Thymic epithelial tumors account for approximately 20% of all mediastinal tumors. Nevertheless, they are rare compared with other malignancies, constituting only 0.2% to 1.5% of all solid tumors.1 The WHO classification system distinguishes thymomas (types A, AB, B1, B2, and B3) from thymic carcinomas (type C) based on the morphology of epithelial tumor cells (with increasing degree of atypia along the spectrum from type A to C), proportion of lymphocytic involvement, and resemblance to normal thymic tissue. Clinically, these diseases can also present differently with a large variety of autoimmune disorders, including myasthenia gravis (30%) occurring in patients with thymoma, whereas patients with thymic carcinoma rarely if ever have autoantibody-induced phenomena.2 Surgery continues to be the most important therapeutic modality for early-stage disease, and a multidisciplinary approach incorporating surgery, radiation, and chemotherapy is recommended in advanced or recurrent disease. Research, however, has been hampered by the rarity of these tumors, which has led to a lack of international consensus surrounding appropriate histopathologic and staging criteria. Much debate has occurred regarding the limitations of the current histologic classifications with regard to both subtype definitions and consistency of diagnosis. The lack of established cell lines and animal models has hindered laboratory investigations, resulting in limited improvements in understanding of tumor biology. In the past decade, newer techniques such as comparative genomic hybridization (CGH), expression array analysis, and next-generation sequencing have resulted in incremental improvements in the understanding of these highly heterogenous tumors. This article focuses on the biological differences between thymomas and thymic carcinomas that may impact treatment decisions, and discusses targeted therapy trials performed to date in the advanced disease setting.
MargaritoraSCesarioACusumanoG. Thirty-five-year follow-up analysis of clinical and pathologic outcomes of thymoma surgery. Ann Thorac Surg2010;89:245–252; discussion 252.
MasaokaAMondenYNakaharaKTaniokaT. Follow-up study of thymomas with special reference to their clinical stages. Cancer1981;48:2485–2492.
Muller-HermelinkHKEngelPKuoTT. Tumours of the thymus. World Health Classification of Tumours In: TravisWDBrambillaEMuller-HermelinkHKHarrisCC. Pathology & Genetics: Tumours of the Lung Pleura Thymus and Heart. Lyon, France: IARC Press. 2004:146–248.
ChenGMarxAChenWH. New WHO histologic classification predicts prognosis of thymic epithelial tumors: a clinicopathologic study of 200 thymoma cases from China. Cancer2002;95:420–429.
HerensCRadermeckerMServaisA. Deletion (6)(p22p25) is a recurrent anomaly of thymoma: report of a second case and review of the literature. Cancer Genet Cytogenet2003;146:66–69.
OkumuraMFujiiTShionoH. Immunological function of thymoma and pathogenesis of paraneoplastic myasthenia gravis. Gen Thorac Cardiovasc Surg2008;56:143–150.
ScarpinoSDi NapoliAStoppacciaroA. Expression of autoimmune regulator gene (AIRE) and T regulatory cells in human thymomas. Clin Exp Immunol2007;149:504–512.
BurbeloPDBrowneSKSampaioEP. Anti-cytokine autoantibodies are associated with opportunistic infection in patients with thymic neoplasia. Blood2010;116:4848–4858.
InoueMStarostikPZettlA. Correlating genetic aberrations with World Health Organization-defined histology and stage across the spectrum of thymomas. Cancer Res2003;63:3708–3715.
GirardNShenRGuoT. Comprehensive genomic analysis reveals clinically relevant molecular distinctions between thymic carcinomas and thymomas. Clin Cancer Res2009;15:6790–6799.
PanCCChenPCChiangH. KIT (CD117) is frequently overexpressed in thymic carcinomas but is absent in thymomas. J Pathol2004;202:375–381.
StrobelPHartmannMJakobA. Thymic carcinoma with overexpression of mutated KIT and the response to imatinib. N Engl J Med2004;350:2625–2626.
BisagniGRossiGCavazzaA. Long lasting response to the multikinase inhibitor bay 43-9006 (Sorafenib) in a heavily pretreated metastatic thymic carcinoma. J Thorac Oncol2009;4:773–775.
StrobelPBargouRWolffA. Sunitinib in metastatic thymic carcinomas: laboratory findings and initial clinical experience. Br J Cancer2010;103:196–200.
SuzukiESasakiHKawanoO. Expression and mutation statuses of epidermal growth factor receptor in thymic epithelial tumors. Jpn J Clin Oncol2006;36:351–356.
IonescuDNSasatomiECieplyK. Protein expression and gene amplification of epidermal growth factor receptor in thymomas. Cancer2005;103:630–636.
KurupABurnsMDropchoS. Phase II study of gefitinib treatment in advanced thymic malignancies [abstract]. J Clin Oncol2005;23(Suppl):Abstract 7068.
BedanoPMPerkinsSBurnsM. A phase II trial of erlotinib plus bevacizumab in patients with recurrent thymoma or thymic carcinoma [abstract]. J Clin Oncol2008;26(Suppl):Abstract 19087.
PalmieriGMarinoMSalvatoreM. Cetuximab is an active treatment of metastatic and chemorefractory thymoma. Front Biosci2007;12:757–761.
PanCCChenPCWangLS. Expression of apoptosis-related markers and HER-2/neu in thymic epithelial tumours. Histopathology2003;43:165–172.
CimpeanAMRaicaMEncicaS. Immunohistochemical expression of vascular endothelial growth factor A (VEGF), and its receptors (VEGFR1, 2) in normal and pathologic conditions of the human thymus. Ann Anat2008;190:238–245.
SasakiHYukiueHKobayashiY. Elevated serum vascular endothelial growth factor and basic fibroblast growth factor levels in patients with thymic epithelial neoplasms. Surg Today2001;31:1038–1040.
SteeleNLPlumbJAVidalL. A phase 1 pharmacokinetic and pharmacodynamic study of the histone deacetylase inhibitor belinostat in patients with advanced solid tumors. Clin Cancer Res2008;14:804–810.
GiacconeGRajanABermanA. Phase II study of belinostat in patients with recurrent or refractory advanced thymic epithelial tumors. J Clin Oncol2011;29:2052–2059.
GirardNTeruya-FoldsteinJPayabyabEC. Insulin-like growth factor-1 receptor expression in thymic malignancies. J Thorac Oncol2010;5:1439–1446.
ZucaliPAPetriniILorenziE. Insulin-like growth factor-1 receptor and phosphorylated AKT-serine 473 expression in 132 resected thymomas and thymic carcinomas. Cancer2010;116:4686–4695.