Korean Journal of Neuromuscular Disorders 2014 25 HE Lee, et al. | ENKL, Nasal Type of Cauda Equina Presenting as EBV-HLH
Received: March 5, 2014 / Accepted: June 10, 2014 Address for correspondence: Seung Min Kim, MD
Department of Neurology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea Tel: +82-2-2228-1604, Fax: +82-2-393-0705, E-mail: [email protected]
ISSN 2092-5077
Korean Journal of Neuromuscular Disorders Vol. 6, No. 1, June 2014
Case Report
Extranodal NK/T-Cell Lymphoma, Nasal Type of the Cauda Equina Presenting as Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis
Hyo Eun Leea, Ha Young Shina, Se Hoon Kimb, Hyung Seok Leea, Seung Min Kima Departments of aNeurology and bPathology, Yonsei University College of Medicine, Seoul, Korea
KEYWORDS Hemophagocytic
lymphohistiocytosis, NK/T‐cell lymphoma, Epstein‐Barr virus
Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome that may develop in association with various kinds of lymphoma and its clinical course is often fatal. Epstein‐Barr virus (EBV) is the major triggering factor for HLH. We describe a patient with extranodal NK/T‐cell lymphoma (ENKL), nasal type of the cauda equina presenting as EBV‐associated HLH (EBV‐HLH), initially considered as simple EBV polyradiculitis.Awareness of the association between NK/T‐cell lymphoma and EBV‐associated HLH is important for early initiation of life‐saving therapy.
Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome featuring a severe hyperinflammatory condition with prolonged fever, cytopenia, hepatosplenomegaly, and hemophagocytosis by aberrantly-activated macrophages.1,2 In adults, HLH often develops in association with various kinds of lymphoma including the extranodal NK/T-cell lymphoma (ENKL), nasal type.1 The clinical course of NK/T-cell lymphoma associated with HLH is often fulminant and results in fatality.3 Epstein-Barr virus (EBV) is the major triggering factor for HLH and associated with NK/T-cell lymphoma, especially in the Far East.4 Despite the fulminant and fatal clinical course, initially HLH may masquerade as a simple infection since all symptoms could also occur in immunocompetent patients.2
Here we report a patient with ENKL, nasal type of the cau- da equina presenting as EBV-associated HLH (EBV-HLH), initially considered as simple EBV polyradiculitis.
Case Report
A 44-year-old woman was admitted to our hospital with fe-
ver and leg pain since one week ago. Her vital sign was body temperature 38.8°C, blood pressure 100/66 mmHg, pulse rate 117 beats/min, and respiratory rate 16 breaths/min. On examination, pinprick and light touch sensations were dimin- ished on the lateral and posterior parts of both calves. There was mild weakness in the distal parts of both legs (MRC grade 4+/5). Deep tendon reflexes were absent in both legs.
A lumbar spine MRI demonstrated enhancement of lep- tomeninges and nerve roots without mass (Fig. 1A). Complete blood count showed pancytopenia (WBC: 1510/μL, Hb: 9.0 g/dL, and platelets: 31000/μL). Serum ferritin level was 665.7 ng/mL. Cerebrospinal fluid (CSF) showed high open- ing pressure(110 mmH2O), elevation of WBC (24 cells/mm3 , 95% lymphocytes), protein 197.3 mg/dL, and glucose 46.3 mg/dL (serum glucose 149 mg/dL). Malignant cells were not showed in CSF. The result of an electrophysiologic test was consistent with lumbosacral polyradiculopathy. She was started on ceftriaxone, acyclovir, isoniazid, rifampin, etham- butal, pyrazinamide, and pyridoxine for presumed infective lumbosacral polyradiculopathy and meningitis. Platelets were infused for thrombocytopenia.
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Figure 1. Lumbosacral spine MRI (A and B) and surgical finding (C). (A) Initial lumbosacral spine T1-weighted image reveals gadolinium enhancement of leptomeninges and nerve roots. (B) Follow-up lumbosacral spine T1-weighted image shows gadolinium enhancing bulky mass involving cauda equina and packing the lumbosacral spinal canal. (C) For biopsy, the dura and arachnoid membrane were opened. Gelatinous substances packed the lumbosacral subarachnoid space as demonstrated by follow-up MRI (B).
Figure 2. Hemophagocytic histiocytes engulfing nucleated cells within their cytoplasms.
Additional tests were performed. Bacterial and fungal blood cultures were sterile. CSF cultures for bacteria, tuber- culosis, and fungus were also negative. In Exception of EBV, any infectious evidence of viral and bacterial were not detected. IgM-EBV antibody against the early antigen was negative. IgG EBV antibody against early antigen and EBV nuclear antigen were positive. A very high level of EBV DNA was detected (345,000 DNA copies per milliliter of plasma).
Positron emission tomography-computed tomography for pancytopenia evaluation revealed hepatosplenomegaly and diffuse fluorodeoxyglucose uptake within the bone marrow of vertebral bodies and the sternum. Bone marrow biopsy specimen showed hypocellular marrow with hemophagocy- tosis (Fig. 2).
Based on these findings, EBV-HLH was diagnosed. The patient was closely monitored without specific treatment for EBV-HLH because fever subsided, pancytopenia was im- proved (WBC: 3030/μL, Hb: 9.0 g/dL, and platelets 396000 /μL), and her neurologic symptoms were stable. However, two weeks after EBV-HLH diagnosis, her neurologic defi- cits were worsened rapidly. She could not walk or control urination. Treatment with glucocorticoids and intravenous
immune globulin was initiated. A lumbar spine MRI was per- formed again, revealing a bulky enhancing mass involving the cauda equina (Fig. 1B). An open biopsy of the lumbo- sacral nerve rootlet and arachnoid membrane was performed (Fig. 1C). Diffuse infiltration of small- to medium-sized lym- phoid cells with abundant apoptosis was found (Fig. 3A-B).
Immunohistochemical staining showed that these cells were A B C
Korean Journal of Neuromuscular Disorders 2014 27 HE Lee, et al. | ENKL, Nasal Type of Cauda Equina Presenting as EBV-HLH
Figure 3. Pathologic findings. Hematoxylin and eosin staining demonstrates diffuse infiltration of atypical cells on low power view (A, H-E ×40) and small- to medium-sized lymphoid cells with abundant apoptosis on high power view (B, H-E ×600). (C) CD3 immunohistochemical staining shows positive reactions in small lymphoid cells (×400). CD56 (D), and granzyme B (E) staining reveals positive reactions in medium-sized atypical lymphoid cells (×400). (F) Epstein Barr viral early RNAs are detected in these medium-sized cells by in situ hybridization for EBERs (EBER-ISH, ×400).
positive for CD3, CD56, and granzyme B (Fig. 3C-E). A di- agnosis of ENKL, nasal type was made. EBV-encoded RNA was detected in lymphoma cells by in situ hybridization (Fig. 3F).
The patient received chemotherapy for ENKL, nasal type.
However, clinical status deteriorated without responding to treatment, and she died six months after the onset of symptoms.
Discussion
We report a case study of a patient presenting with fever and progressive cauda equina syndrome. Testing for EBV antibodies was suggestive of past infection, and the level of EBV DNA was very high. EBV can affect multiple parts of the entire neuraxis and may cause polyradiculitis by diffuse involvement of the leptomeninges.5 Viral infection includ- ing EBV can induce pancytopenia. Therefore, reactivation of chronic latent EBV infection or new EBV infection was considered to be the cause of fever and cauda equina syndrome. Unexpected hemophagocytosis was detected in a bone marrow biopsy specimen. Hepatosplenomegaly and
hyperferritinemia were also demonstrated. HLH was diag- nosed because five of the eight diagnostic criteria for HLH were satisfied: fever, splenomegaly, pancytopenia, hyper- ferritinemia, and hemophagocytosis.2
Adult HLH is associated with various disorders like viral infections, malignancies, autoimmune disease, and medi- cation, and the prognosis depends on the underlying disorder.2, 6 In a previous study, the mortality rate of lympho- ma-associated HLH was found to be 88%, whereas 94% of patients with virus-associated HLH achieved remission, a mortality rate of only 6%.7 EBV-HLH, however, seems to be different from the other virus-associated HLH. In adults, EBV-HLH often develops in association with various lym- phomas including the ENKL, nasal type, and the clinical courses of these cases are often fulminant and result in a poor outcome.1,4 Our patient also expired two months after diagnosis of EBV-HLH.
Only one case of primary ENKL, nasal type originating from the cauda equina has been reported.8 The case pre- sented similar clinical features to those of our patient but was not associated with HLH.
High level of EBV DNA was the reason why EBV in- A B C
D E F
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fection was considered as the cause of cauda equina syn- drome in this case. A high level of EBV DNA can also be de- tected in the plasma or serum from patients with EBV-asso- ciated tumors. In tumor cells of ENKL, EBV DNA is almost always detected. High levels of EBV DNA have been corre- lated with a poor prognosis in ENKL, nasal type.9 The de- tected EBV DNA molecules may be released into circu- lation by apoptosis of tumor cells instead of active viral replication. Determination of the length of detected EBV DNA fragments may have helped to detect underlying ENKL, nasal type in the early phase of this case.
In conclusion, EBV-HLH may be a warning sign for un- derlying lymphoma, which could be misdiagnosed as simple EBV infection. ENKL, nasal type should be considered in patients who present with a progressive cauda equina syn- drome associated with EBV-HLH, especially in the Far East.
It is necessary to continue the search for a malignant process in the case of EBV-HLH, even for patients with a stable clin- ical course.
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