Intravascular Lymphoma as a Cause of Recurrent Strokes – Case Report and Review of the Literature

Abstract

Background

Intravascular lymphoma is an uncommon cause of ischemic strokes. Because of its rarity and atypical pattern, most diagnoses are made post-mortem.

Case study

We present a case of a 68-year-old male with multiple cardiovascular risk factors and recent SARS-CoV-2 infection who presented with recurrent strokes. Because of his stroke risk factors, he was initially managed with a sequentially escalating antithrombotic regimen. A malignant process was low on the differential at this point given his lack of systemic symptoms. When he continued to have new strokes despite these measures, including a spinal cord infarct, a broad workup was sent including for hypercoagulable states, vasculitis, and intravascular lymphoma. Eventually, a skin biopsy of a cherry angioma returned positive for lymphoma cells. He was treated with methotrexate followed by chemotherapy and rituximab. Unfortunately, he did not improve and was made comfort measures only by his family.

Conclusion

This case illustrates the importance of considering intravascular lymphoma as a potential etiology of recurrent strokes, as early diagnosis and treatment are important for preventing irreversible neurological damage.

Introduction

Intravascular lymphoma (IVL) is a malignancy of B cells predominantly within the lumen of blood vessels. Initially described in 1959, ¹ it was later determined to be a malignancy of large B cells marked by CD20 expression. ² In the classical form, patients present with constitutional symptoms along with central nervous system (CNS) and skin lesions. A cutaneous-only variant is associated with better outcomes, and a hemophagocytic variant seen in Asian populations is associated with a rapid course of decline. ² In this case, we describe a patient who developed recurrent multifocal strokes who was eventually diagnosed with IVL by skin biopsy.

Case Description

A 68-year-old Hispanic male with a history of Diabetes Mellitus, hyperlipidemia, hypertension, and SARS-CoV-2 infection three months prior presented with recurrent strokes. On the first presentation, his neurologic exam was significant for right arm pronator drift and decreased strength in his bilateral lower extremities (Medical Research Council scale 4/5), along with mild ataxia on heel-to-shin on his right side and gait ataxia. MRI showed multifocal diffusion restricting lesions with bilateral fluid-attenuated inversion recovery (FLAIR) hyperintensities involving the bilateral anterior-middle cerebral (ACA-MCA) artery territories, right splenium of the corpus callosum, and right ventral pons (Figure 1A). Stroke workup was significant for an elevated hemoglobin A1c (5.9%) and focal moderate (50-69%) stenosis of the right A1 segment of the ACA. As he was already on aspirin and a statin, clopidogrel was added to his secondary stroke prevention regimen.

Figure 1.

MRI brain of the first presentation (A) and second admission (B) three weeks later. Diffusion-weighted imaging (DWI, left) and apparent diffusion coefficient (ADC, right) are shown, with red arrows pointing to areas of restricted diffusion. A: MRI brain obtained at the first admission shows diffusion restricting lesions in the bilateral anterior-middle cerebral artery territories (top), right splenium of the corpus callosum (middle) supplied by the posterior cerebral artery, and right ventral pontine (bottom) supplied by basilar artery branches. B: MRI brain at the second admission showed extension of the previous infarcts in addition to evolution of prior infarcted areas (top), and new lesions in the left frontal cortex (middle) and new bilateral lateral cerebellar lesions (bottom).

3 weeks after discharge, he re-presented with dysphagia, bilateral weakness, and word-finding difficulties. Review of systems was negative for any constitutional symptoms, including fever, weight loss, or night sweats. On exam, he was oriented to self only and was intermittently able to follow simple commands; he also exhibited dysarthria and his bilateral lower extremities weakness (3/5) had progressed compared to his prior presentation. MRI brain showed numerous new multifocal diffusion-restricting lesions throughout the cerebrum and cerebellum (Figure 1B) without contrast enhancement (not shown).

Admission labs for his second admission were significant for macrocytic anemia (hemoglobin 9.6 g/dL, mean corpuscular volume 104.1 fL). His transthoracic echocardiogram and telemetry were unremarkable. CSF studies revealed a CSF-to-serum glucose ratio of .58, elevated protein (149 mg/dL, reference range 5-55 mg/dL), and 3 nucleated cells, with negative Herpes Simplex virus (HSV) and Varicella Zoster virus (VZV) PCR. Nonspecific serum inflammatory markers were elevated (lactate dehydrogenase, LDH 490 U/L, C-reactive protein, CRP 42.9 mg/L, erythrocyte sedimentation rate, ESR 20 mm/h, β2-microglobulin 2.92 mcg/mL, D-dimer 934 ng/mL), but screening for systemic inflammatory conditions (antibodies against small nuclear ribonucleic protein, Smith, antineutrophil cytoplasmic antibodies, Sjogren’s Syndrome A/B, and Complement 3/4) and autoimmune encephalitis (Mayo Clinic encephalopathy, autoimmune/paraneoplastic panel) was negative. Hypercoagulability tests, including testing for antiphospholipid syndrome, were unrevealing. Infectious workup including testing for HIV, Hepatitis B and C, Cytomegalovirus (CMV), Epstein-Barr virus (EBV), and syphilis, was negative in the serum. A CT chest/abdomen/pelvis with contrast did not reveal any malignancy. His peripheral and CSF flow cytometry was normal, and CSF pathology, MYD88 gene mutation, and IgH gene rearrangement studies were also negative.

A few days into his hospital course, his encephalopathy acutely worsened. On exam, he was stuporous, not following commands, and exhibited a right gaze preference. He had new flaccid paralysis and areflexia of the bilateral lower extremities. Vital signs were significant for hypotension and bradycardia. He was transferred to the Neuro-ICU, intubated for airway protection, and initiated on pressors. 24-hour EEG did not show seizure activity. A repeat MRI brain did not show any new changes (not shown); however, MRI of the cervical, thoracic, and lumbar spine showed a diffusion restricting lesion in the anterior cord extending across the T4-T6 levels, with corresponding STIR and T2 hyperintensities (Figure 2) without contrast enhancement (not shown).

Figure 2.

MRI of the thoracic spine with red arrows pointing to the spinal cord infarct. A: MRI spine STIR sequence shows a longitudinal hyperintense lesion extending from T4-T6. B: Axial view of the thoracic spine (T5) depicts T2 hyperintensity in the distribution of the anterior spinal artery. C, D: DWI (C) and ADC (D) sequences of the thoracic spine depicts diffusion restriction of the lesion.

Magnetic resonance angiography (MRA) 3T high resolution vessel wall imaging showed multifocal areas of smooth vessel wall enhancement which were not completely circumferential, consistent with intravascular lymphoma or vasculitis (Figure 3). A skin biopsy of 2 cutaneous angiomas was performed which came back positive for intravascular large B-cell lymphoma in one of the 2 biopsied angiomas (Figure 4). IVL was thought to be the etiology of his ischemic strokes and he was treated with high-dose methotrexate followed by R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone). After the first cycle of therapy, he started following simple commands, but his mental status did not improve further, and his lower extremities remained flaccid. He was converted to comfort measures only and died on hospital day 35.

Figure 3.

MRA vessel wall imaging with red arrows pointing to areas of contrast enhancement. A: Post-contrast T1 image showing vessel wall enhancement of the bilateral middle cerebral arteries. B: Enhancement of the left posterior cerebral artery. The smooth wall enhancement supports the diagnosis of intravascular lymphoma or vasculitis.

Figure 4.

Histopathological findings of a skin biopsy of cutaneous angioma. A: Ectatic vascular spaces contain erythrocytes (white arrows) and large atypical tumor cells (black arrows) (hematoxylin and eosin stain, 200x magnification). B: The tumor cells have high nuclear to cytoplasmic ratios (hematoxylin and eosin, 400x magnification). C: The tumor cells are highlighted by immunohistochemical stain for CD20 (brown, 200x). D: The presence of CD20+ large atypical cells allows for a diagnosis of intravascular B-cell lymphoma (400× magnification).

Discussion

This case describes a patient with recurrent strokes in multiple vascular distributions, including a spinal cord infarct. An extensive stroke workup was initially negative until MRA with vessel wall imaging and subsequent skin biopsy led to the diagnosis of IVL. Unfortunately, despite initiation of chemotherapy, the patient’s improvement was minimal and his family transitioned him to comfort care only. Whereas this case highlights IVL as a cause of recurrent strokes, without a brain biopsy or autopsy to confirm the etiology, other rare causes of recurrent strokes may be considered. Specifically, vasculitis and hypercoagulability of malignancy were also on our differential, although the latter was less likely given the patient's normal CT body scan. In addition, hypercoagulability due to COVID infection was also considered, but the 3-month gap between his infection to onset of strokes made this unlikely. In the following discussion, we provide a brief overview of the clinical presentation, imaging findings, laboratory studies, and treatment of CNS IVL.

The clinical presentation of IVL is varied. Besides fever and other B symptoms, dyspnea (indicating pulmonary involvement) and skin lesions are common presenting symptoms, all of which our patient did not have. IVL does not typically cause lymphadenopathy, unlike diffuse large B-cell lymphoma (DLBCL) with which it shares molecular and genetic signatures. ³ IVL can rarely cause strokes: ⁴ In an analysis of all published cases from 1957 to 2012 of 654 patients, ⁵ around half presented with neurological symptoms. Within this group, cognitive impairment/dementia was the most common CNS symptom. 21 out of the 654 patients (3.2%) had stroke-like episodes but without confirmed strokes.

Imaging findings reflect pathophysiology: Malignant cells are found in all-sized blood vessels, but smaller vessels are thought to be more affected by perfusion restriction, thus ischemic lesions may be seen in areas supplied by small vessels or the terminal branches of large vessels. ⁶ Our patient’s initial imaging showed involvement of the terminal branches of the MCA-ACA and posterior cerebral artery (PCA) territories, along with paramedian pontine branches of the basilar artery (Figure 1A). Due to the lack of published cases, no pathognomonic imaging finding is associated with the diagnosis. Furthermore, CNS vasculitis may have a very similar appearance, so biopsy is needed to confirm the diagnosis.

In addition to imaging, serum and CSF studies may support the diagnosis. Serum abnormalities include anemia (63% of cases), thrombocytopenia (29%), leukopenia (24%), elevated ESR (43%),^2,7 hypoalbuminemia (18%), and elevated LDH (86%). ⁸ Our patient’s laboratory studies showed a mild anemia and elevated ESR and LDH, which could be an early clue but are nonspecific. Peripheral blood smears (<10%) ⁸ and flow cytometry ⁹ are usually unrevealing. CSF may show elevated protein as seen in our patient. ⁹ Malignant cells commonly exhibit MYD88 L265P, which is also seen in diffuse large B-cell lymphoma, ¹⁰ but the sensitivity of CSF MYD88 mutation analysis has not been characterized. Ultimately, biopsy of multiple affected sites, or if none are found then deep skin biopsies prioritizing vascular lesions^11,12 may improve diagnostic yield. The diagnostic characteristics of skin biopsies have yet to be defined; a small retrospective study reported a sensitivity of 50% and specificity of 100%. ¹³ In our case, if the skin biopsy had been negative, a PET scan followed by biopsy of an fluorodeoxyglucose-avid lesion or a leptomeningeal brain biopsy would have been pursued. Due to the insidious presentation and rapid course, most diagnoses used to be made post-mortem, however recent evidence suggests an improved pre-mortem diagnostic rate over the past 2 decades. ⁹

Prior to the introduction of rituximab, the median overall survival of patients with IVL with anthracycline-based therapies was 3 years. ³ Japanese and European retrospective studies indicate that progression-free survival was significantly improved with rituximab. ³ PRIMEUR-IVL, a phase II trial involving 38 patients, demonstrated safety of rituximab with CHOP, high-dose methotrexate, and intrathecal chemotherapy for intravascular lymphoma without CNS involvement, with a progression-free survival of 76% over 2 years (95% CI 58-87%). ¹⁴

In terms of neuroprognostication, a key challenge with CNS IVL is differentiating between permanently infarcted tissue and lymphomatosis which may improve with chemotherapy. Whereas there is no established method of differentiating between these 2 conditions on imaging, as both can appear as DWI bright/ADC dark lesions on MRI, serial imaging over time can help make this differentiation: Lesions that are due to infarcted tissue undergo typical MRI changes (i.e., ADC normalization) over time as the infarction progresses from the acute to subacute phase, whereas lesions due to lymphomatosis tend to remain diffusion restricting until chemotherapy is initiated. In our patient’s case, a significant amount of tissue underwent the typical evolution of an infarction (Figure 1A and 1B), which correlated with his poor clinical course after therapy initiation.

Conclusion

IVL is a rare but important cause of strokes. Suspicion should be raised in a patient with recurrent strokes in multiple vascular territories, especially in a small-vessel predominant distribution. Although the patient may complain of constitutional, respiratory, or dermatologic symptoms, these symptoms may not always be present, as this case illustrates. There should be a low threshold to perform skin biopsies prioritizing vascular lesions, as this is a relatively simple procedure with minimal complications and early diagnosis and treatment could prevent irreversible neurological damage.

ORCID iD

Charlie Weige Zhao https://orcid.org/0000-0002-8670-0985