REVIEW URRENT C OPINION
What’s new in thymic neoplasms Alberto Antonicelli and Frank Detterbeck
Purpose of review The past 5 years have been marked with major developments in the field of thymic malignancies. Recent findings A lack of progress over decades has been transformed into dramatic advancements over the past 5 years through the creation of the International Thymic Malignancy Interest Group (ITMIG). ITMIG has brought together an engaged worldwide community interested in this field. An unprecedented global database has been developed and is being actively analyzed. Standard definitions have been established to allow collaboration; the histologic classification has been revised and the first formal stage classification system developed. Clinical trials and innovative research approaches are being implemented. The creation of the ITMIG infrastructure has yielded many successes and provides a solid foundation for future progress. Summary Clinicians and researchers should be aware of the knowledge, structure and tools that have been established. ITMIG provides an engaged community for collaboration and progress. Keywords International Thymic Malignancy Interest Group, thymic carcinoma, thymic malignancy, thymoma
INTRODUCTION Thymic neoplasms constitute a collection of rare diseases, that all meet the definition of an orphan disease. This fact has long thwarted meaningful progress. An assessment of the available literature in 2009 revealed that almost 80% of publications on thymoma involved case reports, and less than 5% involved a cohort of more than 100 patients [1]. Furthermore, there had been no improvement in survival for decades [1]. This should come as no surprise, because for a rare disease that is managed in a disseminated fashion, development of an evidence base is essentially impossible when each institution operates more or less in isolation on a small collection of patients accumulated over 20–30 years. However, the possibilities and the state of the art in thymic neoplasms have changed dramatically in the past 5 years. Infrastructure has been developed to allow global collaboration. A worldwide community has coalesced, united by the determination to make a difference and undaunted by the innate challenges confronting a rare disease. This attitude, coupled with a culture of open collaboration for a common good, has created a force that is drastically overcoming decades of stagnation. This article reviews the current accomplishments and active initiatives within the realm of thymic malignancies.
COLLABORATION IS THE KEY TO PROGRESS A realization that progress in a rare disease is impossible without collaboration inspired many individuals active in thymic diseases to come together. This has happened on a regional level, on a global level and within institutions. Undoubtedly, the ability for people to come together has been aided by the many changes that have helped the world to become a smaller place. This includes the widespread development of the internet and technologic platforms that allow communication and collaboration. Major regional groups devoted to thymic neoplasms have arisen. The foundation for progress was created by the establishment of the Japanese Association for Research on the Thymus approximately 30 years ago. This organization provided key initial building blocks and continues to make major contributions to the field. The European Society of Department of Surgery, Division of Thoracic Surgery, Yale School of Medicine, New Haven, Connecticut, USA Correspondence to Frank Detterbeck, MD, Professor and Chief, Department of Surgery, Division of Thoracic Surgery, Yale School of Medicine, 330 Cedar St., BB205, New Haven, CT 06520-8062, USA. Tel: +1 203 785 4931; fax: +1 203 737 2163; e-mail: [email protected] Curr Opin Pulm Med 2015, 21:327–332 DOI:10.1097/MCP.0000000000000172
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Neoplasms of the lung
KEY POINTS
computed tomography (CT) as well as reviews on prognostic factors in thymic malignancies and on pitfalls in applying statistics to a rare disease [3 ,4– 11]. More recently ITMIG launched a second initiative aimed to provide practical guidance in the clinical management of patients. This resulted in another series of articles, summarized in another supplement to the Journal of Thoracic Oncology (Vol 9[9] Suppl 2, 2014), also available with unrestricted access at http://journals.lww.com/jto/toc/ 2014/09002. These articles focus on a standard definition of mediastinal compartments, a node map, assessment of response to therapy, practical guides for clinicians, radiologists in evaluating patients with an anterior mediastinal mass and for pathologists in classifying tissue specimens, and state of the art reviews on genetic abnormalities, paraneoplastic syndromes and immunologic disorders in thymic malignancies [12–14,15 ,16 ,17–20]. &
Progress in a rare disease requires collaboration. Development of a common language, a global database, tissue bank and an engaged community has established an infrastructure to facilitate progress. The first formal stage classification system for thymic malignancies has been developed. Innovative approaches to research are needed in a rare disease.
Thoracic Surgeons has assembled a strong and productive network of primarily European thoracic surgeons and has published several major articles. More recently, the Chinese Alliance for Research in Thymoma has emerged as a high-quality collaboration of 17 centers in mainland China. The overarching organization is the International Thymic Malignancy Interest Group (ITMIG). Founded in 2010 [2], this organization is a worldwide, multispecialty group that represents the vast majority of clinicians and researchers active in thymic malignancies in North and South America, Europe, Asia, Australia and Africa. ITMIG has created the spirit of openness and excitement that has driven many of the advancements in the state of the art in a short time span of 5 years. ITMIG has also supported and promoted the development of the regional organizations just mentioned.
THE CURRENT STATE OF THE SCIENCE Standards and definitions A major problem preventing progress was the fact that different institutions used different outcomes and different definitions of terms. An early initiative of ITMIG was to establish a consensus around definitions of terms and a common standard for reporting outcomes. Multiple workgroups culminating in a 2-day international workshop established these standards, which were essentially uniformly endorsed by the entire ITMIG membership. These terms and standards were summarized and published in a series of articles in a special supplement to the Journal of Thoracic Oncology (6 [7]Suppl 3, 2011), available for download at http://journals. lww.com/jto/toc/2011/07001. These articles address standards for reporting outcomes, for handling of resection specimens by surgeons and pathologists, for radiotherapy and chemotherapy, for minimally invasive resections, for interpretation and reporting on small biopsy specimens and for imaging by 328
www.co-pulmonarymedicine.com
&
&
International Thymic Malignancy Interest Group database A sophisticated retrospective and prospective database was developed, in collaboration with the Cancer Care Engineering project of Purdue University on the HUBzero platform. This is a Health Insurance Portability and Accountability Act (HIPAA)-compliant web-accessible relational global database. A testament to the engagement of the ITMIG community is that the retrospective database was rapidly populated, and now contains over 7000 cases from over 50 institutions in 15 countries [21]. This provides an unprecedented rich resource that is being actively used to address many clinical questions. A much more detailed prospective database was also established and has been accruing cases since 2012.
Histologic classification A source of controversy has been the histologic classification of thymic neoplasms. To address this, ITMIG assembled most of the experts in this field and brought them together for two workshops devoted to addressing weaknesses in the existing classification (New York, 2012 and Mannheim, 2013). This led to improved definitions of subtypes [22 ] as well as practical guides [17]. The output of the ITMIG workshops has formed the basis for the updated WHO Classification Manual [23,24]. In addition, the ITMIG database has been analyzed to elucidate the impact of subtypes of thymic neoplasms in a series of recent articles [25,26,27 ]. This analysis has established more clearly than ever &
&
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What’s new in thymic neoplasms Antonicelli and Detterbeck
before that outcomes of thymic carcinoma are quite distinctly worse than for thymoma, that thymic neuroendocrine tumors have outcomes essentially identical to thymic carcinoma and that the subtypes of thymoma have a subtle impact on outcomes, particularly with respect to recurrence rates. Finally, the results also underscore the consensus that all thymomas are, in fact, malignant neoplasms, despite the continued prevalence of the misleading term ‘benign thymoma’.
Table 2. Stage grouping Stage
T
I
T1
N0
M0
II
T2
N0
M0
IIIa
T3
N0
M0
IIIb
T4
N0
M0 M0
IVa IVb
Stage classification An impediment to collaboration and progress has been the lack of an official stage classification system for thymic malignancies. Sharing data across institutions was difficult, given that 15 stage classification systems have been created. ITMIG partnered with the International Association for the Study of Lung Cancer to develop an evidence-based system for formal adoption in the eighth edition of the Stage Classification of Malignant Tumors in 2016. The ITMIG database was supplemented with additional cases from the Japanese Association for Research on the Thymus and European Society of Thoracic Surgeons, resulting in over 10 000 cases. An extensive statistical analysis was conducted by Cancer Research and Biostatistics with funding provided by the International Association for the Study of Lung Cancer. Multiple perspectives and over 500 graphs of outcomes were considered during this 2-year effort. The proposed stage classification has been published in a series of articles [12,28 , 29 ,30 ]. &&
&
&
N
M
T any
N1
T any
N0,1
M1a
T any
N2
M0,1a
T any
N any
M1b
Reproduced with permission [28
&&
].
The proposed system is summarized in Tables 1 and 2. Particular highlights include the fact that attention to tumor encapsulation is abandoned because of lack of prognostic significance; the T component is structured by ‘levels’ of invasion, in which a given level may or may not include invasion of any lower level structures, and the definition of two node regions (anterior and deep).
WHAT DOES THE FUTURE HOLD? Research efforts The ITMIG retrospective database provides an unprecedented resource for research. Much work has gone into cleaning and refining this data structure to promote its use. Furthermore, to facilitate use without having to first learn the intricacies of the
Table 1. Tumor (T), node (N) and metastasis (M) descriptors Definition (involvement of)a,b
Category T1
a
Encapsulated or unencapsulated, with or without extension into mediastinal fat
b
Extension into mediastinal pleura
T2
Pericardium
T3
Lung, brachiocephalic vein, superior vena cava, chest wall, phrenic nerve, hilar (extrapericardial) pulmonary vessels
T4
Aorta, arch vessels, main pulmonary artery, myocardium, trachea or esophagus
N0
No nodal involvement
N1
Anterior (perithymic) nodes
N2
Deep intrathoracic or cervical nodes
M0 M1
No metastatic pleural, pericardial or distant sites a
Separate pleural or pericardial nodule(s)
b
Pulmonary intraparenchymal nodule or distant organ metastasis &&
Reproduced with permission [28 ]. a Involvement must be pathologically proven in pathologic staging. b A tumor is classified according to the highest T level of involvement that is present with or without any invasion of structures of lower T levels.
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329
Neoplasms of the lung
data structure, ITMIG has developed a statistical core devoted to retrospective database studies. An initial call for research proposals resulted in 17 applications; consistent with the ITMIG culture of collaboration, the database committee brought together institutions that had similar interests. Most of these data analyses have been carried out, and some of the studies have been published [25,26,27 ]. The projects include the analysis of outcomes after the treatment of thymoma, thymic carcinoma and neuroendocrine tumors, the impact of adjuvant radiotherapy, of open versus minimally invasive thymectomy, complete versus partial thymectomy, paraneoplastic syndromes, extrapleural pneumonectomy versus pleurectomy/decortication for stage IVa thymoma, palliative chemotherapy, second malignancies and prognostic factors. A new call for applications will be initiated in 2015. Clinical trials are the best way to solidly establish the therapeutic value of a treatment approach, but require a significant effort to conduct. Carrying out clinical trials in a rare disease is even more challenging. Nevertheless, undaunted by huge challenges, ITMIG has been working to run an international randomized trial on the use of adjuvant radiotherapy for stage III resected thymoma. This effort has been made possible by the help of the International Rare Cancers Initiative, an organization devoted to cutting through the hurdles facing rare tumors and international collaborations. Although it appears promising that this trial will actually take place, the difficulties experienced by ITMIG in overcoming the regulatory, procedural, financial and political challenges have been great, despite the efforts of the International Rare Cancers Initiative. This journey underscores both the huge obstacles that must be overcome to carry out such studies in a rare disease, as well as the fact that with determination and sustained effort even great impediments can be overcome. In order to develop a resource for basic science research, ITMIG launched a virtual tumor bank. Those institutions banking tissue share information on the nature of such tissues in an ITMIG tissue bank registry. Funding, regulatory and political issues have limited this to a virtual bank up to this point; nevertheless, it represents development of a resource that can be used as well as developed further. The Cancer Genome Atlas Project is a US National Institutes of Health initiative to fully sequence the genome of cancers. This provides essentially a road map that greatly facilitates further research. ITMIG lobbied successfully to have thymic malignancies included; many institutions on different continents contributed high-quality fresh-frozen tumor and normal tissue for analysis. The &
330
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sequencing is currently underway, with next steps for basic research being planned by the biology committee of ITMIG once The Cancer Genome Atlas Project results become available.
Innovation Given the difficulties that are inherently present in a rare disease, it is essential to be innovative in order to make progress. Bayesian analysis offers an approach that has particular appeal in a rare disease. Each outcome can be used to add to the knowledge base in real time without being withheld until the data reach maturity. This is because the Bayesian approach is not designed to provide absolute proof or ignore pre-existing data that can present bias in a traditional approach; rather it is designed to use all available data and quantify what is (and is not) known, including investigation of confounding factors. An ITMIG project seeks to use a Bayesian approach, coupled with a structured approach to treatment that seeks to manage local variability. This project builds on the ITMIG prospective database. Another innovative approach being pursued by ITMIG is outlier analysis. The concept here is that a very intensive analysis of an outlier may yield insight better than can be gained from more limited data on a larger number of patients. The analogy is the airline industry – rare events lead to improvements. This project is just beginning to get underway. A goal for patients with thymic malignancies is to find ways to improve the level of care broadly, recognizing that care is by necessity delivered in a relatively sporadic fashion across many disseminated centers. Modern technology offers ways of disseminating information, and making it accessible when and where it is needed. However, what is needed to raise the level of care is not simply information, it is higher level skills such as clinical judgment and problem solving related to particular issues that individual patients present. What is needed is a way of disseminating clinical expertize to broadly dispersed sites. Fortunately, the science of adult learning has progressed, and tools to impart such higher level cognitive skills have been developed. An ITMIG goal is to use these approaches to develop educational tools, and make them broadly accessible through modern technology in order to broadly raise the level of care that can be delivered.
Accomplishments, challenges and opportunities Major building blocks have been created that provide a foundation upon which to build scientific Volume 21 Number 4 July 2015
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What’s new in thymic neoplasms Antonicelli and Detterbeck
progress in thymic neoplasms. An engaged, collaborative community has been created, a common language developed and a critical assessment of the state of the science has been initiated. Resources to permit research have been developed; attempts to build innovative approaches are underway, given the inherent challenges in a rare disease. Nevertheless, major impediments to progress will always continue to confront those trying to make scientific progress in thymic neoplasms. National rules clearly define that completely deidentified data can be shared publicly and used for research without restrictions (http://privacyruleandresearch.nih.gov/pr_08.asp), yet institutional privacy officers are often unaware of the regulations and believe they must restrict release of such data. Bureaucratic regulatory issues related to prospective research studies present a major impediment that is greatly amplified in a rare disease. Existing structures for clinical research are designed for common diseases, and represent a formidable barrier to research studies in rare diseases. The biggest challenge to progress is lack of funding. Although in a rare disease even a small amount of funding can make a big difference, normal sources of research funding are more or less inaccessible for a rare disease. Although some funding is available specifically for rare diseases, it is limited, and philanthropy is the primary source of funding. The progress that has been made in thymic neoplasms has relied primarily on pro-bono donated time by many individuals, but the state of affairs has progressed to a point in which further development of resources and projects cannot be done by volunteerism alone. There is little doubt that funding is the major ratelimiting step to progress in thymic neoplasms.
CONCLUSION The developments in the last 5 years in thymic neoplasms provide proof that seemingly insurmountable hurdles can, in fact, be overcome with sufficient determination. The efforts of the global community of interested individuals have led to major progress and set the stage for significant scientific advancement in the coming years. Once stagnant, a strong sense of excitement and momentum is now palpable in the field of thymic neoplasms. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Detterbeck F. The creation of the international thymic malignancies interest group as a model for rare diseases. In: Govindan Re, editor. 2012 ASCO educational book. Alexandria, VA: American Society of Clinical Oncology; 2012. pp. 471–474. 2. Detterbeck F. ITMIG: a way forward. J Thorac Oncol 2010; 5 (10 Suppl 4): S365–S370. 3. Detterbeck F, Moran C, Huang J, et al. Which way is up? Policies and & procedures for surgeons and pathologicsts regarding resection specimens of thymic malignancy. J Thorac Oncol 2011; 6 (7 Suppl 3):S1730– S1738. This article provides a framework for communication between the surgeon and pathologists and guidance for both in how to handle resection specimens, thus reducing incomplete characterization of the specimen and margins. 4. Detterbeck F, Youssef S, Ruffini E, Okumura M. Review of reported prognostic factors in thymic malignancies. J Thorac Oncol 2011; 6 (7 Suppl 3): S1698–S1704. 5. Girard N, Lal R, Wakelee H, et al. Chemoterapy definitions and policies for thymic malignancies. J Thorac Oncol 2011; 6 (7 Suppl 3):S1749– S1755. 6. Gomez D, Komaki R, Yu J, et al. Radiation therapy definitions and reporting guidelines for thymic malignancies. J Thorac Oncol 2011; 6:S1743– S1748. 7. Gonen M. Bias, biostatistics, and prognostic factors. J Thorac Oncol 2011; 6:S1705–S1709. 8. Huang J, Wang Z, Loehrer P, et al. Standard outcome measures for thymic malignancies. J Thorac Oncol 2010; 5:2017–2023. 9. Marchevsky A, Marx A, Strobel P, et al. Policies and reporting guidelines for small biopsy specimens of mediastinal masses. J Thorac Oncol 2011; 6 (7 Suppl 3):S1724–S1729. 10. Marom E, Rosado-de-Christenson M, Bruzzi J, et al. Standard report terms for chest computed tomography reports of anterior mediastinal masses suspicious for thymoma. J Thorac Oncol 2011; 6 (7 Suppl 3):S1717– S1723. 11. Toker A, Sonett J, Zielinski M, et al. Standard terms, definitions, and policies for minimally invasive resection of thymoma. J Thorac Oncol 2011; 6 (7 Suppl 3):S1739–S1742. 12. Bhora F, Chen D, Detterbeck F, et al. The ITMIG/IASLC thymic epithelial tumors staging project: a proposed lymph node map for thymic epithelial tumors in the forthcoming 8th edition of the TNM classification for malignant tumors. J Thor Oncol 2014; 9 (9 Suppl 2):S88–S96. 13. Benveniste MFK, Korst RJ, Rajan A, et al. A Practical Guide from the International Thymic Malignancy Interest Group (ITMIG) regarding the radiographic assessment of treatment response of thymic epithelial tumors using modified RECIST criteria. J Thorac Oncol 2014; 9 (9 Suppl 2):S119– S124. 14. Carter B, Okumura M, Detterbeck F, Marom E. Approaching the patient with an anterior mediastinal mass: a guide for radiologists. J Thor Oncol 2014; 9 (9 Suppl 2):S110–S118. 15. Carter B, Tomiyama N, Bhora F, et al. A modern definition of mediastinal & compartments. J Thorac Oncol 2014; 9 (9 Suppl 2):S97–S101. This describes a modern, CT-based definition of mediastinal compartments. 16. Carter B, Marom EM, Detterbeck F. Approaching the patient with an & anterior mediastinal mass: a guide for clinicians. J Thorac Oncol 2014; 9 (9 Suppl 2):S102–S109. The clinical evaluation of patients with mediastinal masses is difficult for most clinicians; this article provides a structure for how to proceed. 17. den Bakker M, Roden A, Marx A, Marino M. Histologic classification of thymoma: a practical guide for routine cases. J Thorac Oncol 2014; 9 (9 Suppl 2):S125–S130. 18. Evoli A, Lancaster E. Paraneoplastic disorders in thymoma patients. J Thorac Oncol 2014; 9 (9 Suppl 2):S143–S147. 19. Rajan A, Girard N, Marx A. State of the art of genetic alterations in thymic epithelial tumors. J Thorac Oncol 2014; 9 (9 Suppl 2):S131–S136. 20. Weksler B, Binfeng L. Alterations of the immune system in thymic malignancies. J Thorac Oncol 2014; 9 (9 Suppl 2):S137–S142. 21. Huang J, Ahmad U, Antonicelli A, et al. Development of the international thymic malignancy interest group international database: an unprecedented resource for the study of a rare tumor. J Thor Oncol 2014; 9:1573–1578. 22. Marx A, Strobel P, Badve S, et al. ITMIG consensus statement on the use of & the WHO histological classification of thymoma and thymic carcinoma: refined definitions, histological criteria and reporting. J Thorac Oncol 2014; 9:596–611. Histologic classification has not been applied consistently; this article provides a refinement of the classification for pathologists that should promote better consistency.
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Neoplasms of the lung 23. Marx A. Tumours of the thymus. In: Travis, WD, Brambilla, E, Burke, AP, Marx, A, Nicholson, AG, editors. WHO classification of tumours of the lung, pleura, thymus and heart. 4th ed. IARC:Lyon; 2015. pp. 183-211. 24. Marx A. Thymic carcinoma. In: Travis, WD, Brambilla, E, Burke, AP, Marx, A, Nicholson, AG, editors. WHO classification of tumours of the lung, pleura, thymus and heart. 4th ed. IARC:Lyon; 2015. pp. 212-243. 25. Ahmad U, Yao X, Detterbeck F, et al. Thymic carcinoma outcomes and prognosis: results of an international analysis. J Thorac Cardiovasc Surg 2015; 149:95–101. 26. Filosso P, Yao X, Ahmad U, et al. Outcome of primary neuroendocrine tumors of the thymus: a joint analysis of the International Thymic Malignancy Interest Group and European Society of Thoracic Surgeons Databases. J Thorac Cardiovasc Surg 2015; 149:103–109. 27. Weis C, Yao X, Deng Y, et al. The impact of thymoma histotype on prognosis & in a worldwide database. J Thorac Oncol 2015; 10:367–372. The prognostic value of the WHO classification has been unclear and controversial. This article provides for the first time an assessment of this in a large worldwide database.
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28. Detterbeck F, Stratton K, Giroux D, et al. The ITMIG/IASLC thymic epithelial tumors staging project: proposal for an evidence-based stage classification system for the forthcoming (8th) edition of the TNM classification of malignant tumors. J Thor Oncol 2014; 9 (9 Suppl 2):S65–S72. This is the primary article describing the first official stage classification system for thymic malignancies. 29. Kondo K, van Schil P, Detterbeck F, et al. The ITMIG/IASLC thymic epithelial & tumors staging project: proposals for the N and M components for the forthcoming (8th) edition of the TNM classification of malignant tumors. J Thorac Oncol 2014; 9 (9 Suppl 2):S81–S87. This article describes details of the N and M components in the new stage classification system. 30. Nicholson A, Detterbeck C, Marino M, et al. The ITMIG/IASLC thymic epithelial & tumors staging project: proposals for the T component for the forthcoming (8th) edition of the TNM classification of malignant tumors. J Thorac Oncol 2014; 9 (9 Suppl 2):S73–S80. This article describes details of the T component in the new stage classification system.
&&
Volume 21 Number 4 July 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
What’s new in thymic neoplasms Alberto Antonicelli and Frank Detterbeck
Purpose of review The past 5 years have been marked with major developments in the field of thymic malignancies. Recent findings A lack of progress over decades has been transformed into dramatic advancements over the past 5 years through the creation of the International Thymic Malignancy Interest Group (ITMIG). ITMIG has brought together an engaged worldwide community interested in this field. An unprecedented global database has been developed and is being actively analyzed. Standard definitions have been established to allow collaboration; the histologic classification has been revised and the first formal stage classification system developed. Clinical trials and innovative research approaches are being implemented. The creation of the ITMIG infrastructure has yielded many successes and provides a solid foundation for future progress. Summary Clinicians and researchers should be aware of the knowledge, structure and tools that have been established. ITMIG provides an engaged community for collaboration and progress. Keywords International Thymic Malignancy Interest Group, thymic carcinoma, thymic malignancy, thymoma
INTRODUCTION Thymic neoplasms constitute a collection of rare diseases, that all meet the definition of an orphan disease. This fact has long thwarted meaningful progress. An assessment of the available literature in 2009 revealed that almost 80% of publications on thymoma involved case reports, and less than 5% involved a cohort of more than 100 patients [1]. Furthermore, there had been no improvement in survival for decades [1]. This should come as no surprise, because for a rare disease that is managed in a disseminated fashion, development of an evidence base is essentially impossible when each institution operates more or less in isolation on a small collection of patients accumulated over 20–30 years. However, the possibilities and the state of the art in thymic neoplasms have changed dramatically in the past 5 years. Infrastructure has been developed to allow global collaboration. A worldwide community has coalesced, united by the determination to make a difference and undaunted by the innate challenges confronting a rare disease. This attitude, coupled with a culture of open collaboration for a common good, has created a force that is drastically overcoming decades of stagnation. This article reviews the current accomplishments and active initiatives within the realm of thymic malignancies.
COLLABORATION IS THE KEY TO PROGRESS A realization that progress in a rare disease is impossible without collaboration inspired many individuals active in thymic diseases to come together. This has happened on a regional level, on a global level and within institutions. Undoubtedly, the ability for people to come together has been aided by the many changes that have helped the world to become a smaller place. This includes the widespread development of the internet and technologic platforms that allow communication and collaboration. Major regional groups devoted to thymic neoplasms have arisen. The foundation for progress was created by the establishment of the Japanese Association for Research on the Thymus approximately 30 years ago. This organization provided key initial building blocks and continues to make major contributions to the field. The European Society of Department of Surgery, Division of Thoracic Surgery, Yale School of Medicine, New Haven, Connecticut, USA Correspondence to Frank Detterbeck, MD, Professor and Chief, Department of Surgery, Division of Thoracic Surgery, Yale School of Medicine, 330 Cedar St., BB205, New Haven, CT 06520-8062, USA. Tel: +1 203 785 4931; fax: +1 203 737 2163; e-mail: [email protected] Curr Opin Pulm Med 2015, 21:327–332 DOI:10.1097/MCP.0000000000000172
1070-5287 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-pulmonarymedicine.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Neoplasms of the lung
KEY POINTS
computed tomography (CT) as well as reviews on prognostic factors in thymic malignancies and on pitfalls in applying statistics to a rare disease [3 ,4– 11]. More recently ITMIG launched a second initiative aimed to provide practical guidance in the clinical management of patients. This resulted in another series of articles, summarized in another supplement to the Journal of Thoracic Oncology (Vol 9[9] Suppl 2, 2014), also available with unrestricted access at http://journals.lww.com/jto/toc/ 2014/09002. These articles focus on a standard definition of mediastinal compartments, a node map, assessment of response to therapy, practical guides for clinicians, radiologists in evaluating patients with an anterior mediastinal mass and for pathologists in classifying tissue specimens, and state of the art reviews on genetic abnormalities, paraneoplastic syndromes and immunologic disorders in thymic malignancies [12–14,15 ,16 ,17–20]. &
Progress in a rare disease requires collaboration. Development of a common language, a global database, tissue bank and an engaged community has established an infrastructure to facilitate progress. The first formal stage classification system for thymic malignancies has been developed. Innovative approaches to research are needed in a rare disease.
Thoracic Surgeons has assembled a strong and productive network of primarily European thoracic surgeons and has published several major articles. More recently, the Chinese Alliance for Research in Thymoma has emerged as a high-quality collaboration of 17 centers in mainland China. The overarching organization is the International Thymic Malignancy Interest Group (ITMIG). Founded in 2010 [2], this organization is a worldwide, multispecialty group that represents the vast majority of clinicians and researchers active in thymic malignancies in North and South America, Europe, Asia, Australia and Africa. ITMIG has created the spirit of openness and excitement that has driven many of the advancements in the state of the art in a short time span of 5 years. ITMIG has also supported and promoted the development of the regional organizations just mentioned.
THE CURRENT STATE OF THE SCIENCE Standards and definitions A major problem preventing progress was the fact that different institutions used different outcomes and different definitions of terms. An early initiative of ITMIG was to establish a consensus around definitions of terms and a common standard for reporting outcomes. Multiple workgroups culminating in a 2-day international workshop established these standards, which were essentially uniformly endorsed by the entire ITMIG membership. These terms and standards were summarized and published in a series of articles in a special supplement to the Journal of Thoracic Oncology (6 [7]Suppl 3, 2011), available for download at http://journals. lww.com/jto/toc/2011/07001. These articles address standards for reporting outcomes, for handling of resection specimens by surgeons and pathologists, for radiotherapy and chemotherapy, for minimally invasive resections, for interpretation and reporting on small biopsy specimens and for imaging by 328
www.co-pulmonarymedicine.com
&
&
International Thymic Malignancy Interest Group database A sophisticated retrospective and prospective database was developed, in collaboration with the Cancer Care Engineering project of Purdue University on the HUBzero platform. This is a Health Insurance Portability and Accountability Act (HIPAA)-compliant web-accessible relational global database. A testament to the engagement of the ITMIG community is that the retrospective database was rapidly populated, and now contains over 7000 cases from over 50 institutions in 15 countries [21]. This provides an unprecedented rich resource that is being actively used to address many clinical questions. A much more detailed prospective database was also established and has been accruing cases since 2012.
Histologic classification A source of controversy has been the histologic classification of thymic neoplasms. To address this, ITMIG assembled most of the experts in this field and brought them together for two workshops devoted to addressing weaknesses in the existing classification (New York, 2012 and Mannheim, 2013). This led to improved definitions of subtypes [22 ] as well as practical guides [17]. The output of the ITMIG workshops has formed the basis for the updated WHO Classification Manual [23,24]. In addition, the ITMIG database has been analyzed to elucidate the impact of subtypes of thymic neoplasms in a series of recent articles [25,26,27 ]. This analysis has established more clearly than ever &
&
Volume 21 Number 4 July 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
What’s new in thymic neoplasms Antonicelli and Detterbeck
before that outcomes of thymic carcinoma are quite distinctly worse than for thymoma, that thymic neuroendocrine tumors have outcomes essentially identical to thymic carcinoma and that the subtypes of thymoma have a subtle impact on outcomes, particularly with respect to recurrence rates. Finally, the results also underscore the consensus that all thymomas are, in fact, malignant neoplasms, despite the continued prevalence of the misleading term ‘benign thymoma’.
Table 2. Stage grouping Stage
T
I
T1
N0
M0
II
T2
N0
M0
IIIa
T3
N0
M0
IIIb
T4
N0
M0 M0
IVa IVb
Stage classification An impediment to collaboration and progress has been the lack of an official stage classification system for thymic malignancies. Sharing data across institutions was difficult, given that 15 stage classification systems have been created. ITMIG partnered with the International Association for the Study of Lung Cancer to develop an evidence-based system for formal adoption in the eighth edition of the Stage Classification of Malignant Tumors in 2016. The ITMIG database was supplemented with additional cases from the Japanese Association for Research on the Thymus and European Society of Thoracic Surgeons, resulting in over 10 000 cases. An extensive statistical analysis was conducted by Cancer Research and Biostatistics with funding provided by the International Association for the Study of Lung Cancer. Multiple perspectives and over 500 graphs of outcomes were considered during this 2-year effort. The proposed stage classification has been published in a series of articles [12,28 , 29 ,30 ]. &&
&
&
N
M
T any
N1
T any
N0,1
M1a
T any
N2
M0,1a
T any
N any
M1b
Reproduced with permission [28
&&
].
The proposed system is summarized in Tables 1 and 2. Particular highlights include the fact that attention to tumor encapsulation is abandoned because of lack of prognostic significance; the T component is structured by ‘levels’ of invasion, in which a given level may or may not include invasion of any lower level structures, and the definition of two node regions (anterior and deep).
WHAT DOES THE FUTURE HOLD? Research efforts The ITMIG retrospective database provides an unprecedented resource for research. Much work has gone into cleaning and refining this data structure to promote its use. Furthermore, to facilitate use without having to first learn the intricacies of the
Table 1. Tumor (T), node (N) and metastasis (M) descriptors Definition (involvement of)a,b
Category T1
a
Encapsulated or unencapsulated, with or without extension into mediastinal fat
b
Extension into mediastinal pleura
T2
Pericardium
T3
Lung, brachiocephalic vein, superior vena cava, chest wall, phrenic nerve, hilar (extrapericardial) pulmonary vessels
T4
Aorta, arch vessels, main pulmonary artery, myocardium, trachea or esophagus
N0
No nodal involvement
N1
Anterior (perithymic) nodes
N2
Deep intrathoracic or cervical nodes
M0 M1
No metastatic pleural, pericardial or distant sites a
Separate pleural or pericardial nodule(s)
b
Pulmonary intraparenchymal nodule or distant organ metastasis &&
Reproduced with permission [28 ]. a Involvement must be pathologically proven in pathologic staging. b A tumor is classified according to the highest T level of involvement that is present with or without any invasion of structures of lower T levels.
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Neoplasms of the lung
data structure, ITMIG has developed a statistical core devoted to retrospective database studies. An initial call for research proposals resulted in 17 applications; consistent with the ITMIG culture of collaboration, the database committee brought together institutions that had similar interests. Most of these data analyses have been carried out, and some of the studies have been published [25,26,27 ]. The projects include the analysis of outcomes after the treatment of thymoma, thymic carcinoma and neuroendocrine tumors, the impact of adjuvant radiotherapy, of open versus minimally invasive thymectomy, complete versus partial thymectomy, paraneoplastic syndromes, extrapleural pneumonectomy versus pleurectomy/decortication for stage IVa thymoma, palliative chemotherapy, second malignancies and prognostic factors. A new call for applications will be initiated in 2015. Clinical trials are the best way to solidly establish the therapeutic value of a treatment approach, but require a significant effort to conduct. Carrying out clinical trials in a rare disease is even more challenging. Nevertheless, undaunted by huge challenges, ITMIG has been working to run an international randomized trial on the use of adjuvant radiotherapy for stage III resected thymoma. This effort has been made possible by the help of the International Rare Cancers Initiative, an organization devoted to cutting through the hurdles facing rare tumors and international collaborations. Although it appears promising that this trial will actually take place, the difficulties experienced by ITMIG in overcoming the regulatory, procedural, financial and political challenges have been great, despite the efforts of the International Rare Cancers Initiative. This journey underscores both the huge obstacles that must be overcome to carry out such studies in a rare disease, as well as the fact that with determination and sustained effort even great impediments can be overcome. In order to develop a resource for basic science research, ITMIG launched a virtual tumor bank. Those institutions banking tissue share information on the nature of such tissues in an ITMIG tissue bank registry. Funding, regulatory and political issues have limited this to a virtual bank up to this point; nevertheless, it represents development of a resource that can be used as well as developed further. The Cancer Genome Atlas Project is a US National Institutes of Health initiative to fully sequence the genome of cancers. This provides essentially a road map that greatly facilitates further research. ITMIG lobbied successfully to have thymic malignancies included; many institutions on different continents contributed high-quality fresh-frozen tumor and normal tissue for analysis. The &
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sequencing is currently underway, with next steps for basic research being planned by the biology committee of ITMIG once The Cancer Genome Atlas Project results become available.
Innovation Given the difficulties that are inherently present in a rare disease, it is essential to be innovative in order to make progress. Bayesian analysis offers an approach that has particular appeal in a rare disease. Each outcome can be used to add to the knowledge base in real time without being withheld until the data reach maturity. This is because the Bayesian approach is not designed to provide absolute proof or ignore pre-existing data that can present bias in a traditional approach; rather it is designed to use all available data and quantify what is (and is not) known, including investigation of confounding factors. An ITMIG project seeks to use a Bayesian approach, coupled with a structured approach to treatment that seeks to manage local variability. This project builds on the ITMIG prospective database. Another innovative approach being pursued by ITMIG is outlier analysis. The concept here is that a very intensive analysis of an outlier may yield insight better than can be gained from more limited data on a larger number of patients. The analogy is the airline industry – rare events lead to improvements. This project is just beginning to get underway. A goal for patients with thymic malignancies is to find ways to improve the level of care broadly, recognizing that care is by necessity delivered in a relatively sporadic fashion across many disseminated centers. Modern technology offers ways of disseminating information, and making it accessible when and where it is needed. However, what is needed to raise the level of care is not simply information, it is higher level skills such as clinical judgment and problem solving related to particular issues that individual patients present. What is needed is a way of disseminating clinical expertize to broadly dispersed sites. Fortunately, the science of adult learning has progressed, and tools to impart such higher level cognitive skills have been developed. An ITMIG goal is to use these approaches to develop educational tools, and make them broadly accessible through modern technology in order to broadly raise the level of care that can be delivered.
Accomplishments, challenges and opportunities Major building blocks have been created that provide a foundation upon which to build scientific Volume 21 Number 4 July 2015
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What’s new in thymic neoplasms Antonicelli and Detterbeck
progress in thymic neoplasms. An engaged, collaborative community has been created, a common language developed and a critical assessment of the state of the science has been initiated. Resources to permit research have been developed; attempts to build innovative approaches are underway, given the inherent challenges in a rare disease. Nevertheless, major impediments to progress will always continue to confront those trying to make scientific progress in thymic neoplasms. National rules clearly define that completely deidentified data can be shared publicly and used for research without restrictions (http://privacyruleandresearch.nih.gov/pr_08.asp), yet institutional privacy officers are often unaware of the regulations and believe they must restrict release of such data. Bureaucratic regulatory issues related to prospective research studies present a major impediment that is greatly amplified in a rare disease. Existing structures for clinical research are designed for common diseases, and represent a formidable barrier to research studies in rare diseases. The biggest challenge to progress is lack of funding. Although in a rare disease even a small amount of funding can make a big difference, normal sources of research funding are more or less inaccessible for a rare disease. Although some funding is available specifically for rare diseases, it is limited, and philanthropy is the primary source of funding. The progress that has been made in thymic neoplasms has relied primarily on pro-bono donated time by many individuals, but the state of affairs has progressed to a point in which further development of resources and projects cannot be done by volunteerism alone. There is little doubt that funding is the major ratelimiting step to progress in thymic neoplasms.
CONCLUSION The developments in the last 5 years in thymic neoplasms provide proof that seemingly insurmountable hurdles can, in fact, be overcome with sufficient determination. The efforts of the global community of interested individuals have led to major progress and set the stage for significant scientific advancement in the coming years. Once stagnant, a strong sense of excitement and momentum is now palpable in the field of thymic neoplasms. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Detterbeck F. The creation of the international thymic malignancies interest group as a model for rare diseases. In: Govindan Re, editor. 2012 ASCO educational book. Alexandria, VA: American Society of Clinical Oncology; 2012. pp. 471–474. 2. Detterbeck F. ITMIG: a way forward. J Thorac Oncol 2010; 5 (10 Suppl 4): S365–S370. 3. Detterbeck F, Moran C, Huang J, et al. Which way is up? Policies and & procedures for surgeons and pathologicsts regarding resection specimens of thymic malignancy. J Thorac Oncol 2011; 6 (7 Suppl 3):S1730– S1738. This article provides a framework for communication between the surgeon and pathologists and guidance for both in how to handle resection specimens, thus reducing incomplete characterization of the specimen and margins. 4. Detterbeck F, Youssef S, Ruffini E, Okumura M. Review of reported prognostic factors in thymic malignancies. J Thorac Oncol 2011; 6 (7 Suppl 3): S1698–S1704. 5. Girard N, Lal R, Wakelee H, et al. Chemoterapy definitions and policies for thymic malignancies. J Thorac Oncol 2011; 6 (7 Suppl 3):S1749– S1755. 6. Gomez D, Komaki R, Yu J, et al. Radiation therapy definitions and reporting guidelines for thymic malignancies. J Thorac Oncol 2011; 6:S1743– S1748. 7. Gonen M. Bias, biostatistics, and prognostic factors. J Thorac Oncol 2011; 6:S1705–S1709. 8. Huang J, Wang Z, Loehrer P, et al. Standard outcome measures for thymic malignancies. J Thorac Oncol 2010; 5:2017–2023. 9. Marchevsky A, Marx A, Strobel P, et al. Policies and reporting guidelines for small biopsy specimens of mediastinal masses. J Thorac Oncol 2011; 6 (7 Suppl 3):S1724–S1729. 10. Marom E, Rosado-de-Christenson M, Bruzzi J, et al. Standard report terms for chest computed tomography reports of anterior mediastinal masses suspicious for thymoma. J Thorac Oncol 2011; 6 (7 Suppl 3):S1717– S1723. 11. Toker A, Sonett J, Zielinski M, et al. Standard terms, definitions, and policies for minimally invasive resection of thymoma. J Thorac Oncol 2011; 6 (7 Suppl 3):S1739–S1742. 12. Bhora F, Chen D, Detterbeck F, et al. The ITMIG/IASLC thymic epithelial tumors staging project: a proposed lymph node map for thymic epithelial tumors in the forthcoming 8th edition of the TNM classification for malignant tumors. J Thor Oncol 2014; 9 (9 Suppl 2):S88–S96. 13. Benveniste MFK, Korst RJ, Rajan A, et al. A Practical Guide from the International Thymic Malignancy Interest Group (ITMIG) regarding the radiographic assessment of treatment response of thymic epithelial tumors using modified RECIST criteria. J Thorac Oncol 2014; 9 (9 Suppl 2):S119– S124. 14. Carter B, Okumura M, Detterbeck F, Marom E. Approaching the patient with an anterior mediastinal mass: a guide for radiologists. J Thor Oncol 2014; 9 (9 Suppl 2):S110–S118. 15. Carter B, Tomiyama N, Bhora F, et al. A modern definition of mediastinal & compartments. J Thorac Oncol 2014; 9 (9 Suppl 2):S97–S101. This describes a modern, CT-based definition of mediastinal compartments. 16. Carter B, Marom EM, Detterbeck F. Approaching the patient with an & anterior mediastinal mass: a guide for clinicians. J Thorac Oncol 2014; 9 (9 Suppl 2):S102–S109. The clinical evaluation of patients with mediastinal masses is difficult for most clinicians; this article provides a structure for how to proceed. 17. den Bakker M, Roden A, Marx A, Marino M. Histologic classification of thymoma: a practical guide for routine cases. J Thorac Oncol 2014; 9 (9 Suppl 2):S125–S130. 18. Evoli A, Lancaster E. Paraneoplastic disorders in thymoma patients. J Thorac Oncol 2014; 9 (9 Suppl 2):S143–S147. 19. Rajan A, Girard N, Marx A. State of the art of genetic alterations in thymic epithelial tumors. J Thorac Oncol 2014; 9 (9 Suppl 2):S131–S136. 20. Weksler B, Binfeng L. Alterations of the immune system in thymic malignancies. J Thorac Oncol 2014; 9 (9 Suppl 2):S137–S142. 21. Huang J, Ahmad U, Antonicelli A, et al. Development of the international thymic malignancy interest group international database: an unprecedented resource for the study of a rare tumor. J Thor Oncol 2014; 9:1573–1578. 22. Marx A, Strobel P, Badve S, et al. ITMIG consensus statement on the use of & the WHO histological classification of thymoma and thymic carcinoma: refined definitions, histological criteria and reporting. J Thorac Oncol 2014; 9:596–611. Histologic classification has not been applied consistently; this article provides a refinement of the classification for pathologists that should promote better consistency.
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Neoplasms of the lung 23. Marx A. Tumours of the thymus. In: Travis, WD, Brambilla, E, Burke, AP, Marx, A, Nicholson, AG, editors. WHO classification of tumours of the lung, pleura, thymus and heart. 4th ed. IARC:Lyon; 2015. pp. 183-211. 24. Marx A. Thymic carcinoma. In: Travis, WD, Brambilla, E, Burke, AP, Marx, A, Nicholson, AG, editors. WHO classification of tumours of the lung, pleura, thymus and heart. 4th ed. IARC:Lyon; 2015. pp. 212-243. 25. Ahmad U, Yao X, Detterbeck F, et al. Thymic carcinoma outcomes and prognosis: results of an international analysis. J Thorac Cardiovasc Surg 2015; 149:95–101. 26. Filosso P, Yao X, Ahmad U, et al. Outcome of primary neuroendocrine tumors of the thymus: a joint analysis of the International Thymic Malignancy Interest Group and European Society of Thoracic Surgeons Databases. J Thorac Cardiovasc Surg 2015; 149:103–109. 27. Weis C, Yao X, Deng Y, et al. The impact of thymoma histotype on prognosis & in a worldwide database. J Thorac Oncol 2015; 10:367–372. The prognostic value of the WHO classification has been unclear and controversial. This article provides for the first time an assessment of this in a large worldwide database.
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28. Detterbeck F, Stratton K, Giroux D, et al. The ITMIG/IASLC thymic epithelial tumors staging project: proposal for an evidence-based stage classification system for the forthcoming (8th) edition of the TNM classification of malignant tumors. J Thor Oncol 2014; 9 (9 Suppl 2):S65–S72. This is the primary article describing the first official stage classification system for thymic malignancies. 29. Kondo K, van Schil P, Detterbeck F, et al. The ITMIG/IASLC thymic epithelial & tumors staging project: proposals for the N and M components for the forthcoming (8th) edition of the TNM classification of malignant tumors. J Thorac Oncol 2014; 9 (9 Suppl 2):S81–S87. This article describes details of the N and M components in the new stage classification system. 30. Nicholson A, Detterbeck C, Marino M, et al. The ITMIG/IASLC thymic epithelial & tumors staging project: proposals for the T component for the forthcoming (8th) edition of the TNM classification of malignant tumors. J Thorac Oncol 2014; 9 (9 Suppl 2):S73–S80. This article describes details of the T component in the new stage classification system.
&&
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