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Intravascular Large B-Cell Lymphoma CLINICAL MEDICINE Intravascular Large B-cell Lymphoma Associated with Systemic and Central Nervous System Hemophagocytic Lymphohistiocytosis: A Case Report Aradhana Verma1; Akanksha Sharma, MD2; Ryan Robetorye, MD3; Alyx Porter, MD2; Talal Hilal, MD4 Perm J 2020;24:19.105 E-pub: 12/06/2019 https://doi.org/10.7812/TPP/19.105 ABSTRACT represents up to one-fourth of second- Introduction: We present a case of an ary HLH cases. Among these, the most Asian variant of intravascular large B-cell common are hematologic malignancies, lymphoma associated with systemic and especially T-cell/natural killer-cell lym- central nervous system hemophagocytic phoma or leukemia. In the Asian variant lymphohistiocytosis (HLH) with multiple of IVLBCL, about 25% of patients can neurologic manifestations. present with a broad range of neurologic Case Presentation: A 68-year-old, symptoms, including seizures, strokes, and previously healthy, Korean woman pre- cognitive deficits that can serve as impor- sented with a 4-week history of fever and tant clues toward the diagnosis.2 IVLBCL weight loss. She had pancytopenia with can prove to be a diagnostic challenge for neutropenia, a ferritin level of 5030 μg/L, clinicians and pathologists if the presenta- and elevated liver enzyme levels. Bone tion is subtle or nonspecific, but it should marrow, liver biopsy specimens, and be considered when a secondary cause of cerebrospinal fluid demonstrated hemo- HLH is not detected. phagocytosis. The patient was treated with the HLH-2004 protocol, but her dis- CASE PRESENTATION Figure 1. Axial cut of fluid-attenuated inversion ease relapsed 3 months later. A repeated Presenting Concerns recovery sequence of the brain magnetic resonance liver biopsy specimen confirmed the imaging demonstrates T2 hyperintensity (arrow) in A 68-year-old Korean woman came to the left occipital region. initially missed diagnosis of intravascular the Emergency Department in April 2018 large B-cell lymphoma, a known driver of with a 4-week history of recurrent fever, and aspartate aminotransferase value of HLH in patients of Asian origin. She was weight loss, and generalized weakness. She 67 IU/L. Results from her basic metabolic then treated with lymphoma-directed had been previously healthy until she ex- panel were normal. Her international nor- therapy and had a prompt resolution of perienced a viral illness in the winter, after malized ratio was 1.7. The ferritin level was fever and neurologic symptoms as well which she noticed that her appetite and 5030 μg/L, and the lactate dehydrogenase as normalization of her blood cell counts weight had decreased. She lost approxi- level was 1699 IU/L. Results of computed and ferritin level. mately 10 kg during a 2-month period. tomography scans with contrast enhance- Discussion: This case serves as a re- Her family noted that she had become ment of the abdomen and pelvis showed minder that patients with an Asian variant confused and forgetful. Her temperature mild hepatomegaly, with no other abnor- of intravascular large B-cell lymphoma was peaking at 39°C on a nightly basis. malities and with a normal-appearing frequently present with HLH and neuro- She had no medical problems before this spleen. Hepatitis B surface antigen, core logic manifestations, including seizures, illness. She had no history of travel before antibody, surface antibody, and hepatitis strokes, and cognitive deficits. A high this presentation and no contact with sick C antibody results were negative. Results index of suspicion is needed for prompt individuals. of viral studies, including Epstein-Barr diagnosis and initiation of lymphoma- On physical examination, her tempera- virus polymerase chain reaction and cy- directed therapy. ture was 39.3°C, pulse was 95/min, blood tomegalovirus polymerase chain reaction, pressure was 105/67 mmHg, respiratory INTRODUCTION rate was 15/min, and oxygen saturation Intravascular large B-cell lymphoma was 100% on room air. Her liver was pal- Author Affiliations 1 California Northstate University of Medicine, Elk Grove (IVLBCL) with hemophagocytic lym- pable below the right costal margin. 2 Department of Neurology, Mayo Clinic, Phoenix, AZ phohistiocytosis (HLH) is a rare entity A complete blood cell count showed 3 Department of Pathology, Mayo Clinic, Phoenix, AZ that is typically seen in the Asian variant a white blood cell count of 1300/μL, he- 4 Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ of the condition.1 When present in adults, moglobin level of 9.5 g/dL, and platelet HLH is most commonly caused by under- count of 86,000/μL. Her liver enzyme Corresponding Author lying infection, autoimmune disease, or levels were mildly elevated, with an ala- Talal Hilal, MD ([email protected]) malignancy. Malignancy-associated HLH nine aminotransferase value of 75 IU/L Keywords: central nervous system (CNS), hematology, hemophagocytic lymphohistiocytosis (HLH), intravascular large B-cell lymphoma (IVLBCL), histiocytes, lymphoma The Permanente Journal • https://doi.org/10.7812/TPP/19.105 The Permanente Journal • For personal use only. No other uses without permission. Copyright © 2019 The Permanente Press. All rights reserved.1 CLINICAL MEDICINE Intravascular Large B-cell Lymphoma Associated with Systemic and Central Nervous System Hemophagocytic Lymphohistiocytosis: A Case Report Figure 2. Cerebrospinal fluid demonstrates hemo- Figure 4. Hematoxylin-eosin-stained section from phagocytosis with red blood cells present in the the liver biopsy specimen demonstrates prominent cytoplasm of a macrophage. sinusoidal hemophagocytosis (arrow) (100× magnification). were negative. Fungal studies, including β -D-glucan and Aspergillus antigen test- Figure 3. Axial cut of the diffusion-weighted She completed HLH-directed therapy in ing, yielded negative results. Blood cultures sequence of the brain magnetic resonance imaging July 2018. During treatment, her fevers were obtained, and empirical antibiotic demonstrates multifocal embolic-appearing infarcts subsided, blood cell counts recovered, and (arrow) in the left middle cerebral artery distribution. therapy was initiated. Results of blood and ferritin levels normalized. urine cultures remained negative. In October 2018, she was hospitalized again, with fever, poor appetite, and con- Therapeutic Intervention and Treatment These findings in the cerebrospinal fluid fusion. She was found to have recurrent Because of the pancytopenia, a bone suggested a diagnosis of central nervous pancytopenia and elevated ferritin levels marrow biopsy was performed. The bone system (CNS) involvement of HLH. up to 2000 μg/L, suggestive of relapsed marrow was hypercellular with normal Treatment with intrathecal methotrexate HLH. At this time, a second core needle trilineage hematopoiesis and markedly and hydrocortisone was initiated and given biopsy of the liver was undertaken to con- increased histiocytes, which included he- weekly for 4 doses. firm relapse of HLH. mophagocytic histiocytes. A liver biopsy On day 30, the patient was discharged specimen was obtained and demonstrated to a rehabilitation facility but required Pathologic Findings sinusoidal histiocytic inflammation with readmission to the hospital 1 week later Results of the repeated liver biopsy no malignancy. The overall picture of fever, because of aphasia and altered mental revealed prominent sinusoidal hemo- pancytopenia, elevated ferritin level, and status. Results of magnetic resonance im- phagocytosis (Figure 4). Apart from the presence of hemophagocytosis in both aging demonstrated embolic-appearing sinusoidal histiocytic inflammation, large the bone marrow and liver specimens was infarcts in the left middle cerebral artery atypical-appearing cells exhibiting a B-cell diagnostic of HLH. Although no clear in- territory. Her strokes were attributed to immunophenotype were noted on this fectious, autoimmune, or malignant cause possible paradoxical emboli in the setting sample (Figures 5A and 5B). Results of was identified, given the patient’s age, our of hypercoagulability caused by immobil- a repeated bone marrow biopsy similarly suspicion for an underlying malignant ity (Figure 3), but this suspicion could revealed large B cells in the bone mar- process remained high. not be confirmed. She was started on row sinusoids. A diagnosis of IVLBCL The patient was started on the HLH- anticoagulation therapy with apixaban. was made. 2004 treatment protocol that included etoposide and dexamethasone upfront, with the omission of cyclosporine. On day 5 after initiation of chemotherapy, the patient had 2 generalized tonic-clonic sei- zures. Results of brain magnetic resonance imaging revealed new scattered diffusion restriction and T2 hyperintensity of the right hemisphere as well as the medial left occipital lobe and pons, without any contrast enhancement (Figure 1). A cerebrospinal fluid sample obtained to rule out infection revealed an increased Figure 5. A. Liver sinusoids also demonstrate scattered large atypical-appearing cells and occasional number of histiocytes/macrophages, many small aggregates of abnormal cells (arrow) suggestive of lymphoma (40× magnification). B. Stain for CD20 showing hemophagocytosis (Figure 2). highlights large B cells present in the liver sinusoids (60× magnification). The2 Permanente Journal • For personal use only. No other uses without permission. Copyright © 2019 The Permanente Press. All rights reserved. The Permanente Journal • https://doi.org/10.7812/TPP/19.105 CLINICAL MEDICINE Intravascular Large
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