Intravascular CNS lymphoma: Successful therapy using high-dose methotrexate-based polychemotherapy

  • Sied Kebir1,

    Affiliated with

    • Klaus Kuchelmeister3,

      Affiliated with

      • Pitt Niehusmann3,

        Affiliated with

        • Michael Nelles2,

          Affiliated with

          • Young Kim4,

            Affiliated with

            • Sharmilan Thanendrarajan4,

              Affiliated with

              • Niklas Schäfer1,

                Affiliated with

                • Moritz Stuplich1,

                  Affiliated with

                  • Frederic Mack1,

                    Affiliated with

                    • Björn Scheffler5,

                      Affiliated with

                      • Horst Urbach2,

                        Affiliated with

                        • Martin Glas1, 5 and

                          Affiliated with

                          • Ulrich Herrlinger1Email author

                            Affiliated with

                            Experimental Hematology & Oncology20121:37

                            DOI: 10.1186/2162-3619-1-37

                            Received: 25 October 2012

                            Accepted: 24 November 2012

                            Published: 5 December 2012

                            Abstract

                            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.

                            Keywords

                            Intravascular lymphoma Intravascular CNS lymphoma High-dose methotrexate-based polychemotherapy Angioendotheliomatosis Angiotropic lymphoma

                            Background

                            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 [14]. 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.

                            Case presentation

                            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.
                            http://static-content.springer.com/image/art%3A10.1186%2F2162-3619-1-37/MediaObjects/40164_2012_Article_36_Fig1_HTML.jpg
                            Figure 1

                            MR imaging prior to and after HD-MTX-based chemotherapy (left column FLAIR, right column: contrast enhanced T1-weighted imaging)MR imaging prior to therapy (A) and at follow-up imaging at the end of 6 courses of chemotherapy with a strong reduction of contrast-enhancing lesions (B). Nineteen months after initiation of treatment MR imaging showed complete regression of marked FLAIR hyperintensities and contrast enhancement in the brain stem (C).

                            http://static-content.springer.com/image/art%3A10.1186%2F2162-3619-1-37/MediaObjects/40164_2012_Article_36_Fig2_HTML.jpg
                            Figure 2

                            Histological examination of the tissue obtained by stereotactic biopsy of the brain stem. Histology revealed CD20-immunopositive intravascular lymphoma cells (A) with a very high proliferative activity in MIB-1 immunohistochemistry (B).

                            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 [5]). 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 [69]. Conventional chemotherapy with anthracyline-based protocols (i.e. CHOP in 3 patients), radiotherapy, or corticosteroid therapy was not successful [1012]. 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 [13]. 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 [4]. 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.
                            Table 1

                            Summary of all patients with intravascular lymphomatosis limited to the CNS (cIVL) reported in the literature

                            Author

                            Site of involvement

                            Neurological symptoms

                            Treatment

                            Outcome

                            Baehring et al. [1]

                            Brain

                            Right hemiparesis, dysarthria

                            HD-MTX (induction 5, consolidation 10, maintenance 2)

                            CR 20 months after diagnosis

                            Baehring et al. [1]

                            Brain, spinal cord

                            Proximal spastic paraparesis, psychosis

                            HD-MTX (induction 12)

                            PR 18 months after diagnosis

                            Baehring et al. [1]

                            Brain, nerve roots

                            Dysarthria, gait disturbance, allodynia

                            HD-MTX initially (induction 6, consolidation 4), HD-MTX salvage (6 induction, 7 consolidation)

                            PR until 8 months after diagnosis: PR until 12 months after recurrence

                            Baehring et al. [1]

                            Brain

                            Cognitive decline, homonymous hemianopsia, ataxia

                            HD-MTX (induction 1 cycle)

                            Died of disease progression after first cycle of chemotherapy

                            Calamia et al. [15]

                            CNS

                            NA

                            m-BACOD

                            OS 16 months

                            Calamia et al. [15]

                            CNS

                            NA

                            Pro-MACE-CytaBOM

                            OS 44 months

                            Bergmann et al. [6]

                            Brain

                            Left-sided hemiparesis

                            NA

                            OS 2 months

                            Bergmann et al. [6]

                            Brain

                            Spastic paraparesis, left arm paresis

                            NA

                            OS 2 months

                            DiGiuseppe et al. [3]

                            Brain

                            Mental status changes

                            Pro-MACE-CytaBOM, ifosfamide/VP-16/cisplatin & whole brain irradiation (45 Gy)

                            CR 48 months after diagnosis

                            Kanda et al. [16]

                            CNS

                            Aphasia, apraxia

                            CHOP, VEMP, radiotherapy

                            OS one month

                            Aznar et al. [7]

                            CNS

                            Distal paresthesia of the lower limbs, paraparesis

                            NA

                            OS few months

                            Passarin [8]

                            Brain

                            Progressive cognitive deterioration, tetraparesis

                            NA

                            OS 3–4 weeks

                            Natali-Sora et al. [17]

                            CNS

                            Generalized tonic-clonic seizures

                            Cyclophosphamide, mitoxantrone, BCNU, methylprednisolone

                            CR 46 months after diagnosis

                            Liow et al. [18]

                            CNS

                            NA

                            CHOP

                            OS 13 months

                            Albrecht et al. [9]

                            Brain

                            Cognitive deterioration, aphasia

                            NA

                            OS few weeks

                            Ferreri et al. [10]

                            CNS

                            NA

                            CHOP (3 patients), CVP (one patient)

                            OS less than 4 months

                            Holmøy et al. [12]

                            Brain

                            vertigo, diplopia, left-sided hearing loss, aphasia

                            high-dose corticosteroid pulse therapy

                            OS 18 weeks

                            Momota et al. [14]

                            Brain

                            Left-sided hemiparesis

                            HD-MTX, whole brain irradiation

                            OS 6 months

                            This case

                            Brain

                            Transient amnestic aphasia, gait ataxia

                            Bonn protocol + rituximab

                            CR 29 months after diagnosis

                            Abbreviations: HD-MTX: high dose methotrexate; CR: complete remssion; PR: partial response; NA: not available; OS: overall survival; m-BACOD: cyclophosphamide, doxorubicin, vincristine, bleomycin, dexamethasone, methotrexate; Pro-MACE-CytaBOM: prednisone, methotrexate (with leucovorin rescue), doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine; VP-16: etoposide; CHOP: cyclophosphamide, doxorubicin, vincristine, prednisolone; VEMP: vincristine, cyclophosphamide, mercaptopurine, prednisolone; CVP: cyclophosphamide, vincristine and prednisone; Bonn protocol: HD-MTX, ifosfamide, procarbazin, cytarabine, vinca alkaloids, dexamethasone.

                            Conclusion

                            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.

                            Consent

                            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.

                            Declarations

                            Authors’ Affiliations

                            (1)
                            Division of Clinical Neurooncology, Department of Neurology, University of Bonn Medical Center, Bonn
                            (2)
                            Department of Radiology, University of Bonn Medical Center, Bonn
                            (3)
                            Department of Neuropathology, University of Bonn Medical Center, Bonn
                            (4)
                            Department of Oncology, University of Bonn Medical Center, Bonn
                            (5)
                            Stem Cell Pathologies, Institute of Reconstructive Neurobiology, University of Bonn Medical Center, Bonn

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                            Copyright

                            © Kebir et al.; licensee BioMed Central Ltd. 2012

                            This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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