Search

Objective: The aim of this study is to describe characteristics and survival outcome of patients who underwent surgical treatment for distant thymoma relapse according to the definition of the International Thymic Malignancy Interest Group., Methods: Data of patients affected by thymoma recurrence from four different institutions were collected and retrospectively reviewed. Patients with locoregional metastases who underwent nonsurgical therapies and with incomplete data on follow-up were excluded. According to the International Thymic Malignancy Interest Group distant recurrence definition, patients with recurrence due to hematogenic localization were included. Clinical and pathologic characteristics were described using descriptive statistics, whereas survival outcome was calculated using Kaplan-Meier curves and Cox regression analysis., Results: The analysis was conducted on 40 patients. A single localization was present in 13 patients, the relapse was intrathoracic in 28 cases (70%), and lung involvement was found in 26 cases. The liver was operated in seven cases, whereas other kinds of abdominal involvement were detected in eight cases. Adjuvant treatment was administered in 22 cases (55%).Five- and 10-year overall survival (OS) were 67% and 30%, respectively. Univariable analysis identified as significant favorable factor a low-grade histology (A, B1, B2): five-year OS at 92.3% versus 53.3% in high-grade (B3-C) (p = 0.035). Site of recurrence and number of localization did not influence the prognosis, but in patients with adjuvant therapy administration, there was a survival advantage also if not statistically significant: five-year OS 84.8% versus 54.5% in patients without adjuvant therapy (p = 0.101).Multivariable analysis confirmed as independent prognostic factor low-grade histology: hazard ratio = 0.176, 95% confidence interval 0.042-0.744, p = 0.018., Conclusions: Our study revealed a good survival outcome in patients who underwent surgery for distant thymoma recurrence, independently from the number and site of the relapse localization. Patients with A, B1, or B2 histology presented a significantly better survival than patients with B3-C., Competing Interests: Disclosure All authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Non-small Cell Lung Cancer (NSCLC) with intralobar satellite nodule are defined as T3 (T3SN). We investigated the main features of these tumors and analyzed their impact on Overall Survival (OS)., Methods: This was a retrospective multicentric study including all pT3SN NSCLC operated on between 2005 and 2020, excluding patients with multifocal ground-glass opacities; who received induction therapies; N3 or stage IV. The diameter of largest (LgN) and smallest nodule (SmN), the total diameter (sum of diameter of all nodules, TS), and the number of SN were measured., Results: Among 102 patients, 64.7 % were male. 84.3 % of patients had one SN (84.3 %), 9.8 % two SN while 5.9 % more than 2 SN. 63 patients were pN0. LgN (p = 0.001), SN (p = 0.005) and TS (p = 0.014) were significantly related to lymph-node metastasis; the LgN and TS were related to visceral pleural invasion (p < 0.001). Five-year OS was 65.1 %; at univariable analysis more than 2 satellite nodules, LgN and TS were significantly related to worse OS; at multivariable analysis, TS (Hazard Ratio [HR] 1.116 95 % Confidence Interval [CI] 1.008-1.235, p = 0.034) was an independent prognostic factors for OS. No significant prognostic factors were found for DFS at multivariable analysis. In pN0 patients, LgN (HR 1.051, 95 % CI 1.066-1.099, p = 0.027) and non-adenocarcinoma (HR 5.315 CI 95 % 1.494-18.910, p = 0.010) influenced OS., Conclusions: Tumor size is related to tumor's local invasiveness. TS is an independent prognostic factor for OS. Patients with more than 2 SN seem to be at higher risk for death and recurrence., Competing Interests: Declaration of competing interest Declarations of interest: none., (© 2024 Elsevier Ltd, BASO ∼ The Association for Cancer Surgery, and the European Society of Surgical Oncology. 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 lymph node map is the pillar on which accurate assignment and documentation of nodal classification stands. The International Thymic Malignancy Interest Group created the first map for thymic epithelial malignancies in conjunction with the eighth edition of the TNM classification, representing the first official TNM classification of thymic epithelial malignancies. The map was based on clinical experience and published studies, but it was largely empirical because of limited available data. Dissemination of the map and implementation of a standard thymic stage classification across the world in 2017 have provided more consistent and granular data., Methods: More than twice as many cases of node involvement are available for analysis in the current database compared with that of the eighth edition database, allowing validation of many aspects of the eighth edition map. This article details the process and considerations for refinement of the thymic map for the ninth TNM used by the Thymic Domain of the Staging and Prognostic Factors Committee of the International Association for the Study of Lung Cancer. The committee evaluated a large international collaborative data set, published anatomical and clinical studies pertaining to lymph node spread from thymic epithelial tumors, in conjunction with the analysis underlying refinements of the TNM components for the ninth edition TNM classification., Results: The node map boundaries of the N1 and N2 categories remain unchanged. Visual clarifications have been added to the nomenclature of nodal stations within these regions., Conclusions: On the basis of the recommendation to keep the N component unchanged for the ninth edition TNM classification, the lymph node map remains unchanged as well; however, clarifications have been added to facilitate clinical use., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. 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.)

Introduction: In 2014, a TNM-based system for thymic epithelial tumors was proposed. The TNM stage classification system was published as a result of a joint project from the International Association for the Study of Lung Cancer and the International Thymic Malignancy Interest Group for the eighth edition of the American Joint Commission on Cancer and the Union for International Cancer Control stage classification system. The Thymic Domain of the Staging and Prognostic Factors Committee of the International Association for the Study of Lung Cancer received the mandate to make proposals for the ninth edition of the TNM stage classification., Methods: A central thymic database was collected by the Cancer Research And Biostatistics with the contribution of the major thymic associations in the world., Results: A total of 11,347 patients were collected. Submitting organizations were the following: Japanese Association for Research in the Thymus, European Society of Thoracic Surgeons, Chinese Alliance for Research in Thymoma, Korean Association for Research in the Thymus, International Thymic Malignancy Interest Group, and Réseau tumeurs THYMiques et Cancer. Additional contributions came from centers in the United States, United Kingdom, Turkey, Australia, Spain, and Italy. A total of 9147 cases were eligible for analysis. Eligible cases for analysis came from Asia and Australia (5628 cases, 61.5%), Europe (3113 cases, 34.0%), and North America (406 cases, 4.4%)., Conclusions: This report provides an overview of the database that has informed the proposals for the updated T, N, and M components and the stage groups for the ninth TNM of malignant tumors., (Copyright © 2023. Published by Elsevier Inc.)

Thymic epithelial tumors are presently staged using a consistent TNM classification developed by the International Association for the Study of Lung Cancer (IASLC) and approved by the Union for International Cancer Control and the American Joint Committee on Cancer. The stage classification is incorporated in the eight edition of the TNM classification of thoracic malignancies. The IASLC Staging and Prognostic Factors Committee (SPFC)-Thymic Domain (TD) is in charge for the next (ninth) edition expected in 2024. The present article represents the midterm report of the SPFC-TD: in particular, it describes the unresolved issues identified by the group in the current stage classification which are worth being addressed and discussed for the ninth edition of the TNM classification on the basis of the available data collected in the central thymic database which will be managed and analyzed by Cancer Research And Biostatistics. These issues are grouped into issues of general importance and those specifically related to T, N, and M categories. Each issue is described in reference to the most recent reports on the subject, and the priority assigned by the IASLC SPFC-TD for the discussion of the ninth edition is provided., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Thymoma and myasthenia gravis share several pathogenetic aspects including the role of surgery as a therapeutic option. Extended thymectomy is associated with excellent survival and good local control, especially in early stages, and its role for the neurologic disease has been recently validated. The aim of this study is evaluating oncologic and neurologic outcomes of myasthenic patients with thymoma who underwent extended thymectomy., Methods: We retrospectively collected surgical, oncologic, and neurologic data of all myasthenic patients with thymoma who underwent extended thymectomy at our department from January 1994 to December 2016. Clinical and pathologic data, neurologic remission rate, and overall survival and disease-free interval were analyzed., Results: In all, 219 patients underwent extended thymectomy. The B2 histotype was the most represented thymoma (24.2%), and the most prevalent pathologic Masaoka stage was IIB (37.9%). The overall survival and disease-free survival were statistically different between early stage and advanced stage. During the surveillance, 33 patients (15.1%) had recurrences, treated in 21 cases with iterative surgery. Regarding neurologic outcomes, 75 patients (34.2%) reached a complete stable remission, 84 (38.4%) a pharmacologic remission, 51 (23.3%) had an improvement of their symptoms, and in 9 patients (4.1%) myasthenia was unchanged or worsened., Conclusions: Surgery is a cornerstone in the treatment of patients with both thymoma and myasthenia gravis. Extended thymectomy, as proposed by Masaoka, offers considerable oncologic outcomes with an excellent survival and low recurrence rate of thymoma; moreover, surgery leads to remarkable neurologic results., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction: The International Thymic Malignancy Interest Group (ITMIG) classifies thymoma recurrences on the basis of the topographic location, but its effectiveness in prognosis prediction has not been well investigated yet. Aims of this study are to analyze survival outcome of patients surgically treated for thymoma recurrence according to the ITMIG recurrence classification and to investigate possible alternatives., Methods: From January 1, 1990, to January 7, 2017, data on 135 surgically treated patients for thymoma recurrence from three high-volume centers were collected and retrospectively analyzed. Patients were classified according to the ITMIG classification as local, regional, and distant. The ITMIG classification and alternative classifications were correlated to overall survival (OS)., Results: According to the ITMIG classification, recurrence was local in 17 (12.5%), regional in 97 (71.8%), and distant in 21 (15.7%) patients, with single localization in 38 (28.2%) and multiple localizations in 97 (71.8%). The 5- and 10-year OS were 79.9% and 49.7% in local, 68.3% and 52.6% in regional, and 66.3% and 35.4% in distant recurrences, respectively, but differences were not statistically significant (p = 0.625). A significant difference in survival was present considering single versus multiple localizations: 5- and 10-year OS of 86.2% and 81.2% versus 61.3% and 31.5% (p = 0.005, hazard ratio = 7.22, 95% confidence interval: 0.147-0.740), respectively. Combining the localization number with the recurrence site, ITMIG locoregional single recurrence had a statistically significant better survival compared with patients with ITMIG locoregional multiple recurrence or ITMIG distant recurrence (p = 0.028). Similarly, a significant difference was present considering intrathoracic single versus intrathoracic multiple versus distant recurrence (p = 0.024)., Conclusions: The ITMIG classification for thymoma recurrence did not have significant survival differences comparing local, regional, and distant recurrences. Integrating this classification with the number of the localizations may improve its effectiveness in prognosis prediction., (Copyright © 2021. Published by Elsevier Inc.)

Objectives: The International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee-Thymic Domain conducted a web-based cross-sectional survey to assess the acceptance of the TNM thymic staging system in the thoracic community., Methods: A 50-item, web-based questionnaire was circulated among the members of the major thymic organizations worldwide from September to December 2018. The survey consisted of six sections (general information; overall perception of the TNM system; pretreatment staging; T category; N category; and perioperative treatments)., Results: In total, 217 responses were collected from 37 countries in four continents. The TNM classification was considered useful by 78% of the responders (N = 169); the Masaoka-Koga staging system was being used by 87% of the responders (N = 189). With regard to the T category, most responders (mostly surgeons) felt that the capsular and mediastinal pleural involvements should be considered separate T categories. As for the N category, 48% of the responders (N = 105) used the International Thymic Malignancies Interest Group/International Association for the Study of Lung Cancer thymic nodal map, and lymph node dissection (N1/N2) was performed for 50%/21% thymomas and 66%/41% thymic carcinomas. While analyzing the results by the three continents (Europe, Asia, and Americas), responders in Asia were found to report the largest use of the TNM system, the greatest attention to the N category, and the best participation in international thymic databases., Conclusions: The survey indicates that the Union for International Cancer Control/American Joint Committee on Cancer TNM stage classification of thymic tumors is gaining acceptance among the scientific community. The present results will guide the work of the Staging and Prognostic Factors Committee-Thymic Domain for the revision of the ninth edition of the TNM stage classification of thymic tumors., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Phrenic nerve infiltration has been described in as many as 33% of advanced thymomas; en bloc resection causes diaphragmatic loss of function, with detrimental effects on pulmonary function. We report the outcomes of selected patients operated on for invasive thymoma with a nerve-sparing technique., Methods: From 1990 to 2015 we used nerve-sparing surgery with the intention to treat all patients with advanced stage thymomas without preoperative evidence of hemidiaphragmatic palsy, but with macroscopic evidence of phrenic nerve involvement. All patients underwent adjuvant radiotherapy (45 to 60 Gy) with or without chemotherapy. Long-term outcomes and the pattern of recurrence were retrospectively analyzed., Results: Among 140 patients with stage III and IVa operated on during the study period, 19 women and 18 men with a median age of 52 years received a nerve-sparing resection. Myasthenia gravis was associated in 25 cases. In 12 patients, phrenic palsy was observed postoperatively, and eventually 4 of them recovered. Recurrence was found in 10 patients (7 stage IVa, 3 stage III) requiring additional therapies. Three patients died of cancer-related causes, with an overall survival of 265.4 months and a disease-free survival of 233.2 months., Conclusions: Phrenic nerve preservation in cases of invasive thymomas is feasible and may warrant an acceptable local control of disease, if associated with radiotherapy. According to these results, this technique could be proposed to all patients with invasive thymoma, especially in those affected by severe comorbidities or with a poor performance status., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

In order to broaden knowledge on the pathogenesis of malignant pleural mesothelioma (MPM), we reviewed studies on the MPM-transcriptome and identified 119 deregulated genes. However, there was poor consistency among the studies. Thus, the expression of these genes was further investigated in the present work using reverse transcriptase-quantitative PCR (RT-qPCR) in 15 MPM and 20 non-MPM tissue samples. Fifty-nine genes showed a statistically significant deregulation and were further evaluated in two epithelioid MPM cell lines (compared to MET-5A, a non-MPM cell line). Nine genes (ACSL1, CCNO, CFB, PDGFRB, SULF1, TACC1, THBS2, TIMP3, XPOT) were deregulated with statistical significance in both cell lines, 12 (ASS1, CCNB1, CDH11, COL1A1, CXADR, EIF4G1, GALNT7, ITGA4, KRT5, PTGIS, RAN, SOD1) in at least one cell line, whereas 7 (DSP, HEG1, MCM4, MSLN, NME2, NMU, TNPO2) were close but did not reach the statistical significance in any of the cell line. Patients whose MPM tissues expressed elevated mRNA levels of BIRC5, DSP, NME2, and THBS2 showed a statistically significant shorter overall survival. Although MPM is a poorly studied cancer, some features are starting to emerge. Novel cancer genes are suggested here, in particular those involved in cell-cell and cell-matrix interactions., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Introduction: Soluble mesothelin related peptide (SMRP) was proposed as a promising diagnostic marker for malignant pleural mesothelioma (MPM). In a previous study, we found that rs1057147 within the 3' untranslated region of MSLN gene was associated with SMRP levels. Thus, we aimed to (1) confirm the previous association on a large series of volunteers and (2) test the hypothesis that the SNP could affect microRNA binding sites., Methods: The association analysis was verified in 759 subjects. Then, in silico predictions highlighted miR-611 and miR-887 as candidate miRNAs binding to the polymorphic site. Thus, chimeric constructs bearing the alternative alleles (G > A) were assayed alone or in cotransfection with the miRNA mimics, with dual luciferase reporter assay in non-MPM Met-5A cells. The miRNAs were also assayed by western blot analysis for their ability to down-regulate endogenous mesothelin in the MPM Mero-14 cell line., Results: We confirmed that, among non-MPM volunteers, GG homozygotes have the lowest SMRP levels. When the genotype is taken into account, the specificity of SMRP as biomarker improves from 79.7% to 85.3%. Dual-luciferase assays showed a significantly lower reporter activity when the vector harbored the G allele as compared to A allele. miR-887 mimic caused a reduced reporter activity of vectors harboring A or G alleles, while miR-611 was effective only on the vector harboring the G allele. Transfection of these miRNAs into Mero-14 cells significantly reduced endogenous MSLN protein., Conclusion: SMRP performance as diagnostic biomarker improved by considering the genotype rs1057147. This polymorphism most likely affects a binding site for miR-611.

Background: Our knowledge of thymic malignancies has largely been derived from small, single-institution series. Recognition of the need for broad collaboration led to the creation of the International Thymic Malignancy Interest Group (ITMIG) and the development of a large, centralized database to advance knowledge of these rare tumors., Methods: A multidisciplinary Database Committee was convened to define a common set of data elements a priori. Retrospective data were solicited from ITMIG members and collated using standardized fields. Patients with thymoma, thymic carcinoma, or thymic carcinoid were included., Results: Over a 6-month period, 47 institutions spanning 15 countries contributed a total of 6097 cases (mean, 129 [range, 10-1209]). The sex distribution was equal for thymomas, but there was a greater proportion of men with thymic carcinoma and thymic carcinoid (p < 0.0001). Nearly all cases (99%) were treated surgically. WHO type B2 was the most frequent histologic classification among thymomas, whereas squamous was the most common among thymic carcinomas. In total, 38% of patients with thymoma had myasthenia gravis compared with less than or equal to 5% for thymic carcinoma and thymic carcinoid. Median overall survival was 18.9 years (95% confidence interval [CI], 17.4-20.3) for thymoma, 6.8 years (95% CI, 5.5-7.9) for thymic carcinoma, and 7.5 years (95% CI, 6.5-8.5) for thymic carcinoid., Conclusions: The rapid creation of the ITMIG database demonstrates the feasibility of international collaboration for this rare set of malignancies and attests to the engagement of its membership. This database represents the largest collective data set ever assembled and provides an unprecedented resource for research of these tumors.

Despite longstanding recognition of thymic epithelial neoplasms, there is no official American Joint Committee on Cancer/Union for International Cancer Control stage classification. This article summarizes proposals for classification of the T component of stage classification for use in the 8th edition of the tumor, node, metastasis classification for malignant tumors. This represents the output of the International Association for the Study of Lung Cancer and the International Thymic Malignancies Interest Group Staging and Prognostics Factor Committee, which assembled and analyzed a worldwide database of 10,808 patients with thymic malignancies from 105 sites. The committee proposes division of the T component into four categories, representing levels of invasion. T1 includes tumors localized to the thymus and anterior mediastinal fat, regardless of capsular invasion, up to and including infiltration through the mediastinal pleura. Invasion of the pericardium is designated as T2. T3 includes tumors with direct involvement of a group of mediastinal structures either singly or in combination: lung, brachiocephalic vein, superior vena cava, chest wall, and phrenic nerve. Invasion of more central structures constitutes T4: aorta and arch vessels, intrapericardial pulmonary artery, myocardium, trachea, and esophagus. Size did not emerge as a useful descriptor for stage classification. This classification of T categories, combined with a classification of N and M categories, provides a basis for a robust tumor, node, metastasis classification system for the 8th edition of American Joint Committee on Cancer/Union for International Cancer Control stage classification.

A universal and consistent stage classification system, which describes the anatomic extent of a cancer, provides a foundation for communication and collaboration. Thymic epithelial malignancies have seen little progress, in part because of the lack of an official system. The International Association for the Study of Lung Cancer and the International Thymic Malignancies Interest Group assembled a large retrospective database, a multispecialty international committee and carried out extensive analysis to develop proposals for the 8th edition of the stage classification manuals. This tumor, node, metastasis (TNM)-based system is applicable to all types of thymic epithelial malignancies. This article summarizes the proposed definitions of the T, N, and M components and describes how these are combined into stage groups. This represents a major step forward for thymic malignancies.

Although the presence of nodal disease is prognostic in thymic malignancy, the significance of the extent of nodal disease has yet to be defined. Lymph node dissection has not been routinely performed, and there is currently no node map defined for thymic malignancy. To establish a universal language for reporting as well as characterize the staging of this disease more accurately, an empiric node map is proposed here. This was developed using prior classification systems, series reporting specifics of nodal involvement, anatomical studies of lymphatic drainage, and preexisting node maps of the chest as defined by the International Association for the Study of Lung Cancer and the neck as defined by the American Academy of Otolaryngology-Head and Neck Surgery and the American Society for Head and Neck Surgery. The development of this node map was a joint effort by the International Thymic Malignancy Interest Group and the Thymic Domain of the IASLC Staging and Prognostic Factors Committee. It was reviewed and subsequently approved by the members of ITMIG. This map will be used as an adjunct to define node staging as part of a universal stage classification for thymic malignancy. As more data are gathered using definitions set forth by this node map, a revision may be undertaken in the future.

Stage classification is an important underpinning of management of patients with cancer, and rests on a combination of three components: T for tumor extent, N for nodal involvement, and M for more distant metastases. This article details an initiative to develop proposals for the first official stage classification system for thymic malignancies for the 8th edition of the stage classification manuals. Specifically, the results of analysis of a large database and the considerations leading to the proposed N and M components are described. Nodal involvement is divided into an anterior (N1) and a deep (N2) category. Metastases can involve pleural or pericardial nodules (M1a) or intraparenchymal pulmonary nodules or metastases to distant sites (M1b).

The lack of an official-stage classification system for thymic malignancies is an issue that hampers progress in this rare disease. A collaborative effort by the International Association for the Study of Lung Cancer and the International Thymic Malignancies Interest Group is underway to develop proposals for such a system. A database of more than 10,000 cases worldwide has been assembled to provide a solid basis for analysis. This report outlines the structure of the effort and the process that has been designed.

Introduction: Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm associated with asbestos exposure. Currently, the molecular mechanisms that induce MPM development are still unknown. The purpose of this study was to identify new molecular biomarkers for mesothelial carcinogenesis., Methods: We analyzed a panel of 84 genes involved in extracellular matrix remodeling and cell adhesion by polymerase chain reaction (PCR) array in 15 samples of epithelioid mesothelioma and 10 samples of reactive mesothelial hyperplasia (MH; 3 of 25 samples were inadequate for mRNA analysis). To validate the differentially expressed genes identified by PCR array, we analyzed 27 more samples by immunohistochemistry, in addition to the 25 samples already studied., Results: Twenty-five genes were differentially expressed in MPM and MH by PCR array. Of these we studied matrix metalloproteinase 7 (MMP7), MMP14, CD44, and integrin, alpha3 expression by immunohistochemistry in 26 epithelioid MPM and 26 MH samples from the entire series of 52 cases. We observed higher MMP14 and integrin, alpha3 expression in MPM samples compared with MH samples (p = 0.000002 and p = 0.000002, respectively). Conversely, CD44 expression was low in most (57.7%) mesothelioma samples but only in 11.5% of the MH samples (p = 0.0013). As regards MMP7, we did not observe differential expression between MH and MPM samples., Conclusions: We have extensively studied genes involved in cell adhesion and extracellular matrix remodeling in MPM and MH samples, gaining new insight into the pathophysiology of mesothelioma. Moreover, our data suggest that these factors could be potential biomarkers for MPM.

Background: Primary neuroendocrine tumors of the thymus (NETT) are rare tumors and represent a distinct category of tumors collectively displaying morphologic and biological neuroendocrine features. We sought to evaluate factors influencing long-term survival in patients with primary NETT., Methods: From January 1990 to April 2011, 35 patients (27 male patients and 8 female patients) were surgically treated for primary NETT at 5 institutions., Results: No operative (30-day) mortality occurred. Morbidity was 37.14% (13/35 patients). All patients were followed for a total of 2,703 months. Fourteen patients had associated paraneoplastic syndrome. Twenty-four patients are alive, 19 of whom are free of disease and 5 of whom continue to have disease. The median overall survival was 153 months. The overall 5-year and 10-year actuarial survival rates were 84.34% and 60.82%, respectively. The 10-year survival was evaluated according to histologic type (typical carcinoid, 77.92%; atypical carcinoid, 54.55%; large-cell neuroendocrine carcinomas, 0%; Masaoka staging (stage I, 100%; stage II, 66.67%; stage III, 61.9%; stage Iva, 25%; stage IVb, 0%), presence of paraneoplastic syndrome (no = 70.67%; yes = 32.14%), postoperative radiotherapy (yes = 39.71%; no = 85.71.%), Surveillance, Epidemiology, and End Results (SEER) staging system (localized disease, 83.3%; regional disease, 53.3%; distant disease, 0%), tumor size (<7 cm = 90.9%; ≥7cm = 28.7%; p = 0.0007), and Ki67 expression, which was available in 23 patients (<10% = 85.71%; ≥10% = 0%; p = 0.0037)., Conclusions: The prognosis of primary NETT is statistically significantly related to tumor size >7 cm and to the proliferation index (evaluated by Ki67 expression >10%). The histologic type of the neoplasm, the presence of a paraneoplastic syndrome, the Masaoka staging, the evidence of distant disease, and postoperative radiotherapy also impact prognosis., (Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction: Malignant pleural mesothelioma (MPM) is a lethal tumor related to asbestos exposure. At present, the only instruments for screening and diagnosis are based on radiological tests, posing evident economic and radio-protectionist problems. Some authors are evaluating biological indicators, such as plasma osteopontin (pOPN) and serum soluble mesothelin-related peptides (SMRP). This study aimed to evaluate whether a combination of these two markers could increase sensitivity and specificity in diagnosis of epithelioid MPM., Methods: We enrolled 93 healthy subjects, 111 individuals with benign respiratory disease (BRD), and 31 patients with MPM, histologically and/or cytologically confirmed. SMRP and pOPN levels were determined using commercially available enzyme-linked immunosorbent assay kits. Though a logistic regression analysis, SMRP and pOPN were combined and translated into a new index, called "combined risk index.", Results: Differences in both SMRP and pOPN mean values between epithelial MPM patients and healthy subjects or BRD patients were statistically significant (p < 0.0001), whereas there was no difference in SMRP and pOPN mean values between healthy subjects and BRD patients. The performance in MPM diagnosis resulted improved by the combination of the two markers. The results of our study should be confirmed by a larger scale and, possibly, a multicenter study, which could better take into consideration the influence of some possible confounding factors such as glomerular filtration rate and other blood parameters., Conclusions: We combined SMRP and pOPN dosages to increase diagnostic accuracy. This study showed for the first time that combined SMRP and pOPN measurements can increase both sensitivity and specificity in terms of combined risk index.

Thymomas are neoplasms arising from the epithelial thymic cells, with a recurrence rate after complete resection ranging from 5 to 50%, according to the initial stage of disease. The pleura is the most frequent site of relapse, while distant metastases occur in less than 5% of the cases. Data in the literature show that recurrences can occur several years after the resection of a thymoma; unfortunately, few reports have analyzed the treatment of recurrences of thymoma. There is no standard treatment for the recurrent disease, and most of the treatments proposed by the authors are based more on their personal experience and individualized treatment than on 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. Surgery for recurrent thymoma is indicated if complete resection is feasible, whereas in the case of predicted debulking surgery, it may be considered as part of a multidisciplinary protocol. In the literature, a few case reports of the surgical treatment of metachronous distant metastases to liver or brain from thymoma have been described, but they are really 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, and it should always be considered because the other treatment modalities are not curative.

Introduction: Malignant pleural mesothelioma is a highly aggressive neoplasm with an incidence that is increasing world-wide. Mast cells are part of the innate immune system and have been associated with different solid tumors, but there is controversy surrounding their pro- and antitumorigenic effects in cancers. There are two subsets of human mast cells, resulting from the expression of different enzymes: tryptase positive mast cells and chymase positive mast cells. The purpose of this study was to determine the presence and prognostic significance of tumor infiltrating mast cells in mesothelioma., Methods: Tryptase and chymase mast cell counts were determined by immunohistochemistry in 60 patients with mesothelioma. All pathologic samples were from patients who underwent treatment with intrapleural preoperative interleukin-2 (18 x 10(6) IU/d for 3 days). After one day of recovery, patients underwent surgery. Pleural samples were also immunostained for CD34 to evaluate microvessel count., Results: High tryptase mast cells counts were found in the majority (73.3%) of the cases studied, and the results were significantly associated with both overall survival (p = 0.02) and time to progression (p = 0.01). This finding was confirmed using multivariate analysis: a higher tryptase mast cells count emerged as an independent favorable prognostic factor (p = 0.02). However, tryptase mast cells count did not show significant correlation with microvessel count., Conclusions: These results suggest that tumor infiltrating tryptase mast cells, after interleukin-2 preoperative induction therapy, predict improved clinical outcome in patients with malignant pleural mesothelioma, and highlight the critical role of the local inflammatory response in mesothelioma cancer progression.

Background: Treatment approaches in malignant pleural mesothelioma (MPM) patients range from mere palliation to aggressive anticancer therapy, and there is currently no consensus on the optimal therapeutic strategy. In 1999, we began a phase II study to investigate four-modality treatment of advanced stage MPM., Methods: From 1999 to 2004, 49 patients with International Mesothelioma Interest Group stage II-III MPM underwent four-modality treatment with intrapleural preoperative interleukin-2 (18 x 10(6) UI/day for 3 days), pleurectomy/decortication, intrapleural postoperative epidoxorubicin (25 mg/m2 for 3 days), interleukin-2 (18 x 10(6) UI/day for 3 days), adjuvant radiotherapy (30 Gy), systemic chemotherapy (cisplatin 80 mg/m2 day 1, gemcitabine 1250 mg/m2 days 1 and 8 for up to six courses) and long-term subcutaneous interleukin-2 (3 x 10(6) UI/day on 3 days per week)., Results: Patients included 41 men and eight women with a median age of 61 years (range, 41-77). All patients were diagnosed with MPM by thoracoscopy before inclusion. There was no postoperative mortality. Postoperative morbidity included bleeding (n = 1) and arrhythmias (n = 3). After a median follow-up of 59 months (range, 14-81), 13 patients are still alive and the median actuarial survival is 26 months (31 and 21 months for stages II and III, respectively). The 2- and 5-year actuarial survival rates were 60.2% and 23.3%, respectively. Baseline Eastern Cooperative Oncology Group performance status significantly influenced survival time (p = 0.02)., Conclusion: The four-modality treatment that we adopted for advanced-stage MPM was feasible, well tolerated by most of the patients, and produced a favorable median survival. This treatment approach warrants further investigation.

Background: Since 1989 we have enrolled patients with clinical-radiological stage III-IVA thymomas, independent of the surgeon's judgment of resectability, into a prospective study of neoadjuvant chemotherapy-surgery and postoperative radiotherapy. In this article, we review our long-term experience of neoadjuvant chemotherapy of advanced stage (III-IVA) thymomas., Methods: From 1989 to 2004, 30 patients with Masaoka stage III and IVA thymomas underwent neoadjuvant chemotherapy, surgery, and postoperative radiotherapy. The neoadjuvant and adjuvant chemotherapy consisted of three courses of cisplatin, epidoxorubicin, and etoposide every 3 weeks. Adjuvant radiotherapy consisted of 45 Gy for complete resections or 60 Gy for incomplete resections., Results: The preoperative diagnosis of invasive thymomas was obtained for 16 patients: five by mediastinotomy, seven by video-assisted thoracic surgery, and four by fine needle aspiration. For 14 patients, no histological diagnosis was available, but a thymus-related syndrome was present in all.Twenty-seven patients are still alive (25 disease-free) and three have died (one disease-free). The 10-year survival rates were 85.7% and 76.1% for stage III and IVA thymomas, respectively (difference not significant). Only the World Health Organization pathological diagnosis significantly affected the survival, with type B3 having a worse prognosis than type AB, B1, and B2 thymomas (p = 0.02)., Conclusion: The multimodality treatment of stage III and IVA thymomas by means of neoadjuvant chemotherapy provides good long-term outcomes in both stages of the disease.

Background: With the aim of evaluating the results of multidisciplinary approaches, we reviewed our experience in multimodality treatment of advanced stage (III and IVA) thymic tumors., Methods: From 1976 to 2003, 56 patients with Masaoka stage III and IVA thymic tumors underwent a multimodality treatment. Thirty-six patients underwent neoadjuvant chemotherapy, surgery, and postoperative radiotherapy; 20 patients were treated by primary surgery and postoperative radiotherapy (n = 12), chemotherapy (n = 1) or chemoradiotherapy (n = 7). The neoadjuvant or adjuvant chemotherapy consisted of three courses of cisplatin, epidoxorubicin, and etoposide every 3 weeks. Adjuvant radiotherapy consisted of 45 Gy for complete resections or 60 Gy for incomplete resections., Results: The preoperative diagnosis of invasive thymomas was performed in a total of 29 cases: 15 by mediastinotomy, 6 by video-assisted thoracoscopic surgery, and 8 by fine-needle aspiration. In 27 cases no diagnosis was available, but in most of them a thymus-related syndrome was present. Thirty-four patients are still alive (31 disease-free), and 22 have died (2 disease-free). Ten-year survival was 48% and 45.7% for stage III and IVA thymomas, respectively. The presence of myasthenia gravis (p = 0.04) and neoadjuvant chemotherapy (p = 0.004) affected survival significantly., Conclusions: The multimodality treatment of stage III and IVA thymic tumors allows a good long-term outcome; the neoadjuvant chemotherapy improves the resectability rate and the survival of both stages of the disease.