Surgical,Radiation, and Systemic Treatments of Patients With Thymic Epithelial Tumors: A Systematic Review

IntroductionThymic epithelial tumors are rare and are classified as thymoma, thymic carcinoma, and thymic neuroendocrine tumors. The objective of this systematic review was to evaluate the treatment options for patients with thymic epithelial tumors.MethodsThis systematic review was developed by Ontario Health (Cancer Care Ontario)’s Program in Evidence-Based Care and by the Lung Cancer Disease Site Group. MEDLINE, EMBASE, and the Cochrane Library were searched for studies comparing surgical, radiotherapy, or systemic treatments against any combination of these treatments in patients with thymic epithelial tumors. Meta-analyses were conducted with clinically homogenous studies.ResultsA total of 106 studies were included, mainly from observational studies. There was an overall survival benefit with postoperative radiotherapy for patients with thymic carcinoma (hazard ratio = 0.65, 95% confidence interval: 0.47–0.89) and for patients with thymoma (hazard ratio = 0.70, 95% confidence interval: 0.59–0.82), especially for those with a high risk for mortality. Patients with thymic carcinoma or thymoma had a response to chemotherapy. Selection bias affected the results for studies that evaluated neoadjuvant chemotherapy or minimally invasive surgical techniques. Furthermore, the overall survival benefit found for adjuvant chemotherapy may have been confounded by the administration of postoperative radiotherapy.ConclusionsFor patients with thymoma or thymic carcinoma, the literature is of low quality and subject to bias. There were overall survival benefits with postoperative radiotherapy. The results of this systematic review were used to inform treatment recommendations in a clinical practice guideline. Future large-scale prospective studies that control for confounders are needed.     

Central Nervous System Metastases in Thymic Epithelial Tumors: A Brief Report of Real-World Insight From RYTHMIC

Thymic epithelial tumors (TETs) are rare malignancies ranging from indolent thymoma A to aggressive thymic carcinomas (TCs). Brain metastases are extremely infrequent for TETs and have only been described in case reports or small single-center series. RYTHMIC (Réseau tumeurs THYMiques et Cancer) is a French nationwide network mandated to systematically review every TET case and prospectively includes all consecutive patients discussed by national or regional tumor boards. We analyzed patients with TETs and central nervous system (CNS) metastasis during their cancer history from this large French registry. In an 8-year period, 2909 patients were included in the database, including 248 TCs (8.5%). A total of 14 patients had CNS metastases, five (36%) at diagnosis and nine (64%) at relapse. Among them, 12 patients (86%) had a diagnosis of TC and two (14%) had thymoma A and B3. Surgical biopsies were performed, and the histologic subtype for non-TC tumors was centrally confirmed. Median overall survival was 22 months (95% confidence interval [CI]: 9.8–34.2), with longer, albeit not significant, overall survival when CNS metastases were present at diagnosis versus relapse (not reached versus 17 mo; p = 0.29); median progression-free survival was 13 versus 8 months (p = 0.06), respectively. A higher risk of death (hazard ratio = 5.34, 95% CI: 1.3–21.9, p = 0.02) and relapse (hazard ratio = 1.89, 95% CI: 0.9–3.7, p = 0.06) was observed for patients suffering from TC with brain metastases compared with those without CNS extension. CNS disease was extremely rare in our TET cohort (0.48%), reported at both diagnosis and progression, present primarily in TC, with prevalence rising to 4.9%.     

p53蛋白与PCNA在胸腺上皮性肿瘤中的表达及其意义

目的　探讨p5 3蛋白和增殖细胞核抗原 (PCNA )在胸腺上皮性肿瘤中表达的意义及相互关系。方法　采用S P免疫组化法 ,检测良性胸腺瘤 18例 ,恶性胸腺瘤 16例 ,胸腺癌 16例的 p5 3蛋白与PCNA的表达。 结果　p5 3蛋白和PCNA的Ⅲ～Ⅳ级指数在 3组胸腺上皮性肿瘤中阳性表达率分别为 3 3 .3 % ( 6/18) ,62 .5 % ( 10 /16) ,81.3 % ( 13 /16)和 3 8.9% ( 7/18) ,68.8% ( 11/16) ,81.3 % ( 13 /16) ,(P <0 .0 5 ) ;其阳性表达率与临床分期、淋巴结转移密切相关 (P <0 .0 5 )。结论　p5 3蛋白和PCNA阳性表达率可提示肿瘤恶性程度及其侵袭力和转移能力。     

A Phase 2 Study of Palbociclib for Recurrent or Refractory Advanced Thymic Epithelial Tumors (KCSG LU17-21)

IntroductionThymic epithelial tumors (TETs) are rare but are the most common tumors of the anterior mediastinum. Platinum-based combination chemotherapy is the standard of care for such tumors and is associated with a 50% to 90% objective response rate (ORR) in metastatic disease. Nevertheless, there is no standard chemotherapeutic option after failure of platinum-based combination chemotherapy. Genetic alterations associated with the cell cycle, including pRB, p16^INK4A, and cyclin D1, are most often observed in TETs. On the basis of these results, we conducted a phase 2 trial to evaluate the efficacy and safety of palbociclib in patients with recurrent or refractory advanced TETs.MethodsThis is a phase 2, multicenter, open-label, single-arm study of palbociclib monotherapy in patients with recurrent or metastatic advanced TETs who failed one or more cytotoxic chemotherapies. The patients received 125 mg of oral palbociclib daily for 21 days, followed by a 7-day break. The primary end point was progression-free survival (PFS). The secondary end points were ORR, duration of response, overall survival, and safety.ResultsBetween August 2017 and October 2019, a total of 48 patients were enrolled. The median number of previous chemotherapies was one (range: one to four), and 21 (43.7%) of 48 patients received thymectomy. By the WHO classification, the patients were type A (n = 1), type B1 (n = 2), type B2 (n = 8), type B3 (n = 13), thymic carcinoma (n = 23), and unknown (n = 1). With a median follow-up of 14.5 months (range: 0.8–38.2), the median number of cycles of palbociclib monotherapy was 10 (range: 1–40). The ORR was 12.5% (four partial responses in thymoma and two partial responses in thymic carcinoma). The PFS at 6 months was 60.2%, and the median PFS was 11.0 months (95% confidence interval: 4.6–17.4). The median overall survival was 26.4 months (95% confidence interval: 17.4–35.4). The most common treatment-related adverse events of any grade were neutropenia (62.5%), anemia (37.5%), and thrombocytopenia (29.1%), and the most common grade 3/4 treatment-related hematologic adverse event was neutropenia (41.7%). Neutropenia above grade 3 was reversible, and there were no cases with neutropenic fever.ConclusionsPalbociclib monotherapy was well tolerated and had encouraging efficacy in patients with TETs who failed platinum-based combination chemotherapy.     

外周型原始神经外胚叶瘤临床特征及治疗分析

目的 探讨外周型原始神经外胚叶瘤（peripheral primitive neuroectodermal tumors, pPNET）的临床特征及治疗方法。方法 回顾性分析重庆医科大学附属第一医院2005年11月—2014年4月收治的10例pPNET患者的临床病理特征、治疗方案等资料,并用直接计算法计算其生存率。结果 10例患者中以青少年男性居多,免疫组织化学CD99、NSE表达率高。6例行手术治疗,其中5例行术后放疗+化疗。2例行放疗+化疗,1例行化疗+HIFU治疗,1例行中药治疗。治疗后1、2、5年生存率分别为80.0%（8/10）、71.4%（5/7）、40.0%（2/5）。结论 pPNET的临床表现缺乏特异性,以细胞形态学联合免疫组织化学确诊,采取手术、放疗、化疗为主的综合治疗。     

Trends in Incidence and Survival of Patients With Thymic Epithelial Tumor in a High-Incidence Asian Country: Analysis of the Korean Central Cancer Registry 1999 to 2017

IntroductionTo report the trends in incidence and survival associated with thymic epithelial tumors (TETs) in Korea.MethodsData from 1999 to 2017 were obtained from the Korean Central Cancer Registry. Age-standardized incidence rates and average annual percentage changes (AAPCs) were calculated. Net survival (NS) was estimated by the Pohar-Perme method.ResultsAmong 5812 patients diagnosed with having TETs, 58.9%, 38.1%, and 3.0% were diagnosed with having thymoma, thymic carcinoma, and thymic neuroendocrine tumor (NET), respectively. Age-standardized incidence rates were 0.50, 0.30, 0.18, and 0.02 per 100,000 for all TETs and the respective subtypes. There was an increase in incidence of all TETs (AAPC = 6.1%) and subtypes: thymoma (AAPC = 5.6%), thymic carcinoma (AAPC = 7.0%), and thymic NET (AAPC = 3.4%). Proportions of patients with thymoma, thymic carcinoma, and thymic NET were 58.9%, 38.1%, and 3.0%, respectively. For thymoma, the relative proportion of distant stage decreased (19.4% in 2005 to 8.8% in 2017) and low-grade WHO subtype (A, AB, B1) increased faster than high-grade WHO type (B2, B3) (AAPC = 19.8% versus 9.6%). For thymoma, the 5-year NS was 82.3%. This increased from 64.3% in 1999 to 2002 to 90.6% in 2013 to 2017. For thymic carcinoma, the 5-year NS was 46.2% and only slightly increased from 39.4% in 1999 to 2002 to 47.9% in 2013 to 2017.ConclusionsThis study indicates a high incidence of TET and its continuous increase in Korea. The proportion of thymic carcinoma was relatively higher than in the United States or Europe. Survival for thymoma improved during the study period, whereas this was not evident for thymic carcinoma or thymic NET.     

Joint-Predominant Rheumatic Complications of Immune Checkpoint Inhibitor Therapy in Patients with Thymic Epithelial Tumors

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced cancers. However, activation of the immune system can occasionally cause life-threatening toxicity involving critical organs. Induction of immune-mediated toxicity is a significant concern for patients with thymic epithelial tumors (TETs) due to defects in immune tolerance. An increased risk of skeletal and cardiac muscle inflammation following treatment with ICIs is well recognized in patients with advanced TETs. However, uncommon musculoskeletal and rheumatic complications can also occur. The cases presented in this report highlight the spectrum of presentation of immune-mediated, joint-predominant musculoskeletal adverse events in patients with advanced TETs treated with ICIs, including polymyalgia rheumatica-like illness and inflammatory arthritis.     

A Recurrence Predictive Model for Thymic Tumors and Its Implication for Postoperative Management: a Chinese Alliance for Research in Thymomas Database Study

ObjectiveOur aim was to investigate appropriate postoperative management based on the risk of disease recurrence in thymic epithelial tumors after complete resection.MethodsThe 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.ResultsA 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.ConclusionsA 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.     

Relationship Between Computed Tomography Manifestations of Thymic Epithelial Tumors and the WHO Pathological Classification

Objective: To explore the relationship between computed tomography (CT) manifestations of thymoma andits WHO pathological classification. Methods: One hundred and five histopathologically confirmed cases werecollected for their pathological and CT characteristics and results were statistically compared between differentpathological types of thymoma. Results: Tumor size, shape, necrosis or cystic change, capsule integrity, invasionto the adjacent tissue, lymphadenopathy, and the presence of pleural effusion were significantly different betweendifferent pathological types of thymomas (P <0.05). Type B2, B3 tumors and thymic carcinomas were greater insize than other types. More than 50% of type B3 tumors and thymic carcinomas had a tumor size greater than10 cm. The shape of types A, AB, and B1 tumors were mostly round or oval, whereas 75% of type B3 tumorsand 85% of thymic carcinomas were irregular in shape. Necrosis or cystic change occurred in 67% of type B3thymomas and 57% of thymic carcinomas, respectively. The respective figures for capsule destruction were 83%and 100% . Increases in the degree of malignancy were associated with increases in the incidence of surroundingtissue invasion: 33%, 75%, and 81% in type B2, type B3, and thymic carcinomas, respectively. Pleural effusionoccurred in 48% of thymic carcinomas, while calcification was observed mostly in type B thymomas. Conclusions:Different pathological types of thymic epithelial tumors have different CT manifestations. Distinctive CT featuresof thymomas may reflect their pathological types.     

A Phase II Study of Pemetrexed in Patients with Recurrent Thymoma and Thymic Carcinoma

Introduction

Thymoma and thymic carcinoma (TC) are neoplastic diseases with reported chemosensitivity to a broad range of agents. However, because of the rarity of these diseases, few prospective trials have been conducted in patients with advanced thymic malignancies. We conducted a prospective phase II trial to evaluate the clinical activity of pemetrexed, a multitargeted antifolate agent, in previously treated patients with thymoma and TC.

The International Association for the Study of Lung Cancer Thymic Tumors Staging Project: The Impact of the Eighth Edition of the Union for International Cancer Control and American Joint Committee on Cancer TNM Stage Classification of Thymic Tumors

ObjectivesThe 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.MethodsA 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).ResultsIn 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.ConclusionsThe 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.     

The International Association for the Study of Lung Cancer Thymic Epithelial Tumor Staging Project: Unresolved Issues to be Addressed for the Next Ninth Edition of the TNM Classification of Malignant Tumors

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.