By Rajiv S. Magge, MD
Synopsis: A multicenter, retrospective cohort study of 17 patients with pathology-proven intravascular lymphoma involving the central nervous system identified “red flag” clinical features, imaging patterns, and cerebrospinal fluid characteristics that may help expedite the diagnosis of this rare, complex, and deceptive disease.
Source: Berthet E, Guillonnet A, Houillier C, et al. Unveiling the clinical and imaging signatures of intravascular lymphoma of the central nervous system: A multicentric cohort study. Ann Neurol. 2024; Nov 28. doi: 10.1002/ana.27132. [Online ahead of print.]
Intravascular large B-cell lymphoma (IVLBCL) is an extremely rare subtype of extranodal diffuse large B-cell lymphoma (LBCL) characterized by clonal lymphocytic infiltration of the lumina of small- and medium-sized vessels, especially capillaries and post-capillary venules. With the rare and highly variable clinical presentation of the disease, the diagnosis, unfortunately, often is made at autopsy. An increased index of suspicion and heightened awareness are crucial for catching IVLBCL.
With the potential occlusion of blood vessels throughout the body, patients can present with a wide array of clinical signs, ranging from constitutional symptoms (such as fever, night sweats, and weight loss) to skin changes and rapidly progressive neurologic changes, as vessels in the central nervous system (CNS) often are affected. The diagnosis only can be confirmed by identification of large clonal lymphoma cells within small to medium blood vessels. However, the decision to move forward with a biopsy can be quite challenging, especially since no definitive clinical, imaging, or diagnostic features clearly point to IVLBCL.
In this multicenter, retrospective cohort study, the investigators collected 17 adult patients with confirmed IVLBCL (based on histopathological exam of cerebral or extra-cerebral tissue) and associated symptoms related to CNS involvement. All pre-treatment clinical, biological, and imaging data were retrospectively analyzed, with the latter being classified into six different magnetic resonance imaging (MRI) lesion patterns. In seven patients (40%), neurologic changes were the initial symptom of IVLBCL, most commonly focal neurologic signs (n = 8) and/or cognitive decline (n = 7). Focal neurologic changes typically were of sudden onset, suggesting potential ischemia, but also often fluctuating and more likely to occur earlier than cognitive changes (median 23 days vs. 57 days). Disorientation was the most common type of cognitive impairment (n = 15). Unfortunately, many patients in the cohort experienced psychiatric manifestations (n = 8) as well as seizures (n = 9). Most of the patients also presented with at least one constitutional symptom, such as asthenia, fever, and weight loss.
On evaluation of the patients’ serum testing, most demonstrated an elevated C-reactive protein (14 of 15 patients tested), ferritin (eight of nine patients tested), and fibrinogen (eight of 11 patients tested). Elevated plasma lactate dehydrogenase (LDH) and beta-2 microglobulin, which can be seen in the setting of both systemic and CNS lymphomas, also were commonly seen. All patients in the cohort underwent a lumbar puncture, with 12 patients (71%) having a typically mild pleocytosis. Interestingly, an elevated interleukin (IL)-10/IL-6 ratio was identified in four of the seven patients in whom it was tested.
Almost the entire cohort had brain MRI completed before starting chemotherapy (n = 16). Results were classified into six imaging patterns, including infarct-like lesions, large white matter T2 hyperintensities, small white-matter hyperintensities, mass-like lesions, hemorrhagic lesions, and leptomeningeal lesions. All but one of the patients had multifocal lesions on their first imaging scan. White matter T2 hyperintensities were the most common lesion pattern (n = 14, 87%), ranging from well-delineated focal lesions to more diffuse T2 changes. On follow-up, these white matter lesions often grew and became more numerous.
The second most common were infarct-like lesions (n = 13, 81%) with involvement of both the anterior and posterior circulations. Interestingly many of these lesions only had a small component of diffusion-weighted imaging (DWI) restriction (i.e., deep DWI-positive lesions inside of a broader T2 hyperintense area). Systemic imaging was done in all the patients, but this was not especially helpful for confirming the diagnosis. One patient had pathology-proven IVLBCL from liver biopsy. IVLBCL was diagnosed in 13 patients based on a brain biopsy and in three patients after skin biopsy. Sadly, seven of the 17 patients in the cohort died within the first two months of diagnosis.
Commentary
IVLBCL can present with highly variable clinical symptoms, lab changes, and imaging patterns. This study admirably attempts to identify key clinical and diagnostic signs of a notoriously inscrutable disease. Berthet et al were able to collect 17 patients, which, although a small cohort on its face, is large for such a rare and enigmatic diagnosis.
Key findings include the presence of early systemic symptoms as well as fluctuating stroke-like episodes in most of the patients. Serum testing often identified evidence of an inflammatory syndrome, with cerebrospinal fluid typically associated with a mild pleocytosis. The presence of frequently elevated CSF IL-10/IL-6 ratios supports the measure of these biomarkers when IVLBCL is suspected. MRI brain imaging commonly demonstrated a combination of white matter T2 hyperintensities with smaller associated DWI-positivity, which, interestingly, often grew on subsequent imaging. The identification of systemic lesions on positron emission tomography (PET) and computed tomography (CT) was not especially helpful in making the diagnosis, and the study highlights the importance of expedited brain or skin biopsy when IVLBCL is on the differential.
Limitations of this study are mostly the result of the rarity and chameleon-like nature of IVLBCL. This is a relatively small sample of patients, and the key identified “red flag” clinical and diagnostic features can be seen in a wide variety of neurologic diseases, including cerebrovascular and neuroinflammatory syndromes. However, it impressively highlights the importance of early consideration of IVLBCL in patients with rapidly progressive and/or fluctuating neurologic symptoms with progressive ischemic-appearing lesions. One hopes this can lead to earlier treatment and improved outcomes, which would be a tremendous benefit for patients who have a diagnosis that often is only recognized on autopsy.
Rajiv S. Magge, MD, is Associate Professor of Clinical Neurology, Weill Cornell Medicine, Weill Cornell Brain Tumor Center.
A multicenter, retrospective cohort study of 17 patients with pathology-proven intravascular lymphoma involving the central nervous system identified “red flag” clinical features, imaging patterns, and cerebrospinal fluid characteristics that may help expedite the diagnosis of this rare, complex, and deceptive disease.
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