Intravascular lymphoma not only in the brain – clinical and pathological case-report

This is an unauthorised machine translation into English made using the DeepL Translate Pro translator. The editors do not guarantee that the content of the article corresponds fully to the original language version.

Dear Editor,

We present a patient with a history of ischemic heart disease, aortic valve replacement, chronic renal insufficiency, dyslipidemia, and gout, who was admitted to the hospital in late spring 2023 with loss of appetite, recurrent dizziness, and chills lasting 5 days. The patient’s neighbors reported a progressive decline in his cognitive function over the course of several months.

Initial laboratory tests revealed elevated markers of inflammation (C-reactive protein [CRP] 166 mg/L, procalcitonin [PCT] 0.08 µg/L, white blood cell count 10.^7×10⁹/L). Apart from borderline elevated white blood cell counts at the outset, white blood cell counts did not rise further later on, and CRP remained markedly elevated (the trend is shown in Fig. 1, Part I). Culture results were repeatedly negative; chest X-ray and CT scans of the chest, abdomen, and pelvis showed no evidence of inflammatory infiltration. Transesophageal echocardiography ruled out endocarditis; MRI of the thoracic and lumbar spine ruled out spondylodiscitis; and whole-body PET/CT was negative. Serological testing (syphilis, HIV, hepatitis, Lyme disease, herpes viruses, influenza A/B, SARS-CoV-2, Chlamydia pneumoniae, Mycoplasma pneumoniae, Listeria, tularemia, tick-borne encephalitis), autoimmune and antineuronal antibodies (rheumatoid factor, anti-ENA, anti-SSA/SSB, myositis and paraneoplasia panel, anti-MOG, anti-AQP4, anti-NMDAR, anti-AMPAR, anti-LGI1, anti-CASPR2, anti-GABABR, anti-DPPX, etc.), as well as the QuantiFERON test, were negative.

A brain MRI revealed a retropharyngeal fluid collection (the aspirate was microscopically negative) and two small cortical lesions (right temporo-parietal and left frontal), likely post-ischemic. Cerebrospinal fluid analysis did not reveal any infection. Peripheral blood flow cytometry suggested a suspicion of myelodysplastic syndrome but did not explain the elevated CRP.

After 29 days of hospitalization in the internal medicine department, the patient suddenly developed severe motor impairment in his lower extremities and was transferred to the neurology department. Upon admission, severe peripheral paraparesis of the lower extremities was evident, predominantly acral, with plegia present in the feet; the patient was able to slightly flex both lower extremities at the knees and hips, and the motor impairment was not accompanied by loss of sensation. Furthermore, the patient exhibited signs of cognitive impairment, which was confirmed by the Montreal Cognitive Assessment with a score of 20 out of 30 points. The patient exhibited signs of motor apraxia, had slowed psychomotor speed, a pronounced prefrontal syndrome (correlating with the report of long-standing cognitive problems), and presented with anosognosia.

A follow-up MRI of the thoracic and lumbar spine was performed, revealing post-contrast enhancement of the anterior wall of the dural sac in the T10–L1 region and enhancement of several caudal nerve roots (Fig. 1, Part II). Based on this finding, a follow-up cerebrospinal fluid (CSF) analysis was performed, which revealed a protein-cytological association (28 cells/3 µl and 1.5 g/l protein). A follow-up brain MRI revealed a new subdural effusion in the right parietal region. EMG findings were consistent with the axonal variant of motor polyneuropathy; however, a follow-up examination 3 weeks later showed no progression.

A follow-up brain MRI revealed multiple new lesions consistent with encephalitis and marked progression of global atrophy compared to the examination 20 days earlier.

After transfer to the neurology department, treatment with linezolid and amikacin was initiated. Corticosteroids (prednisone 40 mg/day) were administered only briefly (due to suspicion of an inflammatory disease of the nerve roots and peripheral nerves). The patient’s condition worsened, and he died of septic shock at the end of May (53 days after admission to the hospital).

The autopsy revealed B-lymphoblasts in the small vessels of the pituitary gland, brain, spinal cord, and several organs (oropharynx, lungs, liver, gallbladder, kidneys, spleen), often accompanied by fresh, non-occlusive thrombi. No solid tumor was found in either the organs or the lymph nodes. The final findings were most consistent with a diagnosis of intravascular large B-cell lymphoma (IVLBCL) (Fig. 2).

We present the case of a 73-year-old patient with a postmortem diagnosis of IVLBCL—a rare type of extranodal non-Hodgkin lymphoma defined as malignant B cells confined solely to the vascular lumen. It most commonly affects older patients (~70 years of age), with an incidence of less than 0.5 per 1,000,000 per year. Diagnosis is often delayed or made only postmortem. The clinical presentation is nonspecific—typical features include fever, signs of CNS involvement, and skin lesions [1], skin eruptions (≈43%), weight loss (≈30%), cytopenia, and confusion; more than half of patients have multiorgan involvement [2]. IVLBCL can mimic various conditions depending on the affected organ, including infectious, inflammatory, neurological, or ischemic processes. Diagnosis requires histology and immunohistochemistry.

More than one-third of patients had nervous system involvement [2]. Brain MRI typically shows multifocal, polymorphic lesions atypical of ischemic involvement (progressive growth, persistent diffusion restriction), with occasional hemorrhagic or tumor-like lesions [2,3]. Chemotherapy with rituximab may improve outcomes, but the overall prognosis remains very poor.

Our patient had persistently elevated CRP but did not have marked leukocytosis or an elevated PCT—which helps distinguish bacterial from nonbacterial inflammation [4]. Levels are typically higher in Gram-negative infections than in Gram-positive infections. The initial blood culture demonstrated growth of the Gram-positive Streptococcus mitis, which may explain the relatively low PCT despite the presence of bacteremia.

Inflammatory polyneuropathy was considered. Cerebrospinal fluid analysis revealed mild pleocytosis (28 cells/3 µl, normal ≤ 10) and marked hyperproteinorachia, and an MRI of the spine showed post-contrast enhancement of the anterior aspect of the dural sac and nerve roots in the lumbosacral region. However, persistently elevated CRP precluded the therapeutic use of immunomodulatory methods. Case reports indicate mildly elevated cerebrospinal fluid cellularity in more than 50% of patients with IVLBCL without tumor cells detected by flow cytometry [5]; enhancement of the nerve roots was also observed in 50% of patients at initial examination and in 85% at follow-up [5].

The diagnosis of IVLBCL is often made only postmortem. Increased attention to certain symptoms may allow for earlier diagnosis. Recommended steps when intravascular lymphoma is suspected include biopsy of the affected sites (a skin biopsy may be diagnostic even if the skin appears normal) and bone marrow immunophenotyping using flow cytometry, which can detect a small population of monoclonal B lymphocytes.

A histopathological biopsy should be considered early in the evaluation of patients with a high clinical suspicion. The least invasive procedure is a skin biopsy, which can detect intravascular infiltration even in the absence of skin manifestations, with a sensitivity of 50–83% [6]. Another possible option is bone marrow biopsy with flow cytometry-based immunophenotyping and histology [7]. In cases of localized neurological findings, a targeted stereotactic brain biopsy or meningeal/nerve root biopsy is indicated. Immunohistochemistry (CD20, PAX5, CD79a), proliferation markers (Ki-67), and tests to identify an intravascular pattern are crucial [8]. A negative biopsy does not rule out the disease; therefore, if suspicion persists, repeat biopsies from a different site are indicated.

IVLBCL should be actively considered in patients with unexplained elevated CRP levels without a clear source of inflammation, rapid progression of neurological deficits despite standard therapy, and negative results from infectious disease screening.

Increased awareness of IVLBCL and its atypical clinical presentations is key to early diagnosis and successful treatment. Early recognition can lead to appropriate treatment, which may improve the patient’s prognosis and quality of life. Similar case reports are essential for a better understanding of this rare lymphoma.

Acknowledgments

We would like to thank all the staff who cared for the patient during his hospitalization.

Conflict of Interest

The authors declare that they have no conflict of interest regarding this case.

Informed Consent

The patient did not sign the informed consent form. We are publishing a case report on a patient who died and who had no close relatives. This case report is presented in a manner that preserves the patient’s anonymity.

Funding

This work was supported by the Ministry of Health of the Czech Republic (MZ ČR-DRO-VFN64165) and by a project of the National Institute for Neurological Research (EXCELES Program, ID: LX22NPO5107)—funded by the European Union—Next Generation EU.