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Thymoma Versus Thymic Carcinoma: Differences in Biology Impacting Treatment

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Thymoma Versus Thymic Carcinoma: Differences in Biology Impacting Treatment Focused 577 Review Thymoma Versus Thymic Carcinoma: Differences in Biology Impacting Treatment Ronan J. Kelly, MD, MBA Abstract hymic epithelial tumors account for approximately A better understanding of the biology of both thymomas and thy- T mic carcinomas has occurred in recent years thanks to advanced 20% of all mediastinal tumors. Nevertheless, they are technologies such as comparative genomic hybridization, expres- rare compared with other malignancies, constituting sion array analysis, and next-generation sequencing. Gene expres- only 0.2% to 1.5% of all solid tumors.1 The WHO clas- sion profiling and genomic clustering studies have shown that sification system distinguishes thymomas (types A, AB, thymic tumors as classified by the 2004 WHO system do have dif- B1, B2, and B3) from thymic carcinomas (type C) based ferent molecular features. Because of the rarity of these tumors, there is a paucity of high-quality clinical research data, and treat- on the morphology of epithelial tumor cells (with in- ment decisions are often guided by the small amount of prospec- creasing degree of atypia along the spectrum from type tive trial data, retrospective series, and individual case reports. A to C), proportion of lymphocytic involvement, and The literature does report on several advanced thymic tumors that resemblance to normal thymic tissue. Clinically, these have responded to new targeted agents, indicating that across the diseases can also present differently with a large variety spectrum of thymic malignancies there may be clinically relevant molecular subsets. Genomic profiling distinguishes type B3 thymo- of autoimmune disorders, including myasthenia gravis ma and thymic carcinoma from type A and B2 thymomas. Further- (30%) occurring in patients with thymoma, whereas more, type B2 thymomas can be separated from other subgroups patients with thymic carcinoma rarely if ever have in that it has a more distinctly lymphocytic component than the autoantibody-induced phenomena.2 Surgery contin- other groups in which epithelial cells predominate. The presence ues to be the most important therapeutic modality for of KIT mutations in thymic carcinomas rather than in thymomas early-stage disease, and a multidisciplinary approach in- further adds to a growing body of evidence showing that underly- ing tumor biology may in the future lead to molecular classifica- corporating surgery, radiation, and chemotherapy is rec- tions, which may enhance therapies for these rare tumors. (JNCCN ommended in advanced or recurrent disease. Research, 2013;11:577–583) however, has been hampered by the rarity of these tu- mors, which has led to a lack of international consen- sus surrounding appropriate histopathologic and staging criteria. Much debate has occurred regarding the limita- tions 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 From The Sidney Kimmel Comprehensive Cancer Center at Johns past decade, newer techniques such as comparative ge- Hopkins, Baltimore, Maryland. nomic hybridization (CGH), expression array analysis, Submitted February 19, 2013; accepted for publication April 10, 2013. and next-generation sequencing have resulted in in- The author has disclosed that he has no financial interests, cremental improvements in the understanding of these arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their highly heterogenous tumors. This article focuses on the competitors. biological differences between thymomas and thymic Correspondence: Ronan J. Kelly, MD, MBA, The Bunting Blaustein Cancer Research Building, The Sidney Kimmel Comprehensive carcinomas that may impact treatment decisions, and Cancer Center at Johns Hopkins, 1650 Orleans Street, Room G93, discusses targeted therapy trials performed to date in the Baltimore, MD 21231. E-mail: [email protected] advanced disease setting. © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 11 Number 5 | May 2013 578 Focused Review Kelly Staging and Pathologic Classification antigen and for central thymic T-cell education and of Thymomas and Thymic Carcinomas deletion of autoreactive clones.9,10 Patients with thy- The most widely used system for staging thymic ma- momas have higher rates of autoantibodies to cyto- 11 lignancies is the Masaoka staging system, which was kines than patients with thymic carcinomas, and originally developed in 1981 and focuses on the in- also have a higher risk of developing second malig- tegrity of the thymic capsule, the presence of micro- nancies, most notably, non-Hodgkin’s lymphoma. A or macroscopic invasion into adjacent structures, greater understanding of immunity and autoimmu- and metastatic spread.3 The WHO histologic clas- nity in thymoma is needed and may lead to future sification of thymomas and thymic carcinomas, first incorporation of immunotherapeutic strategies into published in 1999 and updated in 2004,4 has helped treatment paradigms for thymomas. alleviate some of the prior confusion caused by the presence of several previous classification systems. Types A, AB, and B1 have an excellent overall sur- Molecular Biology Differences Between vival rate of greater than 90% to 95% at 10 years.5 Thymomas and Thymic Carcinomas Five-year survival for types B2 and B3 and thymic Cytogenetic studies have revealed chromosomal carcinoma are 75%, 70%, and 48%, respectively.6 abnormalities in all histologic subtypes, including Thymic carcinomas account for fewer than 1% of t(15;19) translocations and 6p22–p25 deletions.6 thymic malignancies and are much more aggressive The most frequent genetic alterations identified tumors than thymomas.7 Clinically thymic carcino- across the spectrum of thymomas occur on chromo- mas are more likely to metastasize to the liver, lymph some 6p21.3 (MHC locus) and 6q25.2–25.3.12–14 nodes, and bones compared with thymomas, which Although thymic carcinomas are a distinct entity in rarely spread beyond the site of origin. Several sub- the WHO classification system, they do share some types of thymic carcinoma exist, including squamous similarities with type B3 thymomas, most notably in cell, basaloid, sarcomatoid, mucoepidermoid, papil- the gain of 1q and loss of chromosome 6.13 Addition- lary, lymphoepithelioma-like, and undifferentiated al data from CGH analysis performed on thymic car- carcinomas. Knowledge of the tumor biology under- cinomas have demonstrated frequent copy number lying the different phenotypes between thymomas gains of 17q and 18 and loss of 3p, 16q, and 17p.13,15 and thymic carcinomas has improved in recent years. The degree of genomic and recurrent copy number alterations increases from type A to type B3 and thy- mic carcinoma (Figure 1). Additional aberrations Immunologic Differences Between that have been described include multiple losses of Thymomas and Thymic Carcinomas genetic material and microsatellite instability in dif- In addition to differing clinically, thymomas and ferent chromosomes (3p22–24.3; 3p14.2 [FHIT gene thymic carcinomas have distinctive immunologic, locus]; 5q21 [APC gene]; 6p21; 6p21–22.1; 7p21–22; genetic, and molecular characteristics. Morphologic 8q11.21–23; 13q14 [RB gene]; and 17p13.1 [p53 differences are outlined in the WHO classification, gene]).15,16 In addition to the losses in the long arm of but immunohistochemical markers such as expres- chromosome 6, the loss of heterozygosity (LOH) on sion of major histocompatability complex (MHC) chromosome 5 (5q21; APC gene) may be the most class II or AIRE (autoimmune regulator gene) are significant. Inoue et al14 showed that alterations in becoming apparent. Approximately 30% to 40% chromosome 6 vary according to the WHO subtype of patients with thymoma develop an autoimmune (type A, 10%; type AB, 12%; type B, 20%–26%; condition, 50% of which will be myasthenia gravis.8 thymic carcinoma, 35%) and with clinical stage at Unlike those with thymomas, patients with thymic diagnosis (stage I, 7%; stage II, 27%; stage III, 21%; carcinomas rarely develop autoantibody-induced stage IV, 24%). In this study, the authors found ge- phenomena. The molecular basis underlying defec- netic aberrations on chromosome 6 in 31 of 40 thy- tive AIRE expression in thymoma versus thymic moma cases evaluated (77.5%), and these occurred carcinoma is not understood. The AIRE gene is in 5 separate hot spots. The most frequent LOHs located on chromosome 21q22.3 and is considered (48.6%) occurred in region 6q25.2. Another hot important for ectopic expression of peripheral self- spot showing LOH in 32.4% of tumors was located © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 11 Number 5 | May 2013 Focused Review 579 Thymoma Versus Thymic Carcinoma Type A thymomas (n=8) Porportion Aberrant 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Genomic Position Type B2 thymomas (n=22) Porportion Aberrant 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Genomic Position Type B3 thymomas (n=8) Porportion Aberrant 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Genomic Position Type carcinoma (n=7) Porportion Aberrant 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Genomic Position Figure 1 Correlation of thymic epithelia histotypes with specific genomic abnormalities. Red represents the frequency of copy num- ber (CN) gain, and blue represents the frequency of CN loss for 8 type A thymomas, 22 type B2 thymomas, 8 type B3 thymomas, and 7 thymic carcinomas. From Girard N, Shen R, Guo T, et al. Comprehensive genomic analysis reveals clinically relevant molecular distinctions between thymic carcinomas and thymomas. Clin Cancer Res 2009;15:6798; with permission. on 6q25.2–25.3. The third hot spot (30%) show- and thymic carcinomas sharing chromosome 6 loss. ing LOH appeared in region 6p21.31, including the The group separately analyzed thymoma types A and MHC locus, and the fourth (26.3%) was detected on B and thymic carcinoma to identify recurrent gene 6q14.1–14.3.
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