J Neurol (2014) 261:1018–1020 DOI 10.1007/s00415-014-7295-x
LETTER TO THE EDITORS
CNS involvement at diagnosis in mantle cell lymphoma with atypical MRI features Ge´raldine Faivre • Julien Lagarde • Sylvain Choquet • Elisabeth Maillart Catherine Lubetzki
•
Received: 14 January 2014 / Revised: 18 February 2014 / Accepted: 20 February 2014 / Published online: 9 March 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Dear Sirs, Mantle cell lymphoma (MCL) is a rare non-Hodgkin Lymphoma (NHL), usually diagnosed in advanced stage diseases, with multiple lymphadenopathies and extranodal site involvement. Central nervous system (CNS) involvement occurs in 4–23 % [1–5] of patients and leads to poorer prognosis, with a median survival of 3 months [4]. MRI shows leptomeningeal enhancement or, more rarely, parenchymal infiltration [1, 2]. We report an unusual case of CNS involvement revealing MCL, with atypical imaging. A 59-year-old man with a recent history of facial nerve palsy and trigeminal hypoesthesia developed confusion within several months, lower extremities spasticity, cerebellar syndrome, and a 20 kg weight loss. Brain and spine MRI showed bilateral asymmetrical T2 hypersignals throughout the CNS with linear, nodular, and perivascular Gadolinium enhancement (Fig. 1). Both white and grey matter were affected, especially brainstem, cerebellum, and internal capsules. Neurosarcoidosis, lymphoma, and CLIPPERS syndrome were thus suspected. Lumbar puncture showed inflammation (14 cells, 0.94 g/L of protein),
G. Faivre J. Lagarde E. Maillart C. Lubetzki Department of Neurology, AP-HP, Pitie´-Salpeˆtrie`re Hospital, Paris, France G. Faivre (&) Neurology Department, Memorial Sloan Kettering Cancer Center, Research Office 7th Floor, 1275 York Avenue, New York, NY 10065, USA e-mail: [email protected]; [email protected] S. Choquet Department of Clinical Hematology, AP-HP Pitie´-Salpeˆtrie`re Hospital, Paris, France
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but no meningitis, either malignant cell or bacterial. More specific studies such as virus PCR and antibodies in the CSF were not accessible, and a brain biopsy was disapproved. In the hypothesis of CLIPPERS syndrome or neurosarcoidosis, high-dose steroids were given and resulted in dramatic clinical and radiological improvement. Corticosteroids were progressively reduced, and 1 year later, the patient worsened, with significant cognitive impairment, severe ataxia, and a tetrapyramidal syndrome. Brain MRI lesions had reappeared and extended, with the same type of perivascular enhancement. Cardiac MRI, chest/abdomen/pelvic scan, complete ophthalmologic exam were normal. Accessory salivary gland biopsy was irrelevant. A large standard blood test, including angiotensin-converting enzyme, HIV serology, and a large autoimmune antibody panel were normal except for an LDH level of 485 UI/L (N \ 248 UI/L). Regulatory T lymphocyte count and Quantiferon tests were also negative. Lumbar puncture showed three cells, 1.13 g/L of protein, reactive non malignant lymphocytes on cytology, and normal IL 10 and IL 6 levels. Finally, blood and CSF flow cytometry and PCR for clonal immunoglobulin gene rearrangement revealed monoclonal lambda CD5? B lymphocytes. Moreover, bone marrow chromosomal studies and histology showed t(11;14) translocation and overexpression of cyclin D1, which led to the diagnosis of stage IV systemic MCL involving the CNS. The patient partially improved with chemotherapy. Rituximab, Dexamethasone, Cytarabine, and intrathecal Methotrexate injections were given in association with Cisplatin because this drug can go through the blood–brain barrier. Unfortunately, 11 days after the start of chemotherapy, he developed a septic shock while on aplasia and subsequently died from a probable macrophagic activation syndrome as a complication of the treatment.
J Neurol (2014) 261:1018–1020
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Fig. 1 Atypical Brain and Spinal cord MRI (a) Brain MRI, FLAIR: bilateral asymmetrical hypersignals around the ventricles (b–c) Brain MRI, T1 with contrast: heterogenous, linear and perivascular
enhancement in both white and grey matter in brainstem and hemispheres (d) Spinal cord MRI, T2 multiple thoracic intra-spinal hypersignals (arrows)
This observation expands the clinical and radiological spectrum of CNS involvement in MCL. Neurological symptoms usually occur at relapse or 12–25 months after the diagnosis [1–4] but exceptionally at presentation [1, 6]. Moreover, the MRI lesions of our patient were atypical (Fig. 1) by their localizations and their aspects. Spinal cord infiltration is rare in NHL and especially in MCL. Brain localizations in NHL are described as similar to Primary CNS Lymphoma lesions (with homogeneous enhancement). Our patient presented with heterogeneous nodular, linear and perivascular enhancing components, improving with steroids, which were first suggestive of sarcoidosis, lymphoma or CLIPPERS syndrome. We must acknowledge that the presence of clonal B lymphocytes in CSF does not necessarily mean CNS involvement: malignant cells can be found in the meninges because of inflammation-induced increased permeability of the blood–brain barrier. However, in our case, CSF clones were present at the same proportion as blood clones and all CSF B lymphocytes were malignant, confirming CNS infiltration by MCL cells. This report illustrates the importance of specific blood and CSF tests in cases of neurological symptoms associated
with atypical leptomeningeal and/or brain lesions in order to rule out NHL disease and especially MCL. These tests should be performed ideally at first and before steroids; in our case, it may have been more useful to have them done before considering CLIPPERS syndrome as a differential diagnosis. CSF flow cytometry and PCR for clonal immunoglobulin gene rearrangement should be studied and result in the identification of monoclonal CD20?, CD19?, and CD5? malignant lymphocytes in case of MCL [7]. In addition, peripheral blood B lymphocyte phenotyping and a bone marrow biopsy are also needed because of frequent bone marrow infiltration in MCL, with or without CNS involvement (50–90 %) [1, 4, 5, 7]. These analyses might avoid a brain biopsy, which can be hazardous and inconclusive if steroids were given. They can also be time saving for these patients whose prognosis is often poor, either because of extension of this aggressive disease or complication of the treatment. Acknowledgments
No funding.
Conflicts of interest On behalf of all authors, the corresponding author states that there is no conflict of interest.
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References 1. Cheah CY, George A, Gine E, Chiappella A, Kluin-Nelemans HC, Jurczak W, Krawczyk K, Mocikova H, Klener P, Salek D, Walewski J, Szymczyk M, Smolej L, Auer RL, Ritchie DS, Arcaini L, Williams ME, Dreyling M, Seymour JF (2013) Central nervous system involvement in mantle cell lymphoma: clinical features, prognostic factors and outcomes from the European Mantle Cell Lymphoma Network. Ann Oncol 24(8):2119–2123. doi:10.1093/annonc/mdt139 2. Conconi A, Franceschetti S, Lobetti-Bodoni C, Stathis A, Margiotta-Casaluci G, Ramponi A, Mazzucchelli L, Bertoni F, Ghielmini M, Gaidano G, Cavalli F, Zucca E (2013) Risk factors of central nervous system relapse in mantle cell lymphoma. Leuk Lymphoma 54(9):1908–1914. doi:10.3109/10428194.2013.767454 3. Montserrat E, Bosch F, Lopez-Guillermo A, Graus F, Terol MJ, Campo E, Rozman C (1996) CNS involvement in mantle-cell lymphoma. J Clin Oncol 14:941–944
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J Neurol (2014) 261:1018–1020 4. Ferrer A, Bosch F, Villamor N, Rozman M, Graus F, Gutierrez G, Mercadal S, Campo E, Rozman C, Lopez-Guillermo A, Montserrat E (2008) Central nervous system involvement in mantle cell lymphoma. Ann Oncol 19(1):135–141. doi:10.1093/annonc/ mdm447 5. Oinonen R, Franssila K, Elonen E (1999) Central nervous system involvement in patients with mantle cell lymphoma. Ann Hematol 78(3):145–149. doi:10.1007/s002770050491 6. Finsterer JM, Lubec DM, Jellinger KM, Mamoli BM (1996) Recovery from coma caused by primary CNS mantle cell lymphoma presenting as encephalitis. Neurology 46(3):824–826 7. Valdez R, Kroft SH, Ross CW, Schnitzer B, Singleton TP, Peterson LC, Finn WG (2002) Cerebrospinal fluid involvement in mantle cell lymphoma. Mod Pathol 15(10):1073–1079. doi:10.1097/01.mp.0000030088.28684.5b
LETTER TO THE EDITORS
CNS involvement at diagnosis in mantle cell lymphoma with atypical MRI features Ge´raldine Faivre • Julien Lagarde • Sylvain Choquet • Elisabeth Maillart Catherine Lubetzki
•
Received: 14 January 2014 / Revised: 18 February 2014 / Accepted: 20 February 2014 / Published online: 9 March 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Dear Sirs, Mantle cell lymphoma (MCL) is a rare non-Hodgkin Lymphoma (NHL), usually diagnosed in advanced stage diseases, with multiple lymphadenopathies and extranodal site involvement. Central nervous system (CNS) involvement occurs in 4–23 % [1–5] of patients and leads to poorer prognosis, with a median survival of 3 months [4]. MRI shows leptomeningeal enhancement or, more rarely, parenchymal infiltration [1, 2]. We report an unusual case of CNS involvement revealing MCL, with atypical imaging. A 59-year-old man with a recent history of facial nerve palsy and trigeminal hypoesthesia developed confusion within several months, lower extremities spasticity, cerebellar syndrome, and a 20 kg weight loss. Brain and spine MRI showed bilateral asymmetrical T2 hypersignals throughout the CNS with linear, nodular, and perivascular Gadolinium enhancement (Fig. 1). Both white and grey matter were affected, especially brainstem, cerebellum, and internal capsules. Neurosarcoidosis, lymphoma, and CLIPPERS syndrome were thus suspected. Lumbar puncture showed inflammation (14 cells, 0.94 g/L of protein),
G. Faivre J. Lagarde E. Maillart C. Lubetzki Department of Neurology, AP-HP, Pitie´-Salpeˆtrie`re Hospital, Paris, France G. Faivre (&) Neurology Department, Memorial Sloan Kettering Cancer Center, Research Office 7th Floor, 1275 York Avenue, New York, NY 10065, USA e-mail: [email protected]; [email protected] S. Choquet Department of Clinical Hematology, AP-HP Pitie´-Salpeˆtrie`re Hospital, Paris, France
123
but no meningitis, either malignant cell or bacterial. More specific studies such as virus PCR and antibodies in the CSF were not accessible, and a brain biopsy was disapproved. In the hypothesis of CLIPPERS syndrome or neurosarcoidosis, high-dose steroids were given and resulted in dramatic clinical and radiological improvement. Corticosteroids were progressively reduced, and 1 year later, the patient worsened, with significant cognitive impairment, severe ataxia, and a tetrapyramidal syndrome. Brain MRI lesions had reappeared and extended, with the same type of perivascular enhancement. Cardiac MRI, chest/abdomen/pelvic scan, complete ophthalmologic exam were normal. Accessory salivary gland biopsy was irrelevant. A large standard blood test, including angiotensin-converting enzyme, HIV serology, and a large autoimmune antibody panel were normal except for an LDH level of 485 UI/L (N \ 248 UI/L). Regulatory T lymphocyte count and Quantiferon tests were also negative. Lumbar puncture showed three cells, 1.13 g/L of protein, reactive non malignant lymphocytes on cytology, and normal IL 10 and IL 6 levels. Finally, blood and CSF flow cytometry and PCR for clonal immunoglobulin gene rearrangement revealed monoclonal lambda CD5? B lymphocytes. Moreover, bone marrow chromosomal studies and histology showed t(11;14) translocation and overexpression of cyclin D1, which led to the diagnosis of stage IV systemic MCL involving the CNS. The patient partially improved with chemotherapy. Rituximab, Dexamethasone, Cytarabine, and intrathecal Methotrexate injections were given in association with Cisplatin because this drug can go through the blood–brain barrier. Unfortunately, 11 days after the start of chemotherapy, he developed a septic shock while on aplasia and subsequently died from a probable macrophagic activation syndrome as a complication of the treatment.
J Neurol (2014) 261:1018–1020
1019
Fig. 1 Atypical Brain and Spinal cord MRI (a) Brain MRI, FLAIR: bilateral asymmetrical hypersignals around the ventricles (b–c) Brain MRI, T1 with contrast: heterogenous, linear and perivascular
enhancement in both white and grey matter in brainstem and hemispheres (d) Spinal cord MRI, T2 multiple thoracic intra-spinal hypersignals (arrows)
This observation expands the clinical and radiological spectrum of CNS involvement in MCL. Neurological symptoms usually occur at relapse or 12–25 months after the diagnosis [1–4] but exceptionally at presentation [1, 6]. Moreover, the MRI lesions of our patient were atypical (Fig. 1) by their localizations and their aspects. Spinal cord infiltration is rare in NHL and especially in MCL. Brain localizations in NHL are described as similar to Primary CNS Lymphoma lesions (with homogeneous enhancement). Our patient presented with heterogeneous nodular, linear and perivascular enhancing components, improving with steroids, which were first suggestive of sarcoidosis, lymphoma or CLIPPERS syndrome. We must acknowledge that the presence of clonal B lymphocytes in CSF does not necessarily mean CNS involvement: malignant cells can be found in the meninges because of inflammation-induced increased permeability of the blood–brain barrier. However, in our case, CSF clones were present at the same proportion as blood clones and all CSF B lymphocytes were malignant, confirming CNS infiltration by MCL cells. This report illustrates the importance of specific blood and CSF tests in cases of neurological symptoms associated
with atypical leptomeningeal and/or brain lesions in order to rule out NHL disease and especially MCL. These tests should be performed ideally at first and before steroids; in our case, it may have been more useful to have them done before considering CLIPPERS syndrome as a differential diagnosis. CSF flow cytometry and PCR for clonal immunoglobulin gene rearrangement should be studied and result in the identification of monoclonal CD20?, CD19?, and CD5? malignant lymphocytes in case of MCL [7]. In addition, peripheral blood B lymphocyte phenotyping and a bone marrow biopsy are also needed because of frequent bone marrow infiltration in MCL, with or without CNS involvement (50–90 %) [1, 4, 5, 7]. These analyses might avoid a brain biopsy, which can be hazardous and inconclusive if steroids were given. They can also be time saving for these patients whose prognosis is often poor, either because of extension of this aggressive disease or complication of the treatment. Acknowledgments
No funding.
Conflicts of interest On behalf of all authors, the corresponding author states that there is no conflict of interest.
123
1020
References 1. Cheah CY, George A, Gine E, Chiappella A, Kluin-Nelemans HC, Jurczak W, Krawczyk K, Mocikova H, Klener P, Salek D, Walewski J, Szymczyk M, Smolej L, Auer RL, Ritchie DS, Arcaini L, Williams ME, Dreyling M, Seymour JF (2013) Central nervous system involvement in mantle cell lymphoma: clinical features, prognostic factors and outcomes from the European Mantle Cell Lymphoma Network. Ann Oncol 24(8):2119–2123. doi:10.1093/annonc/mdt139 2. Conconi A, Franceschetti S, Lobetti-Bodoni C, Stathis A, Margiotta-Casaluci G, Ramponi A, Mazzucchelli L, Bertoni F, Ghielmini M, Gaidano G, Cavalli F, Zucca E (2013) Risk factors of central nervous system relapse in mantle cell lymphoma. Leuk Lymphoma 54(9):1908–1914. doi:10.3109/10428194.2013.767454 3. Montserrat E, Bosch F, Lopez-Guillermo A, Graus F, Terol MJ, Campo E, Rozman C (1996) CNS involvement in mantle-cell lymphoma. J Clin Oncol 14:941–944
123
J Neurol (2014) 261:1018–1020 4. Ferrer A, Bosch F, Villamor N, Rozman M, Graus F, Gutierrez G, Mercadal S, Campo E, Rozman C, Lopez-Guillermo A, Montserrat E (2008) Central nervous system involvement in mantle cell lymphoma. Ann Oncol 19(1):135–141. doi:10.1093/annonc/ mdm447 5. Oinonen R, Franssila K, Elonen E (1999) Central nervous system involvement in patients with mantle cell lymphoma. Ann Hematol 78(3):145–149. doi:10.1007/s002770050491 6. Finsterer JM, Lubec DM, Jellinger KM, Mamoli BM (1996) Recovery from coma caused by primary CNS mantle cell lymphoma presenting as encephalitis. Neurology 46(3):824–826 7. Valdez R, Kroft SH, Ross CW, Schnitzer B, Singleton TP, Peterson LC, Finn WG (2002) Cerebrospinal fluid involvement in mantle cell lymphoma. Mod Pathol 15(10):1073–1079. doi:10.1097/01.mp.0000030088.28684.5b
