1st International Conference on Thymic Malignancies
August 20-21, 2009
Table of contents
Introduction and acknowledgements page 2
Conference agenda pages 3-4
Technical information and shuttle schedules page 5-6
NIH campus map page 7
Presentation Abstracts pages 8- 18
Poster Abstracts pages 19-26
List of participants pages 27-30
Blank notes pages
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Welcome and thank you for joining us at the 1st International Conference on Thymic Malignancies!
We are confident this conference will help initiate future directives for the management of thymic malignancies through promotion of further basic and clinical research by fostering discussions between scientists, pathologists and clinicians. It is expected that consensus statements about the approach to diagnosis and management of this rare group of malignancies will be a result of this conference. Other significant outcomes include research priorities being established, potentially collaborative protocols being developed, diagnosis and monitoring criteria being standardized, as well as development of a patient data base and tissue bank. An exciting prospect of forming a Consortium for Thymic malignancies will also be discussed during the meeting. In conclusion of this first conference on thymic malignancies, we hope the greater outcome will be more current information and improved treatment options available to doctors and patients with thymic cancer.
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We would like to acknowledge the following individuals/groups for their contributions:
ORGANIZERS
Giuseppe Giaccone, Lisa Eiben, Arun Rajan, Medical Oncology Branch Staff, Karen
Kochersberger, SAIC Events Planning
CO-SPONSORS
Alan Neibaurer, Alan Blaustein, Janice Katz, Foundation for Thymic Cancer Research
CONFERENCE CHAIRS
Ronald Gress, Alexander Marx, Maria Merino, James Huang, Frank Detterbeck, Ritsuko Komaki, Cesar Moran, Maureen Zakowski, Patrick Loehrer
FUNDING
Center for Cancer Research, Office of Rare Diseases, Foundation for Thymic Cancer Research
1st International Conference on Thymic Malignancies
Natcher Conference Center Atrium, upper level and E1/E2 Conference Rooms, lower level
August 20 (Thursday)
7:45-8:30 AM Breakfast/Poster Set up in Atrium; Registration/Meeting table on lower level
8:30-8:40 AM Opening Remarks and Welcome – Giuseppe Giaccone
8:40-8:50 AM The Foundation of Thymic Cancer Research– Alan Neibauer
Epidemiology and biology
Chairs: R. Gress and A. Marx
8:50 AM Epidemiology of Thymic Malignancies – Eric Engles
9:20 AM AIRE issues in thymoma- Alexander Marx
9:50 AM Autoimmune syndromes and thymoma: Myasthenia Gravis and others- Arthur Melms
10:20-10:40 AM Coffee/Break and Poster Viewing in Atrium
10:40 AM The Thymus and the Immune System – Ronald E. Gress
11:10 AM Biology of Thymic tumors – Philipp Strobel
11:40 PM Round Table: Research Issues in Immune disorders due to thymic malignancies
12:10-1:10 PM Lunch Break (on own) in Natcher Cafeteria and Poster Viewing in Atrium
Pathology, imaging and natural history of thymomas
Chairs: Maria Merino and James Huang
1:10 PM The WHO classification of thymic malignancies Michael Den Bakker
1:40 PM The need for a new classification – Cesar Moran
2:10 PM Molecular Classification of Thymic Malignancies – Ignacio Wistuba
2:40-3:00 PM Coffee/Break and Poster Viewing in Atrium
3:00 PM Imaging Techniques – Edith Marom
3:30 PM Clinical and Surgical Staging – Akira Masaoka
4:00 PM Case Presentations – Arun Rajan
4:30 PM Thymoma Foundation Patient Advocacy Group – Alan Blaustein
5:00 PM Round Table: Research issues in pathologic and clinical staging
5:30 PM Adjourn of general meeting
5:30-7 PM Global Consortium Meeting
7:15-9:30 PM Speaker’s Reception and Dinner at FAES House (sponsored by FTCR)
August 21(Friday)
7:30-8:30 AM GCSTM committee briefing in E1/E2
7:45-8:30 AM Breakfast and Poster Viewing in Atrium
Treatment options for Early Stage Thymic Malignancies
Chairs: Frank Detterbeck and Ritsuko Komaki
8:30 AM Surgery for primary thymomas – Frank C. Detterbeck
9:00 AM Extended surgery for Thymic Malignancies – Cameron D. Wright
9:30 AM Reresection of recurrent disease – Marco Lucchi
10:00 AM Adjuvant Radiotherapy—Charles Thomas Jr.
10:30 AM Role of chemotherapy in resectable thymoma- Edward Kim
11:00-11:20 AM Coffee/Break and Poster Viewing in Atrium
11:20-11:35 AM Proffered Paper #1- Ritsuko Komaki
11:35-11:50 AM Proffered Paper #2-Angela Vincent
11:50 AM-12:05 PM Proffered Paper #3- Maureen Zakowski
12:05-12:20 PM Proffered Paper #4-by NCI
12:20-1:20 PM Lunch Break (on own) in Natcher Cafeteria and Poster Viewing in Atrium
Chairs: Cesar Moran and Maureen Zakowski
1:20 PM Therapy for thymoma and thymic carcioma in Japan-Kazoya Kondo
1:50 PM Round Table: Research issues for early thymic malignancies
Treatment options for Advanced Thymic Malignancies
Chairs: Patrick Loehrer and Giuseppe Giaccone
2:20 PM Chemotherapy for Thymic Malignancies – Patrick J. Loehrer
2:50 PM Targeted therapy in Thymic Neoplasms – Giuseppe Giaccone
2:50-3:10 PM Coffee/Break and Poster Viewing in Atrium
3:10 PM Combined modality therapy – Gregory Riely
3:40 PM Survivorship issues in thymic malignancies – Ola Landgren
4:10 PM Round Table: Research issues in advanced thymoma
4:40-4:50 PM Closing Remarks- Giaccone
4:50-5:10 PM Adjourn and Poster Removal
Presentation Abstracts
EPIDEMIOLOGY OF THYMIC MALIGNANCIES – Dr. Eric Engels
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland
Thymic malignancies are a rare group of neoplasms (annual incidence 1-2 per million in the U.S. general population). The most common subtype is thymoma, a tumor of thymic epithelial cells normally responsible for T cell maturation. Thymoma is strongly associated with the occurrence of autoimmune diseases, most notably myasthenia gravis. In the U.S., thymoma incidence is similar in males and females, and rises with age. For unclear reasons, thymoma incidence in the U.S. is higher in Asians and blacks than among whites. There have been conflicting reports about whether thymoma is associated with an elevated risk of subsequent malignancies. In a U.S. population-based study using SEER cancer registry data (N=733 thymoma cases), Engels and Pfeiffer (Int J Cancer 2003) found a modest overall increase in second cancer risk (n=66, relative risk 1.5). Risk was most clearly elevated for non-Hodgkin lymphoma (n=7, relative risk 4.7), perhaps reflecting the effects of thymoma-related T cell dysfunction. Thymoma risk is not increased among immunosuppressed individuals, such as HIV-infected people or transplant recipients. However, in several studies, Epstein Barr virus has been detected within tumor cells of the lymphoepithelial variant of thymic carcinoma, suggesting a role for this virus. There are no data on the possible contribution of other risk factors or etiologic agents, such as tobacco and alcohol, radiation, occupation, environmental contaminants, diet and nutrition, or genetic factors.
AIRE Issues in Thymoma – Prof. Alexander Marx
Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, D-68135 Mannheim, Germany; alexander.marx@umm.de
The Autoimmune Regulator (AIRE) is a transcriptional activator expressed in a specialized subset of MHC class IIhigh medullary thymic epithelial cells (mTECs). It promotes expression of “tissue restricted antigens” (TRA). Joint expression of AIRE and TRA endows mTECs and cross-presenting dendritic cells with the capacity to promote central tolerance by enforcing negative selection of maturing thymocytes with (autoreactive) specificity for the respective TRAs. In addition, AIRE in concert with high MHC class II expression levels promotes generation of FoxP3+ “natural” regulatory T cells (Tregs). The relevance of AIRE in humans was shown by the association of various AIRE mutations with a rare, phenotypically variable monogenic autoimmune disease (AID), auto-immune-polyendo-crinopathy-candidiasis-ectodermal-dysplasia (APECED). Recently, we detected AIRE deficiency in >95% of thymomas (Strobel P et al. J. Pathol 211:563, 2007). Only some cases of the rarest thymoma subtype (WHO type B1) harboured AIRE+ mTECs in “medullary islands”. Of note, i) presence of the most common thymoma-associated AID, paraneoplastic myasthenia gravis (p-MG) did not segregate with the MG status of thymoma patients; ii) MG is not a facet of APECED; and iii) typical APECED symptoms have not been reported (autoimmune hypoparathyroidism) or are rare (adrenal insufficiency, candidiasis) in thymoma patients, showing that global AIRE deficiency in APECED patients and isolated lack of AIRE in thymomas (adjacent to AIRE-proficient non-neoplastic thymic tissue) entail different types of immunologic intolerance. Indeed, a role of AIRE deficiency in thymoma-associated AIDs is likely for the following reasons: thymomas show a) thymopoiesis of intolerant CD4+ T helper cells; b) deficient capacity to generate Tregs; c) intrathymomatous production of neutralizing autoantibodies to type I interferons and Il-12 that are unique and diagnostically relevant autoantibodies in ~100% of APECED and ~70% of thymoma patients (with a higher prevalence in MG(+) thymomas (Meager A et. al. Clin Exp. Immunol. 132:128, 2003; PLoS Med 3: e289, 2006; Strobel P et al. 2007 (see above); Ann N Y Acad Sci 1132:143, 2008).
Autoimmune syndromes and thymomas: myasthenia gravis and others– Arthur Melms
Dept. of General Neurology and Hertie-Institute of Clinical Brain Research, University of Tübingen Medical Center
Thymomas may be associated with a variety of paraneoplastic autoimmune syndromes. In most cases the paraneoplastic syndrome is symptomatic before the thymoma is detected. A high level of suspicion is essential for early detection and treatment of the underlying tumor. Thymomas are a heterogeneous group of thymic tumors. Some subtypes show a strong association with certain paraneoplastic autoimmune syndromes including myasthenia gravis, polymyositis, neuromyotonia, limbic encephalitis, dermatological disorders and immunodeficiencies. The most frequently observed autoimmune syndrome in thymomas is myasthenia gravis in about 35%. Converse, thymomas are found in approximately 15% of patients with myasthenia gravis, an autoimmune neuromuscular disease mediated by autoantibodies to acetylcholine receptors (AchR-abs). Almost all cases of the classical form of MG have AchR-abs and other autoantibodies to proteins of skeletal muscle like titin or ryanodine receptor. Thymomas are very rare in variants of myasthenic syndromes without AchR-abs.
Thymomas associated with paraneoplastic autoimmune syndromes usually provide a microenvironment for extensive lymphopoesis like the physiological thymus cortex. It is reasonable to assume that an altered microenvironment promotes the maturation of thymocytes with an autoimmune potential. Increased numbers of thymocytes may bypass the physiological check points of selection which involves cell contact and interaction with self-peptide-loaded MHC molecules on thymic antigen presenting cells. Autoimmunity triggered by the thymoma ususally persists after resection of the tumor and requires specific treatment which may be different from the regime to control the thymoma or its relapse.
The Thymus and the Immune System: Layered Levels of Control – Dr. Ronald Gress
Experimental Transplantation and Immunology Branch, Center for Cancer Research, NCI, Bethesda, MD
The thymus is governed by interdependent interactions of thymocytes and thymic epithelial cells (TEC) such that the differentiation of TEC cell subpopulations is dependent on T cell lineage commitment, and thymocyte precursor immigration and maturation is dependent on TEC. The adult thymus is also responsive to external stimuli such as signaling by androgens, IGF-1, and KGF and subject to regulation by genes expressed in TEC. In investigating the mechanisms of this responsiveness, we found that cessation of androgen signaling results in increased proliferation of TEC and up-regulation of CCL25 expression by medullary TEC with consequent increase in immigration of thymocytes precursor populations and increase of thymopoiesis as assessed by recent thymic emigrants in the circulating pool of mature T cells. IGF-1 receptor (IGF-1R) is expressed on multiple immune cell types including marrow lymphocyte precursors, thymocytes, TEC, and mature lymphocytes. Using T-cell-specific IGF-1R knock-out mice, we found that the cell population critical for responsiveness of the thymus to IGF-1 stimulation was TEC. In studies to identify genes expressed in TEC which exert control over thymus function, we identified SPATIAL which acts as a negative regulator of thymopoiesis. Mice not expressing SPATIAL had delay in thymus involution and more rapid T cell reconstitution following marrow transplantation compared to controls. Expression of SPATIAL inversely correlated with TEC expression including in animals undergoing increased thymopoiesis following cessation of androgen signaling. It was found that the protein encoded by SPATIAL regulates the NEDD8 pathway which is essential to cell cycle progression and thereby can potentially affect rates of TEC proliferation. These studies suggest that although interactions of thymocytes and TEC involve key signaling events that are essential to the integrity of thymus development and function, a primary point of control in the function of the adult thymus is integration of signals mediated directly through TEC.
The biology of thymic tumors – Prof. Philipp Stroebel
Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, D-68135 Mannheim, Germany; philipp.stroebel@umm.de
Thymomas and thymic carcinomas are rare tumors of the thymic epithelium with a broad spectrum of differing morphological and clinical features. Since 1999, increasing acceptance of the World Health Organisation (WHO) classification of thymic tumors1 has greatly helped to improve the comparison of international studies and it has been shown to be of prognostic significance2-5. The WHO classification of thymomas rests on the histological assessment of the morphology of the neoplastic epithelial cells (spindle, plump etc) and the relative amount of a non-neoplastic lymphocytic component. Recent genetic, molecular and biochemical as well as clinical findings have revealed major differences between the thymoma subtypes and were therefore implemented in the revised WHO classification of 20046. Although our current data seem to indicate that thymomas arise from a single stem or progenitor cell with maturation blocks at different stages of its development towards either cortical or medullary epithelial cells, it is important to understand that the tumors that result from these different mutations will show a very different biology and clinical behaviour.
The most frequent genetic alterations in thymomas and thymic squamous cell carcinomas affect chromosome 6q25.2-25.37, a region containing genes such as MTLC8 TIAM29 or GTF2H510. The identification of a common genetic alteration across all histologic tumor subtypes suggests the presence of a yet undefined common tumor suppressor gene with relevance for tumorigenesis in this region. In type A thymomas, genetic alterations other than on chromosome 6 are rare, in line with their clinically benign behavior7,11,12. In type AB thymoma, genetic alterations seem to be intermediate between those of type A and those of type B, but are somewhat more closely related to type B, as indicated by the finding of “B-type” losses of heterozygosity (LOH) of the APC locus at chromosome 5q21-22 in some type AB but not in type A thymomas. Interestingly, a few type A and AB thymomas with a clinically benign course may show genetic imbalances (e.g. on chromosome 8p11.21) that are associated with a poor prognosis if encountered in type B2 and B3 thymomas or thymic squamous cell carcinomas. This finding suggests the presence of a so far unidentified tumor suppressor gene preventing a clinically malignant behavior in spite of a “high risk” genetic imbalance in a subset of type A and AB thymomas. There are no published data on the cytogenetic findings in type B1 thymomas. Type B2 thymomas are genetically related to type B3 thymomas. Specifically, type B2 thymomas share recurrent genetic alterations at chromosomes 5q21-22, 7p15 and 8p11 with a subset of type B3 thymomas7. The most frequent recurrent gains of chromosomal material in B3 are on chromosomes 1q (69%) and Xq (19%), the most frequent recurrent losses affect the whole or parts of chromosome 6 (38%) and for 13q (31%). Together, these findings suggest that some type B3 thymomas develop through progression from type B2 tumors. In contrast, combined losses at chromosomal regions 5q21-22 (APC), 13q14.3 (RB), and 17p13.1 (p53) unique to a subset of more invasive type B3 thymomas, thus indicating the existence of at least two major pathways in the tumorigenesis of type B3 thymoma. These pathways are not mutually exclusive. A third oncogenic pathway may be through the development of microsatellite instability, which has been described in rare cases of type AB and B2 thymomas7.
In conclusion, the major histological subtypes that are currently recognized in the WHO classification are characterized not only by their distinctive morphology, but also by specific chromosomal alterations. Current findings suggest that all of these subtypes may arise from a single progenitor cell with different developmental blocks. Precise understanding of the biology of thymic tumors is key to our ability to develop specific new therapeutic strategies.
The WHO classification of thymic malignancies – Prof. Michael den Bakker
Dept. of Pathology, Erasmus MC, Rotterdam, The Netherlands
Tumor classification systems are important for patient management and predominantly aimed at providing prognostic and predictive information. However, many tumor classification systems provide additional information beyond the absolute minimum required for patient management. Moreover, some classification systems which are still in use today, were not designed at all with patient management in mind. For instance, the main current groupings of lung cancer types, were first suggested, over 80 years ago, solely as morphological categories not taking account prognosis and survival. Even today within these main categories of lung cancer many subcategories are recognized which do not impact on treatment and only in some cases have prognostic implications. Similarly, the 2004 WHO thymoma classification essentially is a morphological histogenetic classification encompassing previous schemes in which the categories also provide prognostic information. There are however drawbacks in the application of the WHO scheme. For instance, many thymoma cases do not fit neatly in a single category and sometimes multiple patterns may be recognized in one single tumor. These observations have resulted in a poor inter-observer agreement. It has been suggested that an alternative scheme, proposed by Drs. Suster & Moran, comprising fewer categories (i.e. thymoma, atypical thymoma and thymic carcinoma) would result in improved agreement in typing and thus more accurate patient stratification. Although this classification in part is based on architectural features and degree of atypia, detailed information of histological features is lost in the final allocation to one of the three proposed categories. The WHO categories can be condensed in to the three categories of the alterative scheme. However, problem areas remain For instance, the distinction between WHO categories B2 / Suster-Moran thymoma and B3 / Suster-Moran atypical thymoma is not always straightforward in either classification scheme.
Thymomas: Is there a need for a new classification? – Dr Cesar Moran
The University of Texas, M D Anderson Cancer Center, Department of Pathology, Houston, TX
Over the years several classification systems have been offered to classy thymic epithelial neoplasms, namely thymomas; however, most of the current classification systems if not all, have fall short in addressing the entire spectrum of these tumors. In addition, in some classification systems the use of alternate names to designate these tumors have created confusion not only in the pathology community but also in the surgical and oncological groups. More recently, the World Health Organization in an attempt to clarify some of the issues with previous classification systems, and to establish a universal nomenclature produce a schema in which letters and numbers were given to some thymomas with specific histology, and at the same time provided a grading system that respectively appears to address each one of the conditions considered in this schema. However, such schema of letters and numbers has also generated controversy not only in the interpretation and diagnosis of the different types of thymomas; but also different studies have concluded with different results than those presented by the WHO. In consequence it is apparent that a new approach may be need in which all the known elements of these tumors should be taken into consideration. Furthermore, it is also possible that in light of new studies regarding survival of these patients with thymomas not only a new classification should be sought but also a practical new pathological staging system.
Molecular pathology of thymic epithelial neoplasms. – Dr. Ignacio Wistuba
Ignacio I. Wistuba, Elisabetta Kuhn, Ara Vaporciyan, Edward Kim, Cesar Moran.
Department of Pathology and Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
The etiology and molecular pathogenesis of thymic tumors are unknown. However, during the last two decades there has been some progress on elucidating the genetic abnormalities present and molecular pathways altered in thymic epithelial tumors. These abnormalities, while bearing distinctions and similarities to those described in other epithelial neoplasms, can be organized under the “hallmarks of cancer”. These changes include self-sufficiency in growth signaling, insensitivity to antigrowth signals, ability to evade apoptosis, limitless replicative potential, ability to sustain angiogenesis, and tissue invasion and metastasis. Recently, we and others have performed several studies in the role of HER family receptors (oncogenes) in the pathogenesis of thymomas and thymic carcinomas, as well as the study of abnormalities involving several putative and known tumor suppressor genes. However, this progress is still limited and has not led to better tumor classifications, prognostication of outcome, and design of novel molecular targeted therapy strategies.
THYMOMA: IMAGING TECHNIQUES – Dr. Edith Marom
Thymic neoplasms are rare lesions and account for less than 1% of all adult malignancies. Because they are rare, knowledge regarding their imaging, prognostic factors and treatment effect is based mainly on small retrospective series, most of which are old. Imaging thymoma is most often performed with a chest radiograph as in a third of the patients, the thymoma is discovered incidentally as an anterior mediastinal mass in an asymptomatic individual, a third are evaluated for paraneoplastic symptoms and a third may present due to symptoms related to mass effect or local invasion by the neoplasm. This is routinely followed by chest CT. In certain circumstances, other imaging modalities are used such as MRI, or nuclear medicine studies. The goal of imaging is to identify the tumor and stage it appropriately, with emphasis on local invasion and distant spread because invasion has been known as the most significant factor for survival. It has become crucial to identify stage III and IV disease prior to surgery as neoadjuvant chemotherapy prior to surgery is currently the accepted practice for advanced thymomas. The objectives of this presentation are to discuss the normal appearance of the thymus, the advantages and limitations of each imaging modality in establishing the diagnosis, staging and prognosis of thymoma.
Staging System of Thymoma – Prof. Akira Masaoka
The Second Department of Surgery, Nagoya City University, Nagoya, Japan.
In 1981, we proposed a staging system for thymoma that is described below. Stage I: Macroscopically completely encapsulated and microscopically no capsular invasion, Stage II: 1. Macroscopic invasion into surrounding fatty tissue or mediastinal pleura, or 2. Microscopic invasion into capsule, Stage III: Macroscopic invasion into neighboring organ, i.e., pericardium, great vessels, or lung, Stage IVa: Pleural or pericardial dissemination, Stage IVb: Lymphogenous or hematogenous metastasis (Masaoka A et al, Cancer, 48:2485-2492, 1981) Fortunately, this staging system was accepted by many surgeons and pathologists. On the other hand, in 1980s, the extended thymectomy was introduced as the standard procedure for thymoma, instead of the simple thymomectomy. This change promoted chances, which we encountered the thymomas with lymphogenous metastases. So, we proposed a TNM classification system in 1991, without revise of the staging system. In 2004, WHO proposed a new TNM classification system and staging system. There are 2 points of difference between mine and WHOs. First, invasion into only mediastinal pleura is T2 in mine, and T3 in WHOs. Second, N1 case belongs stage IVb in mine, and Stage IV in WHOs. I would like to analyze these points, based on the follow-up results of 211 cases of Nagoya City University series.
Case Presentations-Arun Rajan1
David Schrump2, Giuseppe Giaccone1
1 Medical Oncology Branch, National Cancer Institute, Bethesda, MD 2 Surgical Oncology Branch, National Cancer Institute, Bethesda, MD
Case #1
The patient is a 41-year-old female who was diagnosed with advanced stage lymphocyte predominant thymoma in January 2009 after she developed progressive dyspnea associated with a dry cough. A CT scan showed a large right-sided pleural effusion and a very large lobulated mass of heterogeneous density present in the medial and anterior right hemithorax measuring up to 12 cm in size. Multiple pleural-based nodules were also seen in the right hemithorax. A CT guided biopsy of mass revealed lymphocyte predominant thymoma. In February the patient started receiving chemotherapy consisting of doxorubicin 40 mg/m2, cisplatin 70 mg/m2, cyclophosphamide 1,000 mg/m2, and prednisone 100 mg by mouth daily for 3 days. Treatment was repeated every three weeks and a total of four cycles were administered. In May 2009 the patient underwent surgery for stage IV-A thymoma. The operation consisted of a median sternotomy with resection of the thymic mass, en bloc right extrapleural pneumonectomy and mediastinal lymph node dissection. The predominant histology of the resected specimen was consistent with Type B2 thymoma with foci of Type B1 disease. In July 2009 the patient started receiving adjuvant radiation therapy to decrease the chances of local recurrence of disease.
Past Medical History: Non-contributory
Past Surgical History: Tonsillectomy.
Current Medications: Ativan, Prozac, Zofran, Hydromorphone, Senna/Colace, Megace, Multivitamin, Ibuprofen
Allergies: None
Social History: No history of smoking or alcohol intake.
Family History: The patient’s maternal grandmother had cervical cancer, paternal grandfather had prostate cancer, and paternal grandmother died from a brain malignancy.
Case #2
The patient is a 53 year-old female who was found to have a large anterior mediastinal mass in January 2009 after she presented with worsening cough, significant weight loss, anorexia, fatigue, progressive dyspnea and increasing right scapular pain over a period of about three months. A CT scan revealed an anterior mediastinal mass measuring 9 cm x 7.5 cm x 9.4 cm extending into the right superior hilum with right hilar lymphadenopathy. Multiple small mediastinal lymph nodes and multiple bilateral pulmonary nodules were also noted. There was vascular encasement of the superior vena cava and right upper lobe pulmonary arteries and bronchi. Biopsy of an anterior mediastinal mass showed a poorly differentiated thymic carcinoma, lymphoepithelial type. Beginning in February 2009 she received a total of five cycles of chemotherapy consisting of Cisplatin, Adriamycin, and Cyclophosphamide (PAC). Following chemotherapy tumor shrinkage by > 50% was noted. In July 2009 the patient underwent surgery consisting of a median sternotomy with resection of primary thymic carcinoma. Histology of the resected specimen confirmed a diagnosis of thymic carcinoma (positive for cytokeratin AE1/AE3, p63 and CD5, negative for chromogranin, synaptophysin, and TTF-1). At present the patient is doing well and continues to recover satisfactorily after surgery.
Past Medical History: Halothane-induced hepatitis; Vertigo; Allergic rhinitis
Past Surgical History: Cesarean Section.
Medications: Furosemide, Potassium Chloride, Percocet, Metoclopramide, Colace/ Senna/ Milk of Magnesia, Ondansetron, Scopolamine patch, Ibuprofen, Mometasone
(Nasonex), Albuterol as needed, Multivitamin, Levocetirizine (Xyzal)
Allergies: Compazine and Halothane.
Social History: No history of smoking or alcohol intake.
Family History: Mother died of metastatic carcinoma (details not known) at age 87.
Patient Advocacy – Mr. Alan Blaustein
Foundation for Thymic Cancer Research
The Foundation for Thymic Cancer Research’s mission is to support patients with thymic neoplasms by fostering research and awareness of this aggressive, difficult-to-treat, and little-understood disease. There is a very active Yahoo group where people affected in some way by thymoma or thymic carcinoma can find others to ask questions of, obtain support from, and to gain information. In addition, by registering online with the Foundation, patients and patients’ families are put in contact with Mr. Alan Neibauer. The Foundation was founded by Mr. Neibauer and his wife, Barbara, a thymic carcinoma patient. Mr. Neibauer’s focus is on patient awareness and outreach.
The Foundation is helping to create the Global Consortium for the Study of Thymic Malignancies. The goal of this organization is to focus on the advancement of clinical and basic science pertaining to thymic malignancies and related conditions. Through this group, the hope is to more aggressively undertake research projects to work towards a cure for thymoma and thymic carcinoma.
Surgery for Primary Thymomas – Dr. Frank Detterbeck
Surgery is the mainstay of treatment for thymoma, and the ability to accomplish a complete resection appears to be the most important prognostic factor. There appears to be little, if any, benefit of partial resection (debulking), whereas there is a good track record for aggressive complete resection including the central veins, pericardium and lung. Therefore, every effort must be made at the time of resection to achieve this. Variability in survival results among reports may be correlated with the experience and commitment of the surgeons to achieving a complete resection. Furthermore, thymomas are responsive to chemotherapy and RT, and surgery must be also considered in the context of a multimodality approach.
Extended resections for thymic tumors – Dr. Cameron Wright
Division of Thoracic Surgery, MGH 55 Fruit St Boston, MA, 02114
Almost all series reporting on the results of resection in thymic tumors indicate that the performance of a complete resection is probably the most important prognostic factor. This issue is not a factor in Masaoka stage I and II tumors which are almost always easily completely resected. Masaoka stage III tumors which invade the pericardium, lung or great vessels have relatively higher incomplete resection rates and significantly higher recurrence rates. Experienced thoracic surgeons can safely resect the pericardium, lung and great vessels in many cases leading to the opportunity for long-term survival. There is limited data on the outcome of pericardial or lung invasion with thymic tumors as these more mundane structures are not usually discussed other than generic stage III tumors. There are several small reports on the efficacy of resection of the great veins when involved by a thymic malignancy with low morbidity and meaningful long-term survival (one series 45% at 5 years). SVC reconstruction is commonly performed by a PTFE, venous or pericardial graft. These cases can usually be identified preoperatively and thus be considered for induction therapy. Since these types of cases are almost always of marginal respectability in terms of obtaining a true en-bloc resection, there is increasing enthusiasm for offering induction therapy in an effort to enhance respectability. Preliminary results suggest increased R0 resection rates and improved survival. The optimal induction treatment is unknown. Recurrence patterns after resection of Stage III tumors suggest the pleura is involved most commonly, followed by lung, distant sites and then (somewhat surprisingly) the local area. This recurrence pattern suggests chemotherapy, or novel strategies (such as intrapleural chemotherapy), rather than radiation therapy may be of more benefit when considering adjuvant therapies. The ultimate extended surgery for advanced thymic tumors is an extrapleural pneumonectomy (EPP) done for extensive pleural disease (Masaoka stage IVA). These rarely performed operations are done for both IVA disease found at initial presentation and for recurrent disease as a salvage procedure. Our own small series of 5 patients who required EPP had a 5 year survival of 75%. Again these advanced patients are probably best managed by induction chemotherapy followed by resection.
Resection of Recurrent Thymoma – Dr. Marco Lucchi and A. Mussi
Cardiac and Thoracic Department – Division of Thoracic Surgery. Azienda Ospedaliero-Universitaria Pisana; Pisa
Thymomas are neoplasms arising from the epithelial thymic cells. These tumors rarely metastasize distantly; on the contrary, they can show pleural implants or local relapse more frequently during follow-up. Recurrence after complete resection of thymoma ranges from 5% to 40% according to the initial stage of disease. Pleural relapses are the most frequent (about 50% of the cases) while distant metastases occur in less than 5% of the cases. A complete surgical resection is still the cornerstone of the therapy of thymic tumours; on the contrary there is no standard treatment for the recurrent disease. The three most important predictors of recurrence after thymoma resection are stage of disease at the moment of the first treatment, World Health Organization (WHO) histologic classification, and completeness of resection. Data in the literature show that recurrences can also occur several years after the resection of a thymoma; unfortunately, few reports have analyzed the treatment of recurrences of thymoma.
Because of the relative rarity of thymomas, most of the treatments proposed by the authors are based more upon their personal experience and individualized treatment than upon an evidence-based method.
Moreover, most series concerning surgery for recurrent thymomas suffer from a selection bias: patients with limited disease and better performance status are usually selected for surgery, with an anticipated survival advantage in the surgical group.
Thymomas are very sensitive to radiation, but adjuvant radiotherapy after thymoma resection does not decrease the incidence of pleural or distant relapses inasmuch as the implants are set out of the radiation field. Surgery for recurrent thymoma is surely indicated if complete resection is feasible, while in case of predicted debulking surgery it may be considered as part of a multidisciplinary protocol.
The surgical approach depends on the site of the recurrence with re-sternotomy, thoracotomy, double thoracotomy, hemi-clamshell, clamshell, VATS already described. Also the invasiveness of the operation depend on the entity of the relapse, with simple resection of the implant or metastasis, radical pleurectomy-decortication (PD) and even extrapleural pneumonectomy (EPP) offered in selected cases. Aiming to improve the local control of the disease hyperthermic intrapleural chemotherapy or low-dose hemithorax radiotherapy have been associated to the surgical treatment. In literature a few case reports about the surgical treatment of metachronous liver or brain metastasis of thymoma have been described, but they are rare and a decision about their treatment is always on a single patient basis.
We can conclude that reoperation for thymoma recurrences is feasible and relatively safe. Which kind of operation should be performed in case of a pleural relapse from thymoma is a question without answer and the choice is still based on the status of the disease, on the status of the patient, and on the policy of the surgeon.
The take-home message is this: Do not give up in this indolent disease. Always consider a re-resection, because, up to now, everything else is based on speculation and theory.
Conditional overall survival and conditional cause specific survival of thymoma patents: An analysis of 1,792 cases from the SEER registry (1988-2006) – Dr. Charles Thomas Jr.
Kim E, Fuller CD, Housman D, Wang SJ, Thomas CR Jr. Background: Thymomas are rare and there are few thymoma studies with large population sets. The specific aim of this study was to study the 5-year conditional overall survival (OS) and cause specific survival (CSS) of a large population of thymoma patients.
Methods: The entire cohort comprised of 1,792 cases of cancer in the thymus extracted from the Surveillance, Epidemiology, and End Results (SEER) registry from 1988 to 2006, which were reclassified to Masaoka staging. OS and CSS were determined by the Kaplan-Meier method using SPSS 13th Edition, and conditional analysis was calculated using these results and the formula CS(y|x)=S(x+y)/S(x) where S(x) is Kaplan-Meier survival at time x and CS(y|x) is the probability of surviving y years given already survived x years.
Results: The total 1,792 cases were restaged into the following stage groups: Stage 1 (305, 17.0%), Stage 2 (193, 10.8%), Stage 3 (414, 23.1%), Stage 4 (247, 13.8%), Unknown stage (633, 35.3%). The mean age was 58, ranging from 8 to 94. The male to female ratio as 1.17.
|
5-Year Conditional OS |
Year 0 |
1 |
2 |
3 |
4 |
5 |
|
Stage 1 |
.818 |
.839 |
.851 |
.870 |
.886 |
.872 |
|
Stage 2 |
.831 |
.837 |
.859 |
.833 |
.812 |
.739 |
|
Stage 3 |
.661 |
.722 |
.715 |
.730 |
.732 |
.725 |
|
Stage 4 |
.487 |
.531 |
.597 |
.652 |
.675 |
.694 |
Conclusion: Five-year conditional OS increased then decreased in all stages; but 5-year conditional CSS gently decreased except stage 4, which increased then plateaued.
Edward S. Kim
A majority of patients will present with a localized tumor in which surgical resection is the standard procedure of choice. The addition of adjuvant radiotherapy may improve local disease control. In more advanced and recurrent disease, systemic chemotherapy produces objective response rates of 50% to 80%. Therefore, complete surgical resection is an important factor for locally advanced malignant thymoma, making it critical to convert locally advanced unresectable tumors (stage III and IVA) to resectable ones. However, complete surgical resection of advanced tumors is not feasible because of local invasion into mediastinal structures including major blood vessels, the pericardium, or other vital structures. The use of induction chemotherapy to optimize surgical resectability of thymoma followed by radiation therapy and consolidation chemotherapy lead to good control of residual disease and high overall survival rates. We designed a prospective study using a multimodal treatment regimen consisting of chemotherapy surgery, and radiotherapy to improve tumor resectability and to determine the disease-free and overall survival times of patients with locally advanced unresectable malignant thymoma. Consolidation chemotherapy was added to target microscopic disease that potentially recurs outside of the radiation portals. We believe that this combined multidisciplinary approach prolongs lives and may cure locally advanced unresectable malignant thymomas. Future prospective multi-institutional studies are needed to further verify or define the best treatment for this patient population.
Advanced Technology of Radiation Treatment to Reduce Normal Tissue Toxicity for Patients with Thymic Neoplasia – Dr. RITSUKO KOMAKI
Ritsuko Komaki1, Lei Dong2, Zhongxing Liao3, Mary Fran McAleer4, Edward Kim5, Joe Chang6, Michael OReilly8, James Cox9 UT M.D. Anderson Cancer Center, Houston, TX1-8
Tumors of the thymus are uncommon, and most are benign or indolent. Complete resection of the tumor should be accomplished if at all possible. Encapsulated (stage I) and minimally invasive (stage II) thymomas are virtually always resectabel unless there are medical contraindications to thoracotomy. At least 20% of obviously invasive (stage III) thymomas are unresectable. For every patient with an invasive thymoma that cannot be completely resected, definitive radiation therapy is necessary. Such tumors have a considerable propensity to disseminate within the pleural cavity and to spread beyond the thorax. Previously, prophylactic irradiation of one or both supraclavicular fossae, the entire mediastinum and both hila was recommended, although the improvement of survival from prophylactic radiation therapy was undetermined. Prophylactic hemithoracic radiation therapy has been done by intensity modulated radiation therapy (IMRT) to reduce local recurrence with minimal toxicity. However, prophylactic radiotherapy has been minimized because of more frequent and efficacious application of adjuvant chemotherapy. The dose required to control invasive thymoma is not clear. A total dose of 50 Gy or higher after complete tumor resection had less recurrent disease compared to less total dose. When only a partial resection or biopsy is performed, higher total doses are advisable. Although the published experience is not sufficient to know the control rate at total doses of 60 Gy and above, the substantial failure rate at lower doses suggests that the total dose should be as high as can be tolerated by the surrounding normal tissues. Since majority of patients with thymoma are young and live long enough to manifest late normal tissue toxicity such as lung fibrosis and or cardiac toxicity. This is one of the reasons why unresectable thymoma was not treated by adequate dose or volume. Recently, we are able to use IMRT or proton to reduce normal tissue toxicity to prolong their survival with better quality of life which will be presented.
Thymoma and antibody-mediated CNS syndromes – Dr. Angela Vincent
Angela Vincent, Sarosh Irani and Bethan Lang
Department of Clinical Neurology, University of Oxford, Oxford, OX3 9DU, UK
Myasthenia gravis is the neurological disorder most commonly associated with thymomas, but there are central nervous system (CNS) disorders that also associate with this tumour. In the 1990s patients with the peripheral nerve hyperexcitaibility syndrome, acquired neuromyotonia, were shown to have antibodies to voltage-gated potassium channels (VGKCs) measured by immunoprecipitation of radioactively-labelled VGKCs from detergent extracts of rabbit brain tissue. About 20% of these patients had thymomas (and a few also had myasthenia gravis). From that time, we have increasingly detected high titres of VGKC antibodies in patients with limbic disturbance (Vincent et al 2004), with isolated epilepsy (Irani et al 2008), and with Morvans syndrome (Irani et al in preparation). Recently, we have shown that Morvans syndrome and thymoma are strongly associated with an antibody to CASPR2, a protein that forms part of the VGKC complex. CASPR2 antibodies and thymomas are infrequent in limbic encephalitis. Although relatively rare, the co-occurence of CASPR2 antibodies and Morvans syndrome suggests that there is a direct link between the two. There is also a recent report of AMPA receptor antibodies associated with cases of limbic encephalitis and thymoma (Lai et al Ann Neurol 2009 on line).
The role of cytology in the diagnosis of thymic neoplasms. – Dr. Maureen Zakowski
M.D. Department of Pathology Memorial Sloan-Kettering Cancer Center New York, NY USA
The use of fine needle aspiration cytology to diagnose mediastinal lesions is well established. Fine needle aspiration cytology can accurately diagnose thymic neoplasms, both thymomas and thymic carcinomas. It is also and effective means of establishing the presence of metastases. It is less effective in subtyping thymomas. The efficacy and problems associated with cytologic sampling of thymic tumors is discussed.
Comprehensive genomic analysis reveals clinically relevant molecular distinctions between thymic carcinomas and thymomas – Dr. Nicolas Girard
Nicolas GIRARD1, Ronglai Shen2, Tianhua Guo3, Maureen F. Zakowski3, Adriana Heguy4, Gregory J. Riely5, James Huang6, Christopher Lau1, Alex E. Lash7, Marc Ladanyi1,3, Agnes Viale8, Cristina R Antonescu3, William D. Travis3, Valerie W. Rusch6, Mark G. Kris5,9, William Pao1,5,9
Background: Because of their rarity, current knowledge about the biology of thymic tumors is limited, and extensive molecular studies have not yet been performed. Methods: Frozen tumor specimens were analyzed using array comparative genomic hybridization (aCGH), mRNA expression profiling, and mutational profiling of selected genes (EGFR, KIT, TP53, KRAS, HRAS, NRAS, BRAF, PIK3CA, AKT1, ERBB2, and MEK1). For immunohistochemical studies, a tissue microarray was constructed using matched formalin-fixed, paraffin-embedded tumor tissue samples. Results: We analyzed 21 thymomas (type A n=5, type B2 n=14, type B3 n=2), and 6 thymic carcinomas. Regarding the EGFR signaling pathway, high EGFR staining was associated with stage III-IV tumors (p=0.021, Chi-2 test), and somatic RAS mutations were identified in 2 of 27 tumors: one KRAS G12V mutation in a thymic carcinoma, and one HRAS G13V mutation in a type A thymoma. We also assessed the status of KIT. Two thymic carcinomas displayed strong staining with an anti-KIT antibody. Only these two KIT-positive cases harbored somatic KIT mutations (one V560del and one H697Y). The growth of stable Ba/F3 transfectants expressing the V560del mutant was readily inhibited by imatinib and sunitinib. Gene expression profiling was possible on 23 tumor specimens. Unsupervised hierarchical cluster analysis of gene expression data revealed 2 major groups: cluster 1 (n=8), associated with B2 histology, and cluster 2 (n=15), associated with thymoma type A and thymic carcinoma (p=0.023, Chi-2 test). Hierarchical clustering analysis of aCGH data generated 2 distinct clusters: cluster 1 (n=17) was associated with thymomas and characterized by infrequent copy number alterations, whereas cluster 2 (n=10) was associated with thymic carcinoma (p<0.001, Chi-2 test) and showed multiple chromosomal aberrations. Conclusion: Thymic carcinomas are genetically distinct from thymomas and should be considered as a separate entity for therapeutic trials. Additional analyses on more tumors are currently ongoing and will be presented at the meeting.
Therapy for thymoma and thymic carcioma in Japan. – Prof. Kazuya Kondo
Department of Oncological Medical Services, Institute of Health Biosciences, The University of Tokushima Graduate School
Thymic epithelial tumor is the most common tumor of the anterior mediastinum. Thymic epithelial tumors mainly consist of thymoma, thymic carcinoma, and thymic carcinoid. Thymic carcinoma and carcinoid are very rare neoplasms. Due to the relative rarity of the thymic epithelial tumor, only series with small numbers of patients have been published so far.
We sent a questionnaire on thymic epithelial tumors to 185 institutes certificated as special institutes by The Japanese Association for Chest Surgery, and received replies from 115 institutes (62%). We compiled records of 1,320 patients with thymic epithelial tumors who were treated between 1990 and 1994.
Thymic epithelial tumors consisted of 1,093 thymomas (83%), 186 thymic carcinomas (14%), and 41 thymic carcinoids (3%). Myasthenia gravis was associated with 270 cases (25%) of thymoma. Final pathologic staging was perfomed based on Masaoka’s staging system. In thymoma, 48% patients were in stage I, 23% in stage II, 19% in stage III, 7% in IVA, and 3% in IVB. Most of patients with stage I thymoma underwent only surgery. About half of the patients with stage II thymoma and three-fourths of the patients with stage III thymoma underwent surgery with adjuvant therapy. Most of the adjuvant therapy in stages I, II, and III thymomas consisted of radiotherapy. Seventy percent of patients with stage IV thymoma underwent surgery with adjuvant therapy. In more than half, adjuvant therapy included chemotherapy. The resectability rates of stage I, II, III, and IV thymomas were 100%, 100%, 85%, and 42%, respectively. The recurrence rates in stages I, II, III, and IV were 1%, 4%, 28%, and 34%, respectively. The 5-year survival rates of stage I, II, III, IVA, and IVB thymomas were 100%, 98%, 89%, 71%, and 53%, respectively. A clear-cut distinction of survival rates between stage I and II thymomas is not always feasible, whereas the distinctions between stage II and III and stage III and IV thymomas are more obvious. Masaoka clinical stage is an excellent indicator predicting the prognosis of thymoma.
The 5-year survival rates for thymoma, thymic carcinoid, and thymic carcinoma, including inoperable cases, were 94%, 84%, and 51%, respectively. Sixty percent of thymic carcinoma is squamous cell carcinoma. In thymic carcinoma, 5% patients were in stage I, 6% in stage II, 39% in stage III, 14% in IVA, and 33% in IVB. Fifty-one percent of patients with carcinoma underwent a total resection, and 51% of patients developed recurrence. Fifty-eight percentage of patients with carcinoma underwent surgery with adjuvant therapy. In more than half, adjuvant therapy included chemotherapy. The 5-year survival rates of stage I plus II, III, and IV thymic carcinoma were 88%, 52%, and 38%, respectively.
Total resection of the tumor is the most important factor in survival rate in invasive thymoma and thymic carcinoma. The 5-year survival rates of total resection, subtotal resection, and inoperable groups were 93%, 64%, and 36%, respectively, in III and IV thymoma. There were significant differences in survival rate among the three surgical types. Subtotal resection of invasive thymoma may yield a surprisingly high survival rate compared with inoperable cases, including partial resection or biopsy. On the other hand, in thymic carcinoma, the 5-year survival rates of total resection, subtotal resection, and inoperable groups were 67%, 30%, and 24%, respectively. No significant difference in survival rate between the subtotal resection and inoperable groups was observed. These data suggest that there is a value of so-called “debulking procedures” in invasive thymoma, but not in thymic carcinoma.
The recurrent rates of completely resected stage II and III thymomas were 4.7% and 23% in patients with postoperative radiotherapy and 4.1% and 26% in patients without radiotherapy, respectively. We doubt that postoperative radiotherapy is valuable in patients with totally resected stage II and III thymoma, although we believe in the value of postoperative radiotherapy in patients with incompletely resected stage II and III thymoma.
In conclusion, complete resection is the most important factor in the treatment of thymic epithelial tumor. the Masaoka clinical stage is an excellent indicator predicting the prognosis not only of thymoma but also of thymic carcinoma. Lymph node metastasis strongly influenced the survival in patients with thymic carcinoma compared with those with thymoma. Prophylactic radiotherapy can not prevent local recurrence effectively in patients with totally resected stage II and III thymoma. There is a value of so-called “debulking procedures” in invasive thymoma, but not in thymic carcinoma.
Chemotherapy for thymic malignancies- Patrick J. Loehrer, Sr., MD.
Indiana University Melvin and Bren Simon Cancer Center.
Thymomas and thymic carcinomas are rare epithelial tumors arising from the thymus gland. These are the most common tumors of the anterior mediastinum. Prospective studies on the treatment of thymic epithelial tumors are very limited due to the very low incidence of these tumors. Multimodality
Surgery is the mainstay of treatment for most thymic tumors, but up to one third of patients with thymoma and the majority of patients with thymic carcinoma will have locally advanced or metastatic disease that requires systemic agents as part of the therapy. The most active agents appear to be cisplatin,144 corticosteroids,145,146 doxorubicin147 and alkylating agents, but the clinical trials with single agents remains limited. Only in the last 10 to 20 years have prospective trials been initiated to evaluate the role of chemotherapy in thymic malignancies. Prospective trials include evaluation of drugs such as Ifosfamide, octreotide (with or without prednisone), gefitinib, imatinib, pemetrexed. Most combination regimens have been platin-based with cisplatin, doxorubicin and cyclophosphamide (PAC) with or without other agents, cisplatin plus etoposide (PE), or carboplatin plus paclitaxel as commonly used regimens. Investigational trials have looked at other combination regimens, but anthracycline-based therapies appear to be associated with the highest response rates. While it is clear that combination chemotherapy clearly has an impact on patients with advanced disease, the optimal regimen and timing of chemotherapy has not yet been determined. This presentation will provide an overview of the past clinical trials and discuss issues relevant to future clinical and translational research.
TARGETED THERAPIES IN THYMIC NEOPLASMS- Giuseppe Giaccone
Arun Rajan, National Cancer Institute, Bethesda, MD, USA
There is very little known about the biology of thymomas in general, with very few studies looking at genetic alterations. It is commonly appreciated that better differentiated tumors possess little or no alterations, as detected by CGH, whereas more complex genetic alterations are present in undifferentiated tumors, such as thymic carcinomas. A few studies have looked at specific targets by immunohistochemistry or mutation analysis, but so far none have been recognized as potential targets for treatment.
Given the rarity of this disease, clinical studies have also been few and sparse, using so-called “targeted agents”. The first example of targeted therapy is with octreotide. In patients with a somatostatin positive scan, response to octreotide was 10.5%, and 31.6% when combined with prednisone (Loehrer et al JCO 2004). Responses were only seen in thymomas and were of relative short duration.
Two clinical studies have been performed with imatinib mesylate, which targets c-kit. One study included 7 patients (Giaccone e al JTO in press) with B3 and C type thymomas; the other included 11 patients with thymic carcinoma with c-kit expression od PDGFRA expression (Salter et a. ASCO 2008). No responses were observed. C-kit is known to be overexpressed in particular in thymic carcinomas, but has low expression in thymomas. Mutations have so far been only sporadically seen in a couple of patients with thymic carcinomas who had a response on imatinib in case reports, and in the first study no mutations were found in 3 tested. The real incidence of c-Kit mutations needs to be assessed using sensitive techniques in a large population. Potentially the selection of patients with c-kit mutations might be of interest for further studies.
We performed a phase II study of Belinostat, an HDAC inhibitor with activity in cutaneous T cell lymphoma and other hematological malignancies. Of a total of 32 patients enrolled so far, we observed two major responses in thymomas, but none in thymic carcinomas. We also observed a large number of patients with thymomas who enjoyed a prolonged stabilization of disease (over one year). Belinostat is being moved to front-line chemotherapy in combination with PAC chemotherapy. The study will open by the end of 2009 in multiple centers.
IGF1R is potentially an interesting target, especially for more undifferentiated tumors, where expression of this receptor is higher (Petrini et al, Girard et al, abstracts at this meeting). A phase II study is starting shortly with IMC-A12.
Inhibitors of EGFR have been tested. A phase II of gefitinib has been presented: one partial response of 5 month duration was observed in 26 patients evaluable for response (Kurup et al. ASCO 2005). A combination of erlotinib and bevacizumab did not have major activity in 18 patients (Bedano et al. ASCO 2008). Expression of EGFR has been mainly associated with thymomas, but no activating mutations have so far been described.
Sporadic reports of responses have been published as case reports or as part of phase I studies with several targeted agents. A more systematic study of the biology of this tumor and its genetic make-up will likely lead to a more rationale design of phase II studies in this rare disease.
Dr. Gregory Riely
Achieving a complete resection remains the key to treatment of locally advanced thymoma. Complete resection in patients with locally advanced, up to stage IVA thymoma, is generally possible in only 60-70% of cases. A multimodality approach incorporating induction chemotherapy prior to surgery may improve resectability and outcomes in locally advanced thymoma. Chemotherapy response rates in this setting range from 47-100% utilizing a variety of different regimens. To optimize the opportunity for surgical resection, we are exploring the addition of targeted therapies to chemotherapy in the neoadjuvant setting. Overexpression of EGFR protein in thymoma is frequent. Cetuximab is a monoclonal antibody to EGFR that has demonstrated activity in patients with multiple EGFR expressing cancers. This led us to hypothesize that induction therapy with cetuximab and cytotoxic chemotherapy may improve response rates, resectability, and pathologic complete response rate in patients with advanced thymoma.
To test this hypothesis, we will evaluate the combination of cetuximab with cisplatin, doxorubicin, and cyclophosphamide (CAP) chemotherapy in the neo-adjuvant setting.
Eligible patients will have locally advanced thymoma and be fit to receive combination chemotherapy. The patients enrolled in the trial will undergo treatment initially with cetuximab (C) alone. Following 4 weeks of therapy with cetuximab alone, patients will have a repeat CT scan performed and then begin chemotherapy with intravenous cisplatin, doxorubicin and cyclophosphamide every 21 days along with concurrent weekly cetuximab (C-CAP). C-CAP will be repeated every 21 days for 4 cycles. Radiographic response will be determined by CT scan after 2 and 4 cycles of C-CAP. All patients without evidence of extrathoracic spread of disease who are fit for surgery will then undergo surgical resection with the goal of a total thymectomy and a complete R0 resection. The primary endpoint will be frequency of near-complete pathologic response (<10% residual tumor cells).
Mortality and morbidity patterns among 681 thymoma patients diagnosed in Sweden: a population-based study – Dr. Ola Landgren
Ola Landgren1, Shahinaz Gadalla2,3, Arun Rajan1, Sigurdur Kristinsson4, Magnus Bjorkholm4, Giuseppe Giaccone1
1 Medical Oncology Branch and 2 Clinical Genetics Branch, National Cancer Institute, Bethesda, Maryland, USA; 3Cancer Prevention Fellowship Program, National Cancer Institute, Bethesda, Maryland, USA; 4 Department of Medicine, Karolinska Institute, Stockholm, Sweden
Background. A limited number of smaller studies have evaluated outcomes in thymoma patients following therapeutic intervention (systemic chemotherapy, targeted therapy and radiation therapy). We have conducted the first large population-based study designed to quantify mortality and morbidity patterns in thymoma.
Methods. Using the high-quality Swedish Cancer Registry, we identified 681 thymoma patients (median age 59 years; 47% males) diagnosed 1958-2004 and with a median follow-up of 10.2 years. We also used the Swedish Population Registry to identify 2,719 population-based matched controls (up to 4 controls per thymoma patient). For both thymoma patients and controls, we obtained information on comorbidity through record-linkage with the nationwide Hospital Inpatient/Outpatient Discharge Registry. We constructed Kaplan-Meier curves and applied log-rank tests to test for survival differences between thymoma patients versus controls. Also we fit Cox proportional hazards models and computed standardized incidence ratios as measures of risk for second tumors following thymoma.
Results. Compared to controls, thymoma patients had a significantly (p<0.0001) poorer 5-year (70% vs. 91%), 10-year (56% vs. 78%), and 20-year (34% vs. 55%) overall survival. When we compared overall survival rates for thymoma patients diagnosed at three calendar intervals (1958-1972, 1973-1987, and 1988-2004) there was a significant (p<0.001) improvement over time. Further, when we assessed survival patterns for thymoma patients by age, we found 5-year, 10-year, and 20-year overall survival to be significantly (p<0.0001) better for younger patients (<41 years: 75%, 69%, 56%; 41-60 years: 76%, 66%, 45%; 61+ years: 62%, 42%, 12%). In analysis stratified by sex, we found male thymoma patients to have a significantly (p<0.007) poorer 5-year (66% vs. 73%), 10-year (50% vs. 62%), and 20-year (30% vs. 40%) overall survival than female thymoma patients. There were 225/681 (33.4%) thymoma patients with a hospital discharge diagnosis of autoimmunity; the most frequent autoimmune diseases were myasthenia gravis 164/681 (24.1%), systemic lupus erythematosus 16/681 (2.3%), and red cell aplasia 8/681 (1.2%). Among thymoma patients with a diagnosis of myasthenia gravis (females:males=1.2:1), the vast majority (156/164; 95.1%) were diagnosed around (within 1 year) or after (up to 38.2 years) diagnosis of thymoma. When we quantified risks for second tumors, compared to controls, male thymoma patients had a 2.6-fold (95% CI 1.5-4.6) elevated risk for prostate cancer, and, based on small numbers (n=5), female thymoma patients had a 4.1-fold (95% CI 1.3-9.4) increased risk for non-Hodgkin lymphoma. Further, male and female thymoma patients had a 4.9-fold (95% CI 2.1-11.0) and 3.5-fold (95% CI 1.5-8.0) elevated risk for non-melanoma skin cancer, respectively.
Conclusions. Although we found improved survival for thymoma patients over time, on average, thymoma patients still have a 20% lower overall survival than matched controls. The observed varying survival patterns for male versus female thymoma patients suggest there might be disease heterogeneity by sex. We found about a third of the thymoma patients to have a discharge diagnosis of autoimmunity. Myasthenia gravis was the most common autoimmune disease and almost all cases were found around/after thymoma diagnosis. Finally, our study did not show broadly excess risks for solid or hematologic malignancies following a diagnosis of thymoma.
Poster Abstracts
Molecular classification of Thymomas – Dr. Sunil Badve
S Badve, R Nelson, Y Lui, Q Zhou, Y Gokmen-Polar, J Henley, N Zaheer, M Thorat, Nicholas J. Miller, , R Jain, OW Cummings, K Kessler, G Sledge, P Loehrer.
Background: Thymomas are rare tumors that are difficult to classify and prognosticate. The current classifications are based on intra-operative findings (intact capsule), success of surgery, histology (Muller-Hermelick; WHO subtypes) and stage of tumor. However, all of these are associated with significant shortcomings. In this study, we attempt to develop a molecular classification and correlate the sub-types with clinical behavior.
Methods: Thirty-seven fresh frozen thymic tumors and two normal pediatrics thymuses were available for analysis. The histology from these cases was reviewed by 2 pathologists (SB & JH) and tumors were re-classified as per WHO classification. The cases were then grouped in 4 categories: Normal; A & A/B; B1 & B2; B3 & C. RNA was extracted using Qiagen kits and quantified by nanodrop. 200 ng of cDNA was used to determine whole-genome gene expression (24,000 transcripts) using cDNA Annealation Selection and Ligation (DASL™) technique using the protocol described by the manufacturer (Illumina®). The data obtained was analyzed using PAM software and the cluster analysis was performed to identify subtypes
Results: A classifier using ~ 1500 genes could sub-classify tumors into 4 distinct categories. Expression of 962 genes was associated with stage of tumors and 325 genes predicted likelihood of relapse. Of these, 11 genes predicted both stage and likelihood of relapse. Some of these genes included genes associated with interferon, prostaglandin receptor family as well as solute carrier family. Additional analyses for correlation of molecular subtypes with stage of disease, relapse and response to chemotherapy are currently being performed.
Conclusions: The gene expression analysis revealed 4 distinct classes of thymomas. It is hoped that this might provide additional insights into the biology of disease as well as offer novel therapeutic targets.
Prevalence and spectrum of anticytokine autoantibodies and opportunistic infection in thymoma patients – Dr. Sarah Browne
Sarah K. Browne1, Peter D. Burbelo2, Elizabeth P. Sampaio1, Kathyrn H. Ching2, Arun Rajan3, Ervand Kristosturyan1, Giuseppe Giaccone3, Michael J. Iadarola2, Steven M. Holland1
1National Institute of Allergy and Infectious Diseases, 2National Institute of Dental and Craniofacial Research, 3National Cancer Institute Background Anti-cytokine autoantibodies are increasingly recognized as important in disease pathogenesis. Examples include pure red-cell aplasia (anti-erythropoietin autoantibodies), pulmonary alveolar proteinosis (anti-GM-CSF autoantibodies), and opportunistic infections associated with anti-interferon (IFN) gamma autoantibodies. Anti-cytokine autoantibodies are seen frequently in thymoma, although the prevalence, functional significance, and spectrum of these autoantibodies in differing clinical states are largely undefined. Methods Using the luciferase immunoprecipitation system (LIPS) we have screened plasma samples from patients with thymoma (17) and blood bank controls (30) for anti-cytokine autoantibodies. Using immunoblot, flow cytometry and gene expression analysis; the functional significance of some of these autoantibodies was characterized in vitro. Results Out of 17 patients with thymic neoplasm (7 with thymic carcinoma; 10 with thymoma) 10 had autoantibodies. Although the majority of patients with autoantibodies had thymoma, 2 patients with thymic carcinoma had multiple autoantibodies. Five of the 17 patients have had opportunistic infections, all of whom had > 4 anti-cytokine autoantibodies. Infections included disseminated varicella zoster (2), chronic mucocutaneous candidiasis (3), disseminated Cryptococcus (1), Mycobacterium avium complex (1) and Scedosporium apiospermum (1). Two of the 6 patients had more than one opportunistic infection. In thymoma patients we identified autoantibodies against IFNs alpha, beta, omega, and lambda, interleukins (IL)-1 alpha, IL-6, IL-12 p40, IL-12 p35, IL-17, APRIL, and EBI-1 but none to IFN gamma, epsilon, IL-1β, IL-2, IL-7, IL-8, IL-15, TGF beta, Fas ligand, erythropoietin, G-CSF or GM-CSF. The autoantibodies to IFN alpha prevented phosphorylation of STAT-1 and STAT-4 and abolished gene expression induced by IFN alpha1 in normal PBMCs and monocytes in vitro; autoantibodies to IL-12 p35 but not p40 prevented IL-12p70 mediated STAT-4 phosphorylation. Conclusions and Future Directions Anti-cytokine autoantibodies occur in many diseases. Multiple autoantibodies against cytokines are common in thymoma. Anti-IFN alpha and anti-IL-12 p35 autoantibodies block biologic activity in vitro; the other autoantibodies are under study with functional bioassays. Anti-cytokine autoantibodies may be causally associated with the clinical phenotype of thymoma, potentially through the modulation of specific immune pathways.
Arlene Berman, RN for help with patient recruitment. This work was supported by the Division of Intramural Research, NIAID
Unveiling STAT3 as molecular target for malignant thymoma – Dr. Angelo Cardoso
Oscar Cano, Kenneth Fearn, Yesim Polar, Jixin Ding, Yunlong Liu, Ken Kesler, George Sledge, Sunil Badve, Patrick Loehrer Sr., Angelo A. Cardoso
Indiana University School of Medicine, IU Simon Cancer Center, Indianapolis, IN
Specific therapies for thymic epithelial cancers are lacking, and studies on the identification and validation of molecular targets for these malignancies are greatly needed. Using a new thymoma cell line (IU-TAB1), we developed a pharmaco-functional screening in which >90 specific antagonists of major signaling/metabolic pathways were assessed for their impact on thymoma survival and proliferation. This screening revealed 16 compounds that markedly inhibit thymoma cells, with at least 50% reduction of proliferation. We started by performing proof-of-concept studies focusing on STAT3, since its blockade showed potent inhibitory effects in our screening. Molecular studies showed that IU-TAB1 cells exhibit constitutive activation of STAT3 (Tyr705-phosphorylation), without STAT1 or STAT5 activation. STAT3 transcriptional activation was shown in a luciferase reporter assay, and by transcriptional modulation of STAT3 target genes (Survivin/Bcl-xL/c-Myc). In IU-TAB1 cells, STAT3 activity is insensitive to confluency status, but is abrogated by serum starvation. Interestingly, STAT3 activation is markedly upregulated by hypoxia, which is significant as these cancers develop under low oxygen tension. STAT3 activation was seen also in cells from thymic tumors of Tim1 mice, a strain that develops spontaneous thymoma. Functional studies using STAT3 inhibitors STATTIC and S31-201, and Jak inhibitor WP1066 showed that these agents markedly inhibit IU-TAB1 proliferation, with STATTIC showing the most potent activity (IC50: 2.5-5mM). STATTIC inhibits STAT3 phosphorylation in a dose-dependent manner in IU-TAB1 and Tim1-derived thymoma cells. Interestingly, STATTIC inhibited thymoma luminal-like morphogenesis in synthetic matrices, and mechanistic studies indicate that STAT3 blockade results in cell apoptosis. Studies are underway to determine the putative prognostic value of STAT3 on thymic epithelial cancers, and to assess the anti-tumor efficacy of STAT3 inhibitors in a xenograft model of human thymoma. In summary, our studies suggest that STAT3 signaling play a significant role in malignant thymoma biology and indicate STAT3 signaling as a potential molecular target for these cancers.
Establishment and characterization of a novel cell line derived from human thymoma A/B tumor-Dr. Yesim Gokmen-Polar
Yesim Gökmen-Polar1, Kerry L. Sanders1, Qianqian Zhao2, Yunlong Liu2, Gail H. Vance3, Narjis A. Zaheer4, Kenneth A. Kessler5, Robert P. Nelson, Jr.1, Sunil Badve1,4, Patrick J. Loehrer, Sr.1, George W. Sledge, Jr.1,4
Departments of 1Medicine, 2 Biostatistics, 3Medical and Molecular Genetics, 4Pathology and Laboratory Medicine, and 5Surgery, Indiana University School of Medicine, Indianapolis, IN
Background: Thymomas are low-grade epithelial tumors of the anterior mediastinum. The complexity of the disease and the lack of effective models hamper the development of better therapeutics. In this study, we report a novel cell line, designated as IU-TAB-1, which was established from a patient with the stage II thymoma (WHO type A/B).
Methods: We characterized this cell line in comparison to the primary tumor using histological and immunohistochemical staining for epithelial and lymphoid markers. Further characterization of IU-TAB-1 cell line included cytogenetic analysis and an in vivo NOD/SCID xenograft model. We performed Illumina Whole Genome – cDNA- annealing, selection, and ligation (DASL) assay and compared the IU-TAB-1 cells in vitro with in vivo IU-TAB-1 tumors as well as with 37 primary thymomas.
Results: The IU-TAB-1 cell line demonstrated morphologic and immunohistochemical features of epithelial tumor cell lines. Cytogenetic analysis revealed a complex karyotype with multiple numerical and structural abnormalities. IU-TAB-1 cells implanted with Matrigel in vivo reached the tumor volume of 1000 mm3 faster at 130 days after implantation compared to the cells implanted alone (148 days). IU-TAB-1 (in vitro and in vivo) co-clustered with 6 of the 37 thymomas analyzed. Molecular characterization of IU-TAB-1 cells revealed that 1449 genes are significantly different (FDR<=0.10) in both set 1 [cells in vitro vs. Matrigel in vivo (1449/1587)] and set 2 [cells in vitro vs. cell in vivo(1449/6521)], while no significant differences were observed for set 3 (cells in vivo vs. Matrigel in vivo). Detailed pathway analysis and identification of specific targets are underway.
Conclusions: We established and characterized a novel cell line from a thymoma A/B patient.Our results suggest that this cell line will provide a new tool to investigate the molecular pathology of this malignancy and evaluate the efficacy of novel therapeutics both in vitro and in vivo.
Gene Methylation Pattern in Thymic Epithelial Tumors-Dr. Elisabetta Kuhn
Kuhn E1, Corvalan A1,2, Kim E2, Moran CA1, Wistuba I1,2
Departments of Pathology1, and Thoracic/Head and Neck Medical Oncology2, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
(Supported by in part by the Foundation for Thymic Cancer Research).
Background: Tumorigenesis is the result of modified pattern of gene expression caused by a combination of genetic and epigenetic alterations. Epigenetic are modifications of gene expression without alteration of the primary DNA sequence such as genomic DNA methylation and histone modification. Of these two, the better characterized epigenetic abnormality in cancer is the aberrant hypermethylation of promoter region CpG islands. Few studies have investigated the methylation in thymic epithelial tumors. The aim of this study was to examine the DNA methylation profiles of thymic epithelial tumors and adjecting thymus.
Material and Methods: We analyzed the DNA methylation status of nine cancer-related genes (MGMT, p16, SPARC, RPRM, AXIN2, DKK1, SFRP2, SFRP5 and WIF1) in 114 primary thymic epithelial tumors, and adjacent thymus obtained from patients that underwent to thymectomia for thymic tumor, including 94 thymomas and 20 thymic carcinomas. We also performed immunoistochemical analysis of protein expression of p16, DKK1, SFRP2, SFRP5 and SPARC.
Results: Our findings are as follows: (a) Methylation rates of the nine genes examined in thymic epithelial tumors were MGMT 21%, p16 32%, SPARC 36%, RPRM 19%, AXIN2 55%, DKK1 65%, SFRP2 70%, SFRP5 71%, and WIF1 5%; (b) a lower frequency of methylation was present in adjacent nonmalignant thymus for some of the genes analyzed AXIN2 40%, DKK1 42%, SFRP2 47%, and SFRP5 58%; (c) AXIN2, DKK1 and SFRP2 methylation rates were significantly higher in tumors compared with adjacent nonmalignant thymus (P=0.0155, P=0.0004, and P=0.0008 respectively); and, (d) significant difference of SPARC methylation was detected between thymomas and thymic carcinomas (p=0.0005).
Conclusions: Our results suggest that aberrant methylation of specific genes, including genes from WNT pathway (AXIN2, DKK1, SFRP2 and SFRP5), may be important in the pathogenesis of thymic epithelial tumors.
Molecular Characterization of EGFR and HER2 Abnormalities in Thymic Carcinoma-Dr. Elisabetta Kuhn
Kuhn E1, Tang X2, Kim E2, Moran CA1, Wistuba I1,2 Departments of Pathology1, and Thoracic/Head and Neck Medical Oncology2, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. Supported by in part by the Foundation for Thymic Cancer Research.
Background. Thymic carcinoma is an extremely rare primary thymic epithelial tumor which is distinguished from thymoma based on overtly malignant cytologic features and a rapidly ominous clinical outcome. The molecular pathogenesis of thymic carcinoma has rarely been investigated. Epidermal growth factor receptor (EGFR) and HER2 abnormalities are frequent in epithelial tumors, and they have not fully characterized in thymic carcinoma.
Material and Methods. We investigated the frequency of EGFR and HER2 copy number abnormalities using fluorescent in situ hybridization (FISH) in 20 surgically resected thymic carcinomas, and correlated those findings with the clinico-pathological features of the cases. In addition, we examined the immunohistochemical (IHC) expression of EGFR and phosphorylated (p)-EGFR and the ligand TGF- and Her2, as well as the nuclear expression of the tumor suppressor gene p53 and the proliferation marker Ki67. EGFR (exons 19 and 21) and KRAS (codon 12) mutation analysis was also performed using PCR-based sequencing from DNA extracted from the tumors.
Results. A relatively high level of EGFR (14 cases, 70%) and TGF- (20 cases, 100%) expression was detected in thymic carcinomas. EGFR amplification was detected in 1 (5%) thymic carcinoma. Her2 protein overexpression was found in 9 cases (45%) and HER2 amplification in 10 (50%) tumors. A positive correlation (85%) was detected between Her2 protein expression and gene amplification. No mutations in EGFR and KRAS were detected in the tumors examined.
Conclusion. Our data indicate that EGFR and HER2 abnormalities are frequently detected in thymic carcinomas. These findings of frequent HER2 amplification and protein overexpression suggest that these abnormalities play an important role in the pathogenesis and progression of thymic carcinoma.
1. Number and % of cases over-expressing EGFR and TGF-a.
2. Number and % of cases showing Her2 overexpression, membrane?; KRAS mutation data?; correlation data between HER2 FISH and IHC; correlation between HER2 and EGFR changes and p53 and Ki67]
* following the criteria applied in breast cancer (HER-2 protein overexpression must meet a threshold criteria for the intensity and pattern of membrane staining (2+ or greater on a scale of 0
to 3+) and for the percent positive tumor cells (greater than 10%).
Thymic epithelial tumors (TET) and paraneoplastic syndromes: an Italian multicenter analysis between 1985-2009 – Dr. Gerardina Merola
Gerardina Merola1, Giuseppe Di Lorenzo1,Liliana Montella2, Piera Federico1, Carmela Merola3, Luigi Petillo1, Davide Leopardo1, Amelia Evoli4, Mirella Marino5, Martina Imbimbo1, Elide Matano1, Giovannella Palmieri1.
1)Dept of Molecular and Clinical Endocrinology and Oncology, Federico II University, Naples, Italy; 2) Medical Oncology Unit San Giovanni di Dio Hospital, Frattaminore, Naples, Italy 3)Unit of Oncology, Hospital Villa Maria, Mirabella Eclano, Italy 4) Dept. of Neurosciences, Catholic University of Rome, Italy; 5)Dept. of Pathology,Regina Elena National Cancer Institute, Rome, Italy; PURPOSE. Old data have shown that prognosis of Thymic epithelial tumors (TET) is related to stage of disease. However there is a variability among patients with same stage, grade and receiving similar treatment. We have reviewed paraneoplastic syndromes (PS) in patients with TET to analyze its prognostic role. PATIENTS AND METHODS. The medical records of 98 patients with TET treated at our Italian instititution were retrospectively reviewed. All patient-characteristics were specifically scrutinized and prognostic role of PS (lymphopenia, hypogammaglobulinemia and myasthenia) were evaluated. RESULTS. Between January 1985 and January 2009, 98 patients (57 men and 41 women, median age 60 years, range 37-78) were included in this analysis. 25, 8 and 65 patients were stage I-II, III and IV according WHO staging, respectively. Among 65 patients with stage IV, 24 were alive while 41 were dead at median follow-up of 8 years (range 1-27 years). We have found 13 patients who do not reported PS in their history while 18 patients had all 3 PS. Among 13 patients without PS 7 (54%) were alive and 6 (46%) dead while among 18 patients with all 3 PS 5 were alive (28%) and 13 dead (72%) (p: 0.02). Only lymphopenia, hypogammaglobulinemia and both were observed in 5, 2 and 12 patients, respectively. CONCLUSION. The presence of all 3 PS was strongly related with poor prognosis of TET patients. Further prospective trials are necessary to confirm our preliminary results.
Immunological Evaluations in Patients with Thymic Neoplasms – Dr. Robert P. Nelson, Jr.
Nicholas J. Miller, M.S.
Indiana University and Melvin and Bren Simon Cancer Center, Division of Hematology and Oncology, Indiana University School of Medicine Indianapolis, IN Affiliation above works for all authors There is a longstanding association between thymic neoplasms, immunologically-mediated and immunodeficiency diseases. The purpose of this retrospective study is to document the clinical/ laboratory immunological abnormalities in a selected subset of patients with thymic neoplasms. Sixty (14.5%) of 413 patients with thymic neoplasms underwent immunological work-ups as part of their clinical evaluation. Laboratory evaluations included complete blood counts, lymphocyte immunophenotyping, total serum immunoglobulins and specific antibody titers to diphtheria, tetanus and Streptococcus pneumoniae. The median age of the cohort was 52 years. There were 37 (61.7%) females and 23 (38.3%) males. Twenty-four of 37 (64.9%) of patients were protected to diphtheria (normal > 0.10 IU/ml). Forty-five (95.7%) of 47 were protected to tetanus (normal > 0.10 IU/ml). All of 43 had protective strain-specific immunity to Streptococcus pneumoniae. These findings further define the immunological dysregulation observed in patients with thymic neoplasia. The decline in lymphocyte numbers seen in approximately half of the patients occurs disproportionately at the expense of CD4 and CD19 cells. There appears to be an unexpected disparity between humoral immune responses to protein versus polysaccharide antigens. These findings warrant additional study to explain this disparity, which may have clinical implications with respect to immunization requirements for patients with thymic neoplasms.
Prognostic Indicators Following Surgery for Thymoma – Dr. Ikenna Okereke
Ikenna Okereke1, Mohammed Morad1, Karen Rieger1, Thomas Birdas1, Deming Mi2, Mark Turrentine1, Sunil Badve3, Patrick Loehrer4, Kenneth Kesler1
1Department of Cardiothoracic Surgery, Indiana University School of Medicine, Indianapolis, IN 2Division of Biostatistics, Indiana University School of Medicine, Indianapolis, IN 3Department of Pathology, Indiana University School of Medicine, Indianapolis, IN 4Department of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN
Objectives Masaoka stage and WHO (World Health Organization) cellular classification have been considered the most important variables which determine survival following surgery for thymoma. We undertook a 20-year retrospective institutional study to investigate prognostic indicators within an institutional treatment strategy. Methods Between 1989 and 2009, 72 patients with thymoma were surgically treated at Indiana University Medical Center. Patient demographics, use of neoadjuvant/adjuvant therapy, and pathologic data, including Masaoka stage and WHO classification, were recorded when available and analyzed with respect to survival outcome. Results The majority (54%, n=39) of patients were female. Average age was 50.0 years. The distribution of Masaoka stages I, II, III and IV was 33% (n=24), 21% (n=15), 14% (n=10), and 32% (n=23) respectively. Sixty-five percent of patients with Masaoka stages III/IV received preoperative platin-based chemotherapy. Conversely, only 33% of patients with Masaoka stage II or greater underwent postoperative radiation therapy. WHO cell types included A/AB in 10% and B1-3 in 90%. Complete resection was achieved in all patients. Of all variables, only Masaoka stage groups were significantly predictive of survival. Patients in Masaoka Stages I and II had increased survival compared to patients in Masaoka Stages III and IV (Figure 1, p = 0.02). After mean follow-up of 59 months, 78% (n=56) of patients were alive and 64% (n=46) were alive without disease. Conclusions Complete resection of Masaoka stages I and II thymoma may result in not only excellent but also equivalent long-term survival. Patients with Masaoka stages III and IV may also experience long-term survival with multimodality therapy.
Impact of Epidermal Growth Factor Receptor (EGFR) gene characterization on anticancer drug citotoxicity in Thymic Epithelial Tumors (TET): preliminary data. – Dr. Giovannella Palmieri
Giovannella Palmieri1, Mirella Marino2, Gerardina Merola1, Piera Federico1, Carmela Merola3, Davide Leopardo1, Liliana Montella4, Stefano Sioletic2, Robert Martucci2, Martina Imbimbo1, Luigi Petillo1, Amelia Evoli5, Libero Lauriola6, Giuseppe Di Lorenzo1, Salvatore Conti2
1)Dept of Molecular and Clinical Endocrinology and Oncology, Federico II University, Naples, Italy; 2) Dept. of Pathology,Regina Elena National Cancer Institute, Rome, Italy; 3)Unit of Oncology, Hospital Villa Maria, Mirabella Eclano,Italy 4) Medical Oncology Unit San Giovanni di Dio Hospital, Frattaminore, Naples, Italy 5) Dept. of Neurosciences, Catholic University of Rome, Italy; 6) Dept. of Pathology, Catholic University of Rome, Italy;
EGFR hyperexpression is frequent in TET and it correlated with clinicopathological-characteristics. We started a pilot study of EGFR gene in TET by multiple approaches. The genetic status/regulatory pathways involved in the Receptor TK-family activity in TET are unknown. Only two cases of EGFR gene mutations in exon21 and one case of KIT mutation (exon11) have been described; no K-RAS mutation have been found. Recently a novel EGFR transcriptional regulatory mechanism has been described dependent on the length of a CA repeat in intron1 [CA simple sequence repeat1 (CASSRI)] of the EGFR gene, where the number of CA repeats was inversely correlated to pre-mRNA synthesis. 21 TET were analyzed for the EGFR (exon21), K-RAS (codon12-13) mutational status and for microsatellite analysis of CASSRI locus. The data were correlated to the efficacy of treatment with monoclonal antibody therapy on EGFR (Cetuximab) in 5 cases. 8 TET patients chemorefractory were treated with Cetuximab. Tumour control rate was obtained in 7pts, objectives response in 2 (1PR and 1CR). In 5 out of 8 cases we are performing biopathological analysis of the EGFR gene. Preliminary data indicated no EGFR and K-RAS mutations in 2 cases with objective response, both heterozygous for CASSRI locus: one had a combination of 16 and 20 CA repeats, the other 16 and 21 CA repeats. Both cases showed a strong EGFR expression by immunohistochemistry. On the basis of EGFR expression data these patients received Cetuximab and reported up to 1 year of response. Monoclonal antibody to EGFR may be a useful therapeutic choice in advanced pretreated TET. Preliminary data from genetic study are suggestive for an alternative hyperexpression mechanism with respect to EGFR gene amplification and point mutation and they could play a role in activating the EGFR proliferative pathways.
Reproducibility of the WHO classification for thymomas in relation to prognosis-Dr. Iacopo Petrini
Iacopo Petrini1, Hye Seung Lee1, Luca Di Tommaso2,Maria Merino1, Paolo Andrea Zucali2, Matteo Incarbone2, Santoro Armando2, Giuseppe Giaccone1.
1: National Cancer Institute, Bethesda, MD, USA. 2: Istituto Clinico Humanitas IRCCS, Rozzano (Milan), Italy.
Background: Thymomas are heterogenous tumors derived from the thymic epithelial cells. Although prognosis is relatively good compared to other epithelial cancers, there is a great variability in survival depending on the degree of differentiation; furthermore there is a high degree of heterogeneity within the tumor. The WHO classification updated in 2004 describes this heterogeneity introducing combined thymoma categories.1 The 1999 classification was shown to be able to predict the clinical course in several retrospective studies.2-5 However, this classification has been subject of criticism, due to the potential lack of reproducibility, especially in the presence of limited tumor material (resection specimen vs biopsy). We investigated the reproducibility of the WHO classification when performed by different pathologists and its prognostic implication on a large series of resected thymic malignancies.
Materials and methods: The series consisted of 134 patients who underwent surgery at one institution (Humanitas Hospital, Milan, Italy). The original histological diagnosis (CLAS1) produced at the time of surgery was available in all cases, as well as the clinical history. Samples were selected for collaborative molecular studies to be performed at NIH, and the histological classification was reviewed by a single pathologist of the same institution (CLAS2) before samples were sent out. Two independent pathologists at NIH reclassified all cases (CLAS3, CLASS4) based on a single H&E slide from each case, in a blinded fashion. We evaluated the global correlation of these four classifications and the pairwise correlation by Fleiss’ kappa coefficient.6 Disease related survival and progression free survival (PFS) curves were generated according to the Kaplan-Meier method and comparisons between curves were made using the log-rank test.
Results: The frequencies reported by the four pathologists are summarized in the table:
|
|
A |
AB |
B1 |
B2 |
B3 |
C |
B1,B2 |
B2,B3 |
|
CLAS1 |
14.6% |
23.8% |
13.8% |
8.5% |
16.2% |
10.8% |
4.6% |
7.7% |
|
CLAS2 |
10.2% |
21.9% |
18.0% |
6.3% |
18.8% |
11.7% |
4.7% |
8.6% |
|
CLAS3 |
12.4% |
19.4% |
17.1% |
15.5% |
17.8% |
16.3% |
0.0% |
1.6% |
|
CLAS4 |
17.2% |
19.5% |
4.7% |
31.3% |
18.0% |
9.4% |
0.0% |
0.0% |
The Kappa correlation coefficient was 0.58. The K coefficient between CLAS1 and 2 was 0.813; CLAS2-3 was 0.61; CLAS3-4 0.52; CLAS1-3 0.59; CLAS1-4 0.49 and CLAS2-4 0.45.
Histological tumor subtype predicted the disease-related survival in a statistically significant manner using the classification produced by 3 pathologists (CLAS1 p=0.004, CLAS2 p=0.028, CLAS4 p=0.001) but not by CLAS3 (p=0.131).
Considering all 4 classifications, the histotype-related 10 year-survival is 100% for type A and between 94-100% for AB, 93-100% for B1, 70-88% for B2, 76-83 for B3, 58-72% for C and 85-86% for B2,B3.
The histotype was able to predict the PFS with a statistically significant LogRank=0.025 for CLAS2 and <0.0001 for all the others.
The 5y PFS is 100% for type A, AB, B1 and B1,B2 and range between 87-91% for B2, 82-90% for B3, 47-71% for C, 83-85% for B2,B3.
Conclusion:The WHO classification identifies histotypes predicting the outcome with increasing aggressive behaviours from type A to C. The combined thymoma categories show aggressiveness intermediate between the individual types. Although the overall correlation between different pathologists is only moderate (K-correlation coefficient 0.41-0.61) this has only a minor effect on the ability to predict survival.
Array Comparative Genomic Hybridization analysis of resected thymomas on paraffin embedded material.- Dr. Iacopo Petrini
Petrini I. 1, Zucali P.A. 2, Meltzer P. 1, Killian K. 1, Di Tommaso L2, Incarbone M2, Suuriniemi M. 1, Merino M. 1, Wang Y. 1, Santoro A2, Giaccone G1.
1: National Cancer Institute, Bethesda (MD), USA. 2: Istituto Clinico Humanitas IRCCS, Rozzano (Milan), Italy.
Introduction: Thymomas are rare tumors derived from the thymic epithelial cells. They show heterogeneous biological characteristics and survival outcome. The WHO classification identifies different histotypes with prognostic implications. They range from type A with around 100% 10-year survival to the most aggressive type C with 0% 10 years survival reported. There is very little known of the biology of thymomas and of the genetic alterations present in these tumors. Array comparative genomic hybridization (CGH) is a powerful technique to define compy number abnormalities.
Materials and Methods: We selected 60 thymoma samples showing a proportion of cancer cells > 80% from 151 formalin fixed paraffin embedded samples of 134 patients who underwent surgery at Humanitas Hospital, Milan, Italy. The DNA extraction and labeling was performed according to Genomic DNA ULS Labeling Kit (Agilent, Santa Clara, California, USA). We used as reference Human Genomic DNA: Male (Promega, Madison, Wisconsin, USA). Eleven samples were hybridized on Human Genome CGH Array 105A (Agilent) and 29 on SurePrint G3 Human CGH Array 180K (Agilent). Slides were scanned on a laser-based microarray scanner (Agilent). The data were extracted and normalized by Feature Extraction 10.5 (Agilent). We performed data analysis using Nexus 4.0 (Biodiscovery Inc, El Segundo California, USA) by Log Rank segmentation algorithm. We selected for the analysis 40 samples with a Robust Variance Sample QC< 0.2 as recommended. We evaluated aberration of autosomal chromosomes. Common Aberrant Region (CAR) are defined by a imbalance frequencies of 50% in type C and of 35% in the remaining categories.
Results: In 40 thymoma samples we identified 12 common aberrant regions: 6 are gains involving 1037 genes and 6 are losses involving 96 genes. These aberrations are present in each histotype. In 9 type A thymoma samples we discovered 11 common aberrant gains (CAG) involving 112 genes and 3 common aberrant losses (CAL) involving 11 genes. For the 11 AB specimens we identified 18 CAG involving 931 genes and 3 CAL involving 56 genes. We evaluated 15 B3 samples presenting 10 CAG involving 1172 genes and 9 CAL involving 389 genes. Five thymic carcinomas showed 20 CAG with 1356 genes and 8 CAL with 540 genes involved.
Conclusion: CGH analysis is feasible using FFPE samples commonly stored for diagnosis. The number of genes involved in karyotypic aberration increase from type A to the more aggressive type C. Chromosome imbalance is present in each histotype analyzed.
Neoadjuvant therapy of primary inoperable thymoma with Sandostatin-LAR ™ plus prednisolon.- Primary results. – Prof. Berthold Schalke
Berthold Schalke1, Joerg Marienhagen2,Karsten Wiebe3,Stefan Hofmann3,Gerhard Schuierer4,Christian Hosius5,Ulrich Bogdahn1,Phillip Stroebel6, Alexander Marx6.
University Medical Center Regensburg, 1Dep of Neurology,2Nuclear Medicine,3Thoracic Surgery,4Neuroradiology, 5Novartis Pharma Nuernberg,6University Medical Center, Mannheim/ Heidelberg Dep of Pathology.
Longterm survival in patients with primary inoperable thymoma is critically associated with the resection status (R0/R1). neoadjuvant therapy may reduce tumor volume and subsequently enhance the probability to remove the complete tumor. We used Sandostatin-LAR™ plus prednisolon in a prospective, open label, single arm study. Primary end point was defined as tumor volume reduction >20%. 10patients finished a 3 or 6 month period of treatment. All patients were positive in the somatostsatin receptor szintigraphy, had a tumor biopsy and a proven histological diagnosis of thymoma (WHO A to C). They recieved Sandostatin-LAR™ 30mg i.m. every 2 weeks plus prednisolon 0,6mg/kg/day, CT control was performed at week 0,6,12 and if necessary 18 and 24. The tumor volume was measured semi-automatically . Initial tumor volume was between 61ml and 842ml. volume reduction was between 25% (117ml – 88ml) and 83% (167ml – 28ml). The largest tumors showed a reduction from 842ml – 327ml (62%) and 840ml – 616ml (27%).
Conclusion: Neoadjuvant treatment of primary inoperable thymoma with Sandostatin-LAR™ plus prednisolon is an excellent therapy to reduce tumor volume. This may open the chance for complete surgical removal of the tumor and that may improve longterm survival.
Results of Video Assisted Thoracoscopic (VAT) Thymothymectomy in Myasthenia Gravis (MG) Patients Dr. Alper Toker
“Alper Toker”1, Serhan Tanju1, Suat Erus1, Berker Ozkan1, Zerrin Sungur2, Mert Senturk2, Sukru Dilege1
1Istanbul University, Istanbul Faculty of Medicine, Thoracic Surgery Department 2Istanbul University, Istanbul Faculty of Medicine, Anesthesiology Department Background: Results of VAT thymothymectomy in MG patients have been reported rarely. Methods: Prospectively recorded data of 20 MG patients with a thymoma who had VAT resection was analyzed. Means of preoperative variables, and intra-postoperative results were presented. Results: Mean age was 42.2 years (range 16-82 years), Mean Modified Ossermann Classification score was 2.7 +/- 1.2. Eight patients needed preoperative intravenous immunoglobulin treatment. Mean length of postoperative stay was 3.4 days +/- 1.8 days. Mean tumor size was 3.1 +/- 1.3 cm. No mortality and morbidity occurred. One patient needed conversion to open surgery. Four patients were at Masaoka stage 3, 6 patients were at stage 2 and 11 patients were at stage 1. All had complete resection. Four patients needed an access thoracotomy,1 patient needed a VAT diaphragmatic plication at the same setting to the contra lateral diaphragm due to resection of the phrenic nerve. Three patients needed intensive care unit stay with a mean of 22.9 hours. Nine patients had an adjuvant treatment. Mean follow up time was 27.4 months +/- 22 months (4-68 months). No recurrence developed during the follow up. Conclusion: Other than cosmetic factors, sternum preservation and lesser postoperative stay were main advantages of VAT thymothymectomy in MG patients. Besides, smooth postoperative period for MG and good oncological outcomes were appreciated.
Histologic grading versus histologic classification of thymic elithelial tumors: different but inter-related methods of assessment – Dr. William Travis
William D. Travis1, James Huang2, Nicolas Girard3, Cami Sima4, David S. Klimstra1, Maureen F. Zakowski1, Gregory J. Riely3.
1Dept of Pathology, 2Thoracic Service, Dept. of Surgery, 3Thoracic Oncology Service, 4Dept of Epidemiology and Biostatistics; Memorial Sloan Kettering Cancer Center, New York, NY
Introduction: Histologic classification and grading are completely different, though interrelated, methods of evaluating tumors. The 2004 WHO classification of TET groups tumors according to histologic appearance. Implicit in this classification is the understanding that these tumor groups have different grades that correspond to different degrees of clinical aggressiveness. Methods: 138 surgical resected TET were classified by the 2004 WHO classification and analyzed for clinical features and survival. Results: We found thymoma, type A (12), AB (19), B1 (8), B2 (48), B3 (26), micronodular (1), metaplastic (1) and thymic carcinoma (23). Tumors were grouped into three grades (GR): GR1 (A, AB, B1, micronodular, metaplastic; n=41; 25F, 16M; age:mean 61 yrs, 23-87), GR2 (B2 & B3; n=74; 37F, 37F; age:mean 55 yrs, 31-84) and GR3 (carcinoma; n=23, 8F, 15M; age:mean 58 yrs, 34-83). A higher percentage of patients with GR3 were Masaoka stage III or IV (17/23; 74%) compared to GR2 (44/74, 60%) and GR1 (5/39, 13%, p<0.001). 5 yr disease free survival by Kaplan-Meier analysis was significantly reduced for GR2: 69% and GR3:36% compared to GR1: (77%, p<0.001). Survival was significantly worse for GR2 compared to GR1 (p=0.02) and G3 compared to GR2 (p=0.003). Overall survival was not significant for comparisons between the three groups (GR1:87%, GR2:89%, GR3:56%), but GR3 tumors had significantly reduced survival compared to GR2 (p=0.034). Conclusion: The 2004 WHO categories from type A to AB, B1, B2, B3 and thymic carcinoma represent increasing histologic grades with varying degrees of more aggressive behavior. While there is justification to think of a simplified grading scheme to group TET into three categories of low, intermediate and high grade, the 2004 WHO categories have morphologic differences that remain the basis for maintaining a histologic classification separate from grading subgroups.
IGFR and pAKT protein expression in tumor samples of a series of all WHO-defined subtypes of thymoma patients.-Dr. Paolo Zucali
Zucali PA1, Petrini I2, Lorenzi E1, Merino M2, Di Tommaso L1, Lee H2, Cao L2, Incarbone M1, Walter Rodriguez B2, Santoro A1, and Giaccone G2.
1: Istituto Clinico Humanitas IRCCS, Rozzano (Milan), Italy. 2: National Cancer Institute, Bethesda (MD), USA.
Background: Thymic malignancies are rare tumors, but they are the most common anterior mediastinal tumors in adults. Little is known about the molecular mechanisms of thymoma oncogenesis. The aim of the present study was to evaluate the IGFR and pAKT protein expression in tumor samples of a series of resected thymoma patients.
Materials and methods: A tissue micro-array of specimens from resected tumors of 134 thymoma patients was constructed. IGFR and pAKT expression was detected by immunohistochemistry (Cell Signaling). The analysis of the specific protein staining (IGFR: membranous and cytoplasmic; pAKT: nuclear) took into consideration both the percentage of positive tumor cells and the staining intensity of positive tumor cells.
Results: IGFR and pAKT expression were evaluable in 111 (92 primary and 19 relapsed tumors) and 105 (86 primary and 19 relapsed tumors) tumors, respectively. The IGFR membrane staining was present in 30/92 primary tumors (subtype A-B2: 10 samples; subtype B3-C: 20 samples) and 10/19 relapsed tumors (subtype A-B2: 1 sample; subtype B3-C: 9 samples). The nuclear pAKT was expressed in 52/86 primary tumors (subtype A-B2: 32 samples; subtype B3-C: 20 samples) and 13/19 relapsed tumors (subtype A-B2: 5 samples; subtype B3-C: 8). The membrane IGFR and nuclear pAKT expression were both associated with more aggressive subtypes of thymoma (B3 and C) in primary tumors (IGFR: p<0.001; AKT: nuclear, p= 0.040); IGFR membrane expression was also associated to more aggressive subtypes in relapsed tumors but not pAKT (IGFR: p=0.020; AKT: nuclear, p=1.00). No significant correlation was observed between IGFR and pAKT expression and other clinical characteristics or survival.
Conclusion: The IGFR and pAKT proteins are expressed in all WHO-defined subtypes of thymoma. Their expression is significantly associated with aggressive subtypes. The lack of correlation with survival may be due to the relatively low mortality rate in this series.
Belinostat treatment in recurrent thymoma or thymic carcinoma-Ronan Kelly
G. Giaccone, A. Rajan, R. Kelly, C. Carter, A. Lopez-Chavez, A. Berman, J. Spittler, I. Espinoza-Delgado, M. Lee, J. Trepel, P. Loehrer; National Cancer Institute, Bethesda, MD; Indiana University Medical Center, Indianapolis, IN
Background: Thymic malignancies are rare tumors. Chemotherapy is used for advanced disease. There is no established role of second-line therapy in patients with refractory or recurrent disease. Belinostat is a HDAC inhibitor with activity in cutaneous and peripheral T cell lymphoma and is being investigated in several solid tumors. One prolonged minor response (31 m) was seen in a phase I study of this agent in a patient with thymoma.
Methods: Patients with recurrent thymoma or thymic carcinoma, progressing after platinum-based chemotherapy were eligible. They were also required to have measurable disease, PS 0-2 and normal organ functions. Belinostat was given iv at 1.0 g/m2 on days 1-5 of a 21-day cycle until disease progression or intolerable side effects. Correlative markers of activity in blood and tumor were performed.
Results: From December 07 to August 09, 38 patients have been accrued from 2 institutions; 20 patients were males, with a mean age of 54 (24-84), 22 thymomas and 16 thymic carcinomas, mean number of prior regimens 3.1 (1-10), 22 prior tumor resection/debulking and 4 had myasthenia gravis. The mean number of cycles of therapy is 5.4 (1-20+). Treatment was well tolerated, with nausea being the most common side effect and well controlled with prophylactic antiemetics. 33 patients are evaluable for response: 2 had a partial response (13m, 16m), 18 stable disease (3-18+ m) and 13 progression. No responses were seen in 16 evaluable patients with thymic carcinomas. Acetylated lysine and tubulin were analyzed in lymphocytes and monocytes by multiparameter flow cytometry. An increase of protein acetylation (2-10 fold) over baseline was observed at 1 hour post-infusion on day 3 of the first cycle in all patients analyzed. Other correlative markers are being investigated.
Conclusions: The thymoma cohort has been expanded to the second stage of the study. Belinostat has activity in patients with recurrent or refractory thymoma.