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Late onset progressive multifocal leukoencephalopathy in Hodgkin lymphoma
Journal of Clinical Neuroscience xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Case report
Late onset progressive multifocal leukoencephalopathy in Hodgkin lymphoma Whitley W. Aamodt a,⇑, James E. Siegler a, Angela N. Viaene b, Michael N. Rubenstein a a b
Department of Neurology, Hospital of the University of Pennsylvania, 3W Gates Building, 3400 Spruce Street, Philadelphia, PA 19104, USA Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA
a r t i c l e
i n f o
Article history: Received 5 February 2017 Accepted 22 April 2017 Available online xxxx Keywords: Progressive multifocal leukoencephalopathy JC virus Hodgkin disease
a b s t r a c t Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease resulting from infection of oligodendrocytes in the central nervous system with John Cunningham virus. Although PML is commonly diagnosed in immunocompromised patients with human immunodeficiency virus, it can also arise in other immunodeficient states. In this report, we present an unusual case of PML occurring 40 years after chemoradiation therapy for Hodgkin lymphoma in a patient with normal total lymphocyte counts on annual surveillance. Although current guidelines recommend annual complete blood counts for patients in remission, this testing may be insufficient to monitor patients with chronic CD4+ lymphopenia. Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction Progressive multifocal leukoencephalopathy (PML) is a white matter disease caused by the John Cunningham virus (JCV) that leads to progressive demyelination in individuals with impaired cellular immunity. Although 50–90% of adults have been exposed to JCV, it remains dormant in immunocompetent hosts [1]. Clinical disease later occurs when the virus is reactivated in latently infected B-cells and renal epithelial cells during periods of severe immunosuppression [2]. Although T-cell lymphopenia is a primary risk factor, PML was first associated with B-cell lymphoproliferative disorders such as non-Hodgkin and Hodgkin lymphoma (HL) [1]. With the emergence of the human immunodeficiency virus (HIV), 85% of cases now occur in HIV patients [3]. New cases have also developed following use of monoclonal antibodies for treatment of autoimmune and hematologic diseases [4].
vincristine, procarbazine, prednisone (MOPP), and para-aortic radiotherapy. He was cured in 1977. There were no complications until 2016, when he presented with two months of progressive dysarthria, left-sided dysmetria, and gait ataxia. An MRI brain demonstrated a non-enhancing lesion in the left cerebellar hemisphere and middle cerebellar peduncle (Fig. 1). Routine lymphocyte counts from the preceding decade were normal (Table 1). Admission serum studies were notable for a negative HIV antibody, elevated JCV antibody, and CD4+ count of 260 cells/uL. Lumbar puncture revealed normal cell counts, protein, glucose, culture, flow cytometry, and cytopathology, with four oligoclonal bands and negative JCV by polymerase chain reaction. A stereotactic biopsy of his cerebellar lesion was performed, confirming PML (Fig. 2). He was subsequently referred to the National Institutes of Health for a clinical trial.
3. Discussion 2. Case report A 69-year-old man with history of stage IA nodular sclerosing HL was initially diagnosed in 1976 following biopsy of a mediastinal mass with staging laparotomy and splenectomy. He received mantle radiotherapy, followed by six cycles of methchlorethamine, ⇑ Corresponding author. E-mail addresses: [email protected] (W.W. Aamodt), james. [email protected] (J.E. Siegler), [email protected] (A.N. Viaene), [email protected] (M.N. Rubenstein).
To our knowledge, this is the first case of PML developing 40 years after chemoradiation therapy for HL despite appropriate monitoring. Current National Comprehensive Cancer Network (NCCN) guidelines recommend annual complete blood counts for HL patients in remission [5]. While our patient’s total white blood cell and lymphocyte counts were normal, CD4+ counts were not checked until he presented to our clinical attention. Although late onset PML can occur in the setting of relapsed HL, our patient had no signs of recurrent malignancy or other opportunistic disease. We hypothesize that the combination of CD4+ lymphopenia with
http://dx.doi.org/10.1016/j.jocn.2017.04.030 0967-5868/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Aamodt WW et al. Late onset progressive multifocal leukoencephalopathy in Hodgkin lymphoma. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.04.030
2
Case Report / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
Fig. 1. Axial T1-weighted MRI shows a crescent-shaped hypointensity in the left cerebellum and left medial cerebellar peduncle (A). Axial T2-FLAIR post-contrast shows a corresponding non-enhancing hyperintensity (B).
Table 1 Routine white blood cell and absolute lymphocyte counts collected over the preceding decade. Relative date
WBC (103 per lL) (Range 4.0–11.0)
ALC (103 per lL) (Range 1.00–5.00)
CD4+ (cells per lL) (Range 560–1840)
108 months prior 96 months prior 84 months prior 69 months prior 57 months prior 45 months prior 33 months prior 21 months prior 17 months prior 5 months prior Presentation
8.1 8.0 7.5 8.1 8.2 7.9 7.1 7.0 8.0 6.4 8.1
NM NM 1.20 1.39 1.37 1.27 1.10 1.24 NM 0.94 1.20
NM NM NM NM NM NM NM NM NM NM 260
WBC = white blood cell count, ALC = absolute lymphocyte count, NM = not measured.
Fig. 2. Hematoxylin and eosin section (400) revealed hypercellular cerebellar parenchyma with viral inclusions (arrows) in a background of macrophages and chronic inflammatory cells (A). In situ hybridization (400) was positive for JC virus (B).
Please cite this article in press as: Aamodt WW et al. Late onset progressive multifocal leukoencephalopathy in Hodgkin lymphoma. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.04.030
Case Report / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
underlying B-cell dysregulation from prior HL increased his risk of PML, but it remains unclear why he did not develop other opportunistic infections. Treatment of PML involves addressing the underlying mechanism for impaired cellular immunity. Because therapeutic options are limited in cases of CD4+ lymphophenia, clinical trials are currently underway.
4. Conclusion Impaired cellular immunity can persist for decades following diagnosis and treatment of HL. However, current NCCN guidelines for disease surveillance may overlook CD4+ lymphopenia in HL survivors. Larger cohort studies are needed to determine which patients remain at risk for opportunistic CNS infections despite current standards of care, which may allow for new surveillance and treatment guidelines.
3
Sources of support This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors. References [1] Bellizzi A, Anzivino E, Rodio DM, et al. New insights on human polyomavirus JC and pathogenesis of progressive multifocal leukoencephalopathy. Clin Dev Immunol 2013:1–17. [2] Garcia-Suarez J, de Miguel D, Krsnik I, et al. Changes in the natural history of progressive multifocal leukoencephalopathy in HIV-negative lymphoproliferative disorders: Impact of novel therapies. Am J Hematol 2005;80(4):271–81. [3] Berger JR, Concha M. Progressive multifocal leukoencephalopathy: the evolution of a disease once considered rare. J Neurovirol 1995:5–18. [4] Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. N Engl J Med 2005;353:362–8. [5] Hoppe RT, Advani RH, Bierman PJ, et al. Hodgkin disease/lymphoma. Clinical practice guidelines in oncology. J Natl Compr Canc Netw 2006;4(3):210–30.
Please cite this article in press as: Aamodt WW et al. Late onset progressive multifocal leukoencephalopathy in Hodgkin lymphoma. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.04.030
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Case report
Late onset progressive multifocal leukoencephalopathy in Hodgkin lymphoma Whitley W. Aamodt a,⇑, James E. Siegler a, Angela N. Viaene b, Michael N. Rubenstein a a b
Department of Neurology, Hospital of the University of Pennsylvania, 3W Gates Building, 3400 Spruce Street, Philadelphia, PA 19104, USA Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA
a r t i c l e
i n f o
Article history: Received 5 February 2017 Accepted 22 April 2017 Available online xxxx Keywords: Progressive multifocal leukoencephalopathy JC virus Hodgkin disease
a b s t r a c t Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease resulting from infection of oligodendrocytes in the central nervous system with John Cunningham virus. Although PML is commonly diagnosed in immunocompromised patients with human immunodeficiency virus, it can also arise in other immunodeficient states. In this report, we present an unusual case of PML occurring 40 years after chemoradiation therapy for Hodgkin lymphoma in a patient with normal total lymphocyte counts on annual surveillance. Although current guidelines recommend annual complete blood counts for patients in remission, this testing may be insufficient to monitor patients with chronic CD4+ lymphopenia. Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction Progressive multifocal leukoencephalopathy (PML) is a white matter disease caused by the John Cunningham virus (JCV) that leads to progressive demyelination in individuals with impaired cellular immunity. Although 50–90% of adults have been exposed to JCV, it remains dormant in immunocompetent hosts [1]. Clinical disease later occurs when the virus is reactivated in latently infected B-cells and renal epithelial cells during periods of severe immunosuppression [2]. Although T-cell lymphopenia is a primary risk factor, PML was first associated with B-cell lymphoproliferative disorders such as non-Hodgkin and Hodgkin lymphoma (HL) [1]. With the emergence of the human immunodeficiency virus (HIV), 85% of cases now occur in HIV patients [3]. New cases have also developed following use of monoclonal antibodies for treatment of autoimmune and hematologic diseases [4].
vincristine, procarbazine, prednisone (MOPP), and para-aortic radiotherapy. He was cured in 1977. There were no complications until 2016, when he presented with two months of progressive dysarthria, left-sided dysmetria, and gait ataxia. An MRI brain demonstrated a non-enhancing lesion in the left cerebellar hemisphere and middle cerebellar peduncle (Fig. 1). Routine lymphocyte counts from the preceding decade were normal (Table 1). Admission serum studies were notable for a negative HIV antibody, elevated JCV antibody, and CD4+ count of 260 cells/uL. Lumbar puncture revealed normal cell counts, protein, glucose, culture, flow cytometry, and cytopathology, with four oligoclonal bands and negative JCV by polymerase chain reaction. A stereotactic biopsy of his cerebellar lesion was performed, confirming PML (Fig. 2). He was subsequently referred to the National Institutes of Health for a clinical trial.
3. Discussion 2. Case report A 69-year-old man with history of stage IA nodular sclerosing HL was initially diagnosed in 1976 following biopsy of a mediastinal mass with staging laparotomy and splenectomy. He received mantle radiotherapy, followed by six cycles of methchlorethamine, ⇑ Corresponding author. E-mail addresses: [email protected] (W.W. Aamodt), james. [email protected] (J.E. Siegler), [email protected] (A.N. Viaene), [email protected] (M.N. Rubenstein).
To our knowledge, this is the first case of PML developing 40 years after chemoradiation therapy for HL despite appropriate monitoring. Current National Comprehensive Cancer Network (NCCN) guidelines recommend annual complete blood counts for HL patients in remission [5]. While our patient’s total white blood cell and lymphocyte counts were normal, CD4+ counts were not checked until he presented to our clinical attention. Although late onset PML can occur in the setting of relapsed HL, our patient had no signs of recurrent malignancy or other opportunistic disease. We hypothesize that the combination of CD4+ lymphopenia with
http://dx.doi.org/10.1016/j.jocn.2017.04.030 0967-5868/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Aamodt WW et al. Late onset progressive multifocal leukoencephalopathy in Hodgkin lymphoma. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.04.030
2
Case Report / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
Fig. 1. Axial T1-weighted MRI shows a crescent-shaped hypointensity in the left cerebellum and left medial cerebellar peduncle (A). Axial T2-FLAIR post-contrast shows a corresponding non-enhancing hyperintensity (B).
Table 1 Routine white blood cell and absolute lymphocyte counts collected over the preceding decade. Relative date
WBC (103 per lL) (Range 4.0–11.0)
ALC (103 per lL) (Range 1.00–5.00)
CD4+ (cells per lL) (Range 560–1840)
108 months prior 96 months prior 84 months prior 69 months prior 57 months prior 45 months prior 33 months prior 21 months prior 17 months prior 5 months prior Presentation
8.1 8.0 7.5 8.1 8.2 7.9 7.1 7.0 8.0 6.4 8.1
NM NM 1.20 1.39 1.37 1.27 1.10 1.24 NM 0.94 1.20
NM NM NM NM NM NM NM NM NM NM 260
WBC = white blood cell count, ALC = absolute lymphocyte count, NM = not measured.
Fig. 2. Hematoxylin and eosin section (400) revealed hypercellular cerebellar parenchyma with viral inclusions (arrows) in a background of macrophages and chronic inflammatory cells (A). In situ hybridization (400) was positive for JC virus (B).
Please cite this article in press as: Aamodt WW et al. Late onset progressive multifocal leukoencephalopathy in Hodgkin lymphoma. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.04.030
Case Report / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
underlying B-cell dysregulation from prior HL increased his risk of PML, but it remains unclear why he did not develop other opportunistic infections. Treatment of PML involves addressing the underlying mechanism for impaired cellular immunity. Because therapeutic options are limited in cases of CD4+ lymphophenia, clinical trials are currently underway.
4. Conclusion Impaired cellular immunity can persist for decades following diagnosis and treatment of HL. However, current NCCN guidelines for disease surveillance may overlook CD4+ lymphopenia in HL survivors. Larger cohort studies are needed to determine which patients remain at risk for opportunistic CNS infections despite current standards of care, which may allow for new surveillance and treatment guidelines.
3
Sources of support This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors. References [1] Bellizzi A, Anzivino E, Rodio DM, et al. New insights on human polyomavirus JC and pathogenesis of progressive multifocal leukoencephalopathy. Clin Dev Immunol 2013:1–17. [2] Garcia-Suarez J, de Miguel D, Krsnik I, et al. Changes in the natural history of progressive multifocal leukoencephalopathy in HIV-negative lymphoproliferative disorders: Impact of novel therapies. Am J Hematol 2005;80(4):271–81. [3] Berger JR, Concha M. Progressive multifocal leukoencephalopathy: the evolution of a disease once considered rare. J Neurovirol 1995:5–18. [4] Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. N Engl J Med 2005;353:362–8. [5] Hoppe RT, Advani RH, Bierman PJ, et al. Hodgkin disease/lymphoma. Clinical practice guidelines in oncology. J Natl Compr Canc Netw 2006;4(3):210–30.
Please cite this article in press as: Aamodt WW et al. Late onset progressive multifocal leukoencephalopathy in Hodgkin lymphoma. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.04.030