572241
research-article2015
MSJ0010.1177/1352458515572241Multiple Sclerosis JournalR Iorio et al.
MULTIPLE SCLEROSIS MSJ JOURNAL
Case Report
Neuromyelitis optica spectrum disorder as a paraneoplastic manifestation of lung adenocarcinoma expressing aquaporin-4
Multiple Sclerosis Journal 2015, Vol. 21(6) 791–794 DOI: 10.1177/ 1352458515572241 © The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Raffaele Iorio, Guido Rindi, Carmen Erra, Valentina Damato, Michela Ferilli and Mario Sabatelli
Abstract Background: The observations of neuromyelitis optica spectrum disorders (NMOSD) occurring in the setting of cancer suggest that aquaporin-4 (AQP4) autoimmunity may in some cases be paraneoplastic. Results: We describe a 72-year-old patient who developed a longitudinally extensive transverse myelitis associated with AQP4 autoantibodies in the setting of a lung adenocarcinoma recurrence. AQP4 expression was demonstrated in tumor cells. IgG in patient’s cerebrospinal fluid bound to tumor cells co-localizing with AQP4 immunoreactivity. Conclusions and relevance: This case expands the spectrum of paraneoplastic AQP4 autoimmunity highlighting the importance of considering an oncological screening in patients with late-onset NMOSD.
Keywords: Paraneoplastic, neuromyelitis optica Date received: 16 December 2014; revised: January 1 2015; accepted: 7 January 2015 Introduction Paraneoplastic neurological disorders (PNDs) are remote effects of cancer caused by an autoimmune response initiated by neural self-antigens expressed by tumor cells.1 The detection of neural autoantibodies in patients with PNDs aids the neurological diagnosis and predicts a limited number of potentially associated cancer types.1 Neuromyelitis optica (NMO) is an autoimmune astrocytopathy that preferentially affects the optic nerves and the spinal cord.2 An immunoglobulin-G (IgG) specific for the aquaporin-4 (AQP4) water channel, is a reliable biomarker that distinguishes NMO and its partial forms (neuromyelitis optica spectrum disorders; NMOSDs) from multiple sclerosis.2,3 The detection of AQP4IgG unifies the diverse neurological manifestations of NMOSD including optic neuritis, transverse myelitis, intractable vomiting/hiccups, inappropriate antidiuresis, narcolepsy and encephalopathy.2,4–6 AQP4-IgG binds to the extracellular domain of the water channel and it has pathogenic potential.7 Observations of NMO and NMOSD in the setting of cancer suggest that AQP4 autoimmunity can be paraneoplastic.8 Here we describe a patient diagnosed
with lung adenocarcinoma who 3 months after surgery developed NMOSD. Report of a case A 72-year-old woman with a history of multiple nonmelanoma skin cancers underwent a left lower lobectomy for surgical treatment of a non-small cell lung cancer (NSCLC). Pathological analysis of the tumor revealed acinar lung adenocarcinoma. The postoperative course was uneventful. After 3 months a total body positron emission tomography revealed hypercaptation of 2-fluoro-deoxy-d-glucose in the left pulmonary pleura and lymph nodes above the diaphragm. One week later the patient was admitted to our clinic for limb weakness and cervical pain. Examination revealed severe weakness of the upper limbs associated with hypotonia and thermal-pain hypoesthesia and mild weakness of the inferior limbs. A brain and spinal cord magnetic resonance imaging showed a T2-hyperintense lesion of the corpus callosum and a T2-hyperintense lesion extending from the cervicomedullary junction to D1, both without enhancement after gadolinium administration (Figure 1). A chest
Correspondence to: Raffaele Iorio Institute of Neurology, Department of Geriatrics, Neuroscience and Orthopedics, Catholic University, L. go Gemelli, 8 00168 Roma, Italy. [email protected] Raffaele Iorio Carmen Erra Valentina Damato Michela Ferilli Mario Sabatelli Institute of Neurology, Catholic University, Rome, Italy Guido Rindi Institute of Anatomic Pathology, Catholic University, Rome, Italy
http://msj.sagepub.com 791
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Multiple Sclerosis Journal 21(6)
Figure 1. Brain and spinal cord magnetic resonance imaging. (a) Sagittal T2-weighted image showing a hyperintense lesion extending longitudinally from the cervicomedullary junction to D1. (b) Axial T2 image of the spinal cord at C3 level showing the centromedullary hyperintense lesion. (c) Axial T2-weighted image of the brain showing a hyperintense lesion involving the corpus callosum.
computed tomography detected hypodense, enhancing tissue on the left pleura, consistent with tumor recurrence. Cerebrospinal fluid (CSF) analysis showed increased protein (125 mg/dL) and no oligoclonal bands. AQP4-IgG was detected in patient’s serum (titer 1:1920) and CSF (1:50) by a cell-based assay. Testing for onconeural antibodies proved negative. Immunohistochemistry on formalin-fixed paraffin embedded sections of the patient’s lung adenocarcinoma revealed AQP4-positive tumor cells. IgG in the patient’s CSF bound to tumor cells co-localizing with AQP4 immunoreactivity (Figure 2). The patient was treated with intravenous steroids (methylprednisolone 250 mg/day for 5 days) and plasma exchange (five cycles) with improvement of limb weakness. A radiotherapy regimen was then started. Discussion The immunological mechanisms underlying the initiation of AQP4 autoimmunity are currently unknown. However, it has been observed that in some NMOSD patients the immune response may be initiated against tumoral AQP4.8 The demonstration of AQP4 expression in this patient’s lung adenocarcinoma and the
binding of the patient’s IgGs to tumoral AQP4 further support a paraneoplastic etiology for some NMOSD cases. NMOSDs have been described in the setting of several types of cancer, with breast carcinoma and thymoma being the most frequent.8 NSCLC, carcinoid and ovarian teratoma have also been reported.9–11 However, AQP4 expression in cancer tissue has been investigated only in a few cases of paraneoplastic NMOSD. To the best of our knowledge this is the first report to demonstrate AQP-4 expression in a lung adenocarcinoma of a patient with paraneoplastic NMOSD. Aquaporins have been recognized to promote tumor progression, invasion, and metastasis.12 A recent study demonstrated high AQP4 expression in lung adenocarcinomas with acinar differentiation, as in the patient reported here.13 The median onset age for idiopathic NMOSD is 39 years,14 but patients with paraneoplastic NMOSD are generally older than 48 years of age,15 as the patient here described. Recent reports indicate that ≈15% of patients with NMOSD are older than 50 years of age at initial diagnosis.16 Larger studies are needed to establish if cancer screening should be recommended in patients with ‘late-onset’ NMOSD.
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R Iorio, G Rindi et al.
Figure 2. Indirect immunofluorescence assays on patient’s tumor specimen. Staining with rabbit aquaporin-4immunoglobulin-G (AQP4-IgG) (AbNova, PAB20767, dilution 1:250) detected by Dylight 550-conjugated anti-rabbit IgG (1:250) (red) reveals intense immunoreactivity of luminal epithelial cells (a), (d) and (g). No immunoreactivity of acinar cells but only autofluorescent elastic fibers were observed when the tumor sections were incubated with Alexa Fluor 488-conjugated anti-human IgG (1:250) alone (b) and (c), or with cerebrospinal fluid (CSF) (1:5) from a patient with multiple sclerosis (e) and (f), followed by the anti-human secondary antibody. IgG in the patient’s CSF (1:5) bind to acinar cells co-localizing with AQP4 immunoreactivity (h) and (i) (Scale bar=100um).
Author contributions Dr Iorio has full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Dr Iorio. Acquisition of data: Drs Erra, Ferilli, Iorio, Rindi, Sabatelli. Analysis and interpretation of data: Drs Damato, Iorio, Rindi. Drafting of the manuscript: Dr Iorio. Critical revision of the manuscript for important intellectual content: All authors.
Conflict of interest The authors have no conflicts of interest to declare. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
References 1. Iorio R and Lennon VA. Neural antigen-specific autoimmune disorders. Immunol Rev 2012; 248(1): 104–121.
http://msj.sagepub.com 793
Downloaded from msj.sagepub.com at UNIV CALGARY LIBRARY on May 27, 2015
Multiple Sclerosis Journal 21(6) 2. Iorio R and Pittock SJ. Neuromyelitis optica and the evolving spectrum of autoimmune aquaporin-4 channelopathies. Clin Exp Neuroimmunol 2014; 5(2): 175–187.
9. De Santis G, Caniatti L, De Vito A, et al. A possible paraneoplastic neuromyelitis optica associated with lung cancer. Neurol Sci 2009; 30(5): 397–400.
3. Jiao Y, Fryer JP, Lennon VA, et al. Updated estimate of AQP4-IgG serostatus and disability outcome in neuromyelitis optica. Neurology 2013; 81(14): 1197–1204.
10. Frasquet M, Bataller L, Torres-Vega E, et al. Longitudinally extensive transverse myelitis with AQP4 antibodies revealing ovarian teratoma. J Neuroimmunol 2013; 263(1–2): 145–147.
4. Iorio R, Lucchinetti CF, Lennon VA, et al. Syndrome of inappropriate antidiuresis may herald or accompany neuromyelitis optica. Neurology 2011; 77: 1644–1646.
11. Figueroa M, Guo Y, Tselis A, et al. Paraneoplastic neuromyelitis optica spectrum disorder associated with metastatic carcinoid expressing aquaporin-4. JAMA Neurol 2014; 71(4): 495–498.
5. Iorio R, Lucchinetti CF, Lennon VA, et al. Intractable nausea and vomiting from autoantibodies against a brain water channel. Clin Gastroenterol Hepatol 2013; 11(3): 240–245.
12. Verkman AS. Aquaporins in clinical medicine. Annu Rev Med 2012; 63: 303–316.
6. Iorio R, Damato V, Mirabella M, et al. Distinctive clinical and neuroimaging characteristics of longitudinally extensive transverse myelitis associated with aquaporin-4 autoantibodies. J Neurol 2013; 260(9): 2396–2402. 7. Iorio R, Fryer JP, Hinson SR, et al. Astrocytic autoantibody of neuromyelitis optica (NMO-IgG) binds to aquaporin-4 extracellular loops, monomers, tetramers and high order arrays. J Autoimmun 2013; 40: 21–27. Visit SAGE journals online http://msj.sagepub.com
SAGE journals
8. Pittock SJ and Lennon VA. Aquaporin-4 autoantibodies in a paraneoplastic context. Arch Neurol 2008; 65(5): 629–632.
13. Warth A, Muley T, Meister M, et al. Loss of aquaporin-4 expression and putative function in non-small cell lung cancer. BMC Cancer 2011; 11: 161–170. 14. Quek AM, McKeon A, Lennon VA, et al. Effects of age and sex on aquaporin-4 autoimmunity. Arch Neurol 2012; 69(8): 1039–1043. 15. Ontaneda D and Fox RJ. Is neuromyelitis optica with advanced age of onset a paraneoplastic disorder? Int J Neurosci 2014; 124(7): 509–511. 16. Collongues N, Marignier R, Zéphir H, et al. Neuromyelitis optica in France: a multicenter study of 125 patients. Neurology 2010; 74(9): 736–742.
794 http://msj.sagepub.com
Downloaded from msj.sagepub.com at UNIV CALGARY LIBRARY on May 27, 2015
research-article2015
MSJ0010.1177/1352458515572241Multiple Sclerosis JournalR Iorio et al.
MULTIPLE SCLEROSIS MSJ JOURNAL
Case Report
Neuromyelitis optica spectrum disorder as a paraneoplastic manifestation of lung adenocarcinoma expressing aquaporin-4
Multiple Sclerosis Journal 2015, Vol. 21(6) 791–794 DOI: 10.1177/ 1352458515572241 © The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Raffaele Iorio, Guido Rindi, Carmen Erra, Valentina Damato, Michela Ferilli and Mario Sabatelli
Abstract Background: The observations of neuromyelitis optica spectrum disorders (NMOSD) occurring in the setting of cancer suggest that aquaporin-4 (AQP4) autoimmunity may in some cases be paraneoplastic. Results: We describe a 72-year-old patient who developed a longitudinally extensive transverse myelitis associated with AQP4 autoantibodies in the setting of a lung adenocarcinoma recurrence. AQP4 expression was demonstrated in tumor cells. IgG in patient’s cerebrospinal fluid bound to tumor cells co-localizing with AQP4 immunoreactivity. Conclusions and relevance: This case expands the spectrum of paraneoplastic AQP4 autoimmunity highlighting the importance of considering an oncological screening in patients with late-onset NMOSD.
Keywords: Paraneoplastic, neuromyelitis optica Date received: 16 December 2014; revised: January 1 2015; accepted: 7 January 2015 Introduction Paraneoplastic neurological disorders (PNDs) are remote effects of cancer caused by an autoimmune response initiated by neural self-antigens expressed by tumor cells.1 The detection of neural autoantibodies in patients with PNDs aids the neurological diagnosis and predicts a limited number of potentially associated cancer types.1 Neuromyelitis optica (NMO) is an autoimmune astrocytopathy that preferentially affects the optic nerves and the spinal cord.2 An immunoglobulin-G (IgG) specific for the aquaporin-4 (AQP4) water channel, is a reliable biomarker that distinguishes NMO and its partial forms (neuromyelitis optica spectrum disorders; NMOSDs) from multiple sclerosis.2,3 The detection of AQP4IgG unifies the diverse neurological manifestations of NMOSD including optic neuritis, transverse myelitis, intractable vomiting/hiccups, inappropriate antidiuresis, narcolepsy and encephalopathy.2,4–6 AQP4-IgG binds to the extracellular domain of the water channel and it has pathogenic potential.7 Observations of NMO and NMOSD in the setting of cancer suggest that AQP4 autoimmunity can be paraneoplastic.8 Here we describe a patient diagnosed
with lung adenocarcinoma who 3 months after surgery developed NMOSD. Report of a case A 72-year-old woman with a history of multiple nonmelanoma skin cancers underwent a left lower lobectomy for surgical treatment of a non-small cell lung cancer (NSCLC). Pathological analysis of the tumor revealed acinar lung adenocarcinoma. The postoperative course was uneventful. After 3 months a total body positron emission tomography revealed hypercaptation of 2-fluoro-deoxy-d-glucose in the left pulmonary pleura and lymph nodes above the diaphragm. One week later the patient was admitted to our clinic for limb weakness and cervical pain. Examination revealed severe weakness of the upper limbs associated with hypotonia and thermal-pain hypoesthesia and mild weakness of the inferior limbs. A brain and spinal cord magnetic resonance imaging showed a T2-hyperintense lesion of the corpus callosum and a T2-hyperintense lesion extending from the cervicomedullary junction to D1, both without enhancement after gadolinium administration (Figure 1). A chest
Correspondence to: Raffaele Iorio Institute of Neurology, Department of Geriatrics, Neuroscience and Orthopedics, Catholic University, L. go Gemelli, 8 00168 Roma, Italy. [email protected] Raffaele Iorio Carmen Erra Valentina Damato Michela Ferilli Mario Sabatelli Institute of Neurology, Catholic University, Rome, Italy Guido Rindi Institute of Anatomic Pathology, Catholic University, Rome, Italy
http://msj.sagepub.com 791
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Multiple Sclerosis Journal 21(6)
Figure 1. Brain and spinal cord magnetic resonance imaging. (a) Sagittal T2-weighted image showing a hyperintense lesion extending longitudinally from the cervicomedullary junction to D1. (b) Axial T2 image of the spinal cord at C3 level showing the centromedullary hyperintense lesion. (c) Axial T2-weighted image of the brain showing a hyperintense lesion involving the corpus callosum.
computed tomography detected hypodense, enhancing tissue on the left pleura, consistent with tumor recurrence. Cerebrospinal fluid (CSF) analysis showed increased protein (125 mg/dL) and no oligoclonal bands. AQP4-IgG was detected in patient’s serum (titer 1:1920) and CSF (1:50) by a cell-based assay. Testing for onconeural antibodies proved negative. Immunohistochemistry on formalin-fixed paraffin embedded sections of the patient’s lung adenocarcinoma revealed AQP4-positive tumor cells. IgG in the patient’s CSF bound to tumor cells co-localizing with AQP4 immunoreactivity (Figure 2). The patient was treated with intravenous steroids (methylprednisolone 250 mg/day for 5 days) and plasma exchange (five cycles) with improvement of limb weakness. A radiotherapy regimen was then started. Discussion The immunological mechanisms underlying the initiation of AQP4 autoimmunity are currently unknown. However, it has been observed that in some NMOSD patients the immune response may be initiated against tumoral AQP4.8 The demonstration of AQP4 expression in this patient’s lung adenocarcinoma and the
binding of the patient’s IgGs to tumoral AQP4 further support a paraneoplastic etiology for some NMOSD cases. NMOSDs have been described in the setting of several types of cancer, with breast carcinoma and thymoma being the most frequent.8 NSCLC, carcinoid and ovarian teratoma have also been reported.9–11 However, AQP4 expression in cancer tissue has been investigated only in a few cases of paraneoplastic NMOSD. To the best of our knowledge this is the first report to demonstrate AQP-4 expression in a lung adenocarcinoma of a patient with paraneoplastic NMOSD. Aquaporins have been recognized to promote tumor progression, invasion, and metastasis.12 A recent study demonstrated high AQP4 expression in lung adenocarcinomas with acinar differentiation, as in the patient reported here.13 The median onset age for idiopathic NMOSD is 39 years,14 but patients with paraneoplastic NMOSD are generally older than 48 years of age,15 as the patient here described. Recent reports indicate that ≈15% of patients with NMOSD are older than 50 years of age at initial diagnosis.16 Larger studies are needed to establish if cancer screening should be recommended in patients with ‘late-onset’ NMOSD.
792 http://msj.sagepub.com
Downloaded from msj.sagepub.com at UNIV CALGARY LIBRARY on May 27, 2015
R Iorio, G Rindi et al.
Figure 2. Indirect immunofluorescence assays on patient’s tumor specimen. Staining with rabbit aquaporin-4immunoglobulin-G (AQP4-IgG) (AbNova, PAB20767, dilution 1:250) detected by Dylight 550-conjugated anti-rabbit IgG (1:250) (red) reveals intense immunoreactivity of luminal epithelial cells (a), (d) and (g). No immunoreactivity of acinar cells but only autofluorescent elastic fibers were observed when the tumor sections were incubated with Alexa Fluor 488-conjugated anti-human IgG (1:250) alone (b) and (c), or with cerebrospinal fluid (CSF) (1:5) from a patient with multiple sclerosis (e) and (f), followed by the anti-human secondary antibody. IgG in the patient’s CSF (1:5) bind to acinar cells co-localizing with AQP4 immunoreactivity (h) and (i) (Scale bar=100um).
Author contributions Dr Iorio has full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Dr Iorio. Acquisition of data: Drs Erra, Ferilli, Iorio, Rindi, Sabatelli. Analysis and interpretation of data: Drs Damato, Iorio, Rindi. Drafting of the manuscript: Dr Iorio. Critical revision of the manuscript for important intellectual content: All authors.
Conflict of interest The authors have no conflicts of interest to declare. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
References 1. Iorio R and Lennon VA. Neural antigen-specific autoimmune disorders. Immunol Rev 2012; 248(1): 104–121.
http://msj.sagepub.com 793
Downloaded from msj.sagepub.com at UNIV CALGARY LIBRARY on May 27, 2015
Multiple Sclerosis Journal 21(6) 2. Iorio R and Pittock SJ. Neuromyelitis optica and the evolving spectrum of autoimmune aquaporin-4 channelopathies. Clin Exp Neuroimmunol 2014; 5(2): 175–187.
9. De Santis G, Caniatti L, De Vito A, et al. A possible paraneoplastic neuromyelitis optica associated with lung cancer. Neurol Sci 2009; 30(5): 397–400.
3. Jiao Y, Fryer JP, Lennon VA, et al. Updated estimate of AQP4-IgG serostatus and disability outcome in neuromyelitis optica. Neurology 2013; 81(14): 1197–1204.
10. Frasquet M, Bataller L, Torres-Vega E, et al. Longitudinally extensive transverse myelitis with AQP4 antibodies revealing ovarian teratoma. J Neuroimmunol 2013; 263(1–2): 145–147.
4. Iorio R, Lucchinetti CF, Lennon VA, et al. Syndrome of inappropriate antidiuresis may herald or accompany neuromyelitis optica. Neurology 2011; 77: 1644–1646.
11. Figueroa M, Guo Y, Tselis A, et al. Paraneoplastic neuromyelitis optica spectrum disorder associated with metastatic carcinoid expressing aquaporin-4. JAMA Neurol 2014; 71(4): 495–498.
5. Iorio R, Lucchinetti CF, Lennon VA, et al. Intractable nausea and vomiting from autoantibodies against a brain water channel. Clin Gastroenterol Hepatol 2013; 11(3): 240–245.
12. Verkman AS. Aquaporins in clinical medicine. Annu Rev Med 2012; 63: 303–316.
6. Iorio R, Damato V, Mirabella M, et al. Distinctive clinical and neuroimaging characteristics of longitudinally extensive transverse myelitis associated with aquaporin-4 autoantibodies. J Neurol 2013; 260(9): 2396–2402. 7. Iorio R, Fryer JP, Hinson SR, et al. Astrocytic autoantibody of neuromyelitis optica (NMO-IgG) binds to aquaporin-4 extracellular loops, monomers, tetramers and high order arrays. J Autoimmun 2013; 40: 21–27. Visit SAGE journals online http://msj.sagepub.com
SAGE journals
8. Pittock SJ and Lennon VA. Aquaporin-4 autoantibodies in a paraneoplastic context. Arch Neurol 2008; 65(5): 629–632.
13. Warth A, Muley T, Meister M, et al. Loss of aquaporin-4 expression and putative function in non-small cell lung cancer. BMC Cancer 2011; 11: 161–170. 14. Quek AM, McKeon A, Lennon VA, et al. Effects of age and sex on aquaporin-4 autoimmunity. Arch Neurol 2012; 69(8): 1039–1043. 15. Ontaneda D and Fox RJ. Is neuromyelitis optica with advanced age of onset a paraneoplastic disorder? Int J Neurosci 2014; 124(7): 509–511. 16. Collongues N, Marignier R, Zéphir H, et al. Neuromyelitis optica in France: a multicenter study of 125 patients. Neurology 2010; 74(9): 736–742.
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Downloaded from msj.sagepub.com at UNIV CALGARY LIBRARY on May 27, 2015
