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T-lymphoblastic lymphoma (T-LBL) and thymoma are two rare primary tumors of the thymus deriving either from T-cell precursors or from thymic epithelial cells, respectively. Some thymoma subtypes (AB, B1, and B2) display numerous reactive terminal deoxynucleotidyl transferase-positive (TdT + ) T-cell precursors masking epithelial tumor cells. Therefore, the differential diagnosis between T-LBL and TdT + T-lymphocyte-rich thymoma could be challenging, especially in the case of needle biopsy. To distinguish between T-LBL and thymoma-associated lymphoid proliferations, we analyzed the global DNA methylation using two different technologies, namely MeDIP array and EPIC array, in independent samples series [17 T-LBLs compared with one TdT + lymphocyte-rich thymoma (B1 subtype) and three normal thymi, and seven lymphocyte-rich thymomas compared with 24 T-LBLs, respectively]. In unsupervised principal component analysis (PCA), T-LBL and thymoma samples clustered separately. We identified differentially methylated regions (DMRs) using MeDIP-array and EPIC-array datasets and nine overlapping genes between the two datasets considering the top 100 DMRs including ZIC1, TSHZ2, CDC42BPB, RBM24, C10orf53, and MACROD2. In order to explore the DNA methylation profiles in larger series, we defined a classifier based on these six differentially methylated gene promoters, developed an MS-MLPA assay, and demonstrated a significant differential methylation between thymomas (hypomethylated; n = 48) and T-LBLs (hypermethylated; n = 54) (methylation ratio median 0.03 versus 0.66, respectively; p < 0.0001), with MACROD2 methylation status the most discriminating. Using a machine learning strategy, we built a prediction model trained with the EPIC-array dataset and defined a cumulative score taking into account the weight of each feature. A score above or equal to 0.4 was predictive of T-LBL and conversely. Applied to the MS-MLPA dataset, this prediction model accurately predicted diagnoses of T-LBL and thymoma. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Introduction: Thymomas are rare intrathoracic malignancies that can relapse after surgery. Whether or not Post-Operative RadioTherapy (PORT) should be delivered after surgery remains a major issue. RADIORYTHMIC is an ongoing, multicenter, randomized phase 3 trial addressing this question in patients with completely R0 resected Masaoka-Koga stage IIb/III thymoma. Experts in the field met to develop recommendations for PORT., Methods: A scientific committee from the RYTHMIC network identified key issues regarding the modalities of PORT in completely resected thymoma. A DELPHI method was used to question 24 national experts, with 115 questions regarding the following: (1) imaging techniques, (2) clinical target volume (CTV) and margins, (3) dose constraints to organs at risk, (4) dose and fractionation, and (5) follow-up and records. Consensus was defined when opinions reached more than or equal to 80% agreement., Results: We established the following recommendations: preoperative contrast-enhanced computed tomography (CT) scan is recommended (94% agreement); optimization of radiation delivery includes either a four-dimensional CT-based planning (82% agreement), a breath-holding inspiration breath-hold-based planning, or daily control CT imaging (81% agreement); imaging fusion based on cardiovascular structures of preoperative and planning CT scan is recommended (82% agreement); right coronary and left anterior descending coronary arteries should be delineated as cardiac substructures (88% agreement); rotational RCMI/volumetric modulated arc therapy is recommended (88% agreement); total dose is 50 Gy (81% agreement) with 1.8 to 2 Gy per fraction (94% agreement); cardiac evaluation and follow-up for patients with history of cardiovascular disease are recommended (88% agreement) with electrocardiogram and evaluation of left ventricular ejection fraction at 5 years and 10 years., Conclusion: This is the first consensus for PORT in thymoma. Implementation will help to harmonize practices., Competing Interests: Disclosure The authors have no conflict of interest to disclose concerning the current work., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: R0 resection and radiation therapy have been associated with improved overall survival (OS) in patients with thymic carcinoma (TC). Here, we analyzed which subgroups of patients derive the greatest benefit from postoperative radiation therapy (PORT)., Methods: Clinical, pathologic, treatment, and survival information of 462 patients with TC from the International Thymic Malignancy Interest Group/European Society of Thoracic Surgeons database were analyzed. Variables included age, sex, continent of treatment, paraneoplastic syndrome, carcinoma subtype, tumor size, pathologic Masaoka stage, resection status, and use of chemotherapy. OS was the primary end point using the Kaplan-Meier method. Time to recurrence (TTR) was the secondary end point using a competing risk analysis. A 3-month landmark analysis was performed., Results: PORT was associated with a significant OS benefit (5-y OS 68% versus 53%, p = 0.002). In patients with R0 resection, PORT was associated with increased OS for advanced (stages III-IV, p = 0.04), but not early (stages I-II, p = 0.14) stage TC. In patients with an R1/2 resection of advanced-stage TC, PORT was associated with significantly longer OS (5-y OS 53% versus 38%; p < 0.001). Subset analyses did not reveal clear associations of PORT with TTR. On multivariable analysis, lower pathologic stage, PORT, and R0 resection status were associated with an OS benefit, whereas only higher age and lower pathologic stage had an association with longer TTR., Conclusions: In the largest individual patient data set on patients with TC reported to date, PORT was associated with a meaningful OS benefit in patients with advanced-stage TC after an R0 or R1/2 resection., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: Stage classification is an important underpinning of management in patients with cancer and rests on a combination of three components-T for tumor extent, N for nodal involvement, and M for distant metastases. This article details the revision of the N and the M components of thymic epithelial tumors for the ninth edition of the TNM classification of malignant tumors proposed by the Thymic Domain of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee., Methods: The N and M components of the eighth edition staging system were verified by a large international collaborative data source through a data-driven analysis. A total of 9147 cases were included for analysis, including 7662 thymomas, 1345 thymic carcinomas, and 140 neuroendocrine thymic tumors., Results: Lymph node involvement rates were 1.5% in thymomas and 17.6% and 27.7% in thymic carcinomas and neuroendocrine thymic tumors, respectively. Rates of lymph node metastasis were increasingly higher in tumors with higher T stage and higher-grade histologic type. Survival analysis validated the differences in the N and M categories proposed in the eighth edition staging system. Good discrimination in overall survival was detected among pathologic (p)N and pM categories in patients with thymoma and thymic carcinoma., Conclusions: No changes are proposed from the eighth edition for the N and M components. The proposed stage classification will provide a useful tool for management of the disease among the global thymic community., (Copyright © 2023 International Association for the Study of Lung Cancer. All rights reserved.)

Introduction: A TNM-based stage classification system of thymic epithelial tumors was adopted for the eighth edition of the stage classification of malignant tumors. The Thymic Domain of the Staging and Prognostics Factor Committee of the International Association for the Study of Lung Cancer developed a new database with the purpose to make proposals for the ninth edition stage classification system. This article outlines the proposed definitions for the T categories for the ninth edition TNM stage classification of thymic malignancies., Methods: A worldwide collective database of 11,347 patients with thymic epithelial tumors was assembled. Analysis was performed on 9147 patients with available survival data. Overall survival, freedom-from-recurrence, and cumulative incidence of recurrence were used as outcome measures. Analysis was performed separately for thymomas, thymic carcinomas, and neuroendocrine thymic tumors., Results: Proposals for the T categories include the following: T1 category is divided into T1a (≤5 cm) and T1b (>5 cm), irrespective of mediastinal pleura invasion; T2 includes direct invasion of the pericardium, lung, or phrenic nerve; T3 denotes direct invasion of the brachiocephalic vein, superior vena cava, chest wall, or extrapericardial pulmonary arteries and veins; and T4 category remains the same as in the eighth edition classification, involving direct invasion of the aorta and arch vessels, intrapericardial pulmonary arteries and veins, myocardium, trachea, or esophagus., Conclusions: The proposed T categories for the ninth edition of the TNM classification provide good discrimination in outcome for the T component of the TNM-based stage system of thymic epithelial tumors., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: A TNM-based system for all types of thymic epithelial tumors was introduced in the eighth edition of the TNM classification of thoracic malignancies. The Thymic Domain of the Staging and Prognostic Factors Committee of the International Association for the Study of Lung Cancer, composed of multispecialty international experts, was charged to develop proposals for the ninth edition. This article outlines the proposed definitions for the T, the N, and the M components and their combination into stage groups., Methods: A large central database of 11,347 patients with thymic epithelial tumors was assembled thanks to the contribution of the major thymic organizations worldwide and analyses were carried out for the T, the N, and the M components and the stage groups. Overall survival was the outcome measure for patients with completely and incompletely resected tumors, and recurrence for those with complete resection. When the number of patients was sufficient, analyses were performed separately for thymomas, thymic carcinomas, and neuroendocrine thymic tumors., Results: Tumor size is included in the T1 category as T1a (≤5cm) and T1b (>5 cm); the mediastinal pleura is dropped as a T descriptor; invasion of the lung or phrenic nerve is reclassified as T2 (instead of T3). No changes are proposed for the N and the M components from the eighth edition. The stage groups remain the same., Conclusions: The proposed changes for the ninth edition of the TNM classification set the stage for further progress in the future for these rare tumors., (Copyright © 2023 International Association for the Study of Lung Cancer. All rights reserved.)

Background: Thymic malignancies are rare intrathoracic tumors, which may be aggressive and difficult to treat. They represent a therapeutic challenge in the advanced/metastatic setting, with limited treatment options after the failure of first-line platinum-based chemotherapy. They are frequently associated with autoimmune disorders that also impact oncological management., Materials and Methods: NIVOTHYM is an international, multicenter, phase II, two-cohort, single-arm trial evaluating the activity and safety of nivolumab [240 mg intravenously (i.v.) q2 weeks] alone or with ipilimumab (1 mg /kg i.v. q6 weeks) in patients with advanced/relapsed type B3 thymoma or thymic carcinoma, after exposure to platinum-based chemotherapy. The primary endpoint is progression-free survival rate at 6 months (PFSR-6) based on RECIST 1.1 as per independent radiological review., Results: From April 2018 to February 2020, 55 patients were enrolled in 15 centers from 5 countries. Ten patients (18%) had type B3 thymoma and 43 (78%) had thymic carcinoma. The majority were male (64%), and the median age was 58 years. Among the 49 eligible patients who started treatment, PFSR-6 by central review was 35% [95% confidence interval (CI) 22% to 50%]. The overall response rate and disease control rate were 12% (95% CI 5% to 25%) and 63% (95% CI 48% to 77%), respectively. Using the Kaplan-Meier method, median progression-free survival and overall survival by local assessment were 6.0 (95% CI 3.1-10.4) months and 21.3 (95% CI 11.6-not estimable) months, respectively. In the safety population of 54 patients, adverse events (AEs) of grade 1/2 were observed in 22 (41%) patients and grade 3/4 in 31 (57%) patients. Treatment-related AEs of grade 4 included one case of neutropenia, one case of immune-mediated transaminitis, and two cases of myocarditis., Conclusions: Nivolumab monotherapy demonstrated an acceptable safety profile and objective activity, although it has been insufficient to meet its primary objective. The second cohort of NIVOTHYM is currently ongoing to assess the combination of nivolumab plus ipilimumab., Competing Interests: Disclosure EX: all support for the present manuscript: medical writing, data analysis. SP: consulting fees from Amgen, AstraZeneca, Bayer, Beigene, Blueprint, BMS, Boehringer, Ingelheim, Daiichi Sankyo, Guardant Health, Incyte, Janssen, Lilly, Merck Serono, MSD, Novartis, Roche, Takeda, Pfizer, Seattle Genetics, Turning Point Therapeutics, EQRx. Payment or honoraria from: AstraZeneca, Bayer, Guardant Health, Janssen, Merck Serono, Roche, Takeda, Pfizer. Payment for expert testimony from Roche, Merck Serono. Support for attending meetings and/or travel from Janssen, Roche. Advisory Board as per consulting fees. Leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid: British Thoracic Oncology Group, ALK Positive UK, Lung Cancer Europe, Ruth Strauss Foundation, Mesothelioma Applied Research Foundation, ETOP-IBCSG Partners Foundation Board. SC: payment or honoraria from BMS. Participation on a Data Safety Monitoring Board or Advisory Board from BMS. TB: Advisory Board for Bayer, Janssen, and Roche. ACT: grants, personal fees, and non-financial support from Roche, personal fees and non-financial support from Astra Zeneca, personal fees and non-financial support from MSD, grants, personal fees and non-financial support from BMS, during the conduct of the study; personal fees and non-financial support from Novartis, personal fees and non-financial support from Vifor Pharma, personal fees from Boehringer Ingelheim, grants, personal fees, and non-financial support from Pfizer, personal fees and non-financial support from Amgen, personal fees and non-financial support from Takeda, outside the submitted work. SP: support for the present manuscript from Astra Zeneca, funding to institution to support study conduct; medical writing support (no direct transfer of funds). Principal investigator in trials (institutional financial support for clinical trials) sponsored by Amgen, AstraZeneca, Beigene, Bristol-Myers Squibb, GSK, Merck Sharp and Dohme, Roche/Genentech. All fees to institution. Consulting fees from: AbbVie, AiCME, Amgen, Arcus, AstraZeneca, Bayer, Beigene, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, F-Star, Fishawack, Foundation Medicine, Genzyme, Gilead, GSK, Illumina, Imedex, IQVIA, Incyte, Ipsen, iTeos, Janssen, Medscape, Medtoday, Merck Sharp and Dohme, Merck Serono, Merrimack, Novartis, Novocure, OncologyEducation, Pharma Mar, Phosplatin Therapeutics, PER, Peerview, Pfizer, PRIME, Regeneron, RMEI, Roche/Genentech, RTP, Sanofi, Seattle Genetics, Takeda, Vaccibody. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events: AiCME, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, ecancer, Eli Lilly, Foundation Medicine, Illumina, Imedex, Medscape, Merck Sharp and Dohme, Mirati, Novartis, Peerview, PER, Pfizer, Prime, Roche/Genentech, RTP, Sanofi, Takeda. Support for attending meetings and/or travel: AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Merck Sharp and Dohme, Novartis, Pfizer, Roche/Genentech, Takeda. Participation on a Data Safety Monitoring Board or Advisory Board: AbbVie, Amgen, Arcus, AstraZeneca, Bayer, Beigene, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F-Star, Foundation Medicine, Genzyme, Gilead, GSK, Illumina, Incyte, iTeos, Janssen, Merck Sharp and Dohme, Merck Serono, Merrimack, Novartis, Novocure, Pharma Mar, Phosplatin Therapeutics, Pfizer, Regeneron, Roche/Genentech, Sanofi, Seattle Genetics, Takeda, Vaccibody. HP: grants or contracts from Boehringer Ingelheim, Astra Zeneca, Siemens, European Commission (EU4Health). Payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing or educational events: Boehringer Ingelheim, Astra Zeneca, MSD, BMS, Roche, Janssen, Sanofi. Support for attending meetings and/or travel from Boehringer Ingelheim. Leadership or fiduciary role in EFSUMB, Austrian Society of Roentgenology. Receipt of equipment, materials, drugs, medical writing, gifts, or other services from Boehringer Ingelheim. GR: all support for the present manuscript—provision of study materials. Support for attending meetings and/or travel from Roche, Astra Zeneca, MSD, BMS. Participation on a Data Safety Monitoring Board or Advisory Board from MSD. NG: grants or contracts from Astrazeneca, Janssen, MSD, BMS. Consulting fees from Astrazeneca, Roche, Bristol Myers Squibb, Merck Sharp & Dohme. Payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from Astrazeneca, Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pfizer. Payment for expert testimony from Astrazeneca. Participation on Roche Data Safety Monitoring Board. AJ: support for attending meetings and/or travel from Roche ESMO 2022. YP: employee of EORTC. All other authors have declared no conflicts of interest., (Crown Copyright © 2023. Published by Elsevier Ltd. All rights reserved.)

Background: Thymic malignancies represent a heterogeneous group of rare thoracic cancers, which are classified according to the World Health Organization histopathologic classification, that distinguishes thymomas from thymic carcinomas. Data regarding the biology of those tumors are limited in the literature, and the vast majority have been obtained using surgical specimens from early-stage disease. Meanwhile, treatment of advanced, refractory thymic tumors currently relies on chemotherapy, with limited efficacy. Comprehensive genomic profiling (CGP) of advanced, refractory tumors would open some opportunities for innovative treatments., Patients and Methods: A total of 90 and 174 consecutive patients with thymoma or thymic carcinoma, respectively, for whom formalin-fixed, paraffin-embedded specimens from recurrent, refractory tumor were sequenced, were included. Sequencing was performed using hybridization-captured, adaptor ligation-based libraries to a mean coverage depth of >500× for up to 315 cancer-related genes plus 37 introns from 28 genes frequently rearranged in cancer., Results: Thymomas featured a low frequency of genomic alterations (average of 1.8/tumor), and low levels of TMB. The genomic alterations identified in more than 10% of cases were in the CDKN2A/B and TP53 genes. Amplification in the NTRK1 gene was found in an unresectable, stage III, type B3 thymoma. Thymic carcinomas featured a significantly higher frequency of alterations at 4.0/tumor (P < .0001). Clinically relevant genomic alterations were observed in the CDKN2A, KIT, and PTEN/PI3K/MTOR pathways. Elevated TMB in thymic carcinomas was uncommon with only 6% of cases featuring ≥10 mutations/Mb., Conclusions: Our cohort is the largest available so far, reporting on CGP of thymic epithelial tumors in the setting of advanced disease. The identification of clinically relevant genomic alterations in the KIT, PI3K, CDKN2A/B, or NTRK genes provides a strong rationale for potential precision medicine approaches using targeted agents. A subset of thymic carcinomas show high tumor mutation burden, what may be a predictor of efficacy of immune checkpoint inhibitors., (© The Author(s) 2022. Published by Oxford University Press.)

Thymic epithelial tumors are rare neoplastic proliferations of thymic epithelial cells. The aggressiveness of these malignancies increases as higher is the histologic subtype, being thymic carcinoma the most aggressive subtype, with a greater tendency to metastatic spread. In metastatic setting, there is no standard treatment after progression on platinum-based chemotherapy. In this scenario, monotherapy treatment either with lenvatinib, a multi-tyrosine kinase inhibitor with antiangiogenic properties, or pembrolizumab, an immune-checkpoint inhibitor, has reported clinical activity. Potential combination of both agents may have synergistic activity as reported in other cancer types. PECATI trial is a single-arm, investigator-initiated phase II study aiming to assess the activity and safety of the combination of lenvatinib and pembrolizumab in 43 patients with advanced B3-thymoma or thymic carcinoma who progressed on or after at least one previous line of platinum-based chemotherapy. The primary endpoint of the trial is 5-month progression-free survival rate and the secondary endpoints include overall response rate, duration of response, and overall survival., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2021. Published by Elsevier Inc.)

Thymic carcinomas are rare malignancies that in general arise in the prevascular (anterior) mediastinum. These tumors are usually invasive, often present at advanced stages, and typically behave aggressively. Studies are hampered by the paucity of these tumors, the large variety of carcinoma subtypes, and the lack of unique morphologic and immunophenotypic features. Despite these challenges, advances in diagnostic imaging, surgical approaches, systemic therapies, and radiation therapy techniques have been made. The WHO classification of thymic epithelial tumors has been updated in 2021, and the eighth tumor nodal metastasis staging by the American Joint Committee on Cancer/Union for International Cancer Control included thymic carcinomas in 2017. Molecular alterations that provide more insight into the pathogenesis of these tumors and that potentially permit use of novel targeted therapies are increasingly being identified. New approaches to radiation therapy, chemotherapy, and immunotherapy are under evaluation. International societies, including the International Thymic Malignancy Interest Group, European Society of Thoracic Surgeons, and Japanese, Chinese, and Korean thymic associations, have been critical in organizing and conducting multi-institutional clinical studies. Herein, we review contemporary multidisciplinary perspectives in diagnosis and management of thymic carcinoma., (Copyright © 2022 International Association for the Study of Lung Cancer. All rights reserved.)

Background: Thymic carcinomas are aggressive and difficult to treat a subset of thymic epithelial tumours that represent a heterogeneous group of rare intrathoracic malignancies. The treatment strategy of thymic carcinomas is based on whether surgical resection may be achieved, which represents the most significant favourable prognostic factor on survival. For this study, we took advantage of the unique prospective Réseau tumeurs THYMiques et Cancer (RYTHMIC) database to describe baseline characteristics, analyse treatment strategies in light of existing guidelines and provide landmark patient outcomes data with regards to response and survival of patients in a real-life clinical practice setting., Methods: Inclusion criteria for this analysis were the following: (1) histologically-confirmed thymic carcinomas - excluding neuroendocrine tumours-after pathological review by the RYTHMIC pathology panel, (2) discussion of the case at the RYTHMIC multidisciplinary tumour board, (3) at least one active treatment modality., Results: A total of 213 patients were analysed. Overall, 60 (28%) patients were considered as surgical candidates upfront, 91 (43%) patients received primary chemotherapy, and 62 (29%) patients received exclusive chemotherapy. Median overall survival (OS) was 49.2 months (IC95%: 34.8-63.6); OS was significantly longer in patients with a lower stage at diagnosis (p < 0.001), who were operated on upfront, as opposed to patients who received primary or exclusive chemotherapy (p < 0.001). Surgery, conducted upfront or after primary chemotherapy, was significantly associated with more prolonged OS (p < 0.001); complete resection and postoperative radiotherapy were also predictors of better outcome (p = 0.018 and p = 0.051, respectively)., Conclusions: Our cohort is the first to analyse in-depth outcomes and treatment strategies in a prospective cohort of consecutive patients with thymic carcinoma. While we confirm the major prognostic impact of surgery, our data highlight the need for optimised multidisciplinary management and innovative therapies as the survival of patients remains limited., Competing Interests: Conflict of interest statement N. Girard reports grants and personal fees from BMS, grants and personal fees from MSD, grants and personal fees from Pfizer, during the conduct of the study. Other authors have nothing to disclose., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The definition of the clinical target volume (CTV) for post-operative radiotherapy (PORT) for thymoma is largely unexplored. The aim of this study was to analyze the difference in CTV delineation between radiation oncologists (RTO) and surgeons., Methods: This retrospective multi-center study enrolled 31 patients who underwent PORT for a thymoma from five hospitals. Three CTVs were delineated per patient: one CTV by the RTO, one CTV by the surgeon (blinded to the results of the RTO) and a joint CTV after collaboration. Volumes (cm 3 ), Hausdorff distances (HD) and Dice similarity coefficients (DSC) were analyzed., Results: RTO delineated significantly bigger CTVs than surgeons (mean: 93.9 ± 63.1, versus 57.9 ± 61.3 cm 3 , p = 0.003). Agreement was poor between RO and surgeons, with a low mean DSC (0.34 ± 0.21) and high mean HD of 4.5 (±2.2) cm. Collaborative delineation resulted in significantly smaller volumes compared to RTO (mean 57.1 ± 58.6 cm 3 , p < 0.001). A mean volume of 18.9 (±38.1) cm 3 was included in joint contours, but missed by RTO. Conversely, a mean volume of 55.7 (±39.9) cm 3 was included in RTO's delineations, but not in the joint delineations., Conclusions: To the best of our knowledge, this is the first study investigating CTV definition in thymoma. We demonstrated a significant variability between RTO and surgeons. Joint delineation prompted revisions in smaller CTV as well as favoring the surgeons' judgement, suggesting that surgeons provided relevant insight into other risk areas than RTO. We recommend a multidisciplinary approach to PORT for thymomas in clinical practice., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Thymic tumours are rare thoracic malignancies, that may be aggressive and difficult to treat. The pillars of the management include pathological review, consideration of differential diagnoses, staging and multidisciplinary discussion. Assessment of resectability is key to drive the treatment sequencing. Association with autoimmune diseases, especially myasthenia gravis, is observed, which impacts the oncological management. Networks are being built at the national and international levels. This article provides an overview of the most recent findings in the diagnosis, staging, histology, and management strategies of thymic tumours., Competing Interests: Conflict of interest: C. Girard has nothing to disclose. Conflict of interest: N. Basse has nothing to disclose., (Copyright ©The authors 2021.)

Micronodular thymic carcinoma with lymphoid hyperplasia (MNTCLH) is a rare form of thymic carcinoma. We present the experience of RYTHMIC, the French national network devoted to the treatment of thymic epithelial tumors through multidisciplinary tumor boards with a review of all tumors by pathologists for classification and staging. Six cases of MNTCLH were diagnosed during a review of 1007 thymic epithelial tumors. Histologically, epithelial cells with atypia and mitoses formed micronodules that were surrounded by an abundant lymphoid background with follicles. There was neither obvious fibro-inflammatory stroma nor necrosis. Spindle cells areas were common. Initial diagnosis was micronodular thymoma in two cases, cellular atypia being overlooked, eclipsed by the micronodular pattern. Immunohistochemistry with a panel of five antibodies showed that cytokeratins (AE1-AE3) and p63-positive epithelial cells also expressed CD5 and that there was no TdT-positive cells within the tumors. CD20 highlighted the lymphoid hyperplasia. Additionally epithelial cells also expressed CD117 and diffusely Glut 1. Twenty-seven micronodular thymomas with lymphoid stroma diagnosed during the same period did not show the CD5 and CD117 positivities seen in MNTCLH and contained TdT-positive lymphocytes. Three of the 6 patients with MNTCLH had adjuvant radiotherapy. Three patients with follow-up information were alive without recurrence at 38, 51, and 95 months. Our study shows that immunohistochemistry, such as that used in the RYTHMIC network with a small panel of antibodies, may easily help to confirm the correct diagnosis of MNTCLH, a rare and low-aggressive form of thymic carcinoma, and avoid the misdiagnosis of micronodular thymoma., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Introduction: Thymomas are rare intrathoracic malignancies that may be aggressive and difficult to treat. Knowledge and level of evidence for treatment strategies are mainly based on retrospective studies or expert opinion. Currently there is no strong evidence that postoperative radiotherapy after complete resection of localized thymoma is associated with survival benefit in patients. RADIORYTHMIC is a phase III, randomized trial aiming at comparing postoperative radiotherapy versus surveillance after complete resection of Masaoka-Koga stage IIb/III thymoma. Systematic central pathologic review will be performed before patient enrollment as per the RYTHMIC network pathway., Patients and Methods: Three hundred fourteen patients will be included; randomization 1:1 will attribute either postoperative radiotherapy (50-54 Gy to the mediastinum using intensity-modulated radiation therapy or proton beam therapy) or surveillance. Stratification criteria include histologic grading (thymoma type A, AB, B1 vs B2, B3), stage, and delivery of preoperative chemotherapy. Patient recruitment will be mainly made through the French RYTHMIC network of 15 expert centers participating in a nationwide multidisciplinary tumor board. Follow-up will last 7 years. The primary endpoint is recurrence-free survival. Secondary objectives include overall survival, assessment of acute and late toxicities, and analysis of prognostic and predictive biomarkers., Results: The first patient will be enrolled in January 2021, with results expected in 2028., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Pure red cell aplasia (PRCA) is a rare paraneoplastic syndrome observed in 2-5 % of thymomas. Literature reports great variability in its management. Based on an illustrative clinical case, we present a systematic literature review whose main objective is to evaluate the therapeutic management of PRCA. The literature search was performed based on the PICO method in the Medline and Scopus databases. The reference clinical case concerns a 51-year-old woman with stage IVa thymoma. After initial response to chemotherapy, a locoregional progression occurred with PRCA development that responded favorably under second line chemotherapy. The patient finally died in a context of bicytopenia with febrile neutropenia. The systematic review covers 135 articles published between 1950 and 2019. Thymectomy alone or in combination with other therapies showed a 31 % complete remission (CR) rate for PRCA of, whereas none was reported with anti-tumor treatments without thymectomy. Among immunomodulatory therapies, cyclosporin gave the highest percentage of CR (74 %). Finally, the combination of thymectomy and immunomodulatory treatments showed a CR rate of 45 %. Thymectomy appeared to be the most effective anti-tumor treatment for PRCA. Immunomodulatory therapies, particularly cyclosporine, are shown effective, but the risk of infectious complications must be considered. The optimal place of anti-tumor and immunomodulatory therapies against PRCA has yet to be determined., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: Lymph node dissection (LND) and nodal metastases in thymomas remain controversial and understudied. The aim of our study was to evaluate the incidence of nodal metastasis and the short term outcomes of systematic LND in thymomas., Material and Methods: From December 2017 to September 2020, we performed 54 LND conducted according to the International Thymic Malignancy Interest Group (ITMIG) lymph node map. This group was compared to a historical control group of 55 patients who underwent surgery in our center from January 2015 to November 2017., Results: LND was performed in 72 % and in 5 % of the cases in the study cohort group and historical control group, respectively. The number of lymph nodes retrieved was significantly higher in the study cohort group (3.89 per patient vs. 1.62, p = 0.0021). In the whole population studied, nodal metastases were found in 3 patients (2.8 % of all patients) with 5.6 % in the cohort study group vs. 0 % in the control group (p = 0.12). Patients with nodal metastasis had larger tumors (> 7 cm), and a higher histology grade (B2 and B3). There was a trend towards higher risk of laryngeal nerve palsy in the cohort study group (9.3 % vs. 1.8 %, p = 0.11)., Conclusion: Systematic LND increases the number of lymph node harvested and detects more lymph node metastases, which remains infrequent in thymomas. The impact of LND and the true prognostic significance of lymph node metastases remains controversial. Given the potential complications, LND or sampling should not be perfomed in small, encapsulated and low grade thymomas., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The RYTHMIC network, supported by the French National Cancer Institute is dedicated to the management of patients with thymic epithelial tumors through regional and national multidisciplinary tumor boards. Tumor board decisions are based on the initial pathology diagnoses. However, following clinical inclusion in the network, a central pathology review is organized, implicating a panel of pathologists, for histotype and stage classification, which is different from a classical second opinion from pathologist to pathologist for a difficult case. Thanks to the participation of all French pathologists, more than 1000 cases have been reviewed by the panel. The aim of this review is to share with the French pathology community, the experience of the group. It underlines the importance of macroscopy and surgeon-pathologist involvement to allow a good central review, the main histopathological and immunophenotypical patterns of the most frequent thymomas and thymic carcinoma types, the differential diagnoses, as well as the difficulties for the panel to reproducibly assess on slides, stage, for some cases., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Competing Interests: "Les auteurs déclarent n’avoir aucun lien d’intérêts."

Objective: Our aim was to investigate appropriate postoperative management based on the risk of disease recurrence in thymic epithelial tumors after complete resection., Methods: The Chinese Alliance for Research in Thymomas retrospective database was reviewed. Patients having stage I to IIIa tumors without pretreatment and with complete resection were included. Clinicopathologic variables with statistical significance in the multivariate Cox regression were incorporated into a nomogram for building a recurrence predictive model., Results: A total of 907 cases, including 802 thymomas, 88 thymic carcinomas, and 17 neuroendocrine tumors, were retrieved between 1994 and 2012. With a median follow-up of 52 months, the 10-year overall survival rate was 89.5%. Distant and/or locoregional recurrences were noted in 53 patients (5.8%). The nomogram model revealed histologic type and T stage as independent predictive factors for recurrence, with a bootstrap-corrected C-index of 0.86. On the basis of this model, patients with T1 thymomas or T2 or T3 type A, AB, or B1 thymomas had a significantly lower incidence of recurrence (low-risk group) than those with T2 or T3 type B2 or B3 thymomas and all thymic carcinomas and neuroendocrine tumors (high-risk group) (2.7% versus 20.1% [p < 0.001]). In the high-risk group, more than half of the recurrences (55.2% [16 of 29]) were seen within the first 3 postoperative years, whereas all recurrences but one were recorded within 6 years after surgery. Recurrence occurred quite evenly over 10 postoperative years in the low-risk group., Conclusions: A 6-year active surveillance should be considered in high-risk patients regardless of adjuvant therapy. For low-risk patients, annual follow-up may be sufficient. Studies examining postoperative adjuvant therapies would be plausible in high-risk patients., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

The pathogenesis of thymic epithelial tumors remains poorly elucidated. The PIK3/Akt/mTOR pathway plays a key role in various cancers; interestingly, several phase I/II studies have reported a positive effect of mTOR inhibitors in disease control in thymoma patients. A major limit for deciphering cellular and molecular events leading to the transformation of thymic epithelial cells or for testing drug candidates is the lack of reliable in vitro cell system. We analyzed protein expression and activation of key players of the Akt/ mTOR pathway namely Akt, mTOR, and P70S6K in eleven A, B and AB thymomas as well as in normal thymuses. While only Akt and phospho-Akt were expressed in normal thymuses, both Akt and mTOR were activated in thymomas. Phospho-P70S6K was expressed in all thymic tumors whatever their subtypes, and absent in normal thymus. Interestingly, we report the activation of Akt, mTOR and P70S6 proteins in primary thymic epithelial cells maintained for short period of time after their derivation from seven AB and B thymomas. Finally, we showed that rapamycin (100 nM) significantly reduced proliferation of thymoma- derived epithelial cells without inducing cell death. Our results suggest that the activation of the Akt/ mTOR pathway might participate to the cell proliferation associated with tumor growth. Ultimately, our data enhance the potential role of thymic epithelial cells derived from tissue specimens for in vitro exploration of molecular abnormalities in rare thymic tumors., Competing Interests: The authors have declared that no competing interests exist.

Several surgical procedures, from debulking to extrapleural pneumonectomy, may be applied for stage IVa Masaoka thymomas, but their efficiency is still controversial. Case studies have favored R 0 resection as the cornerstone of multimodal therapy for locoregional metastatic extension. This report describes a standardized procedure combining a cytoreductive surgical procedure and intrathoracic chemohyperthermia on a 46-year-old patient presenting with B2 thymoma and synchronous unilateral pleural metastasis., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Thymic tumours are rare diseases that for most of the cases are cured with surgery and eventually adjuvant radiotherapy. However, about 30% of patients present with advanced stage or relapsing tumours, which require administration of chemotherapy. While cisplatin-adriamycin-cyclophosphamide combination is regularly prescribed, other drugs have been assessed in the literature. Our aim is to evaluate the effectiveness (response rate) of systemic treatments, whatever the therapeutic line, including chemotherapy, targeted therapies and immunotherapies, in thymoma and thymic carcinoma, using the principles of evidence-based medicine. A systematic review was designed using the PICO system, by an experienced librarian and clinicians' experts in thoracic oncology, through the Ovid Medline system. Only phase II-IV trials and retrospective studies including at least 14 patients treated with the same regimen were considered. Articles were independently selected by at least two investigators. Fifty-five eligible articles were retrieved. Sixty% were dealing with platinum-based regimens, mainly cisplatin, and showed overall similar activity (mostly response rate above 50%) independently of the line of treatment or histological type (thymoma versus thymic carcinoma). Non-platinum based regimens included octreotide-prednisone and capecitabine-gemcitabine. Promising data of immunotherapy with antiPDL1 antibody (pembrolizumab) requires confirmation. Based on available data, the most popular and active regimens are cisplatin-anthracycline (CAP or ADOC) or cisplatin-etoposide combinations that should be recommended when considering first-line chemotherapy in thymoma or thymic carcinoma., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Thymic epithelial tumors (TETs) are one of the rarest adult malignancies. Among TETs, thymoma is the most predominant, characterized by a unique association with autoimmune diseases, followed by thymic carcinoma, which is less common but more clinically aggressive. Using multi-platform omics analyses on 117 TETs, we define four subtypes of these tumors defined by genomic hallmarks and an association with survival and World Health Organization histological subtype. We further demonstrate a marked prevalence of a thymoma-specific mutated oncogene, GTF2I, and explore its biological effects on multi-platform analysis. We further observe enrichment of mutations in HRAS, NRAS, and TP53. Last, we identify a molecular link between thymoma and the autoimmune disease myasthenia gravis, characterized by tumoral overexpression of muscle autoantigens, and increased aneuploidy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The association between thymoma and autoimmunity is well known. Besides myasthenia gravis, which is found in 15 to 20% of patients with thymoma, other autoimmune diseases have been reported: erythroblastopenia, systemic lupus erythematosus, inflammatory myopathies, thyroid disorders, Isaac's syndrome or Good's syndrome. More anecdotally, Morvan's syndrome, limbic encephalitis, other autoimmune cytopenias, autoimmune hepatitis, and bullous skin diseases (pemphigus, lichen) have been reported. Autoimmune diseases occur most often before thymectomy, but they can be discovered at the time of surgery or later. Two situations require the systematic investigation of a thymoma: the occurrence of myasthenia gravis or autoimmune erythroblastopenia. Nevertheless, the late onset of systemic lupus erythematosus or the association of several autoimmune manifestations should lead to look for a thymoma. Neither the characteristics of the patients nor the pathological data can predict the occurrence of an autoimmune disease after thymectomy. Thus, thymectomy usefulness in the course of the autoimmune disease, except myasthenia gravis, has not been demonstrated. This seems to indicate the preponderant role of self-reactive T lymphocytes distributed in the peripheral immune system prior to surgery. Given the high infectious morbidity in patients with thymoma, immunoglobulin replacement therapy should be considered in patients with hypogammaglobulinemia who receive immunosuppressive therapy, even in the absence of prior infection., (Copyright © 2017 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Background: Pleural recurrences are a hallmark of thymomas, and represent a challenge for multidisciplinary management. The purpose of this study was to assess the feasibility and the results in terms of morbidity, mortality and survival rates, of Intra-Thoracic Chemo-Hyperthermia (ITCH) for the treatment of pleural recurrences of thymomas., Methods: Retrospective analysis of 19 consecutives patients between 1997 and 2015 treated by surgical cytoreduction (pleurectomy) followed by ITCH with 25mg/m 2 of mitomycin, and 50mg/m 2 of Cisplatin., Results: There were 8 men and 11 women with a median age of 44 years. ITCH was combined with pleurectomy alone in 4 (22%) patients, pleurectomy and wedge resections in 14 (74%) patients; 1 (5%) patient had a pleuropneumonectomy. There were no perioperative deaths, and 5 patients (26%) presented with postoperative complication, including 3 (16%) cases related to chemotherapy (one case of reversible grade 2 bone marrow aplasia, and 2 cases of reversible, acute kidney failure). The median length of stay in intensive care unit and hospital were 1day and 10days, respectively. After a median follow-up period of 39 months (range 10-127 months), median disease-free survival was 42 months. Five patients (26%) died during follow-up., Conclusions: Our data indicate that ITCH is a feasible option for selected patients with pleural recurrence of thymomas. ITCH clearly provides long local control, without major safety issues, and prolonged survival may be achieved in selected patients. This therapeutic option should be discussed at a multidisciplinary tumor board., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Thymic tumors. Thymic epithelial tumors are rare malignancies, that may be aggressive and difficult to treat, with variable prognosis. The histopathological classification distinguishes two major tumor types: thymomas and thymic carcinomas. Autoimmune manifestations are observed in nearly one third of patients at diagnosis; myasthenia gravis is the most common, followed by pure red cell aplasia and hypogammaglobulinemia. Assessing the resectability of the tumor represents the first stage of the therapeutic strategy, as complete resection is the most significant prognostic factor on patient survival. For unresectable thymic tumors, treatment is then based on induction chemotherapy followed by surgical resection or radiotherapy. Following a call of the French National Cancer Institute, a network of expert centers for the management of thymic malignancies started in in 2012: RYTHMIC., Competing Interests: N. Girard déclare des interventions ponctuelles pour les entreprises BMS, MSD, AstraZeneca, Boehringer Ingelheim, Pfizer, Roche, Novartis et Teva. C. Merveilleux du Vignaux déclare n’avoir aucun lien d’intérêts. B. Besse et T. Molina n’ont pas transmis de déclaration d'intérêts.

Background: Sunitinib is a potent oral tyrosine kinase inhibitor of VEGFRs, KIT, and PDGFRs. In a single arm phase II trial, sunitinib has demonstrated its potential activity in refractory thymic carcinoma (TC) and thymoma (T). Taking advantage of the French RYTHMIC network prospective database, we investigated the off-label efficacy of sunitinib in previously-treated thymic epithelial tumors (TETs) patients not included in a clinical trial., Methods: RYTHMIC database started in 2012, and prospectively collects clinical, imaging, treatment, and follow-up data of all patients diagnosed with TET, for whom management is discussed at a national multidisciplinary tumor board. All patients who received sunitinib were selected for this analysis., Results: 28 patients from 7 institutions were identified, including 20 TC and 8T; 32% of patients were females, and median age was 50 years. Fifteen patients (54%) received sunitinib as ≥4th line treatment. The initial daily dose of sunitinib was 50mg in 11 patients, 37.5mg in 16 patients and 25mg in 1 patient. Sunitinib adverse events were all manageable and tolerable; 8 patients had to stop sunitinib due to toxicity after a median duration of treatment of 2.7 months. In the overall population, disease control rate was of 63% (86% for T, and 55% for TC); overall response rate was 22% (29% for T, and 20% for TC). Median PFS in the whole population was 3.7 months (5.4 months for T, and 3.3 months for TC, p=0.097). The median overall survival in the whole population was 15.4 months: survival was not reached for T, and was 12.3 months for TC patients (p=0.043)., Conclusion: Sunitinib is an active treatment in TETs irrespective of histological subtype, supporting the use of tyrosine kinase inhibitors with anti-angiogenic activity as alternative treatment options in refractory disease., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objectives: To describe the clinical features, treatment, and outcome of autoimmune diseases (AD) in a cohort of patients with thymoma., Design: Pathological records from three university hospitals, between 2005 and 2011, were reviewed to identify patients with thymoma. Patients with thymoma and AD were compared with patients with thymoma without AD., Results: 47/85 (55%) cases of thymoma had AD, including myasthenia gravis (MG) (n=33), Hashimoto's thyroiditis (n=4), Isaac's syndrome (n=3), Morvan syndrome (n=2), pure red cell aplasia (n=2), systemic lupus (n=2), lichen planus (n=2), and one case of each following conditions: aplastic anemia, autoimmune hemolytic anemia, Good's syndrome, pemphigus, autoimmune hepatitis, Graves' disease, limbic encephalitis, and inflammatory myopathy. Six patients (7%) presented at least 2 ADs. The median duration of follow-up after surgery was 60 months (40-78 months). In 32 patients, the diagnosis of AD preceded the diagnosis of thymoma, in 9 patients, thymoma was diagnosed at the same time as the AD and 7 patients had been operated on when they developed an AD. We found a significative difference on the Masaoka stage between the MG patients and the patients who present another AD (p=0.028). No risk factor for developing an AD after thymectomy was identified., Conclusions: We describe here the long-term follow-up of a large series of AD related to thymoma. Our results confirm previous data concerning AD occurrence in patients with thymoma and suggest that preexisting autoimmunity is not a risk factor for developing autoimmune manifestations after thymectomy., (Copyright © 2015 Elsevier B.V. All rights reserved.)

This overview of the 4th edition of the World Health Organization (WHO) Classification of thymic tumors has two aims. First, to comprehensively list the established and new tumor entities and variants that are described in the new WHO Classification of thymic epithelial tumors, germ cell tumors, lymphomas, dendritic cell and myeloid neoplasms, and soft-tissue tumors of the thymus and mediastinum; second, to highlight major differences in the new WHO Classification that result from the progress that has been made since the 3rd edition in 2004 at immunohistochemical, genetic and conceptual levels. Refined diagnostic criteria for type A, AB, B1-B3 thymomas and thymic squamous cell carcinoma are given, and it is hoped that these criteria will improve the reproducibility of the classification and its clinical relevance. The clinical perspective of the classification has been strengthened by involving experts from radiology, thoracic surgery, and oncology; by incorporating state-of-the-art positron emission tomography/computed tomography images; and by depicting prototypic cytological specimens. This makes the thymus section of the new WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart a valuable tool for pathologists, cytologists, and clinicians alike. The impact of the new WHO Classification on therapeutic decisions is exemplified in this overview for thymic epithelial tumors and mediastinal lymphomas, and future perspectives and challenges are discussed.

Introduction: The 2004 version of the World Health Organization classification subdivides thymic epithelial tumors into A, AB, B1, B2, and B3 (and rare other) thymomas and thymic carcinomas (TC). Due to a morphological continuum between some thymoma subtypes and some morphological overlap between thymomas and TC, a variable proportion of cases may pose problems in classification, contributing to the poor interobserver reproducibility in some studies., Methods: To overcome this problem, hematoxylin-eosin-stained and immunohistochemically processed sections of prototypic, "borderland," and "combined" thymomas and TC (n = 72) were studied by 18 pathologists at an international consensus slide workshop supported by the International Thymic Malignancy Interest Group., Results: Consensus was achieved on refined criteria for decision making at the A/AB borderland, the distinction between B1, B2, and B3 thymomas and the separation of B3 thymomas from TCs. "Atypical type A thymoma" is tentatively proposed as a new type A thymoma variant. New reporting strategies for tumors with more than one histological pattern are proposed., Conclusion: These guidelines can set the stage for reproducibility studies and the design of a clinically meaningful grading system for thymic epithelial tumors.

Thymic epithelial neoplasms are rare malignancies with about 250 new incident cases in France every year. The WHO histologic classification distinguishes thymoma and thymic carcinoma which are tumors with different biological and clinical behaviors and outcomes. The Masaoka-Koga staging system is considered as a reference and is also of prognosis value. Diagnosis, multimodal treatment and follow-up of thymic epithelial neoplasms require a multidisciplinary approach where surgery is the cornerstone treatment. A national expert center coordinates thymic epithelial neoplasms management with 12 other regional expert centers through the French organization named RYTHMIC (www.rythmic.org). Patient's files have to be discussed at regional or national multidisciplinary staff. A group of expert pathologists will centrally review tumors when the diagnosis or classification is a matter of controversy. Among its objectives, RYHTMIC has to promote medical education, patient's information and research. This review focuses on RYTHMIC guidelines and data regarding multimodal management and targeted therapies in epithelial thymic neoplasms.

Radiotherapy is a major therapeutic modality for thymic malignancies. The exact role of adjuvant radiotherapy after complete resection is still debated for stage II through III tumors. Histology or size, capsular invasion, and even molecular data may be included in the decision making. Radiotherapy may be recommended for stage III thymomas, thymic carcinoma, or after incomplete surgical resection. Combination with chemotherapy may be useful, and must be further evaluated using validated end points, including 5- and 10-year time-to-progression and overall survival. Several initiatives have been taken worldwide to launch collaborative studies in the field, including prospective trials specifically readdressing the role of radiotherapy for thymic malignancies., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Introduction: Thymic malignancies are rare intrathoracic tumors that may be aggressive and difficult to treat in advanced stage. Over the past years, significant efforts have been conducted to dissect the molecular pathways involved in the carcinogenesis of these tumors. Insights have been made following anecdotal clinical responses to targeted therapies, and large-scale genomic analyses have been conducted., Methods: Review of the literature, 1990-2010., Results: The Epidermal Growth Factor Receptor (EGFR) is frequently overexpressed in thymomas and thymic carcinomas, but EGFR mutations are exceptional, and this does not support the use of EGFR tyrosine kinase inhibitors. On the contrary, single observations of responses create a basis for further evaluation of cetuximab in thymomas. KIT-mutant thymic carcinomas represent a small molecular subset of thymic tumors. The clinical relevance of KIT mutations is more limited in thymic carcinoma than in GIST as KIT mutations are far less frequent (7% of thymic carcinomas) and are not correlated with KIT expression; furthermore, KIT mutants are not uniformly sensitive to imatinib. Beyond EGFR and KIT signaling pathways, other molecular alterations with potential prognostic or predictive relevance are emerging in thymic malignancies., Conclusions: Given the rarity of these tumors, translation of preclinical findings to the clinic may be quick and represents one of the most promising therapeutic approaches for advanced-stage thymic malignancies.

Introduction: Thymic epithelial tumors are rare mediastinal malignancies that can be invasive and difficult to treat. Insulin-like growth factor-1 receptor (IGF-1R) is a transmembrane receptor implicated in the regulation of cell metabolism, growth, and survival. As higher levels of IGF-1R protein expression may be associated with relative sensitivity to anti-IGF-1R antibody treatment, we investigated IGF-1R expression in thymic malignancies., Methods: Sixty-three thymic tumors (56 thymomas and seven thymic carcinomas) were analyzed for total IGF-1R expression using immunohistochemistry with a specific antibody (clone G11, Roche-Ventana, Tucson, AZ). Expression levels were correlated with relevant clinical and pathologic variables, including epidermal growth factor receptor and KIT expression, and patient outcome., Results: IGF-1R staining was negative in 13 (21%) cases, low (1+) in 20 (32%) cases, moderate (2+) in 20 (32%) cases, and high (3+) in 10 (16%) cases. Moderate to high IGF-1R staining was observed in 6 of 7 (86%) thymic carcinomas and in 24 of 56 (43%) thymomas (p = 0.039). Moderate to high IGF-1R staining was associated with high epidermal growth factor receptor staining (p = 0.015). By multivariate analysis, only tumor stage and histologic type were significant prognostic factors on time to progression (hazard ratio [HR] = 4.12, 95% confidence interval [CI]: 1.98-14.23; p = 0.010 and HR = 2.79, 95% CI: 1.62-12.50; p = 0.018, respectively). There was no association between IGF-1R expression and time to progression (HR = 3.07, 95% CI: 0.38-24.59; p = 0.291)., Conclusion: A majority of thymic malignancies display moderate to high expression of IGF-1R. The lack of preclinical models prevented us to further study the functional consequences of anti-IGF-1R therapy in this setting. However, given correlations in other cancers, these data support the evaluation of anti-IGF-1R inhibitors in thymic tumors.

Purpose: Thymomas and thymic carcinomas are rare intrathoracic malignancies that can be invasive and refractory to conventional treatment. Because these tumors both originate from the thymus, they are often grouped together clinically. However, whether the underlying biology of these tumors warrants such clustering is unclear, and the optimum treatment of either entity is unknown., Experimental Design: All thymic tumors were profiled for mutations in genes encoding components of the EGFR and KIT signaling pathways, assessed for EGFR and KIT expression by immunohistochemistry, and analyzed by array-based comparative genomic hybridization. Previously untreated tumors were subjected to global gene expression arrays., Results: We analyzed 45 thymic tumors [thymoma, n = 38 (type A, n = 8; type B2, n = 22; type B3, n = 8); thymic carcinoma, n = 7]. One thymoma and one thymic carcinoma harbored KRAS mutations (G12A and G12V, respectively), and one thymoma had a G13V HRAS mutation. Three tumors displayed strong KIT staining. Two thymic carcinomas harbored somatic KIT mutations (V560del and H697Y). In cell viability assays, the V560del mutant was associated with similar sensitivities to imatinib and sunitinib, whereas the H697Y mutant displayed greater sensitivity to sunitinib. Genomic profiling revealed distinct differences between type A to B2 thymomas versus type B3 and thymic carcinomas. Moreover, array-based comparative genomic hybridization could readily distinguish squamous cell carcinomas of the thymus versus the lung, which can often present a diagnostic challenge., Conclusions: Comprehensive genomic analysis suggests that thymic carcinomas are molecularly distinct from thymomas. These data have clinical, pathologic, and therapeutic implications for the treatment of thymic malignancies.

Thymomas are rare intrathoracic malignant tumors. Commonly used staging system is the Masaoka classification, based on peroperative and histopathological findings. Surgery is the cornerstone of the management of thymomas, initially being useful for precise histopathological diagnosis and staging, and in most cases ensuring the first step of the therapeutics simultaneously. After tumor stage, complete resection is the most constant and significant prognostic factor for progression-free and overall survival. Postoperative radiotherapy is recommended in incompletely resected thymomas. Completely resected stage II and III tumors may also benefit from adjuvant radiotherapy to reduce local recurrence rates but without impact on survival. In primary unresectable thymomas, multimodal strategy nowadays includes neoadjuvant chemotherapy, extensive surgery, adjuvant radiotherapy, and in some cases, adjuvant chemotherapy. The most popular chemotherapy regimens combine cisplatin, adriamycin, etoposide, cyclophophamide, or ifosfamide.The management of thymomas is a paradigm of cooperation between clinicians, surgeons, and pathologists from establishing the diagnosis to organizing the therapeutic strategy and evaluating the prognosis. As a consequence of their rarity, no prospective randomized trials are available and collaborative studies are warranted to evaluate and improve current therapeutic standards, taking into account recent improvements in techniques, such as robotic surgery, radiotherapy, and supportive treatments.