Fulminant intravascular lymphomatosis mimicking acute haemorrhagic leukoencephalopathy

Journal of the Neurological Sciences 320 (2012) 141–144

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Fulminant intravascular lymphomatosis mimicking acute haemorrhagic leukoencephalopathy D. Marino a, F. Sicurelli a, A. Cerase b, S. Tripodi c, M. Cintorino c, S. Lazzi c, A. Federico a,⁎ a b c

Department of Neurological, Neurosurgical and Behavioural Sciences, University of Siena, Italy Unit NINT Neuroimaging and Neurointervention, Department of Neurological and Sensorial Sciences, University Hospital of Siena, Italy Institute of Pathology, University Hospital of Siena, Italy

a r t i c l e

i n f o

Article history: Received 19 February 2012 Received in revised form 15 April 2012 Accepted 21 May 2012 Available online 21 June 2012 Keywords: Intravascular lymphomatosis IVL Acute haemorrhagic leukoencephalopathy AHLE

a b s t r a c t Background: Intravascular lymphomatosis (IVL) is a rare non-Hodgkin's lymphoma, usually of B cell lineage, characterized by massive angiotropic growth. The clinical presentation of IVL may include changes in mental status, non-localizing neurological deficits, seizures, fever of unknown origin and skin changes. Because of its rarity and the absence of specific diagnostic procedures except for cerebral biopsy, diagnosis is often postmortem. Brain MRI usually shows non-specific abnormalities. The purpose of this case report is to increase the knowledge of clinical and neuroimaging features of IVL by describing the findings observed in a 71year-old patient. Case report: A 71-year-old male was admitted for right hemiparesis, acute cognitive impairment and febricula. A bone marrow biopsy resulted normal. He then developed a rapid progressive impairment of his mental status and left hemisoma motor seizures. Brain CT and MRI were interpreted as consistent with acute haemorrhagic leukoencephalopathy (AHLE), including multiple areas of restricted diffusion without gadolinium enhancement and a small focal area of gadolinium enhancement in the left temporal lobe white matter. The patient died within a few days and the autopsy led to the diagnosis of IVL. Conclusion: IVL may present with a variety of clinical signs and symptoms, including stroke and hemiparesis. IVL may mimic AHLE at brain MRI. However, the evidence of multiple areas of restricted diffusion without gadolinium enhancement and of a small area of gadolinium enhancement could have led to the correct diagnosis. IVL should be added to the differential diagnosis of AHLE at brain MRI. © 2012 Elsevier B.V. All rights reserved.

1. Introduction Intravascular lymphomatosis (IVL) is a rare, aggressive, multifocal large-cell non-Hodgkin's lymphoma, most commonly of B cell lineage, characterized by a massive neoplastic proliferation within the lumens of capillaries, venules and arterioles, with a predilection for the central nervous system (CNS) and skin [1–3]. Other organs may be involved, including kidneys, adrenal glands, liver, lungs, heart, prostate, thyroid gland, pancreas and genital tract, while cerebrospinal fluid (CSF) and haematopoietic organs are typically mostly spared [4–6]. The clinical presentation of IVL is mainly due to vascular occlusions, however it is frequently non-specific and may consist of changes in mental status, multiple neurological deficits, seizures, fever of unknown origin, cutaneous plaques and nodules [1,2,4]. Because of the rarity of this disease, the absence of specific diagnostic procedures except for cerebral biopsy, and the lack of involvement of haematopoietic organs by the neoplastic ⁎ Corresponding author at: Department of Neurological, Neurosurgical and Behavioural Sciences, University of Siena Medical School, Viale Bracci 2, 53100 Siena, Italy. Tel.: + 39 0577585763, + 39 0577585760; fax: + 39 057740327. E-mail address: [email protected] (A. Federico). 0022-510X/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2012.05.043

process, diagnosis may be difficult during life and is often made after autopsy [4,7,8]. The literature reports several cases of IVL associated with different non-specific neuroimaging patterns [2,6,9–12]. The purpose of this case report is to increase the knowledge of clinical and neuroimaging findings regarding IVL by describing an adult patient who died from fulminant IVL. 2. Case report A 71-year-old man under treatment for a history of hypertension had three episodes of acute consciousness disturbance lasting several minutes. Four months later, he started complaining of loss of weight, febricula, nocturnal itching, dizziness and gait disturbances, and was admitted to another hospital. CT of the abdomen showed a lumboaortic lymph node of 2 cm in diameter with benign features. Bone marrow biopsy, chest radiograph and brain MRI were unremarkable. EEG showed left temporal theta waves during hyperpnea. During admission, the patient presented two episodes of transient motor aphasia followed by consciousness disturbances and right hemisoma paresis. Urgent brain CT and MRI (Fig. 1) revealed an acute ischemic

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lesion in the left pons. He was then moved to the Neurology and Neurometabolic Diseases Unit of our institution for pertinent management. At admission, neurological examination showed a soporous patient with total aphasia, right hemisoma motor deficit, asymmetric deep tendon reflexes (right > left). CSF analysis disclosed increased total proteins. After 3 days he started presenting tonic–clonic seizures involving the left hemisoma and ocular bobbing. Brain CT (Fig. 2) showed a large active leukoencephalopathy with small areas of haemorrhagic infarction in the left lenticular nucleus and occipital lobe. Brain MRI (Fig. 3) disclosed the huge extent of the tumefactive haemorrhagic leukoencephalopathy. Areas of non-gadolinium enhancing restricted diffusion were also seen, as well as a focal area of gadolinium enhancement in the left temporal subcortical white matter. A presumptive diagnosis was made of acute haemorrhagic leukoencephalopathy [13]. Antibodies for HIV and neurotropic viruses in the serum were negative. Mycobacteria and Borrelia in the sputum were negative. In the CSF, PCR detection of HSV types 1–2–6–7–8, Cytomegalovirus and Epstein–Barr virus was negative. The patient developed a rapid progressive impairment of consciousness until coma and died 8 days after admission. Only after the patient's death, the results of the CSF cytological analysis revealed the presence of several lymphoblastic cells. Autopsy (Fig. 4) showed multiple localizations of intravascular large B-cell lymphoma (CD20+, CD3−, CD5−, MUM1+, CD10−) in the brain, adrenal glands, kidneys, stomach and lungs, brain microhaemorrhages, acute haemorrhagic gastritis, bronchopneumonia, and acute pulmonary oedema, leading to a diagnosis of IVL with predominant cerebral involvement. In particular, our case was positive for MUM1/IRF and Bcl-2, and negative for CD10 and BCL-6, indicating a postgerminal centre B-cells [14,15].

3. Discussion Intravascular lymphomatosis is an extremely rare and aggressive form of non-Hodgkin's lymphoma, mostly of B-cell lineage, characterized by the proliferation of malignant cells in the lumen of small vessels, with a predilection for the CNS and the skin [1–3]. The estimated age at onset ranges from 41 to 79 years [7] and the prognosis is very poor for two main reasons. Firstly, early intra vitam diagnosis is difficult. Secondly, IVL shows a poor response to chemotherapy, although sporadic cases of remission after aggressive chemotherapy have been reported [4,8]. The frequent delay in diagnosis is probably due to the absence of specific laboratory findings, since the haematopoietic system is usually spared and only anaemia and increased LDH levels or erythrocyte sedimentation rate have occasionally been observed, as well as CSF proteins, as in the case reported here [4,7,16]. The only known specific diagnostic procedure for this disease is cerebral biopsy, but this is very uncommon intra vitam. Macroscopically, multiple, sometimes haemorrhagic, infarcts are distributed within the brain and spinal cord [7]. Microscopically, the characteristic sign is the distension and occlusion of small blood vessels in the brain by large neoplastic mononuclear cells, which appear as noncohesive and free in the lumina and are predominantly of B-cell lineage, although T-cell types have occasionally been observed [4,7]. Although any organ may be affected, the brain and skin are the main targets. This peculiar susceptibility remains unexplained. It is likely that the endothelial cells of these organs have a high binding affinity to the neoplastic cells, which have a deficit of adhesion molecules [3,5]. The predilection of these malignant cells for CNS and skin has a clear correlation with clinical presentation, since patients

Fig. 1. Magnetic resonance (MR) imaging of the brain obtained in another institution on March 9, 2009. Unenhanced serial nonconsecutive fluid attenuated inversion recovery (FLAIR) (a, d, e), diffusion-weighted (DW) (b), axial apparent diffusion coefficient (c), and T2-weighted coronal image (f) MR images, showing an area of high intensity signal on FLAIR, DW, and T2 images and restricted diffusion in the left pons (arrows). Additional findings include a subtle, nonspecific high intensity signal on FLAIR and T2 images of the subcortical white matter in both cerebral hemispheres.

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Fig. 2. Computed tomography (CT) of the brain obtained on April 22, 2009. Serial non-consecutive unenhanced axial CT scans show a clear-cut active leukoencephalopathy associated with small acute/early sub-acute haemorrhagic changes in the left putamen (black arrow) and subcortical white matter in the left occipital lobe (white arrow). The lesion in the left pons (arrowhead) seems consistent with evolution of gliosis and malacia.

mostly present multiple focal neurological deficits, seizures, rapid cognitive impairment and skin changes. Among CD10 negative patients, CD5 positivity has been associated with a higher prevalence of bone marrow/blood involvement and thrombocytopenia, and a lower frequency of neurological abnormalities [14]; in line with this evidence, our patient presented CD10 negativity and CD5 positivity. Neuroimaging findings in patients with IVL are highly variable, ranging from diffuse involvement of the deep white matter, mimicking acute disseminated encephalomyelitis (with or without contrast enhancement), to infarct-like lesions [2,3,6,9–13,17]. The patient presented here developed neuroimaging signs which were interpreted as consistent with AHLE [12,13,17]. Patchy areas of restricted diffusion without gadolinium enhancement have been interpreted as haemorrhagic areas; the alternative diagnosis of neoplastic disease,

such as lymphoma [18], has not been considered. Another sign that could have lead to a diagnosis of lymphoma was the subtle area of contrast enhancement. Most notably, IVL and lymphoma of the brain may present as only slightly contrast-enhancing or even nonenhancing brain lesions [3,6,19]. Finally, only autopsy resulted in the correct diagnosis. Within this context, the left pons ischemia in the patient presented herein might have been the result of intravascular lymphomatosis growth in the vertebrobasilar trunk. However, the autopsy did not show any pathological changes consistent with this hypothesis. AHLE has been associated with many diseases, such as leukaemia, autoimmune diseases, respiratory tract infections, sepsis, herpes simplex infection and other conditions [12,13,17,20–22]. However there is no evidence in the literature of AHLE mimicking IVL. Nevertheless,

Fig. 3. Magnetic resonance (MR) imaging of the brain obtained on April 27, 2009. Serial non-consecutive fluid attenuated inversion recovery (FLAIR) (a), T2*-weighted (b), diffusion-weighted (c), apparent diffusion coefficient (d), unenhanced T1-weighted (e), and gadolinium enhanced T1-weighted (f) axial MR images confirm and clearly show the evolution of gliosis and malacia in the left pons lesion, as well as the diffuse, extensive, tumefactive haemorrhagic leukoencephalopathy with patchy areas of restricted diffusion (arrowheads). A small area of gadolinium enhancement (arrow) can only be seen in the subcortical white matter of the left superior temporal gyrus. Subtle pachymeningeal thickening and gadolinium enhancement seem to result from the previous lumbar puncture.

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Fig. 4. Pathology. a and b (macroscopy): gross examination revealed multiple petechiae and haemorrhagic suffusions in the brainstem (a) and brain (b). c (microscopy): the intravascular cells present pleomorphic and large nuclei (haematoxylin and eosin ×100). Immunohistochemical analysis (inset) shows the nuclear expression of MUM1 antigen (×200).

this particular MRI pattern is associated with a very poor prognosis, as witnessed in our patient. In conclusion, MRI evidence of acute haemorrhagic leukoencephalopathy associated with non-enhancing areas of restricted diffusion should be added to the features of IVL, despite the lack of large or clear-cut areas of gadolinium enhancement. The clinical presentation of IVL may include stroke. Conflict of interest None of the authors have any conflict of interest to disclose. The work described is consistent with the Journal's guidelines for ethical publication. References [1] Demirer T, Dail DH, Aboulafia DM. Four varied cases of intravascular lymphomatosis and a literature review. Cancer 1994;15(73(6)):1738–45.

[2] Williams RL, Meltzer CC, Smirniotopoulos JG, Fukui MB, Inman M. Cerebral MR imaging in intravascular lymphomatosis. AJNR Am J Neuroradiol 1998;19(3): 427–31. [3] Hsu YH, Tseng BY, Shyu WC, Yen PS. Intravascular lymphomatosis mimicking acute disseminated encephalomyelitis: a case report. Kaohsiung J Med Sci 2005;21(2):93–7. [4] Beristain X, Azzarelli B. The neurological masquerade of intravascular lymphomatosis. Arch Neurol 2002;59(3):439–43. [5] Lui PC, Wong GK, Poon WS, Tse GM. Intravascular lymphomatosis. J Clin Pathol 2003;56(6):468–70. [6] Baehring JM, Henchcliffe C, Ledezma CJ, Fulbright R, Hochberg FH. Intravascular lymphoma: magnetic resonance imaging correlates of disease dynamics within the central nervous system. J Neurol Neurosurg Psychiatry 2005;76(4):540–4. [7] Martin-Duverneuil N, Mokhtari K, Behin A, Lafitte F, Hoang-Xuan K, Chiras J. Intravascular malignant lymphomatosis. Neuroradiology 2002;44(9):749–54. [8] Miller DC, Hochberg FH, Harris NL, Gruber ML, Louis DN, Cohen H. Pathology with clinical correlations of primary central nervous system non-Hodgkin's lymphoma. The Massachusetts General Hospital experience 1958–1989. Cancer 15 1994;74(4): 1383–97. [9] Liow K, Asmar P, Liow M, Spanaki M, Townsend JJ, Buys S, et al. Intravascular lymphomatosis: contribution of cerebral MRI findings to diagnosis. J Neuroimaging 2000;10(2):116–8. [10] Kinoshita T, Sugihara S, Matusue E, Nomura T, Ametani M, Ohama E, et al. Intravascular malignant lymphomatosis: diffusion-weighted magnetic resonance imaging characteristics. Acta Radiol 2005;46(3):246–9. [11] Iijima M, Fujita A, Uchigata M, Katoo H. Change of brain MRI findings in a patient with intravascular malignant lymphomatosis. Eur J Neurol 2007;14(5):e4–5. [12] Lee HY, Chang KH, Kim JH, Na DG, Kwon BJ, Lee KW, et al. Serial MR imaging findings of acute hemorrhagic leukoencephalitis: a case report. AJNR Am J Neuroradiol 2005;26(8):1996–9. [13] Martins HM, Teixeira Jr AL, Lana-Peixoto MA. Brazilian Committee for Treatment and Research in Multiple Sclerosis. Acute hemorrhagic leukoencephalitis mimicking herpes simplex encephalitis: case report. Arq Neuropsiquiatr 2004;62(1): 139–43. [14] Murase T, Yamaguchi M, Suzuki R, Okamoto M, Sato Y, Tamaru J, et al. Intravascular large B-cell lymphoma (IVLBCL): a clinicopathologic study of 96 cases with special reference to the immunophenotypic heterogeneity of CD5. Blood 2007;15(109(2)):478–85. [15] Hsieh MS, Yeh YC, Chou YH, Lin CW. Intravascular large B cell lymphoma in Taiwan: an Asian variant of non-germinal-center origin. J Formos Med Assoc 2010;109(3):185–91. [16] Szots M, Szomor A, Kover F, Pajor L, Komoly S, Kalman E, et al. Intravascular lymphomatosis of the nervous system. J Neurol 2008;255(10):1590–2. [17] Catalan M, Naccarato M, Grandi FC, Capozzoli F, Koscica N, Pizzolato G. Acute hemorrhagic leukoencephalitis with atypical features. Neurol Sci 2009;30(1): 55–7. [18] Fischer L, Koch A, Schlegel U, Koch HC, Wenzel R, Schröder N, et al. Non-enhancing relapse of a primary CNS lymphoma with multiple diffusion-restricted lesions. J Neurooncol 2011;102(1):163–6. [19] Lachenmayer ML, Blasius E, Niehusmann P, Kovacs A, Stuplich M, Eichler O, et al. Non-enhancing primary CNS lymphoma. J Neurooncol 2011;101(2):343–4. [20] Archer H, Wall R. Acute haemorrhagic leukoencephalopathy: two case reports and review of the literature. J Infect 2003;46(2):133–7 (Review). [21] Pagano L, Larocca LM, Vaccario ML, Masullo C, Antinori A, Pierconti F, et al. Acute hemorrhagic leukoencephalitis in patients with acute myeloid leukemia in hematologic complete remission. Haematologica 1999;84(3):270–4. [22] Fontoura P, Mendes A, Correira M, Melo-Pires M. Weston Hurst acute haemorrhagic leukoencephalitis. Neuropathological study of one case. Rev Neurol 2002;35(4): 328–31.