- Case report
- Open Access
Intravascular CNS lymphoma: Successful therapy using high-dose methotrexate-based polychemotherapy
Experimental Hematology & Oncology volume 1, Article number: 37 (2012)
Intravascular diffuse large B-cell lymphoma limited to the CNS (cIVL) is a very rare malignant disorder characterized by a selective accumulation of neoplastic lymphocytes (usually B cells) within the lumen of CNS blood vessels but not in the brain parenchyma. In the past, treatment of cIVL with anthracycline-based regimens was unsatisfactory with very short survival times. In the case of cIVL presented here, high-dose methotrexate-based polychemotherapy according to the Bonn protocol plus rituximab therapy was successful and led to a complete clinical and MRI remission which is ongoing 29 months after diagnosis.
Intravascular lymphoma, also known as intravascular lymphomatosis or angiotropic lymphoma and formerly known as malignant angioendotheliomatosis is a rare neoplastic disorder in which tumour cells are initially confined to the vascular lumen without parenchymal infiltration. While cases of systemic intravascular lymphoma are more frequently encountered, cases of intravascular lymphoma with restricted central nervous system (CNS) involvement (cIVL) are uncommon and only few patients that had been successfully treated have been reported so far [1–4]. We here present a case with a histologically confirmed cIVL that could be successfully treated with a high-dose methotrexate (HD-MTX) and rituximab-based chemotherapy regimen.
A 69-year-old male Caucasian patient presented with recurrent transient amnestic aphasia and gait ataxia. Physical examination at the time of referral did not reveal any further pathological findings. B symptoms were absent. Serum LDH levels were twice the upper limit of normal, all other serum chemistry and differential blood count was negative. Cerebrospinal fluid (CSF) analysis revealed a normal cell count, protein levels were within the reference range, no atypical cells were detected. Initial magnetic resonance imaging (MRI) revealed a contrast-enhancing lesion in the pons (Figure 1A) and additional involvement of the left temporomesial area. A stereotactic biopsy was performed and histology revealed a CD20-antigen-expressing intravascular lymphoma with high proliferative activity (Figure 2A, B). Immunohistological evaluation of B-cell differentiation markers showed a BCL-6+ and MUM-1+−status. Subsequent staging (i.e. examination of the chest, abdomen and pelvis by contrast-enhanced computed tomography (CT) scan, bone marrow biopsy, slit lamp examination of the eye, spinal tap) did not reveal any systemic or additional CNS involvement.
Chemotherapy according to the Bonn protocol was initiated in combination with rituximab therapy. The Bonn protocol comprises six 3-week courses with different combinations of HD-MTX (3 gm/m2 over 24 hours), ifosfamide, procarbazin, cytarabine, vinca alkaloids, and dexamethasone (for details see ). Rituximab was given at each course one day prior to the start of the HD-MTX infusion. During the 5th course, a transient and moderate increase in serum creatinine occurred, without a need for dose reduction in subsequent treatment courses. Vincristine was removed from the treatment protocol after development of mild signs of polyneuropathy. After the second course, the contrast-enhancing lesion showed already a partial remission; after the sixth course, only one small contrast-enhancing lesion remained that had to be qualified as unconfirmed complete remission since it further diminished in subsequent control MRIs without additional therapy (Figure 1A-C). The patient is now in complete clinical and radiographic remission 29 months after initial diagnosis of cIVL.
In this case report we demonstrate the successful therapy of a patient with cIVL, i.e. intravascular lymphoma limited to the CNS. The few reports available on the treatment of this medical condition are summarized in Table 1. All cIVL cases in which progression and death due to systemic failure was explicitly mentioned were not included here. In some cases, lymphoma-directed specific therapy was not applied or the treatment modality was not reported. In these cases, survival did not exceed 4 months [6–9]. Conventional chemotherapy with anthracyline-based protocols (i.e. CHOP in 3 patients), radiotherapy, or corticosteroid therapy was not successful [10–12]. Using anthracycline-based chemotherapy which is effective in systemic intravascular lymphoma does not penetrate the intact blood–brain barrier (BBB), overall survival rarely exceeded 6 months. Our case, on the other hand, is in line with reports demonstrating that BBB-penetrating HD-MTX-based regimens may have considerable efficacy. Seven patients treated with HD-MTX alone or in combination with CHOP survived 6–20 months [1, 13, 14]. In a separate study, three patients with cIVL receiving HD-MTX-based chemotherapy showed progression-free survival times of 2, 20 and 48 month [1–3]. One additional case report presented a patient receiving HD-MTX + R-CHOP followed by consolidation therapy with high-dose chemotherapy (thiotepa, busulfan, and cyclophosphamide) and autologous stem-cell rescue. This patient survived for at least 19 months after treatment . It remains unclear why HD-MTX-based, i.e. blood–brain barrier (BBB)-penetrating therapy is needed for successful therapy of cIVL and which are the optimal combination partners for MD-MTX therapy. Also, it is unclear why regimens that do not penetrate the BBB but are effective in other forms of intravascular lymphoma are not successful in cIVL. This is particularly puzzling since all cIVL tumour cells are by histological definition located within the vessels and not beyond in the brain parenchyma.
Overall, on the base of our case and upon reviewing the literature, we recommend the use of HD-MTX-based polychemotherapy similar to HD-MTX-based protocols for primary (parenchymal) CNS lymphoma in patients with cIVL.
Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Baehring JM, Longtine J, Hochberg FH: A new approach to the diagnosis and treatment of intravascular lymphoma. J Neurooncol 2003, 61: 237–48. 10.1023/A:1022588812415
Debiais S, Bonnaud I, Cottier JP, et al.: A spinal cord intravascular lymphomatosis with exceptionally good outcome. Neurology 2004, 63: 1329–30. 10.1212/01.WNL.0000140618.27569.F6
DiGiuseppe JA, Nelson WG, Seifter EJ, Boitnott JK, Mann RB: Intravascular lymphomatosis: a clinicopathologic study of 10 cases and assessment of response to chemotherapy. J Clin Oncol 1994, 12: 2573–9.
Pless ML, Chen YB, Copen WA, Frosch MP: Case records of the Massachusetts General Hospital. Case 9–2010. A 37-year-old woman with paresthesias and ataxia. N Engl J Med 2010, 362: 1129–38. 10.1056/NEJMcpc0910092
Pels H, Schmidt-Wolf IG, Glasmacher A, et al.: Primary central nervous system lymphoma: results of a pilot and phase II study of systemic and intraventricular chemotherapy with deferred radiotherapy. J Clin Oncol 2003, 21: 4489–95. 10.1200/JCO.2003.04.056
Bergmann M, Terzija-Wessel U, Blasius S, et al.: Intravascular lymphomatosis of the CNS: clinicopathologic study and search for expression of oncoproteins and Epstein-Barr virus. Clin Neurol Neurosurg 1994, 96: 236–43. 10.1016/0303-8467(94)90075-2
Aznar AO, Montero MA, Rovira R, Vidal FR: Intravascular large B-cell lymphoma presenting with neurological syndromes: clinicopathologic study. Clin Neuropathol 2007, 26: 180–6.
Passarin MG, Wen PY, Vattemi E, et al.: Intravascular lymphomatosis and intracerebral haemorrhage. Neurol Sci 2010, 31: 793–7. 10.1007/s10072-010-0284-7
Albrecht R, Krebs B, Reusche E, Nagel M, Lencer R, Kretzschmar HA: Signs of rapidly progressive dementia in a case of intravascular lymphomatosis. Eur Arch Psychiatry Clin Neurosci 2005, 255: 232–5. 10.1007/s00406-004-0551-9
Ferreri AJ, Campo E, Ambrosetti A, et al.: Anthracycline-based chemotherapy as primary treatment for intravascular lymphoma. Ann Oncol 2004, 15: 1215–21. 10.1093/annonc/mdh274
Glass J, Hochberg FH, Miller DC: Intravascular lymphomatosis: A systemic disease with neurologic manifestations. Cancer 1993, 71: 3156–64. 10.1002/1097-0142(19930515)71:10<3156::AID-CNCR2820711043>3.0.CO;2-O
Holmøy T, Nakstad PH, Fredø HL, et al.: Intravascular large B-cell lymphoma presenting as cerebellar and cerebral infarction. Arch Neurol 2007, 64: 754–5. 10.1001/archneur.64.5.754
Moussouttas M: Intravascular lymphomatosis presenting as posterior leukoencephalopathy. Arch Neurol 2002, 59: 640–1. 10.1001/archneur.59.4.640
Momota H, Narita Y, Miyakita Y, et al.: Intravascular lymphoma of the central nervous system presenting as multiple cerebral infarctions. Nagoya J Med Sci 2012, 74: 353–8.
Calamia KT, Miller A, Shuster EA, Perniciaro C, Menke DM: Intravascular lymphomatosis. A report of ten patients with central nervous system involvement and a review of the disease process. Adv Exp Med Biol 1999, 455: 249–65. 10.1007/978-1-4615-4857-7_37
Kanda M, Suzumiya J, Ohshima K, Tamura K, Kikuchi M: Intravascular large cell lymphoma: clinicopathological, immuno-histochemical and molecular genetic studies. Leuk Lymphoma 1999, 34: 569–80.
Natali-Sora MG, Lodi M, Corbo M, Hays AP, Nemni R: Intravascular malignant lymphomatosis with neurological symptoms. J Neurol 1996, 243: 205–6. 10.1007/BF02444016
Liow K, Asmar P, Liow M, et al.: Intravascular lymphomatosis: contribution of cerebral MRI findings to diagnosis. J Neuroimaging 2000, 10: 116–8.
The authors declare that they have no competing interests.
Conceived and designed therapy: UH MG. Performed neuroradiologic analysis: HU MN. Neuropathological diagnosis: KK PN. Wrote the paper: SK UH. Performed treatment and participated in collecting data: SK YK ST MS FM NS. All authors read and approved the final manuscript.
Authors’ original submitted files for images
Below are the links to the authors’ original submitted files for images.
Rights and permissions
Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
About this article
Cite this article
Kebir, S., Kuchelmeister, K., Niehusmann, P. et al. Intravascular CNS lymphoma: Successful therapy using high-dose methotrexate-based polychemotherapy. Exp Hematol Oncol 1, 37 (2012). https://doi.org/10.1186/2162-3619-1-37
- Intravascular lymphoma
- Intravascular CNS lymphoma
- High-dose methotrexate-based polychemotherapy
- Angiotropic lymphoma