Chronic Lymphocytic Leukemia Resulting in Hemorrhagic Brain Masses After Sepsis

Abstract

Chronic lymphocytic leukemia (CLL) rarely results in central nervous system (CNS) involvement. When CLL does affect the CNS, it typically manifests as leptomeningeal involvement, not commonly causing parenchymal involvement unless having undergone a higher grade transformation. We report a case of a patient with untreated CLL who presented with a large right frontal hemorrhagic mass along with additional bilateral masses after being found unresponsive. He had recently been hospitalized with Staphylococcus aureus sepsis. His neurological examination improved after resection of the largest mass however deteriorated again with accumulation of blood in the resection cavity requiring evacuation of the blood products and placement of an external ventricular drain. Pathology from the initial resection revealed sheets of CD20 consistent with untransformed CLL. Additionally, there were areas of necrosis and gram-positive organisms. Given the unusual presentation with large hemorrhagic brain masses, we suspect that the antecedent bacteremia may have resulted in blood–brain barrier breakdown and seeding of the CNS parenchyma with CLL cells.

Introduction

Chronic lymphocytic leukemia (CLL) is the most common hematologic malignancy and is characterized by accumulation of clonal B cells in the blood, bone marrow, and peripheral lymph nodes.¹ Chronic lymphocytic leukemia is thought to rarely result in symptomatic involvement of the central nervous system (CNS); however, the true prevalence remains unknown with estimates varying from 0.4%² to 1% to 2%.³ Asymptomatic involvement of the CNS is likely considerably higher given that autopsy studies have detected CLL cells in the CNS of up to 71%.⁴

When CLL does result in symptomatic CNS manifestations, it usually presents with altered mental status, meningitis, cranial nerve palsies, optic neuropathy, or cerebellar signs.⁵ These symptoms reflect the more typical involvement of the meninges by CLL. A recent study from a tertiary center looked at the prevalence and pattern of CNS involvement in patients with CLL over a 15-year period.² When CLL resulted in parenchymal involvement, the lesions were typically small unless the CLL had undergone Richter transformation.²

We report herein the case of a patient with untreated CLL who was found to have large bilateral parenchymal masses after being found unresponsive. Surgical resection was required for the largest right frontal mass. Pathology confirmed that the masses were caused by untransformed CLL and demonstrated the presence of area of necrosis and inflammation along with gram-positive bacteria. While the factors contributing to CLL involvement of the CNS remain poorly described, we suspect that the antecedent bacteremia may have contributed to CNS seeding by CLL cells.

Case Description

A 67-year-old man with CLL and prostate cancer presented after being found unresponsive. He had been diagnosed with CLL 5 years earlier when routine blood work demonstrated an elevated white blood cell count but received no treatment for either malignancy. One year prior to the current admission, he was found down. Workup revealed no progression of his CLL. Neuroimaging revealed bilateral border-zone infarcts. He was discharged on aspirin and a statin for stroke secondary prevention. He was lost to follow-up until 1 year later, when he presented to an outside hospital with hypoxia and hemoptysis and was diagnosed with pneumonia. He was also found to have bacteremia with blood cultures positive for methicillin-sensitive Staphylococcus aureus and Streptococcus mitis. After clinical improvement, he was discharged to a rehabilitation facility on a 2-week course of nafcillin.

Four days later, he was found comatose. On arrival to the hospital, his Glasgow Coma Scale (GCS) was 7, with his right pupil larger than left (5 and 3 mm, respectively). Brainstem reflexes were intact. His right arm localized to pain while his left arm did not move. His right leg withdrew, and his left leg triple-flexed. Laboratory results on admission revealed INR 1.1, PT 11.7, PTT 24.7, and platelets 173. Head computed tomography (CT) scan revealed a large, right frontal hemorrhagic mass (Figure 1A) and smaller hemorrhagic masses bilaterally both supra- and infratentorially (Figure 1B-D). After administration of dexamethasone and platelet transfusion, he was taken to the operating room (OR) emergently for right frontal craniotomy and tumor resection. Postoperative imaging revealed reduced mass effect, which correlated with clinical improvement to GCS9, resolved anisocoria, and ability to follow simple commands. On postoperative day 2, his right pupil enlarged to 6 mm and became unreactive. Hypertonic saline was administered and hyperventilation initiated followed by urgent head CT showing accumulation of blood in the resection cavity (Figure 1E and F) and worsening hydrocephalus (Figure 1G and H). He was taken for repeat craniotomy with evacuation of intraparenchymal hemorrhage and placement of an external ventricular drain. Postoperatively, he had ongoing elevations in intracranial pressure. The patient’s family decided to pursue comfort care 2 days after the second surgery. Autopsy was declined by the family.

Figure 1.

Representative computed tomography (CT) slices. CT scan obtained after admission with large right frontal hyperintense lesion as well as smaller bilateral supra and infratentorial lesions (A-D). CT scan obtained postoperatively after accumulation of right frontal intraparenchymal hemorrhage (E and F) with blood tracking into the third ventricle causing worsened hydrocephalus (G and H).

Pathologic examination of the tumor from the initial resection demonstrated sheets of small B-cells (Figure 2A and B) that expressed CD20 (Figure 2C), CD5, and CD23, with absent Cyclin D1 and a low Ki-67 proliferation index (Figure 2D). There were scattered foci of necrosis and acute inflammation (Figure 2E), and a Gram-Weigert stain revealed clusters of gram-positive organisms (Figure 2F). No evidence of metastatic prostate cancer was detected.

Figure 2.

Representative pathology. Hematoxylin–eosin (H&E) stain (A and B) demonstrating sheets of B cells. Staining indicating CD-20 positivity (C). Ki-67 staining demonstrating low proliferation index (D). H&E staining demonstrating areas of necrosis and inflammation (E). Gram-Weigert stain showing clusters of gram-positive organisms (F).

Discussion

To our knowledge, this case is the first report of a patient with diffuse, hemorrhagic CNS involvement by CLL. Most reports of clinically significant CLL affecting the CNS are small case reports usually presenting with meningeal involvement.^2,6-8 Among patients with CLL who have imaging performed for neurological symptoms, fewer than 5% have findings suspicious for CNS malignancy.² Patients who initially present with symptoms related to CNS involvement have been reported, with expression of CD49d and CD82 possibly playing a role in predilection for CNS involvement.⁹ Patients with significant parenchymal involvement are more likely to have Richter syndrome (RS).^2,7 Richter syndrome represents transformation of CLL to a more aggressive lymphoma, typically either diffuse large B-cell lymphoma or Hodgkin lymphoma, and is pathologically characterized by increased cell size and proliferation index as well as different molecular markers.¹⁰ Although prior reports suggest that RS may be more likely to lead to parenchymal CNS involvement,² this case demonstrates that low-grade CLL without aggressive pathological features can cause bulky parenchymal masses.

We do not know at which time point our patient’s CNS was seeded with CLL cells. The high frequency of previously asymptomatic CNS involvement of CLL discovered on autopsy^4,5 raises the possibility that CNS seeding by CLL was not recent. However, the presence of bacteria in the biopsy specimen leads us to speculate that blood–brain barrier (BBB) breakdown caused by infection contributed to seeding of the CNS by CLL cells. This is in line with a previous report of meningeal involvement by CLL in a patient with neuroborreliosis.¹¹ Furthermore, the low Ki-67 proliferation index indicates that the CLL had not undergone a higher grade transformation. Although some work has been done to investigate the pathogenesis of CNS involvement of CLL,⁹ the factors determining which patients with CLL will develop symptomatic CNS involvement remain poorly understood. Our report as well as a prior study¹¹ suggest that infection may be a risk factor for symptomatic CNS invasion by CLL cells. Ischemia is also known to affect the BBB by disruption of tight junctions.¹² Although this patient had small border-zone infarcts, it is possible that hypoxia-reoxygenation induced leakiness of the BBB contributed to parenchymal seeding by CLL cells. Prospective studies will be required to systematically investigate the factors contributing to CNS involvement by CLL. This may be aided by genetic data which have recently become available through several platforms testing numerous genetic alternations found in tumors.¹³

Patients with active cancer requiring neurocritical care have been relatively understudied. Certain types of cancer can result in hypercoagulability and lead to an increased risk of stroke,¹⁴ which likely explains the border-zone strokes this patient sustained a year prior. Although our patient was treated with aspirin and a statin for stroke secondary prevention, the optimal treatment for prevention of stroke in patients with active malignancy remains unknown with a recent trial comparing aspirin with enoxaparin.¹⁵ Given the low risk of intracerebral hemorrhage (ICH) related to aspirin use,¹⁶ we do not suspect that aspirin contributed to the hemorrhagic component of the brain masses in this case. Furthermore, patients with cancer who develop ICH have been reported to have worse outcomes.¹⁷ Given that ICH in patients with an underlying tumor results from distinct mechanisms such as coagulopathy, intratumor hemorrhage, or increased vascular permeability due to expression of proteins such as vascular endothelial growth factor,¹⁸ it is unclear whether these patients would benefit from different treatment than other patients with ICH. Although this case did not present with significant coagulopathy, many patients with hematological malignancies and those receiving chemotherapy will be coagulopathic and thrombocytopenic. This patient received a platelet transfusion prior to being taken to the OR due to recent aspirin use. Although platelet transfusion in primary ICH is generally not indicated,¹⁹ the optimal platelet count after ICH in thrombocytopenic patients with ICH remains unknown.

In conclusion, symptomatic CNS involvement by CLL is rare, usually presenting with leptomeningeal or cranial nerve involvement. We suspect that antecedent bacteremia may have contributed to CNS seeding by CLL cells, leading to the development of large bilateral hemorrhagic masses caused by CLL cells. Further research assessing the risk factors for developing CNS involvement in patients with CLL is warranted, as well as the potential contribution of infections.