- Email: [email protected]
Primary Meningeal Lymphoma of T-Cell Origin: A Rare Presentation of Primary Central Nervous System Lymphomas
Case Report Primary Meningeal Lymphoma of T-Cell Origin: A Rare Presentation of Primary Central Nervous System Lymphomas Jose Ponce, Angel Segura, Alejandra Gimenez, Roberto Diaz, Jorge Molina, Laura Palomar, Jose Gomez Codina
Abstract Primary meningeal lymphoma is a rare clinical entity. Central nervous system infiltration by systemic lymphoma should always be excluded. Diagnosis can be difficult, and prognosis is usually poor. Most are of B-cell origin. We present the case of a young man with a primary meningeal lymphoma of T-cell origin. He was treated with systemic chemotherapy with high-dose methotrexate and cytarabine and intraventricular chemotherapy. He had a clinical improvement and a complete remission, with a long overall survival. There is no standard treatment for this rare disease. Traditionally, treatment has been based in craniospinal radiation therapy and intrathecal chemotherapy, with poor overall results. More recently, systemic chemotherapy with high-dose methotrexate has been advocated, which could avoid the long-term toxicity of craniospinal radiation therapy, and could improve the prognosis of these patients.
Clinical Lymphoma & Myeloma, Vol. 7, No. 8, 546-549, 2007 Key words: Craniospinal radiation therapy, High-dose methotrexate, Intrathecal chemotherapy, Non-Hodgkin lymphoma, T-cell lymphoma
Introduction Primary meningeal lymphoma (PML), with no parenchymal cerebral mass or systemic dissemination at diagnosis or during the course of the disease, is a rare form of presentation of the primary central nervous system lymphomas (PCNSLs).1 Prognosis is usually poor, and most cases published are of Bcell origin.2 However, in this article, we report the case of a 34-year-old man diagnosed with a PML of T-cell lineage. He was treated with systemic and intraventricular chemotherapy and had complete remission of the disease. We also review the published literature of this infrequent disease and the scant recommendations regarding the optimal diagnosis and treatment of the condition.
Case Report A 34-year-old man, with no past medical history of interest, was admitted in our hospital in February 2003 with a 2-month Medical Oncology Unit, University Hospital La Fe, Valencia, Spain Submitted: Apr 19, 2006; Revised: May 17, 2006; Accepted: May 21, 2006 Address for correspondence: Jose Ponce, MD, University Hospital La Fe, Avda. Campanar 21, 46009 Valencia, Spain Fax: 96-197-3138; e-mail: [email protected]
history of progressive bilateral leg weakness and patchy lower limb paresthesias. The general physical examination showed a chronically ill patient who was afebrile, with normal consciousness and without meningismus or deficits in higher cortical functions. He had an Eastern Cooperative Oncology Group performance status of 2. The neurologic examination revealed a flaccid paralysis of the lower extremities with absent deep-tendon reflexes, no plantar responses, and a diffuse muscular atrophy. There were no laboratory abnormalities. A computed tomography scan and magnetic resonance imaging (MRI) scan of the brain were normal. A spinal MRI was performed and showed signs of a diffuse meningeal infiltration. The lumbar segment was especially affected, with a diffuse thickening and discrete nodular deposits that readily enhanced after the administration of gadolinium (Figure 1). The electromyographic study showed signs of an axonal multirradiculopathy, predominantly in the lower limbs. A diagnostic lumbar puncture was performed. Cerebrospinal fluid (CSF) examination showed low glucose level (35 mg/dL), elevated protein value (80 mg/dL), and as many as 40 leukocytes per μL, 100% of which were lymphocytes. In the citology analysis of the CSF, numerous lymphoid blasts were seen. By molecular studies, all cells showed monoclonality for the rearrangement of the T-cell γδ receptor gene, which demonstrated the T-cell
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1557-9190, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
546 • Clinical Lymphoma & Myeloma September 2007
Figure 1 Spinal Magnetic Resonance Imaging Scan Before Treatment
Figure 2 Spinal Magnetic Resonance Imaging Scan After Treatment
Lumbar segment, before treatment.
Lumbar segment, March 2006.
origin of the malignant cells. All microbiologic studies of the CSF, including for syphilis, mycobacteria, and fungii, were negative. A total body computed tomography scan and a bone marrow biopsy were normal. No signs of systemic sarcoidosis were seen. No evidence of HIV infection was found. The final diagnosis was of a PML of T-cell lineage. We began systemic chemotherapy in March until July 2003 with fortnightly, alternating cycles of high-dose methotrexate (3.5 g/m2) with leucovorin rescue and cytarabine (2 g/m2) for 6 cycles. The patient was also implanted with an Ommaya intraventricular reservoir and given intraventricular triple chemotherapy with methotrexate, cytarabine, and hydrocortisone twice a week until the CSF was clear of malignant cells. Tolerance of treatment was acceptable except for an episode of meningitis secondary to coagulase-negative staphylococci after the first cycle of chemotherapy, which resolved with antibiotic therapy with vancomycin. There was a clear clinical improvement from the outset of treatment, with a quick improvement in his physical condition, and the flaccid paralysis was partially resolved. After 6 cycles of treatment, the patient had complete remission of the disease, with no abnormalities seen in the CSF analysis and in the control MRI (Figure 2). In June 2004, a ventriculoperitoneal shunt was performed because of secondary obstructive hydrocephaly; at that time, there was no evidence of active malignant disease. In March 2006, after 38 months from the initial diagnosis, the patient is in follow-up in our outpatient clinic, and he leads a normal life.
spinal cord, the eye, and the leptomeninges, and where there is no actual evidence or previous history of systemic lymphoma.3 Primary meningeal lymphomas are PCNSLs in which there is no intraparenchymal cerebral mass at diagnosis and during the course of the disease. They are very infrequent, representing approximately 7% of all PCNSL.4 The symptoms at diagnosis can be quite varied, reflecting the widespread location of the leptomeninges, from an increase in intracranial pressure to multirradiculopathies,2 as was our case. Because of the aggressive nature of the disorders, they usually precede the definitive diagnosis for a short period of time of 2-3 months, although longer intervals of 3 years have been described.5 The brain and spinal cord MRI with gadolinium is the preferred imaging technique to evaluate meningeal infiltration and to rule out intraparenchymal masses.6 Although there have been no series that especially looked at the MRI characteristics of lymphomatous meningitis, the findings are thought to be similar to those of leptomeningeal carcinomatosis.7 Cranial imaging might show enhancement or enlargement of the cranial nerves, communicating hydrocephalus or superficial linear leptomeningeal enhancement. The most common spinal imaging abnormality is diffuse thickening of the nerve roots, which enhance after the administration of gadolinium, although nodular deposits can occasionally be seen. Calcification of the meninges is rare but was reported in 1 case of marginal zone B-cell PML.8 However, the definitive diagnosis of a PML requires a pathologic confirmation of presence of the lymphomatous cells, usually with a thorough analysis of the CSF. As is common in most meningeal infiltrations, the protein count is usually elevated, and there is a low glucose value in up to a third of patients.9 The CSF cytologic diagnosis of malignancy can be notoriously
Discussion Primary central nervous system lymphomas are defined as those extranodal non-Hodgkin lymphomas that appear in the brain, the
Clinical Lymphoma & Myeloma September 2007 • 547
A Rare Presentation of Primary CNS Lymphomas difficult because the false-negative rate with single samples of CSF can be high, and several successive CSF samples should be done. The sensitivity of detecting malignant cytology in the CSF has been increased with the use of immunophenotyping and molecular-based techniques.10 In some cases, a meningeal biopsy is needed for definitive diagnosis, although this can be technically difficult. Unfortunately, in some cases, the diagnosis is reached in the necropsy.11 Although the large majority of PCNSLs are of B-cell origin, T-cell lesions are occasionally seen, and case reports have been described.12-16 The prognosis of PML is poor in most published cases because of the extensive nature of the disease and the poor performance status of patients with multiple neurologic lesions. In the series reported by Lachance and colleagues, the median survival was 8 months, but 2 patients were alive > 1-2 years after diagnosis.2 In effect, in a few cases of PML with indolent histologies, long survival times have been found with no treatment. In particular, a patient was diagnosed with a meningeal biopsy of a B-cell marginal zone PML after 3 years of symptoms.8 The available treatment modalities include irradiation, intrathecal and systemic chemotherapy, and surgery. Many times, all 3 therapeutic modalities are used conjunctionally.1 Surgery is used when necessary for placement of an indwelling intraventricular access device (Ommaya reservoir) or a ventriculoperitoneal shunt. Irradiation in a dose equivalent to 30 Gy in 10 fractions is usually delivered to the most symptomatic area of the neuraxis. This method can consist of irradiation to the whole brain and base of skull for patients with cranial polyneuropathies, cauda equine irradiation for patients with low back pain and leg weakness, or irradiation to more focal fields to relieve radicular pain.17 Because most patients with leptomeningeal lymphoma have disease disseminated throughout the neuraxis, it is tempting to contemplate treatment with total craniospinal irradiation. However, the morbidity of this treatment precludes its applicability abroad. An easier way to treat widespread disease is with chemotherapy (systemic, intrathecal, or both). Intrathecal chemotherapy has been the principal and traditional treatment for lymphomatous meningitis. The drugs can be delivered by lumbar puncture or directly into the ventricular system by way of an Ommaya reservoir. The latter is the preferred method of drug delivery because administration is simpler and safer and distribution is superior compared with repeated lumbar punctures.18 Ommaya reservoir placement is generally safe, although in 1 retrospective series, serious complications including infections, catheter malposition, and intracranial hemorrhage were noted in 10% of the patients.19 In that same series, 10% of the patients required insertion of a ventriculoperitoneal shunt instead to relieve symptoms of raised intracranial pressure caused by communicating hydrocephalus. The ventriculoperitoneal shunt is an effective palliative intervention that usually results in prompt clinical improvement.18 When intrathecal chemotherapy is used, methotrexate and/or cytarabine are typically administered as single agents, alternately or in conjunction twice a week until the CSF is clear of malignant
548 • Clinical Lymphoma & Myeloma September 2007
cells. The frequency of administration can then be reduced to once weekly and then monthly as long as symptoms improve and toxicity is minimal.1 Acute side effects such as headache, nausea, vomiting, or fever are usually a result of chemical meningitis. These symptoms are generally preventable with intrathecal steroids (hydrocortisone), and sometimes a brief course of intravenous (I.V.) or oral steroids is needed. A sustained-release preparation of cytarabine is available, which maintains cytotoxic concentrations of drug in the CSF for > 14 days. It appears to have comparable efficacy to conventional intrathecal methotrexate with the convenience of less frequent administration.20 Traditionally, treatment of these rare conditions has been based in the use of craniospinal radiation therapy (RT) and/ or intrathecal chemotherapy, with generally poor long-term results. Also, chronic leukoencephalopathy and severe longterm neurologic disability are described, especially in younger patients and when the 2 modalities were combined.2 Regardless of which agent is given, drugs injected into the subarachnoid space can penetrate, at most, only a few millimeters into a tumor nodule and rely on bulk flow of the CSF to be distributed widely. Systemic I.V. chemotherapy permeates a disrupted blood brain barrier and is delivered to areas of bulk disease by way of the circulation, making this method of drug delivery an appealing option. High-dose methotrexate, at doses > 3 g/m2, can achieve therapeutic concentration comparable with that seen when methotrexate is delivered intrathecally, but the I.V. route of delivery might also be more effective in clearing malignant cells from the subarachnoid space.21 Also, it is known that high-dose methotrexate with leucovorin rescue before RT improves overall survival and response rates compared with exclusive RT in all patients diagnosed with PCNSL.22 It would seem probable that the subgroup of patients with PML would also benefit from this systemic treatment. Other chemotherapy agents active in lymphomas that penetrate the blood-barrier membrane and could benefit these patients, include cytarabine,23 vincristine, procarbazine, tiothepa, nitrosureas, and teniposide. However, their exact role alongside methotrexate still needs to be established.24
Conclusion Primary meningeal lymphoma is a rare form of PCNSL, with a poor overall prognosis, except in some patients with indolent histologies. There is no standard treatment because of the small number of patients involved. It seems reasonable to give systemic chemotherapy based in high-dose methotrexate. The role of intrathecal chemotherapy is unclear. Radiation therapy should be reserved to patients whose disease does not respond to chemotherapy or to those who experience progression after treatment and retain a good performance status.
References 1. Shenkier TN. Unusual variants of primary central nervous system lymphoma. Hematol Oncol Clin North Am 2005; 19:651-664. 2. Lachance DH, O’Neill BP, Macdonald DR, et al. Primary leptomeningeal lymphoma: report of 9 cases, diagnosis with immunocytochemical analysis, and review of the literature. Neurology 1991; 41:95-100. 3. Henry JM, Heffner RR Jr, Drillard SH, et al. Primary malignant lym-
Jose Ponce et al phomas of the central nervous system. Cancer 1974; 34:1293-1302. 4. Hochberg FH, Miller DC. Primary central nervous system lymphoma. J Neurosurgery 1988; 835:868. 5. Kim HJ, Ha CK, Jeon BS. Primary leptomeningeal lymphoma with long-term survival: a case report. J Neurooncol 2000; 48:47-49. 6. Carlson CL, Hartman R, Ly JQ, et al. Primary leptomeningeal lymphoma of the lumbar spine. Clin Imaging 2003; 27:389-393. 7. Gomori JM, Heching N, Siegal T. Leptomeningeal metastases: evaluation by gadolinium enhanced spinal magnetic resonance imaging. J Neurooncol 1998; 36:55-60. 8. King A, Wilson H, Penney C, et al. An inusual case of primary leptomeningeal marginal zone B-cell lymphoma. Clin Neuropathology 1998; 17:326-329. 9. Balmaceda C, Gaynor JJ, Sun M, et al. Leptomeningeal tumor in primary central nervous system lymphoma: recognition, significance, and implications. Ann Neurol 1995; 38:202-209. 10. Rhodes CH, Glantz MJ, Glantz L, et al. A comparison of polymerase chain reaction examination of cerebrospinal fluid and conventional cytology in the diagnosis of lymphomatous meningitis. Cancer 1996; 77:543-548. 11. Gardiner J, De Graaf AS, Hewlett RH. Diagnostic problems of leptomeningeal lymphoma. A report of 3 cases. S Afr Med J 1987; 71:457459. 12. Gitjenbeek JM, Rosenblum MK, DeAngelis LM. Primary central nervous system T-cell lymphoma. Neurology 2001; 57:716-718. 13. McCue MP, Sandrock AW, Lee JM, et al. Primary T-cell lymphoma of the brainstem. Neurology 1993; 43:377-381. 14. Ponzoni M, Terreni MR, Ciceri F, et al. Primary brain CD30+ ALK1+ anaplastic large cell lymphoma (“ALKoma”): the first case with a com-
bination of “not common” variants. Ann Oncol 2002; 13:1827-1832. 15. Villegas E, Villa S, Lopez-Guillermo A, et al. Primary central nervous system lymphoma of T-cell origin: description of two cases and review of the literature. J Neurooncol 1997; 34:157-161. 16. Groove A, Vyberg M. Primary leptomeningeal T-cell lymphoma: a case and a review of primary T-cell lymphoma of the central nervous system. Clin Neuropathology 1993; 12:7-12. 17. Gray JR, Wallner KE. Reversal of cranial nerve dysfunction with radiation therapy in adults with lymphoma and leukemia. Int J Radiat Oncol Biol Phys 1990; 19:439-444. 18. De Angelis LM. Current diagnosis and treatment of leptomeningeal metastasis. J Neurooncol 1998; 38:245-252. 19. Sandberg DI, Bilsky MH, Souweidane MM, et al. Ommaya reservoirs for the treatment of leptomeningeal metastases. Neurosurgery 2000; 47:49-54. Discussion 54-55. 20. Glantz MJ, LaFollete S, Jaeckle KA, et al. Randomized trial of a showrelease versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis. J Clin Oncol 1999; 17:31103116. 21. Glantz MJ, Cole BF, Recht L, et al. High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy necessary? J Clin Oncol 1998; 16:1561-1567. 22. De Angelis LM. Primary CNS lymphoma: treatment with combined chemotherapy and radiotherapy. J Neurooncology 1999; 43:249-257. 23. Pels H, Deckert-Schluter M, Glasmacher A, et al. Primary central nervous system lymphoma: a clinicopathological study of 28 cases. Hematol Oncol 2000; 18:21-32. 24. Hoang-Xuan K, Delattre JY. Ongoing protocols for non-AIDS primary nervous central system lymphoma. J Neurooncol 1999; 43:287-291.
Abstract Primary meningeal lymphoma is a rare clinical entity. Central nervous system infiltration by systemic lymphoma should always be excluded. Diagnosis can be difficult, and prognosis is usually poor. Most are of B-cell origin. We present the case of a young man with a primary meningeal lymphoma of T-cell origin. He was treated with systemic chemotherapy with high-dose methotrexate and cytarabine and intraventricular chemotherapy. He had a clinical improvement and a complete remission, with a long overall survival. There is no standard treatment for this rare disease. Traditionally, treatment has been based in craniospinal radiation therapy and intrathecal chemotherapy, with poor overall results. More recently, systemic chemotherapy with high-dose methotrexate has been advocated, which could avoid the long-term toxicity of craniospinal radiation therapy, and could improve the prognosis of these patients.
Clinical Lymphoma & Myeloma, Vol. 7, No. 8, 546-549, 2007 Key words: Craniospinal radiation therapy, High-dose methotrexate, Intrathecal chemotherapy, Non-Hodgkin lymphoma, T-cell lymphoma
Introduction Primary meningeal lymphoma (PML), with no parenchymal cerebral mass or systemic dissemination at diagnosis or during the course of the disease, is a rare form of presentation of the primary central nervous system lymphomas (PCNSLs).1 Prognosis is usually poor, and most cases published are of Bcell origin.2 However, in this article, we report the case of a 34-year-old man diagnosed with a PML of T-cell lineage. He was treated with systemic and intraventricular chemotherapy and had complete remission of the disease. We also review the published literature of this infrequent disease and the scant recommendations regarding the optimal diagnosis and treatment of the condition.
Case Report A 34-year-old man, with no past medical history of interest, was admitted in our hospital in February 2003 with a 2-month Medical Oncology Unit, University Hospital La Fe, Valencia, Spain Submitted: Apr 19, 2006; Revised: May 17, 2006; Accepted: May 21, 2006 Address for correspondence: Jose Ponce, MD, University Hospital La Fe, Avda. Campanar 21, 46009 Valencia, Spain Fax: 96-197-3138; e-mail: [email protected]
history of progressive bilateral leg weakness and patchy lower limb paresthesias. The general physical examination showed a chronically ill patient who was afebrile, with normal consciousness and without meningismus or deficits in higher cortical functions. He had an Eastern Cooperative Oncology Group performance status of 2. The neurologic examination revealed a flaccid paralysis of the lower extremities with absent deep-tendon reflexes, no plantar responses, and a diffuse muscular atrophy. There were no laboratory abnormalities. A computed tomography scan and magnetic resonance imaging (MRI) scan of the brain were normal. A spinal MRI was performed and showed signs of a diffuse meningeal infiltration. The lumbar segment was especially affected, with a diffuse thickening and discrete nodular deposits that readily enhanced after the administration of gadolinium (Figure 1). The electromyographic study showed signs of an axonal multirradiculopathy, predominantly in the lower limbs. A diagnostic lumbar puncture was performed. Cerebrospinal fluid (CSF) examination showed low glucose level (35 mg/dL), elevated protein value (80 mg/dL), and as many as 40 leukocytes per μL, 100% of which were lymphocytes. In the citology analysis of the CSF, numerous lymphoid blasts were seen. By molecular studies, all cells showed monoclonality for the rearrangement of the T-cell γδ receptor gene, which demonstrated the T-cell
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1557-9190, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
546 • Clinical Lymphoma & Myeloma September 2007
Figure 1 Spinal Magnetic Resonance Imaging Scan Before Treatment
Figure 2 Spinal Magnetic Resonance Imaging Scan After Treatment
Lumbar segment, before treatment.
Lumbar segment, March 2006.
origin of the malignant cells. All microbiologic studies of the CSF, including for syphilis, mycobacteria, and fungii, were negative. A total body computed tomography scan and a bone marrow biopsy were normal. No signs of systemic sarcoidosis were seen. No evidence of HIV infection was found. The final diagnosis was of a PML of T-cell lineage. We began systemic chemotherapy in March until July 2003 with fortnightly, alternating cycles of high-dose methotrexate (3.5 g/m2) with leucovorin rescue and cytarabine (2 g/m2) for 6 cycles. The patient was also implanted with an Ommaya intraventricular reservoir and given intraventricular triple chemotherapy with methotrexate, cytarabine, and hydrocortisone twice a week until the CSF was clear of malignant cells. Tolerance of treatment was acceptable except for an episode of meningitis secondary to coagulase-negative staphylococci after the first cycle of chemotherapy, which resolved with antibiotic therapy with vancomycin. There was a clear clinical improvement from the outset of treatment, with a quick improvement in his physical condition, and the flaccid paralysis was partially resolved. After 6 cycles of treatment, the patient had complete remission of the disease, with no abnormalities seen in the CSF analysis and in the control MRI (Figure 2). In June 2004, a ventriculoperitoneal shunt was performed because of secondary obstructive hydrocephaly; at that time, there was no evidence of active malignant disease. In March 2006, after 38 months from the initial diagnosis, the patient is in follow-up in our outpatient clinic, and he leads a normal life.
spinal cord, the eye, and the leptomeninges, and where there is no actual evidence or previous history of systemic lymphoma.3 Primary meningeal lymphomas are PCNSLs in which there is no intraparenchymal cerebral mass at diagnosis and during the course of the disease. They are very infrequent, representing approximately 7% of all PCNSL.4 The symptoms at diagnosis can be quite varied, reflecting the widespread location of the leptomeninges, from an increase in intracranial pressure to multirradiculopathies,2 as was our case. Because of the aggressive nature of the disorders, they usually precede the definitive diagnosis for a short period of time of 2-3 months, although longer intervals of 3 years have been described.5 The brain and spinal cord MRI with gadolinium is the preferred imaging technique to evaluate meningeal infiltration and to rule out intraparenchymal masses.6 Although there have been no series that especially looked at the MRI characteristics of lymphomatous meningitis, the findings are thought to be similar to those of leptomeningeal carcinomatosis.7 Cranial imaging might show enhancement or enlargement of the cranial nerves, communicating hydrocephalus or superficial linear leptomeningeal enhancement. The most common spinal imaging abnormality is diffuse thickening of the nerve roots, which enhance after the administration of gadolinium, although nodular deposits can occasionally be seen. Calcification of the meninges is rare but was reported in 1 case of marginal zone B-cell PML.8 However, the definitive diagnosis of a PML requires a pathologic confirmation of presence of the lymphomatous cells, usually with a thorough analysis of the CSF. As is common in most meningeal infiltrations, the protein count is usually elevated, and there is a low glucose value in up to a third of patients.9 The CSF cytologic diagnosis of malignancy can be notoriously
Discussion Primary central nervous system lymphomas are defined as those extranodal non-Hodgkin lymphomas that appear in the brain, the
Clinical Lymphoma & Myeloma September 2007 • 547
A Rare Presentation of Primary CNS Lymphomas difficult because the false-negative rate with single samples of CSF can be high, and several successive CSF samples should be done. The sensitivity of detecting malignant cytology in the CSF has been increased with the use of immunophenotyping and molecular-based techniques.10 In some cases, a meningeal biopsy is needed for definitive diagnosis, although this can be technically difficult. Unfortunately, in some cases, the diagnosis is reached in the necropsy.11 Although the large majority of PCNSLs are of B-cell origin, T-cell lesions are occasionally seen, and case reports have been described.12-16 The prognosis of PML is poor in most published cases because of the extensive nature of the disease and the poor performance status of patients with multiple neurologic lesions. In the series reported by Lachance and colleagues, the median survival was 8 months, but 2 patients were alive > 1-2 years after diagnosis.2 In effect, in a few cases of PML with indolent histologies, long survival times have been found with no treatment. In particular, a patient was diagnosed with a meningeal biopsy of a B-cell marginal zone PML after 3 years of symptoms.8 The available treatment modalities include irradiation, intrathecal and systemic chemotherapy, and surgery. Many times, all 3 therapeutic modalities are used conjunctionally.1 Surgery is used when necessary for placement of an indwelling intraventricular access device (Ommaya reservoir) or a ventriculoperitoneal shunt. Irradiation in a dose equivalent to 30 Gy in 10 fractions is usually delivered to the most symptomatic area of the neuraxis. This method can consist of irradiation to the whole brain and base of skull for patients with cranial polyneuropathies, cauda equine irradiation for patients with low back pain and leg weakness, or irradiation to more focal fields to relieve radicular pain.17 Because most patients with leptomeningeal lymphoma have disease disseminated throughout the neuraxis, it is tempting to contemplate treatment with total craniospinal irradiation. However, the morbidity of this treatment precludes its applicability abroad. An easier way to treat widespread disease is with chemotherapy (systemic, intrathecal, or both). Intrathecal chemotherapy has been the principal and traditional treatment for lymphomatous meningitis. The drugs can be delivered by lumbar puncture or directly into the ventricular system by way of an Ommaya reservoir. The latter is the preferred method of drug delivery because administration is simpler and safer and distribution is superior compared with repeated lumbar punctures.18 Ommaya reservoir placement is generally safe, although in 1 retrospective series, serious complications including infections, catheter malposition, and intracranial hemorrhage were noted in 10% of the patients.19 In that same series, 10% of the patients required insertion of a ventriculoperitoneal shunt instead to relieve symptoms of raised intracranial pressure caused by communicating hydrocephalus. The ventriculoperitoneal shunt is an effective palliative intervention that usually results in prompt clinical improvement.18 When intrathecal chemotherapy is used, methotrexate and/or cytarabine are typically administered as single agents, alternately or in conjunction twice a week until the CSF is clear of malignant
548 • Clinical Lymphoma & Myeloma September 2007
cells. The frequency of administration can then be reduced to once weekly and then monthly as long as symptoms improve and toxicity is minimal.1 Acute side effects such as headache, nausea, vomiting, or fever are usually a result of chemical meningitis. These symptoms are generally preventable with intrathecal steroids (hydrocortisone), and sometimes a brief course of intravenous (I.V.) or oral steroids is needed. A sustained-release preparation of cytarabine is available, which maintains cytotoxic concentrations of drug in the CSF for > 14 days. It appears to have comparable efficacy to conventional intrathecal methotrexate with the convenience of less frequent administration.20 Traditionally, treatment of these rare conditions has been based in the use of craniospinal radiation therapy (RT) and/ or intrathecal chemotherapy, with generally poor long-term results. Also, chronic leukoencephalopathy and severe longterm neurologic disability are described, especially in younger patients and when the 2 modalities were combined.2 Regardless of which agent is given, drugs injected into the subarachnoid space can penetrate, at most, only a few millimeters into a tumor nodule and rely on bulk flow of the CSF to be distributed widely. Systemic I.V. chemotherapy permeates a disrupted blood brain barrier and is delivered to areas of bulk disease by way of the circulation, making this method of drug delivery an appealing option. High-dose methotrexate, at doses > 3 g/m2, can achieve therapeutic concentration comparable with that seen when methotrexate is delivered intrathecally, but the I.V. route of delivery might also be more effective in clearing malignant cells from the subarachnoid space.21 Also, it is known that high-dose methotrexate with leucovorin rescue before RT improves overall survival and response rates compared with exclusive RT in all patients diagnosed with PCNSL.22 It would seem probable that the subgroup of patients with PML would also benefit from this systemic treatment. Other chemotherapy agents active in lymphomas that penetrate the blood-barrier membrane and could benefit these patients, include cytarabine,23 vincristine, procarbazine, tiothepa, nitrosureas, and teniposide. However, their exact role alongside methotrexate still needs to be established.24
Conclusion Primary meningeal lymphoma is a rare form of PCNSL, with a poor overall prognosis, except in some patients with indolent histologies. There is no standard treatment because of the small number of patients involved. It seems reasonable to give systemic chemotherapy based in high-dose methotrexate. The role of intrathecal chemotherapy is unclear. Radiation therapy should be reserved to patients whose disease does not respond to chemotherapy or to those who experience progression after treatment and retain a good performance status.
References 1. Shenkier TN. Unusual variants of primary central nervous system lymphoma. Hematol Oncol Clin North Am 2005; 19:651-664. 2. Lachance DH, O’Neill BP, Macdonald DR, et al. Primary leptomeningeal lymphoma: report of 9 cases, diagnosis with immunocytochemical analysis, and review of the literature. Neurology 1991; 41:95-100. 3. Henry JM, Heffner RR Jr, Drillard SH, et al. Primary malignant lym-
Jose Ponce et al phomas of the central nervous system. Cancer 1974; 34:1293-1302. 4. Hochberg FH, Miller DC. Primary central nervous system lymphoma. J Neurosurgery 1988; 835:868. 5. Kim HJ, Ha CK, Jeon BS. Primary leptomeningeal lymphoma with long-term survival: a case report. J Neurooncol 2000; 48:47-49. 6. Carlson CL, Hartman R, Ly JQ, et al. Primary leptomeningeal lymphoma of the lumbar spine. Clin Imaging 2003; 27:389-393. 7. Gomori JM, Heching N, Siegal T. Leptomeningeal metastases: evaluation by gadolinium enhanced spinal magnetic resonance imaging. J Neurooncol 1998; 36:55-60. 8. King A, Wilson H, Penney C, et al. An inusual case of primary leptomeningeal marginal zone B-cell lymphoma. Clin Neuropathology 1998; 17:326-329. 9. Balmaceda C, Gaynor JJ, Sun M, et al. Leptomeningeal tumor in primary central nervous system lymphoma: recognition, significance, and implications. Ann Neurol 1995; 38:202-209. 10. Rhodes CH, Glantz MJ, Glantz L, et al. A comparison of polymerase chain reaction examination of cerebrospinal fluid and conventional cytology in the diagnosis of lymphomatous meningitis. Cancer 1996; 77:543-548. 11. Gardiner J, De Graaf AS, Hewlett RH. Diagnostic problems of leptomeningeal lymphoma. A report of 3 cases. S Afr Med J 1987; 71:457459. 12. Gitjenbeek JM, Rosenblum MK, DeAngelis LM. Primary central nervous system T-cell lymphoma. Neurology 2001; 57:716-718. 13. McCue MP, Sandrock AW, Lee JM, et al. Primary T-cell lymphoma of the brainstem. Neurology 1993; 43:377-381. 14. Ponzoni M, Terreni MR, Ciceri F, et al. Primary brain CD30+ ALK1+ anaplastic large cell lymphoma (“ALKoma”): the first case with a com-
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