This study was formally reviewed by the local Ethics Committee (Hospital Israelita Albert Einstein Ethics Board) that concluded it does not require ethical approval as it does not attend the criteria of research. The patient's family signed a written informed consent for this publication.
Diffuse involvement of the brain parenchyma by lymphoma is an unusual but well-recognized pattern of infiltration by large diffuse cell CNS lymphomas.[9–17] The term lymphomatosis cerebri was first used in 1999 by Bakshi et al who described two patients with rapidly progressive dementia and diffuse parenchymal infiltration by lymphoma cells. After this first description, 46 other cases of lymphomatosis cerebri were documented.[4–7,18–50] On MR imaging, the typical findings are non-enhancing, T2 hyper-intense diffuse lesions without forming any distinct mass in the subcortical white matter. PET scans may demonstrate hypermetabolism in the areas of MR abnormalities. The median age of patients with lymphomatosis cerebri is 57 years (ranging from 14–81 years), with a mild male predilection (58%). The most common clinical manifestations were a cognitive decline, behavioral changes and/or abnormal gait. The absence of enhancing lesion on MR is thought to occur due to the absence of disruption of the blood-brain barrier.
The unusual radiological finding, associated with clinical presentation of rapidly progressive dementia, opens a wide list of differential diagnosis that includes Creutzfeldt-Jakob disease;[5,6,18,25,41] infectious and inflammatory encephalitis;[4,5,16,19,21,24,25,41,45–48] autoimmune encephalopathy;[22,36,38,47] hypertensive encephalopathy; demyelinating diseases;[4,16,18,21,40,43,45] Binswanger disease (subcortical ischemic vascular dementia)[5,19] and other vascular disorders;[5,21,25] gliomatosis;[5,17,19,27,37,45,50] tumor metastases; toxic and metabolic processes;[5,6,18,30,45] and neurodegenerative diseases.[6,40]
Additionally, the histopathological findings are atypical for the usual CNS lymphoma, that is, deep-seated tumor masses adjacent to the ventricular system with homogeneous contrast enhancement. Indeed, the paucity of neoplastic lymphoma cells intermingled with overwhelming inflammatory infiltrate and the absence a tumor mass makes lymphomatosis cerebri a challenging diagnosis for hematologists, neurologists, pathologists, and radiologists.
In a meta-analysis of clinical presentation of cases of CNS lymphomas with rapidly progressive dementia from 1950 to 2013, Deutsch and Mendez described 20 patients, 14 of which presented lymphomatosis cerebri. When they compared these 14 patients with those with other causes of rapidly progressive dementia, patients with lymphomatosis cerebri more commonly presented impaired memory, apathy, abnormal speech and gait disturbances, without headaches, seizures, or myoclonus. Some of the described autopsied cases of lymphomatosis cerebri underwent neuropathological evaluation.[3,5,19,34,41] In these cases, lymphoma was present in several brain regions, indicating that lymphomatosis cerebri is a diffuse brain disease, even if image studies do not suggest it. In about half of the described cases, CSF analysis showed only mild pleocytosis, and protein levels were elevated in 76% of patients. Importantly, CSF malignant lymphoma cells were absent in the majority of the patients (94%), as is the present case. Flow cytometry was rarely performed in the CSF, but it was described as positive for clonal B lymphocytes in 2 of 3 cases.
The majority of CNS primary lymphomas are high-grade non-Hodgkin diffuse large B cell lymphomas, affecting both immunocompetent or immunodeficient patients. Microscopically, the CNS lymphoma is similar to systemic DLBCL: a high proliferation of large lymphoid cells with perivascular infiltration and high mitotic index. Tumor cells are permeated by reactive small T and B lymphocytes, macrophages, activated microglial cells and reactive astrocytes. Phenotypically, the neoplastic cells express B cell markers, which lack the Ig class switch (IgM and IgD, but not IgG), and often show a pattern of late stage of germinal center (demonstrated by gene expression profiling and by the expression of Bcl6 and IRF4/MUM1 in the majority of the cases).[52,53,54]
In contrast, lymphomatosis cerebri affects immunocompetent patients in the great majority of the cases. Only three cases of lymphomas with non-enhancing lesions have been described in immunodeficient patients.[12,44,46] Microscopically lymphomatosis cerebri is composed of large atypical lymphoid cells, sparsely distributed within a background of activated microglia and macrophages as well as small reactive lymphoid cells. Perivascular neoplastic infiltration may be present. In the current case, there was an occasional perivascular distribution of tumor cells. The majority of the described lymphomatosis cerebri cases were B-cell lymphomas (89%). According to the Hans Algorithm, the putative origin of lymphoma cells in the present case was activated B cells (ABC), similarly to other reports in the literature.[7,22,23] Interestingly, in the current case, lymphoma cells co-expressed Bcl6 and IRF4/MUM1. This co-expression has also been demonstrated in DLBCL of CNS, and some authors suggested that these lymphomas are instead derived from B cells of late germinal center.[53,54]
Indeed, cases of lymphomatosis cerebri were described in association with the usual form of DLBCL of CNS, either with concomitant diffuse infiltration and contrast-enhanced cohesive mass,[37,42] or with lymphomatosis cerebri preceding a usual DLBCL. Brecher et al described a case of PCNSL with mass formation associated with a diffuse pattern of infiltration accompanied with demyelination. Four cases of lymphomatosis cerebri showed a T-phenotype,[25,33,6,7] one of which was described as anaplastic large cell lymphoma. Fuseya et al reported a patient with systemic peripheral T-cell lymphoma who had CNS infiltration mimicking lymphomatosis cerebri.
An uncommon form of lymphoma that involves the brain is intravascular large B-cell lymphoma. It is a rare form of lymphoma characterized by proliferation of B-cell lymphoma in the lumen of small blood vessels that may involve virtually any organ.[57,58] Hishikawa et al described a case of intravascular large B cell lymphoma involving multiple visceral organs, associated with lymphoma of the CNS with a lymphomatosis cerebri-like pattern. Cerebral cortex, white matter, brainstem and spinal cord were infiltrated by scattered large B-cells with perivascular distribution. Atypical lymphoid cells also infiltrated the lumen of small vessels of lungs, myocardium, gastrointestinal tract, liver, spleen, genitourinary tract, endocrine organs, skeletal muscle and bone marrow. Another unusual pattern of CNS infiltration was reported by Chang et al, who described a patient with neurolymphomatosis (lymphoma infiltrating cranial nerves), which evolved to lymphomatosis cerebri.
In comparison with primary DLBCL of CNS, the prognosis of lymphomatosis cerebri is poorer, and most patients die within six months after the diagnosis. In a systematic review of the literature, Izquierdo et al showed that younger age (< 56 years), higher KPS, therapy with methotrexate and B cell histology are independent prognostic factors of a better outcome. The authors reported that patients with early-diagnosed lymphomatosis cerebri who were treated with high doses of methotrexate showed better overall survival (OS): 13.8 months (range: 0.7–56 months) versus OS of 2.95 months (range: 0.33–56 months), when methotrexate was not prescribed.
Histopathological examination of brain tissue is the “gold standard” for the diagnosis of lymphomatosis cerebri because the clinical, radiological and laboratory findings are nonspecific. However, the diagnosis of this entity is also a challenge for pathologists, due to the rarity of this histological form of presentation of CNS lymphoma and the paucity of malignant cells in the tissue. In the current case, the lymphoid cells permeated the brain parenchyma in a sparse distribution, without mass formation, and showed only discreet and focal tendency for perivascular distribution. Since there were more reactive small lymphocytes and macrophages when compared to the amount of large neoplastic cells, our initial histological differential diagnoses were vasculitis and viral encephalitis. Indeed, perivascular cuffing is not always present in lymphomatosis cerebri, but there is a tendency for tumor cell angiocentricity, what may mimic viral encephalitis. Only after the immunohistochemical evaluation highlighted the malignant lymphoid cells, we were able to make the proper diagnosis.
The current case illustrates how important brain biopsy can be in cases of rapidly progressive dementia of unknown causes and also the necessity for a workgroup approach.[18,24] In a review of 53 cases where brain biopsies were performed, the procedure was diagnostic in 60% of them, with PCNSL being the most frequent diagnosis (14 of 53 patients, 26% of total), followed by infarct in 7.5% (4 patients). Of the 14 cases diagnosed with lymphoma, 2 showed lymphomatosis cerebri. In one of these, the proper diagnosis was only achieved in the postmortem examination, since a diagnosis of encephalitis was the result of the biopsy.
Albeit brain biopsies have its known risks, such as CNS hemorrhage infarction and/or infection, early diagnosis, and appropriate treatment with high doses of methotrexate are the most important prognostic factors. But even with open brain biopsies, lymphomatosis cerebri is not an easy diagnosis. In a series of cases from the literature including patients with rapidly progressive dementia and lymphoma, 6 of the 20 original cases (30%) died before the definitive diagnosis was made and 4 out of these 6 patients had lymphomatosis cerebri. Furthermore, since many patients received steroids before the biopsy, the cytotoxic effect delayed the proper diagnosis even further due to massive cell apoptosis.
Lymphomatosis cerebri is a commonly misdiagnosed entity, associated with poor prognosis and unspecific clinical presentation. Herein, we described the diagnostic dilemma we faced with an elderly man with rapid cognitive impairment and a myriad of differential diagnoses, including organic dementia and infectious diseases, before we could properly reach the diagnosis of primary CNS diffuse large B-cell lymphoma with a lymphomatosis cerebri-like pattern. Clinicians, neurologists, pathologists, radiologists, oncologists, and geriatrics should be aware of this unusual clinical and pathological presentation of primary B-cell CNS lymphoma, and hence, enable an early therapeutic approach and better patient outcome.
Conceptualization: Denise da Cunha Pasqualin, Nelson Hamerschlak.
Formal analysis: Mariana Nassif Kerbauy, Denise da Cunha Pasqualin.
Investigation: Mariana Nassif Kerbauy, Denise da Cunha Pasqualin.
Methodology: Mariana Nassif Kerbauy, Denise da Cunha Pasqualin.
Project administration: Mariana Nassif Kerbauy, Luciano Neder.
Supervision: Luciano Neder, Nelson Hamerschlak.
Writing – original draft: Mariana Nassif Kerbauy, Denise da Cunha Pasqualin, Jerusa Smid, Rogerio Iquizli, Lucila Nassif Kerbauy, Ricardo Nitrini, Guilherme Carvalhal Ribas, Luciano Neder, Nelson Hamerschlak.
Writing – review & editing: Denise da Cunha Pasqualin, Jerusa Smid, Rogerio Iquizli, Lucila Nassif Kerbauy, Ricardo Nitrini, Guilherme Carvalhal Ribas, Luciano Neder, Nelson Hamerschlak.
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Keywords:Copyright © 2019 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
dementia; diffuse lymphoma; large B-Cell; lymphoma; nervous system neoplasms