposure to immunosuppressive drugs, and she was seronegative for HIV.
Although it was not a manifestation in the case under discussion, one of the most common symptoms that herald the diagnosis of primary CNS lymphoma is cognitive dysfunction. The headache and gait difficulty in this patient are also typical symptoms at presentation in patients with primary CNS lymphoma.27 In contrast to patients with gliomas, patients with lymphoma rarely present with seizures, probably because the lesions are deep-seated and do not involve the cortex.
Since primary CNS lymphoma can involve any part of the craniospinal axis as well as the eyes, the recommended staging evaluation at the time of diagnosis includes an ophthalmologic examination, with a slit-lamp evaluation; contrast-enhanced brain and spinal MRI; and, if a lumbar puncture can be performed safely, flow cytometry and cytopathological analysis of the cerebrospinal fluid. In addition, most investigators recommend contrast-enhanced CT scans of the chest, abdomen, and pelvis to rule out the unlikely possibility of extraneural sites of lymphoma. Finally, all patients should have serologic testing for HIV, a complete blood count, and assessment of electrolyte and serum lactate dehydrogenase levels as part of the initial evaluation. As is the case for most patients with primary CNS lymphoma, the disease in this patient was confined to the brain parenchyma, according to the imaging studies and ophthalmologic examination. A lumbar puncture was not performed, and the patient was HIV-negative.
According to the Ann Arbor staging system, the lymphoma in the case under discussion, and in all cases of primary CNS lymphoma, was classified as stage IE (on a scale of I to IV, where I is localized and IV is widespread, with E denoting extranodal disease). However, the prognosis for primary CNS lymphoma is much worse than that for systemic stage IE lymphomas. In fact, most lymphoma staging systems do not yield prognostic information for patients with primary CNS lymphoma. However, a prognostic index designed specifically for primary CNS lymphoma did provide an accurate prediction of survival in one study.28 In a historical database maintained by the International Extranodal Lymphoma Study Group, the following indicators were associated with a poor prognosis: an age over 60 years; a performance status greater than 1 (on the basis of the rating system of the Eastern Cooperative Oncology Group), with performance status ranging from 0 (normal) to 5 (dead); an elevated serum lactate dehydrogenase concentration; a high protein concentration in the cerebrospinal fluid; and a tumor location in the deep regions of the brain.
Among 105 patients for whom data for all five indicators were available, a prognostic score could be calculated, and the patients were separated into three groups on the basis of the results. Patients who had 0 to 1, 2 to 3, or 4 to 5 of these indicators had two-year overall survival rates of 80 percent, 48 percent, or 15 percent, respectively. This observation will require confirmation in future studies, but these indicators may provide a practical system for prognostication in patients with primary CNS lymphoma. The patient in the case under discussion could not be classified by this index because a lumbar puncture was not performed. She had only one of the other adverse prognostic factors — a deep-seated lesion. If this is considered along with the already established expression of Bcl-6 marker by the tumor, she may be in a good prognostic group.
Treatment options for patients with newly diagnosed primary CNS lymphoma include corticosteroids, surgery, radiation therapy, and chemotherapy. Corticosteroids were not given before the biopsy was performed in this patient because these agents have lymphotoxic properties and may disrupt the cellular morphology to such an extent that accurate pathological diagnosis cannot be achieved. Corticosteroids are incorporated into standard treatment regimens for most forms of non-Hodgkin's lymphoma. Responses to corticosteroids alone have been reported in as many as 40 percent of patients with primary CNS lymphoma.29 However, most patients relapse rapidly when their only treatment is with corticosteroids.
A stereotactic biopsy, instead of a craniotomy, was performed on this patient for two reasons. First, the mass was located in the corpus callosum and, therefore, could not be safely resected. However, even if the tumor had been located in a region of the brain amenable to resection, biopsy would still have been the recommendation when primary CNS lymphoma was suspected, since resection of the visible tumor mass in patients with primary CNS lymphoma does not provide a therapeutic benefit. Survival after surgery alone is one to four months.30,31 The multifocal pattern of growth and the deep location of tumor masses in primary CNS lymphoma make surgical removal difficult, if not impossible, in most cases.
After the biopsy confirmed the diagnosis of primary CNS lymphoma, the two treatment options to be considered for this patient were radiation therapy and chemotherapy. Irradiation has been an important and beneficial treatment for patients with primary CNS lymphoma. However, because of the multifocal nature of primary CNS lymphoma, radiation must be administered to the whole brain; this increases the likelihood of treatment-related, delayed neurotoxic effects. In one study, whole-brain radiation therapy as the sole treatment for primary CNS lymphoma was associated with a 90 percent response rate but a median survival of only 12.2 months. Sixty-one percent of patients with radiographic responses had relapses, as shown by the presence of tumor within the irradiated field.32 Thus, whole-brain radiation therapy alone does not result in a durable remission for most patients with primary CNS lymphoma. Given its limited efficacy when used as the sole method of therapy and the risk of delayed neurotoxic effects, radiation therapy was not the best option for this patient.
Another option for her would have been combination therapy that consisted of whole-brain radiation therapy and chemotherapy. This strategy was developed with the goal of improving response rates and survival among patients with primary CNS lymphoma. Early studies focused on chemotherapy regimens that were effective in other types of non-Hodgkin's lymphoma. However, because many of the individual drugs in these regimens (e.g., doxorubicin) have poor brain penetration, the results of these studies were disappointing.
Methotrexate, a folate antagonist that interrupts DNA biosynthesis, is the single most effective drug against primary CNS lymphoma. Methotrexate-based chemotherapy combined with whole-brain radiation therapy is associated with radiographic response rates of more than 50 percent and a two-year survival rate of 43 to 73 percent.33 However, the combination of methotrexate and whole-brain radiation therapy is associated with a high risk of neurotoxic effects in patients over the age of 60, and the median survival after the development of neurotoxic effects is only 12 months.34 In one study, clinical neurotoxic effects developed in 100 percent of patients with primary CNS lymphoma over the age of 60 who were treated with a regimen that included whole-brain radiation, with a median time to onset of 13.2 months.35 In contrast, neurotoxicity had developed in only 30 percent of patients under the age of 60 by the time they reached 96 months of follow-up. Patients who receive chemotherapy without whole-brain radiation appear to be at less risk for neurotoxic effects.36 These data have led to interest in using chemotherapy alone for patients with newly diagnosed primary CNS lymphoma.
Methotrexate, either as a single agent or as part of methotrexate-based combination chemotherapy, is now the most widely used drug for the treatment of primary CNS lymphoma. Radiographic responses occur in 52 to 100 percent of patients when methotrexate (at least 1 g per square meter of body-surface area) is administered alone and in 70 to 94 percent of patients when it is used as part of a combination regimen.33 Durable responses are possible, although most patients eventually have a relapse. High-dose methotrexate (8 g per square meter) used as a single agent resulted in a complete-response rate of 52 percent, progression-free survival of 12.8 months, and overall survival of 55.4 months in one multicenter phase 2 study, with minimal-to-moderate toxic effects.37 Toxic effects occur more frequently with methotrexate-based combination regimens than with methotrexate alone.
High-dose chemotherapy followed by autologous stem-cell rescue has been investigated in patients with newly diagnosed primary CNS lymphoma. However, in one study of 14 patients receiving high-dose chemotherapy with the combination regimen of carmustine, etoposide, cytarabine, and melphalan after a radiographic response to induction chemotherapy with methotrexate and cytarabine, the median event-free survival was only 9.3 months; 8 patients had progression of the cancer at a median of 2.3 months after stem-cell rescue.38 These preliminary results of high-dose chemotherapy for primary CNS lymphoma were disappointing, but further studies are needed.
On the basis of the success of methotrexate monotherapy in some patients with primary CNS lymphoma, we decided to proceed with treatment, using methotrexate as a single agent. This patient received methotrexate (8 g per square meter) every 14 days until she had a complete remission; this was followed by two additional doses 14 days apart (consolidation therapy) and then a dose every 28 days for 11 cycles (maintenance therapy). The duration of the infusion was 4 hours; to spare the bone marrow from the toxic effects of methotrexate, treatment with calcium leucovorin was started 24 hours after the start of the methotrexate infusion and was continued until the plasma methotrexate level was less than 0.10 μmol per liter. The patient had a complete radiographic response after seven cycles and a durable first remission.
Dr. Buchbinder: Two weeks after the initiation of high-dose methotrexate chemotherapy, MRI scanning showed a profound early radiographic response (Figure 4A and Figure 4B). In these images, the splenial mass is markedly decreased in size, enhancement, and mass effect. The enhancing right parietal lesion that had been isointense on the T2-weighted MRI has resolved. Adjacent to the lesion, the edema and mass effect that had been hyperintense on T2-weighted MRI have diminished. MRIs obtained six months after the beginning of chemotherapy show a complete radiographic response (Figure 4C and Figure 4D). The abnormal T2-weighted signal and enhancement in the corpus callosum and right parietal lobe have completely resolved.
Figure 4. Axial MRI of the Brain after Therapy.
MRIs obtained two weeks after the initiation of high-dose methotrexate chemotherapy show an early radiographic response. A T2-weighted image (Panel A) shows that the isointense, right parietal lesion has resolved (arrow marks area where the lesion had been located; it has been replaced by a hyperintense region that represents partially treated tumor). The adjacent hyperintense edema and mass effect are diminished as compared with earlier images (arrowheads). A T1-weighted image obtained after contrast material was administered (Panel B) shows that the splenial lesion is diminished in size, enhancement, and mass effect (asterisk). MRI scans obtained six months after the initiation of high-dose methotrexate chemotherapy (Panels C and D) show a complete radiographic response. The earlier abnormal signal in the corpus callosum and right parietal lobe has completely resolved on the T2-weighted image (Panel C), as has the enhancement on the T1-weighted image after the administration of contrast material (Panel D).
Dr. Batchelor: Unfortunately, as happens with the majority of patients with primary CNS lymphoma, this patient had a relapse 53 months after her initial diagnosis, less than 1 month after she delivered a healthy infant. Postpartum relapse has been reported in women with a history of non-Hodgkin's lymphoma, although it is unclear from the few reported cases whether there is a real increase in the risk of disease relapse during pregnancy or in the postpartum period.39 A repeated staging evaluation with cranial MRI, ophthalmologic examination, and CT scanning of her chest, abdomen, and pelvis confirmed that there was an isolated relapse, with a mass in the brain.
Dr. Buchbinder: MRI scans obtained approximately four and a half years after the patient's initial presentation show recurrent primary CNS lymphoma. A new mass in the splenium of the corpus callosum is mildly hyperintense on T2-weighted MRI (Figure 5A) and enhances after the administration of contrast material on T1-weighted MRI (Figure 5B).
Figure 5. Axial MRI Four and a Half Years after Initial Evaluation.
MRI shows the recurrence of primary CNS lymphoma. A T2-weighted image (Panel A) shows mildly hyperintense signal within the splenium of the corpus callosum (asterisk). A T1-weighted image obtained after the administration of contrast material (Panel B) shows enhancement within the recurrent tumor (asterisk).
Dr. Batchelor: There have been few large, prospective studies of treatment for patients with relapsed or refractory primary CNS lymphoma, and there is no standard recommendation for patients with this condition.40 Patients who have disease that is refractory to current first-line therapies are less likely to have durable remissions. In patients, such as the woman in the case under discussion, who have previously had a complete radiographic response to methotrexate, there appears to be a high likelihood that the cancer will respond to a second course of methotrexate.41 High-dose chemotherapy with autologous stem-cell rescue may also represent an effective salvage therapy. In one study, 16 of 20 patients had a complete response after high-dose chemotherapy, and the median overall survival was 91 months.42 However, patients in this study had substantial treatment-related toxic effects. We elected to treat the patient under discussion again with methotrexate at the same dose and on the schedule as before. She had a second complete radiographic response after two cycles and has remained in remission for more than 18 months since her relapse.
As exemplified by the treatment experience of this patient, there is a critical need to identify the most effective chemotherapy regimens to treat patients with newly diagnosed primary CNS lymphoma as well as patients who have a relapse. There are a number of fundamental clinical issues that remain unresolved in the management of primary CNS lymphoma (Table 1). However, since primary CNS lymphoma is an uncommon tumor, it will be difficult to address each research question in the context of a randomized clinical trial. In order to define the best treatment strategies for this tumor, multicenter collaboration is critical. The International Extranodal Lymphoma Study Group has developed a collaborative, multidisciplinary research group to begin to address these important questions.33
Table 1. Unresolved Questions in the Management of Primary Central Nervous System (CNS) Lymphoma.
Anatomical Diagnosis
Primary diffuse large-B-cell lymphoma of the brain.
Source Information
From the Departments of Neurology (T.T.B.), Radiology (B.R.B.), and Pathology (N.L.H.), Massachusetts General Hospital and Harvard Medical School.
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Soussain C, Hoang-Xuan K, Levy V. Results of intensive chemotherapy followed by hematopoietic stem-cell rescue in 22 patients with refractory or recurrent primary CNS lymphoma or intraocular lymphoma. Bull Cancer (Paris) 2004;91:189-192.(Tracy T. Batchelor, M.D.,)
A 35-year-old woman was admitted to the emergency department because of difficulty walking, headache, and nausea.
Two weeks before admission, the patient had noticed that her gait had become increasingly unbalanced, so that she described herself as walking "like a drunk person." Bifrontal and occipital headache and neck pain developed over the next several days. These symptoms worsened, and nausea developed when she bent forward to put on her shoes. She did not experience dizziness or vomiting. Over the next week, her balance deteriorated and on one occasion she fell in the shower. Other people noticed that she tended to neglect her left side. She came to the emergency department of this hospital.
The patient had emigrated from Brazil to the United States nine years earlier. She had had no previous illnesses and had undergone bilateral breast-reduction surgery 10 years before admission. She was allergic to morphine and oxycodone and was taking no medications. She lived with her boyfriend of four years and had no children. She did not smoke or use illicit drugs and drank approximately one beer every six months. She was a self-employed housekeeper.
On physical examination, she appeared well. The blood pressure was 120/84 mm Hg, the pulse 80 beats per minute, and the temperature 37.2°C. Her neck was supple, the lungs were clear on auscultation, and the heart rate and rhythm showed no abnormalities. Her abdomen was soft and nontender.
On neurologic examination, the patient was awake, alert, and oriented to time, place, and person. Her naming, repetition, reading, and calculation abilities were all good. An examination of the cranial nerves showed no abnormalities. There was normal muscle bulk and tone, with full strength in both arms and legs. There was a left pronator drift when she held her arms out in front of her. Proprioception and sensation of light touch and vibration were normal. She tended to ignore her left side. There was ataxia of the left arm on finger-to-nose testing. She was unable to keep her balance while sitting unsupported, and she was unable to stand on her own. She had mild clumsiness in her left arm and leg when performing finger tapping and on heel-to-shin testing. Deep-tendon reflexes were 2+ in both arms and 3+ at both knees, and there were several beats of clonus at both ankles. Plantar responses were flexor bilaterally.
Computed tomographic (CT) scanning of the brain followed by magnetic resonance imaging (MRI) showed two enhancing brain masses. The dominant mass expanded and infiltrated the splenium of the corpus callosum and spread into the parietal white matter bilaterally. A smaller mass within the right temporal and parietal lobes appeared to connect with the main mass. Imaging of the orbits, paranasal sinuses, and skull showed no abnormalities. The levels of blood glucose, electrolytes, calcium, phosphorus, magnesium, protein, amylase, lipase, and lactic dehydrogenase were normal, as were the results of renal- and liver-function tests.
The patient was admitted to the hospital and a diagnostic procedure was performed.
Differential Diagnosis
Dr. Tracy T. Batchelor: May we review the neuroradiologic studies?
Dr. Bradley R. Buchbinder: On CT and MRI scans of the brain (Figure 1), a mass is seen that expands and infiltrates the splenium of the corpus callosum, extending into the parietal white matter bilaterally. Before the administration of intravenous contrast material, the mass is isodense on CT and isointense on T2-weighted MRI, as compared with gray matter. After the administration of contrast material, the mass is intensely and uniformly enhanced on T1-weighted MRI. Feathery, linear enhancing structures emanate from the margins of the lesion, indicating that the mass has spread through the Virchow–Robin perivascular spaces. A satellite mass is present in the right parietal and temporal lobes. Surrounding areas are hypodense on the CT scan and hyperintense on the T2-weighted MRI scan — findings that are consistent with edema. There is no sign of calcification or hemorrhage.
Figure 1. Initial CT and MRI Scans of the Brain.
Axial CT scans without and with contrast material (Panel A and Panel B, respectively) show an infiltrative mass that expands from the splenium of the corpus callosum (asterisk) and spreads into the right parietal lobe (arrow). The mass appears isodense with respect to the gray matter. After the administration of contrast material, the two masses show homogeneous enhancement. Mild, low-attenuation edema surrounds the lesions (arrowheads). An axial T2-weighted MRI scan (Panel C) shows that the splenial lesion (asterisk) and the right parietal lesion (arrow) are isointense with respect to the gray matter. Edema in the right parietal lobe is hyperintense (arrowheads). An axial T1-weighted MRI scan obtained after the administration of contrast material (Panel D) shows that the splenial lesion (asterisk) and right parietal lesion (arrow) enhance intensely. Linear enhancing structures that emanate from the corpus callosum indicate spread through the Virchow–Robin perivascular spaces (thin arrows). The edema is hypointense on the T1-weighted image (arrowheads).
The differential diagnosis of an expansile, infiltrative mass within the corpus callosum includes astrocytoma, primary central nervous system (CNS) lymphoma, and demyelinating disorders. Although these entities are sometimes difficult to distinguish on radiologic imaging, in this case a highly specific feature is present: enhancement along the Virchow–Robin spaces. This finding is common only in primary CNS lymphoma and neurosarcoidosis.1 Identification of primary CNS lymphoma on imaging studies is important, since the approach to the diagnosis differs from that used with glial tumors and other lesions involving the brain.
The radiologic patterns of primary CNS lymphoma differ between patients who are immunocompetent and those who are immunodeficient.2,3,4,5,6,7,8,9 In immunocompetent patients, primary CNS lymphoma most often appears as a solitary mass, but it may also take the form of multiple masses or a diffuse, infiltrative lesion. The most common location is the cerebral hemispheres. Less frequent but characteristic locations are the deep gray-matter nuclei and the corpus callosum.
Primary CNS lymphoma has an appearance that can be readily identified on CT and MRI. Although a majority of pathologic processes in the brain, including neoplasms, are hypodense on CT scans and hyperintense on T2-weighted MRI as compared with normal gray matter, primary CNS lymphoma is often isodense to hyperdense on CT scans and isointense to hypointense on T2-weighted MRI. The former pattern is attributed to increased water content, whereas the latter is usually attributed to high cell density and scant cytoplasm. Whereas other pathologic processes may have this pattern, only gliomas and primary CNS lymphoma have a predilection for involvement of the corpus callosum. Edema may surround the lymphoma, producing mass effect. Primary CNS lymphoma almost always shows enhancement with the administration of contrast material. When central necrosis is present, irregular ring enhancement is seen. In immunocompromised patients, multiple lesions, necrosis, ring enhancement, and surrounding edema are all more common than in immunocompetent patients. Enhancement of the Virchow–Robin spaces, although not constant, is a highly specific feature.1
In this case, the involvement of the corpus callosum by a lesion that is isodense on CT scans and isointense on T2-weighted MRI relative to normal gray matter, with intense homogeneous enhancement, and that has spread through the Virchow–Robin spaces, strongly favors a diagnosis of primary CNS lymphoma.
Pathological Discussion
Dr. Nancy Lee Harris: The diagnostic procedure was a stereotactic biopsy of the lesion. Intraoperative analysis of a frozen section confirmed the presence of tumor and suggested that it was lymphoma. Frozen sections were cut for immunohistochemical analysis and the remainder of the tissue was fixed for permanent sections. The tumor cells were about three times the size of normal lymphocytes, with round or multilobated nuclei, inconspicuous nucleoli, and scant cytoplasm (Figure 2). The morphologic features were typical of lymphoma, but a poorly differentiated nonlymphoid neoplasm needed to be ruled out. Immunohistochemical studies on frozen sections showed that the tumor cells expressed the common leukocyte antigen CD45 and the B-cell antigen CD20 and lacked the T-cell antigen CD3. The staining test did not reveal immunoglobulin kappa or lambda light chains. Together with the morphologic features, these results confirmed the diagnosis of diffuse large-B-cell lymphoma.
Figure 2. Stereotactic Brain-Biopsy Specimen.
The brain tissue (hematoxylin and eosin) is entirely replaced by an infiltrate of cells that are about three times the size of normal lymphocytes and have large nuclei (some with a multilobated appearance), inconspicuous nucleoli, and scant cytoplasm. In other stains the cells expressed CD45 (a pan-leukocyte antigen) and CD20 (a pan-B-cell antigen) and were Bcl-6–positive, confirming the diagnosis of diffuse large-B-cell lymphoma.
Diffuse large-B-cell lymphoma is the most common type of lymphoma worldwide, making up 30 percent of all non-Hodgkin's lymphomas,10 and approximately 90 percent of primary CNS lymphomas.11 It is clinically heterogeneous, both in terms of sites of involvement and in behavior. For this reason, both pathologists and oncologists are actively seeking features that will permit stratification of these tumors in a clinically useful way.
Two types of large B cells are recognized in normal tissues: centroblasts, the proliferating cells of the germinal center, and immunoblasts, cells that are found outside germinal centers, which are assumed to be post–germinal-center cells. Normal centroblasts and immunoblasts can be distinguished to some extent by morphologic,12 immunophenotypic, and genetic features.13,14,15,16,17,18 The neoplastic cells in most large B cells resemble either centroblasts or immunoblasts morphologically; the associations among morphologic appearance, gene-expression profile, and prognosis are controversial.16,17,19,20 At this hospital, in a study of 33 patients who had diffuse large B-cell lymphoma of the brain and who had been treated with high-dose methotrexate, patients whose tumors expressed the nuclear protein Bcl-6, a marker for cells that have been exposed to the germinal center, had a better overall survival than did patients whose tumors did not express Bcl-6 protein (Figure 3).21 The patient under discussion was one of the cases studied, and her tumor cells expressed the Bcl-6 marker.
Figure 3. Overall Actuarial Probability of Survival among Patients with Primary CNS Lymphoma Treated with Methotrexate.
Patients who received treatment with high-dose methotrexate and whose tumors expressed Bcl-6 protein had better overall survival than those whose tumors lacked the protein (adapted from Braaten et al.,21 with permission).
Discussion of Management
Dr. Batchelor: This patient has a rare form of extranodal non-Hodgkin's lymphoma that is confined to the CNS. The most common form of lymphoma involving the nervous system occurs when a systemic lymphoma invades the leptomeninges. Less commonly, as in the present case, the nervous system may be the only site of disease, a condition known as primary CNS lymphoma.22 This rare neoplasm accounted for 2.7 percent of all primary brain tumors diagnosed in the United States from 1995 through 1999.23 The incidence of brain lymphoma increased from 2.7 cases per 10 million population in the period from 1973 through 1975 to 7.5 cases per 10 million in the period from 1982 through 198424; the increase was influenced by the human immunodeficiency virus (HIV) epidemic. Persons infected with HIV have a risk of primary CNS lymphoma that is 3600 times as high as the risk of persons in the general population.25 Although the incidence continued to increase after 1984, recent data suggest that the rates are stabilizing or decreasing slightly.26 Congenital or acquired immunodeficiency is the only established risk factor for primary CNS lymphoma. There was no evidence of congenital immunodeficiency in this patient, and no history of exposure to immunosuppressive drugs, and she was seronegative for HIV.
Although it was not a manifestation in the case under discussion, one of the most common symptoms that herald the diagnosis of primary CNS lymphoma is cognitive dysfunction. The headache and gait difficulty in this patient are also typical symptoms at presentation in patients with primary CNS lymphoma.27 In contrast to patients with gliomas, patients with lymphoma rarely present with seizures, probably because the lesions are deep-seated and do not involve the cortex.
Since primary CNS lymphoma can involve any part of the craniospinal axis as well as the eyes, the recommended staging evaluation at the time of diagnosis includes an ophthalmologic examination, with a slit-lamp evaluation; contrast-enhanced brain and spinal MRI; and, if a lumbar puncture can be performed safely, flow cytometry and cytopathological analysis of the cerebrospinal fluid. In addition, most investigators recommend contrast-enhanced CT scans of the chest, abdomen, and pelvis to rule out the unlikely possibility of extraneural sites of lymphoma. Finally, all patients should have serologic testing for HIV, a complete blood count, and assessment of electrolyte and serum lactate dehydrogenase levels as part of the initial evaluation. As is the case for most patients with primary CNS lymphoma, the disease in this patient was confined to the brain parenchyma, according to the imaging studies and ophthalmologic examination. A lumbar puncture was not performed, and the patient was HIV-negative.
According to the Ann Arbor staging system, the lymphoma in the case under discussion, and in all cases of primary CNS lymphoma, was classified as stage IE (on a scale of I to IV, where I is localized and IV is widespread, with E denoting extranodal disease). However, the prognosis for primary CNS lymphoma is much worse than that for systemic stage IE lymphomas. In fact, most lymphoma staging systems do not yield prognostic information for patients with primary CNS lymphoma. However, a prognostic index designed specifically for primary CNS lymphoma did provide an accurate prediction of survival in one study.28 In a historical database maintained by the International Extranodal Lymphoma Study Group, the following indicators were associated with a poor prognosis: an age over 60 years; a performance status greater than 1 (on the basis of the rating system of the Eastern Cooperative Oncology Group), with performance status ranging from 0 (normal) to 5 (dead); an elevated serum lactate dehydrogenase concentration; a high protein concentration in the cerebrospinal fluid; and a tumor location in the deep regions of the brain.
Among 105 patients for whom data for all five indicators were available, a prognostic score could be calculated, and the patients were separated into three groups on the basis of the results. Patients who had 0 to 1, 2 to 3, or 4 to 5 of these indicators had two-year overall survival rates of 80 percent, 48 percent, or 15 percent, respectively. This observation will require confirmation in future studies, but these indicators may provide a practical system for prognostication in patients with primary CNS lymphoma. The patient in the case under discussion could not be classified by this index because a lumbar puncture was not performed. She had only one of the other adverse prognostic factors — a deep-seated lesion. If this is considered along with the already established expression of Bcl-6 marker by the tumor, she may be in a good prognostic group.
Treatment options for patients with newly diagnosed primary CNS lymphoma include corticosteroids, surgery, radiation therapy, and chemotherapy. Corticosteroids were not given before the biopsy was performed in this patient because these agents have lymphotoxic properties and may disrupt the cellular morphology to such an extent that accurate pathological diagnosis cannot be achieved. Corticosteroids are incorporated into standard treatment regimens for most forms of non-Hodgkin's lymphoma. Responses to corticosteroids alone have been reported in as many as 40 percent of patients with primary CNS lymphoma.29 However, most patients relapse rapidly when their only treatment is with corticosteroids.
A stereotactic biopsy, instead of a craniotomy, was performed on this patient for two reasons. First, the mass was located in the corpus callosum and, therefore, could not be safely resected. However, even if the tumor had been located in a region of the brain amenable to resection, biopsy would still have been the recommendation when primary CNS lymphoma was suspected, since resection of the visible tumor mass in patients with primary CNS lymphoma does not provide a therapeutic benefit. Survival after surgery alone is one to four months.30,31 The multifocal pattern of growth and the deep location of tumor masses in primary CNS lymphoma make surgical removal difficult, if not impossible, in most cases.
After the biopsy confirmed the diagnosis of primary CNS lymphoma, the two treatment options to be considered for this patient were radiation therapy and chemotherapy. Irradiation has been an important and beneficial treatment for patients with primary CNS lymphoma. However, because of the multifocal nature of primary CNS lymphoma, radiation must be administered to the whole brain; this increases the likelihood of treatment-related, delayed neurotoxic effects. In one study, whole-brain radiation therapy as the sole treatment for primary CNS lymphoma was associated with a 90 percent response rate but a median survival of only 12.2 months. Sixty-one percent of patients with radiographic responses had relapses, as shown by the presence of tumor within the irradiated field.32 Thus, whole-brain radiation therapy alone does not result in a durable remission for most patients with primary CNS lymphoma. Given its limited efficacy when used as the sole method of therapy and the risk of delayed neurotoxic effects, radiation therapy was not the best option for this patient.
Another option for her would have been combination therapy that consisted of whole-brain radiation therapy and chemotherapy. This strategy was developed with the goal of improving response rates and survival among patients with primary CNS lymphoma. Early studies focused on chemotherapy regimens that were effective in other types of non-Hodgkin's lymphoma. However, because many of the individual drugs in these regimens (e.g., doxorubicin) have poor brain penetration, the results of these studies were disappointing.
Methotrexate, a folate antagonist that interrupts DNA biosynthesis, is the single most effective drug against primary CNS lymphoma. Methotrexate-based chemotherapy combined with whole-brain radiation therapy is associated with radiographic response rates of more than 50 percent and a two-year survival rate of 43 to 73 percent.33 However, the combination of methotrexate and whole-brain radiation therapy is associated with a high risk of neurotoxic effects in patients over the age of 60, and the median survival after the development of neurotoxic effects is only 12 months.34 In one study, clinical neurotoxic effects developed in 100 percent of patients with primary CNS lymphoma over the age of 60 who were treated with a regimen that included whole-brain radiation, with a median time to onset of 13.2 months.35 In contrast, neurotoxicity had developed in only 30 percent of patients under the age of 60 by the time they reached 96 months of follow-up. Patients who receive chemotherapy without whole-brain radiation appear to be at less risk for neurotoxic effects.36 These data have led to interest in using chemotherapy alone for patients with newly diagnosed primary CNS lymphoma.
Methotrexate, either as a single agent or as part of methotrexate-based combination chemotherapy, is now the most widely used drug for the treatment of primary CNS lymphoma. Radiographic responses occur in 52 to 100 percent of patients when methotrexate (at least 1 g per square meter of body-surface area) is administered alone and in 70 to 94 percent of patients when it is used as part of a combination regimen.33 Durable responses are possible, although most patients eventually have a relapse. High-dose methotrexate (8 g per square meter) used as a single agent resulted in a complete-response rate of 52 percent, progression-free survival of 12.8 months, and overall survival of 55.4 months in one multicenter phase 2 study, with minimal-to-moderate toxic effects.37 Toxic effects occur more frequently with methotrexate-based combination regimens than with methotrexate alone.
High-dose chemotherapy followed by autologous stem-cell rescue has been investigated in patients with newly diagnosed primary CNS lymphoma. However, in one study of 14 patients receiving high-dose chemotherapy with the combination regimen of carmustine, etoposide, cytarabine, and melphalan after a radiographic response to induction chemotherapy with methotrexate and cytarabine, the median event-free survival was only 9.3 months; 8 patients had progression of the cancer at a median of 2.3 months after stem-cell rescue.38 These preliminary results of high-dose chemotherapy for primary CNS lymphoma were disappointing, but further studies are needed.
On the basis of the success of methotrexate monotherapy in some patients with primary CNS lymphoma, we decided to proceed with treatment, using methotrexate as a single agent. This patient received methotrexate (8 g per square meter) every 14 days until she had a complete remission; this was followed by two additional doses 14 days apart (consolidation therapy) and then a dose every 28 days for 11 cycles (maintenance therapy). The duration of the infusion was 4 hours; to spare the bone marrow from the toxic effects of methotrexate, treatment with calcium leucovorin was started 24 hours after the start of the methotrexate infusion and was continued until the plasma methotrexate level was less than 0.10 μmol per liter. The patient had a complete radiographic response after seven cycles and a durable first remission.
Dr. Buchbinder: Two weeks after the initiation of high-dose methotrexate chemotherapy, MRI scanning showed a profound early radiographic response (Figure 4A and Figure 4B). In these images, the splenial mass is markedly decreased in size, enhancement, and mass effect. The enhancing right parietal lesion that had been isointense on the T2-weighted MRI has resolved. Adjacent to the lesion, the edema and mass effect that had been hyperintense on T2-weighted MRI have diminished. MRIs obtained six months after the beginning of chemotherapy show a complete radiographic response (Figure 4C and Figure 4D). The abnormal T2-weighted signal and enhancement in the corpus callosum and right parietal lobe have completely resolved.
Figure 4. Axial MRI of the Brain after Therapy.
MRIs obtained two weeks after the initiation of high-dose methotrexate chemotherapy show an early radiographic response. A T2-weighted image (Panel A) shows that the isointense, right parietal lesion has resolved (arrow marks area where the lesion had been located; it has been replaced by a hyperintense region that represents partially treated tumor). The adjacent hyperintense edema and mass effect are diminished as compared with earlier images (arrowheads). A T1-weighted image obtained after contrast material was administered (Panel B) shows that the splenial lesion is diminished in size, enhancement, and mass effect (asterisk). MRI scans obtained six months after the initiation of high-dose methotrexate chemotherapy (Panels C and D) show a complete radiographic response. The earlier abnormal signal in the corpus callosum and right parietal lobe has completely resolved on the T2-weighted image (Panel C), as has the enhancement on the T1-weighted image after the administration of contrast material (Panel D).
Dr. Batchelor: Unfortunately, as happens with the majority of patients with primary CNS lymphoma, this patient had a relapse 53 months after her initial diagnosis, less than 1 month after she delivered a healthy infant. Postpartum relapse has been reported in women with a history of non-Hodgkin's lymphoma, although it is unclear from the few reported cases whether there is a real increase in the risk of disease relapse during pregnancy or in the postpartum period.39 A repeated staging evaluation with cranial MRI, ophthalmologic examination, and CT scanning of her chest, abdomen, and pelvis confirmed that there was an isolated relapse, with a mass in the brain.
Dr. Buchbinder: MRI scans obtained approximately four and a half years after the patient's initial presentation show recurrent primary CNS lymphoma. A new mass in the splenium of the corpus callosum is mildly hyperintense on T2-weighted MRI (Figure 5A) and enhances after the administration of contrast material on T1-weighted MRI (Figure 5B).
Figure 5. Axial MRI Four and a Half Years after Initial Evaluation.
MRI shows the recurrence of primary CNS lymphoma. A T2-weighted image (Panel A) shows mildly hyperintense signal within the splenium of the corpus callosum (asterisk). A T1-weighted image obtained after the administration of contrast material (Panel B) shows enhancement within the recurrent tumor (asterisk).
Dr. Batchelor: There have been few large, prospective studies of treatment for patients with relapsed or refractory primary CNS lymphoma, and there is no standard recommendation for patients with this condition.40 Patients who have disease that is refractory to current first-line therapies are less likely to have durable remissions. In patients, such as the woman in the case under discussion, who have previously had a complete radiographic response to methotrexate, there appears to be a high likelihood that the cancer will respond to a second course of methotrexate.41 High-dose chemotherapy with autologous stem-cell rescue may also represent an effective salvage therapy. In one study, 16 of 20 patients had a complete response after high-dose chemotherapy, and the median overall survival was 91 months.42 However, patients in this study had substantial treatment-related toxic effects. We elected to treat the patient under discussion again with methotrexate at the same dose and on the schedule as before. She had a second complete radiographic response after two cycles and has remained in remission for more than 18 months since her relapse.
As exemplified by the treatment experience of this patient, there is a critical need to identify the most effective chemotherapy regimens to treat patients with newly diagnosed primary CNS lymphoma as well as patients who have a relapse. There are a number of fundamental clinical issues that remain unresolved in the management of primary CNS lymphoma (Table 1). However, since primary CNS lymphoma is an uncommon tumor, it will be difficult to address each research question in the context of a randomized clinical trial. In order to define the best treatment strategies for this tumor, multicenter collaboration is critical. The International Extranodal Lymphoma Study Group has developed a collaborative, multidisciplinary research group to begin to address these important questions.33
Table 1. Unresolved Questions in the Management of Primary Central Nervous System (CNS) Lymphoma.
Anatomical Diagnosis
Primary diffuse large-B-cell lymphoma of the brain.
Source Information
From the Departments of Neurology (T.T.B.), Radiology (B.R.B.), and Pathology (N.L.H.), Massachusetts General Hospital and Harvard Medical School.
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Soussain C, Hoang-Xuan K, Levy V. Results of intensive chemotherapy followed by hematopoietic stem-cell rescue in 22 patients with refractory or recurrent primary CNS lymphoma or intraocular lymphoma. Bull Cancer (Paris) 2004;91:189-192.(Tracy T. Batchelor, M.D.,)