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 . 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 , Mayo Clinic, Phoenix, AZ that is typically seen in the Asian variant a 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 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), , lymphoma

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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).

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Follow-up and Outcomes of June 2019. A timeline of the case ap- seizures, or focal motor weakness.2 Mul- Lymphoma-directed therapy was pears in Table 1. tifocal cerebral infarcts, as described in initiated with 6 cycles of a combination our patient, have also been reported with DISCUSSION 4 of intravenous rituximab, cyclophos- IVLBCL. phamide, doxorubicin, and prednisone. IVLBCL is a rare, clinically aggressive HLH is a life-threatening condition Vincristine was omitted because of her form of diffuse large B-cell lymphoma that most commonly occurs in adults be- preexisting neuropathy that developed characterized by preferential growth of cause of an underlying infection, autoim- with etoposide therapy. Intravenous neoplastic lymphocytes in blood vessels. mune disease, or malignancy. The clinical methotrexate was used for 3 cycles to Diagnosis can be elusive because of its diagnosis of HLH is based on the criteria prevent CNS relapse. Within 7 days of constellation of nonspecific signs and used in the HLH-2004 trial, requiring 5 the start of treatment, her fever resolved, symptoms, such as fevers and pain, in of the following 8 clinical findings: Fever, 2 mental status normalized, and blood cell addition to CNS and skin involvement. splenomegaly, cytopenia in at least 2 cell counts recovered. Her aphasia slowly Similarly, there are no pathognomonic ra- lines, hypertriglyceridemia or hypofi- 3 improved during the ensuing months. diologic changes to support the diagnosis. brinogenemia, tissue demonstration of She completed chemotherapy in January More than half (52%) of patients present hemophagocytosis, low or loss of natural 2019 and is without evidence of disease with neurologic symptoms, including killer cell activity, elevated serum ferritin 5 recurrence systemically or in the CNS as cognitive impairment, strokelike episodes, level, and an elevated soluble CD25 level.

Table 1: Timeline of the case Relevant medical history and interventions A 68-year-old South Korean woman with no personal history of medical problems and a family history of pancreatic cancer (father), CVA at age 29 (mother), and Hashimoto disease (sister) developed intermittent confusion and unintentional weight loss after a viral upper respiratory tract infection in February 2018. She was given multiple courses of antibiotics, without improvement. Patient originally from South Korea but has lived in Arizona for 30 years. Summaries from initial Date and follow-up visits Diagnostic testing Interventions Late Patient was admitted with fevers, Laboratory values: White blood cell count, 1300/ HLH-directed treatment with etoposide and April mostly at night; cognitive deficits μL; hemoglobin, 9.5 g/dL; platelet count ,86,000/ μL; dexamethasone, completed in July 2018 2018 and confusion; generalized ferritin, 5030 µg/L; ALT, 75 IU/L; AST, 67 IU/L weakness; and lack of appetite Bone marrow biopsy specimen (April 30, 2018): Increased histiocytes with hemophagocytic histiocytes Liver biopsy no. 1: Sinusoidal hemophagocytosis, but no sign of malignancy May Patient had generalized tonic-clonic Brain MRI no. 1: New scattered diffusion restriction Antiepileptic treatment started; seizures controlled with 2018 seizures and T2 hyperintensity of right hemisphere and medial lacosamide, 100 mg twice a day; levetiracetam, 1500 left occipital lobe and pons, without any contrast twice daily; and phenytoin, 100 mg 3 times a day enhancement CSF analysis: Increased number of histiocytes/ Intrathecal methotrexate and hydrocortisone therapy macrophages, many showing hemophagocytosis for CNS involvement with HLH, weekly for 4 doses June Patient’s seizures were controlled 2018 and there were no recurrent fevers; she was deconditioned and discharged to rehabilitation facility July Patient was readmitted with a Brain MRI no. 2: Embolic-appearing infarcts in the left Anticoagulation therapy with apixaban, 10 mg twice a 2018 stroke alert for new-onset aphasia MCA territory; no obvious source day for the loading dose, followed by 5 mg twice daily and altered mental status Echocardiogram was normal Completed HLH treatment course October Patient was readmitted with Ferritin, 2000 µg/L Lymphoma-directed therapy with 6 cycles of IV 2018 recurrent symptoms of fever and rituximab, cyclophosphamide, doxorubicin, and confusion; HLH relapse diagnosed prednisone Liver biopsy no. 2: Large atypical-appearing B cells in CNS prophylaxis with 3 cycles of IV methotrexate liver sinusoids suggestive of lymphoma January Patient presented for follow-up Chemotherapy completed 2019 June Patient was stable and recovering 2019 as an outpatient ALT = alanine aminotransferase; AST = aspartate aminotransferase; CNS = central nervous system; CSF = cerebrospinal fluid; CVA = cerebrovascular accident; HLH = hemophagocytic lymphohistiocytosis; IV = intravenous; MCA = middle cerebral artery; MRI = magnetic resonance imaging.

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CONCLUSION References Although studies report CNS involvement 1. Murase T, Nakamura S, Kawauchi K, et al. An Asian in HLH ranging anywhere from 30% to Primary HLH is extremely rare in variant of intravascular large B-cell lymphoma: 73%, the larger and more systematic stud- Clinical, pathological and cytogenetic approaches adults, and a secondary cause should be to diffuse large B-cell lymphoma associated with ies suggest that approximately two-thirds carefully investigated. Our case serves as haemophagocytic syndrome. Br J Haematol 2000 of patients with HLH have neurologic a reminder that IVLBCL is truly a “cha- Dec;111(3):826-34. DOI: https://doi.org/10.1111/ symptoms.6 2 j.1365-2141.2000.02426.x. meleon with multiple faces.” The Asian 2. Ponzoni M, Campo E, Nakamura S. Intravascular Our patient’s initial clinical symptoms variant of IVLBCL is associated with large B-cell lymphoma: A chameleon with and diagnostic findings were consistent HLH and not uncommonly involves the multiple faces and many masks. Blood 2018 Oct with HLH. On initial presentation, the 11;132(15):1561-7. DOI: https://doi.org/10.1182/ CNS. Prompt diagnosis of IVLBCL in the blood-2017-04-737445. primary cause of the HLH was unclear. appropriate clinical scenario may lead to 3. Fonkem E, Dayawansa S, Stroberg E, et al. v An extensive infectious and autoimmune improved patient outcomes. Neurological presentations of intravascular workup was unrevealing in its results. It lymphoma (IVL): Meta-analysis of 654 patients. Disclosure Statement BMC Neurol 2016 Jan 16;16:9. DOI: https://doi. was only after she had relapse of HLH org/10.1186/s12883-015-0509-8. that a second biopsy specimen revealed Alyx Porter, MD, is a member of a data safety 4. Cruto C, Taipa R, Monteiro C, Moreira I, Melo- IVLBCL, the probable driving condition monitoring committee for a glioblastoma study for Pires M, Correia M. Multiple cerebral infarcts and Syneos Health. intravascular central nervous system lymphoma: A for her initial presentation of HLH. A The other author(s) have no conflicts of interest rare but potentially treatable association. J Neurol review of the first biopsy specimen showed to disclose. Sci 2013 Feb 15;325(1-2):183-5. DOI: https://doi. IVLBCL as well, confirming the hypothe- org/10.1016/j.jns.2012.10.012. 5. Henter J-I, Horne A, Arico M, et al. HLH-2004: sis that IVLBCL was present at the begin- Acknowledgments Diagnostic and therapeutic guidelines for ning of her illness. Malignancy-associated Kathleen Louden, ELS, of Louden Health hemophagocytic lymphohistiocytosis. Pediatr Blood HLH represents 27% of secondary HLH Communications performed a primary copy edit. Cancer 2007 Feb;48(2):124-31. DOI: https://doi. 7 org/10.1002/pbc.21039. cases. Of those, IVLBCL-associated 6. Song Y, Pei R-J, Wang Y-N, Zhang J, Wang Z. HLH is a rare entity that is typically seen How to Cite this Article Central nervous system involvement in in patients from Asian countries. Most Verma A, Sharma A, Robetorye R, Porter A, Hilal T. hemophagocytic lymphohistiocytosis in adults: A Intravascular large B-cell lymphoma associated retrospective analysis of 96 patients in a single patients (73%-100%) present with typical with systemic and central nervous system center. Chin Med J (Engl) 2018 Apr 5;131(7):776-83. features of HLH, such as bone marrow hemophagocytic lymphohistiocytosis: A case DOI: https://doi.org/10.4103/0366-6999.228234. 7. George MR. Hemophagocytic lymphohistiocytosis: involvement, fevers, hepatosplenomegaly, report. Perm J 2020;24:19.105. DOI: https://doi. Review of etiologies and management. J Blood Med and cytopenias, with neurologic presen- org/10/7812/TPP/19.105 2014 Jun 12;5:69-86. DOI: https://doi.org/10.2147/ tations being relatively common.1 The JBM.S46255. hematologic findings are less likely ob- Authors’ Contributions served in the classic or cutaneous variants All authors had access to the data, had a role in of IVLBCL and represent important clues writing the manuscript, and have given final approval to aid in diagnosis. to the manuscript.

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