Abstract
Background
Thymoma is frequently associated with paraneoplastic diseases (PDs), most commonly with myasthenia gravis (MG). This association is thought to depend on thymoma’s capacity to produce and export T lymphocytes.
Objective
(1) To determine the frequency and characteristics of thymoma-associated PDs other than MG; (2) to evaluate T cell maturation in thymomas with and without PDs.
Methods
We studied 260 patients with thymoma (associated with MG in 228). The occurrence of PDs was monitored together with the tumor outcome. Phenotypic characterization of thymocyte subsets in 14 thymoma samples (7 with and 7 without MG) was performed by FACS.
Results
A total of 47 PDs was diagnosed in 41/260 patients (15.8 %). Neurological PDs included neuromyotonia, limbic encephalitis, polymyositis, subacute hearing loss, psychosis and sleep disorders. A broad spectrum of nonneurological PDs were observed, among these, hematological and cutaneous diseases prevailed. Like MG, these disorders occurred either in the presence of the thymoma or at different times after thymomectomy; their onset often heralded a tumor recurrence. In thymomas from MG subjects, we found an increased proportion of fully mature CD4 single positive (SP) thymocytes and a reduced frequency of CD4SPCD25+ cells; the latter finding may reflect a deficient generation of T regulatory cells, a reduced intratumorous activation of T cells, or both.
Conclusions
We confirm the strong association of thymoma with PDs. These disorders often occurred in MG patients and their course in relation to thymoma was similar to that of MG. In accordance with previous observations, we found some alterations in the intratumorous production of mature CD4+ T cells that could be involved in the pathogenesis of paraneoplastic autoimmunity.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Ananth J, Davies R, Kerner B (1984) Psychosis associated with thymoma. J Nerv Ment Dis 172:556–558
Ances BM, Vitaliani R, Taylor RA, Liebeskind DS, Voloschin A, Houghton DJ, Galetta SL, Dichter M, Alavi A, Rosenfeld MR, Dalmau J (2005) Treatment- responsive limbic encephalitis identified by neuropil antibodies: MRI and PET correlates. Brain 128:1764–1777
Bataller L, Rosenfeld MR, Graus F, Vilchez JJ, Cheung NK, Dalmau J (2003) Autoantigen diversity in the opsoclonus–myoclonus syndrome. Ann Neurol 53:347–353
Buckley C, Douek D, Newsom-Davis J, Vincent A, Willcox N (2001) Mature, long-lived CD4+ and CD8+ T cells are generated by the thymoma in myasthenia gravis. Ann Neurol 50:64–72
Chilosi M, Iannucci A, Fiore-Donati L, Tridente G, Pampanin M, Pizzolo G, Ritter M, Bofill M, Janossy G (1986) Myasthenia gravis: immunohistological heterogeneity in microenvironmental organisation of hyperplastic and neoplastic thymuses suggesting different mechanisms of tolerance breakdown. J Immunol 11:191–204
Evoli A, Lo Monaco M, Marra R, Lino MM, Batocchi AP, Tonali PA (1999) Multiple paraneoplastic diseases associated with thymoma. Neuromuscul Disord 9:601–603
Fattorossi A, Battaglia A, Malinconico P, Stoler A, Andreocci L, Parente D, Coscarella A, Maggiano N, Perillo A, Pierelli L, Scambia G (2002) Constitutive and inducible expression of the epithelial antigen MUC1 (CD227) in human T cells. Exp Cell Res 280:107–118
Fattorossi A, Battaglia A, Buzzonetti A, Ciaraffa F, Scambia G, Evoli A (2005) Circulating and thymic CD4 CD25 T regulatory cells in myasthenia gravis: effect of immunosuppressive treatment. Immunology 116:134–141
Halbach M, Homberg V, Freund HJ (1987) Neuromuscular, autonomic and central cholinergic hyperactivity associated with thymoma and acetylcholine receptor-binding antibody. J Neurol 234:433–436
Hart IK, Maddison P, Newsom-Davis J, Vincent A, Mills KR (2002) Phenotypic variants of autoimmune peripheral nerve hyperexcitability. Brain 125:1887–1895
Hoffacker V, Schultz A, Tiesinga JJ, Gold R, Schalke B, Nix W, Kiefer R, Muller-Hermelink HK, Marx A (2000) Thymomas alter the T-cell subset composition in the blood: a potential mechanism for thymoma-associated autoimmune disease. Blood 96:3872–3879
Kadota Y, Okumura M, Miyoshi S, Kitagawa- Sakakida S, Inoue M, Shiono H, Maeda Y, Kinoshita T, Shirakura R, Matsuda H (2000) Altered T cell development in human thymoma is related to impairment of MHC class II transactivator expression induced by interferon-gamma (IFN-gamma). Clin Exp Immunol 121:59–68
Kawamura N, Kawajiri M, Ohyagi Y, Minohara M, Murai H, Kira J (2005) A patient with paraneoplastic limbic encephalitis induced by breast cancer presenting with hypersonnia. Rinsho Shinkeigaku 45:575–578
Inada K, Okumura M, Shiono H, Inoue M, Kadota Y, Ohta M, Matsuda H (2005) Role of positive selection of thymoma-associated T cells in the pathogenesis of myasthenia gravis. J Surg Res 126:34–40
Inoue M, Fujii Y, Okumura M, Miyoshi S, Shiono H, Fukuhara K, Kadota Y, Matsuda H (1999) T-cell development in human thymoma. Pathol Res Pract 195:541–547
Landolfi JC, Nadkarni M (2003) Paraneoplastic limbic encephalitis and possible narcolepsy in a patient with testicular cancer. Neuro-oncology 5:214–216
Lee EK, Maselli RA, Ellis WG, Agius MA (1998) Morvan’s fibrillary chorea: a paraneoplastic manifestation of thymoma. J Neurol Neurosurg Psychiatry 65:857–862
Lindstrom JM, Seybold ME, Lennon VA, Whittingham S, Duane DD (1976) Antibody to acetylcholine receptor in myasthenia gravis. Prevalence, clinical correlates and diagnostic value. Neurology 26:1054–1059
Luther C, Poeschel S, Varga M, Melms A, Tolosa E (2005) Decreased frequency of intrathymic regulatory T cells in patients with myasthenia-associated thymoma. J Neuroimmunol 164:124–128
Marx A, Muller-Hermelink HK, Strobel P (2003) The role of thymomas in the development of myasthenia gravis. Ann N Y Acad Sci 998:223–236
Mathews J, Kumar BN (2003) Autoimmune sensorineural hearing loss. Clin Otolaryngol Allied Sci 28:479–488
Meager A, Visvalingam K, Peterson P, Moll K, Murumagi A, Krohn K, Eskelin P, Perheentupa J, Husebye E, Kadota Y, Willcox N (2006) Anti-interferon autoantibodies in autoimmune polyendocrinopathy syndrome type 1. PLoS Med 3:1152–1164
Muller-Hermelink HK, Marx A (2000) Thymoma. Curr Opin Oncol 12:426–433
Musha M, Tanaka F, Ohuti M (1993) Psychoses in three cases with myasthenia gravis and thymoma—proposal of a paraneoplastic autoimmune neuropsychiatric syndrome. Tohoku J Exp Med 169:335–344
Nenninger R, Schultz A, Hoffacker V, Helmreich M, Wilisch A, Vandekerckhove B, Hunig T, Schalke B, Schneider C, Tzartos S, Kalbacher H, Muller-Hermelink HK, Marx A (1998) Abnormal thymocyte development and generation of autoreactive T cells in mixed and cortical thymomas. Lab Invest 78:743–753
Newsom-Davis J, Buckley C, Clover L, Hart I, Maddison P, Tuzum E, Vincent A. (2003) Autoimmune disorders of neuronal potassium channels. Ann N Y Acad Sci 998:202–210
Okumura M, Miyoshi S, Fujii Y, Takeuchi Y, Shiono H, Inoue M, Fukuhara K, Kadota Y, Tateyama H, Eimoto T, Matsuda H (2001) Clinical and functional significance of WHO classification on human thymic epithelial neoplasms: a study of 146 consecutive tumors. Am J Surg Pathol 25:103–110
Rosai J, Sobin LH (1999) Histological typing of tumors of the thymus. International histologic classification of tumors, 2nd edn. Springer, Berlin Heidelberg New York, pp 9–13
Sakaguchi S (2005) Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 6:345–352
Strobel P, Helmreich M, Menioudakis G, Lewin SR, Rudiger T, Bauer A, Hoffacker V, Gold R, Nix W, Schalke B, Elert O, Semik M, Muller-Hermelink HK, Marx A (2002) Paraneoplastic myasthenia gravis correlates with generation of mature naive CD4(+) T cells in thymomas. Blood 100:159–166
Strobel P, Preisshofen T, Helmreich M, Muller-Hermelink HK, Marx A (2003) Pathomechanisms of paraneoplastic myasthenia gravis. Clin Dev Immunol 10:7–12
Strobel P, Rosenwald A, Beyersdorf N, Kerkau T, Elert O, Murumagi A, Sillanpaa N, Peterson P, Hummel V, Rieckmann P, Burek C, Schalke B, Nix W, Kiefer R, Muller-Hermelink HK, Marx A (2004) Selective loss of regulatory T cells in thymomas. Ann Neurol 56:901–904
Vernino S, Eggenberg ER, Rogers RL, Lennon VA (2002) Paraneoplastic neurologic autoimmunity associated with ANNA-1 antibody and thymoma. Neurology 59:929–932
Vernino S, Lennon VA (2003) Muscle and neuronal autoantibody markers of thymoma: neurological correlations. Ann N Y Acad Sci 998:359–361
Vernino S, Lennon VA (2004) Autoantibody profiles and neurological correlations of thymoma. Clin Cancer Res 10:7270–7275
Vincent A, Willcox N (1999) The role of T-cells in the initiation of autoantibody response in thymoma patients. Pathol Res Pract 195:535–540
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Evoli, A., Minicuci, G.M., Vitaliani, R. et al. Paraneoplastic diseases associated with thymoma. J Neurol 254, 756–762 (2007). https://doi.org/10.1007/s00415-006-0429-z
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00415-006-0429-z