The World Health Organization histologic classification system reflects the oncologic behavior of thymoma: a clinical study of 273 patients

BACKGROUND: Although the histologic classification of thymic epithelial tumors has been confusing and controversial, an agreement on the universal classification system for thymic epithelial tumors was achieved by the World Health Organization (WHO) in 1999. The authors previously reported that the WHO histologic classification system reflects invasiveness and immunologic function of thymic epithelial tumors. In this subsequent study, they examined the prognostic significance of this classification system. METHODS: Clinical features as well as postoperative survival of patients with thymoma, but not thymic carcinoma, were examined with reference to WHO histologic classification based on an experience with 273 patients over a 44-year period. RESULTS: There were 18 type A tumors, 77 type AB tumors, 55 type B1 tumors, 97 type B2 tumors, and 26 type B3 tumors. In patients with type A, AB, B1, B2, and B3 tumors, the respective proportions of invasive tumor were 11.1%, 41.6%, 47.3%, 69.1%, and 84.6%; the respective proportions of tumors with involvement of the great vessels were 0%, 3.9%, 7.3%, 17.5%, and 19.2%; and the respective 20-year survival rates were 100%, 87%, 91%, 59%, and 36%. According to the Masaoka staging system, the 20-year survival rates were 89%, 91%, 49%, 0%, and 0% in patients with Stage I, II, III, IVa, and IVb disease, respectively. By multivariate analysis, the Masaoka staging system and the WHO histologic classification system were significant independent prognostic factors, whereas age, gender, association with myasthenia gravis, completeness of resection, or involvement of the great vessels were not significant independent prognostic factors. CONCLUSIONS: This study showed that histologic appearance reflects the oncologic behavior of thymoma when the WHO classification system is adopted. The WHO classification system may be helpful in clinical practice for the assessment and treatment of patients with thymoma.     

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.     

Understanding the landscape of immunotherapy in thymic epithelial tumors

Thymic epithelial tumors (TETs) are a rare group of malignancies arising from the thymus. Surgery remains the foundation of treatment for patients with early-stage disease. Limited treatment options are available for the treatment of unresectable, metastatic, or recurrent TETs and are associated with modest clinical efficacy. The emergence of immunotherapies in the treatment of solid tumors has generated significant interest in understanding their role in TET treatment. However, the high rates of comorbid paraneoplastic autoimmune disorders, particularly in thymoma, have tempered expectations regarding the role of immune-based therapies. Clinical studies of immune checkpoint blockade (ICB) in thymoma and thymic carcinoma have revealed higher frequencies of immune-related adverse events (IRAEs) and limited efficacy. Despite these setbacks, the growing understanding of the thymic tumor microenvironment and systemic immune system has advanced the understanding of these diseases and provided opportunities for novel immunotherapy modalities. Ongoing studies are evaluating numerous immune-based treatments in TETs with the goal of improving clinical efficacy and mitigating IRAE risk. This review will provide insight into the current understanding of the thymic immune microenvironment, outcomes of previous ICB studies, and review treatments currently being explored for the management of TET.     

Analysis of the tumor microenvironment and mutation burden identifies prognostic features in thymic epithelial tumors

Thymic epithelial tumors (TETs) are one of the rarest adult malignancies in the anterior mediastinum. Thymic carcinomas (TCs) are less prevalent among TETs, but they are more clinically aggressive. Immunotherapy has emerged as a promising therapeutic approach for refractory TETs, even though chemotherapy remains the conventional treatment for the advanced disease. However, limited attention has been paid to the features of the tumor microenvironment (TME) which might provide clinically relevant information and guide treatment regimen design. Especially, to date, there have been only a few studies focusing on the differences between the TME and genomic features preserved by TETs and TCs. We analyzed the TME and genomic characteristics of TETs using RNA sequencing and whole-exome sequencing, finding that distinct characteristics of TME in different pathogenic subtypes of TETs. According to those findings, we found that thymic carcinomas had significantly lower expression of HMGB1, a pro-inflammatory cytokine-related gene, than thymomas, and low HMGB1 expression was linked to a poor prognosis. Additionally, higher mutation burdens were significantly associated with the later stage and more advanced pathological types. Thymoma patients with lower mutation burdens tended to relapse within 3 years. In summary, different characteristics of TME and genomic features between thymoma and thymic carcinoma were associated with clinical outcomes of TETs and presented promisingly predictive value for efficacy and toxicity of immunotherapy.     

Expression and mutation statuses of epidermal growth factor receptor in thymic epithelial tumors

BACKGROUND: Epidermal growth factor receptor (EGFR) gene mutations have been reported to correlate with the sensitivity to the tyrosine kinase inhibitor treatment for advanced lung cancers. Since several reports have shown that invasive thymoma overexpress the EGFR protein, we examined the EGFR expression and mutation statuses in thymoma and thymic carcinoma tissues. METHODS: EGFR mutation statuses from 99 thymic epithelial tumor samples were evaluated by a rapid and sensitive TaqMan assay using Applied Biosysytems 7500 real-time PCR system. Probes were designed according to the 13 different EGFR mutations reported previously in lung cancers. A total of 38 thymoma samples were directly sequenced for the EGFR gene. Protein expressions were evaluated for 56 thymic epithelial tumors by immunohistochemistry. RESULTS: EGFR gene mutations were not detected in any of the thymoma and thymic cancer samples using TaqMan PCR assay. Of the 38 samples 3 showed a heterozygous silent mutation without changes in the protein, a G to A transition at the nucleotide 2361 in exon 18. EGFR expression was significantly higher in invasive thymomas (stages III-IV, 15/19 were positive) than in early stage thymomas (stages I-II, 7/33 were positive) (P < 0.0001). All four carcinomas and all seven B3 thymomas showed EGFR positive staining. CONCLUSIONS: Although EGFR mutation at the tyrosine kinase domain is unlikely to be a therapeutic target for thymoma, the information about EGFR expression would contribute to the further identification of the therapeutic target for advanced thymomas.     

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.     

Molecular Profiling of Thymoma and Thymic Carcinoma: Genetic Differences and Potential Novel Therapeutic Targets

Thymoma and thymic carcinoma are thymic epithelial tumors (TETs). We performed a molecular profiling to investigate the pathogenesis of TETs and identify novel targets for therapy. We analyzed 37 thymomas (18 type A, 19 type B3) and 35 thymic carcinomas. The sequencing of 50 genes detected nonsynonymous mutations in 16 carcinomas affecting ALK, ATM, CDKN2A, ERBB4, FGFR3, KIT, NRAS and TP53. Only two B3 thymomas had a mutation in noncoding regions of the SMARCB1 and STK11 gene respectively. Three type A thymomas harbored a nonsynonymous HRAS mutation. Fluorescence in situ hybridization detected in 38 % of carcinomas a CDKN2A, in 32 % a TP53 and in 8 % an ATM gene deletion, whereas only one B3 thymoma exhibited a CDKNA deletion, and none of the type A thymomas showed a gene loss. Sequencing of the total miRNA pool of 5 type A thymomas and 5 thymic carcinomas identified the C19MC miRNA cluster as highly expressed in type A thymomas, but completely silenced in thymic carcinomas. Furthermore, the miRNA cluster C14MC was downregulated in thymic carcinomas. Among non-clustered miRNAs, the upregulation of miR-21, miR-9-3 and miR-375 and the downregulation of miR-34b, miR-34c, miR-130a and miR-195 in thymic carcinomas were most significant. The expression of ALK, HER2, HER3, MET, phospho-mTOR, p16^INK4A, PDGFRA, PDGFRB, PD-L1, PTEN and ROS1 was investigated by immunohistochemistry. PDGFRA was increased in thymic carcinomas and PD-L1 in B3 thymomas and thymic carcinomas. In summary, our results reveal genetic differences between thymomas and thymic carcinomas and suggest potential novel targets for therapy.     

Treatment Outcome and Prognostic Factors of Malignant Thymoma - A Single Institution Experience

Objective: Our objectives are to investigate the clinicopathological features, treatment modalities, and prognostic and prognostic factors in order to estimate long-term outcomes for patients with thymoma and thymic carcinoma at our institution. Methods: We reviewed all patients diagnosed with thymic malignancies malignancies over a period of 38 years (from 1976 to 2014). Patients were identified using a single institution database at King Faisal Specialist Hospital and Research Center (KFSH and RC), Riyadh. Demographic data, clinical staging, histopathology classification, treatment approaches, and survival data were collected. Data Analysis was performed using both the Kaplan–Meier method and Cox proportional hazards modeling. Results: The fifty-six identified patients consists of 30 females (53.6%) and 26 males (46.4%). The median age at diagnosis was 39 years. About 37% of the patients were diagnosed with myasthenia gravis (MG). There was a significant association between the WHO histologic classification and the Masaoka stage (p= 0.018). The estimated 5-year overall survival rate was 88.6% for patients with thymic malignancies. The median survival time of thymoma and thymic carcinoma was 61 and 14 months, respectively. The univariate analysis suggested that histology (thymoma versus thymic carcinoma, p= 0.044) and Masaoka stage (II-III versus IV, p= 0.048) were independent prognostic factors affecting overall survival. Histology (p = 0.044) was found to be an independent predictor of overall survival. Conclusion: The findings of this study indicates that late Masaoka-Koga staging and histology types are significantly associated with extended overall survival. Similarly, surgical resection and multimodality treatments play a significant role in thymic malignancies neoplasms therapy strategies to prolong survival rates.     

Outcome of surgical treatment for recurrent thymic epithelial tumors with reference to world health organization histologic classification system

BACKGROUND AND OBJECTIVES: The aim of this study was to clarify the significance of surgical treatment for recurrent thymic epithelial tumors with reference to the World Health Organization (WHO) histological classification system. PATIENTS: Among 67 patients with tumor recurrence, 22 underwent a re-resection. There were 1 patient with a type AB tumor, 5 with type B1 tumors, 10 with type B2 tumors, 5 with type B3 tumors, and 1 with a carcinoma. RESULTS: The 10-year survival rate following the initial resection was 70% in patients who underwent a re-resection and 35% in those who did not. The average intervals from the initial resection to re-resection were 10.3, 7.8, 6.0, 2.4, and 2.6 years for patients with type AB, B1, B2, B3 tumors, and carcinoma, respectively. The patient with a type AB tumor was alive at 2.4 years after re-resection, 12.7 years after the initial resection. The 5-year survival rates following re-resection in the patients with type B1, B2, and B3 tumors were 100, 56, and 60, respectively. The patient with a carcinoma died as a result of the tumor 2 years after re-resection. CONCLUSION: WHO histological classification indicates the outcome of surgical treatment for recurrent thymic epithelial tumors.     

Expression Patterns,Prognostic Value,and Intratumoral Heterogeneity of PD-L1 and PD-1 in Thymoma and Thymic Carcinoma

Introduction

Thymic epithelial tumors (TETs) including thymoma and thymic carcinoma are rare tumors with little data available to guide treatment. Immunotherapy with checkpoint blockade has shown promising activity, but data regarding the expression patterns and prognostic implications of programmed death 1 (PD-1) and its ligand (PD-L1) in TETs have yielded conflicting results. Intratumoral heterogeneity of PD-1/L1 expression has been shown in other cancers, but has not been described in the TET literature.

A Tuft Cell–Like Signature Is Highly Prevalent in Thymic Squamous Cell Carcinoma and Delineates New Molecular Subsets Among the Major Lung Cancer Histotypes

IntroductionIn-depth genomic characterization of thymic epithelial tumors (TETs), comprising thymomas and thymic carcinomas (TCs), failed to identify targetable mutations and suggested unique biology of TETs, including KIT expression in most TCs. Recently, tuft cell–like medullary thymic epithelial cells were identified in the murine thymus, and our reanalysis of the published gene expression data revealed that these cells express KIT. In addition, recently, a minor subset of SCLCs with tuft cell–like features was described.MethodsWe interrogated mRNA expression data from our tumor cohorts (N = 60) and publicly available, independent data sets from TETs and NSCLC (N = 1199) for expression of tuft cell genes and KIT. Expression of KIT and of POU2F3 protein, the master regulator of tuft cells, was analyzed in cancer tissue (N = 344) by immunohistochemistry.ResultsNormal human thymic tuft cells and most TCs coexpressed KIT and known tuft cell genes, particularly POU2F3 and GFI1B. Unexpectedly, small subsets of tuft cell–like tumors coexpressing POU2F3, GFI1B, and KIT were also identified among pulmonary squamous cell carcinomas, adenocarcinomas, and large cell neuroendocrine carcinoma and clustered together in each histologic cohort. In addition to the tuft cell–like signature, both thymic and lung tuft cell–like carcinomas had distinct genetic, pathologic, and clinical features in each cohort.ConclusionsWe suggest that the tuft cell–like phenotype defines novel subsets of thymic and pulmonary carcinoma. Its high prevalence in thymic squamous cell carcinomas that have no known toxic or viral etiologies suggests a new mechanism of carcinogenesis that may lead to specific drug susceptibilities.     

82例胸腺瘤新组织学分型与患者临床特征和预后的相关性分析

背景与目的:世界卫生组织(WHO)于1999年制定了新的胸腺瘤组织学分型标准。本研究探讨胸腺瘤WHO组织学分型与临床特征和预后的相关性。方法:回顾性分析82例经外科治疗的胸腺瘤患者的临床资料,经有经验的病理科医生按WHO组织学分型标准重新做出诊断,并结合患者的临床特征和预后进行分析。结果:胸腺瘤A型5例(6.1%),AB型21例(25.6%),B1型14例(17.1%),B2型12例(14.6%),B3型14例(17.1%),C型16例(19.5%)。根据Masaoka临床分期,Ⅰ期29例(35.4%),Ⅱ期13例(15.8%),Ⅲ期32例(39.0%),Ⅳa期8例(9.8%)。临床分期与组织学分型的相关性有显著性意义(χ2=47.29,P<0.001)。肿瘤外侵的程度与组织学分型的相关性也有显著性意义(χ2=30.78,P<0.001)。A﹑AB﹑B1和B2型胸腺瘤合计切除率较B3和C型胸腺瘤合计切除率高(84.6%vs.50.0%,χ2=11.29,P=0.002)。临床Ⅰ、Ⅱ、Ⅲ、Ⅳa期胸腺瘤切除术后5年生存率分别为100%、100%、69.5%和37.5%;10年生存率分别为88.1%、57.1%、47.5%和0。不同临床分期患者生存率的差异(log-rank=40.31,P<0.001)与组织学分型间生存率的差异(log-rank=16.0,P=0.007)均有统计学意义。结论:WHO组织学分型可在一定程度上反映胸腺瘤的生物学行为和临床特征,对临床诊断和治疗胸腺瘤有指导意义。     

Arginase Pathway Markers of Immune-Microenvironment in Thymic Epithelial Tumors and Small Cell Lung Cancer

BackgroundKey regulators of antitumor immunity such as arginase-1 and the adenosine pathway may have an important role in modulating the effect of immunotherapy. Here, we investigated the expression profile of these immune-related biomarkers in thymic epithelial tumors (TETs) and small cell lung cancer (SCLC), 2 solid tumors where immune checkpoint inhibitors have activity.Materials and MethodsImmunohistochemical staining was performed using tissue microarrays of 123 TET (110 thymoma and 13 thymic carcinoma) and 125 SCLC cases. The expression profile of the following immune-related biomarkers was assessed: arginase-1, CD39, CD73, A2AR, PD-L2, and CD15. The expression profile was also correlated with clinical data.ResultsNo sample was positive for arginase-1. In the adenosine pathway, the prevalence of positive staining for CD39, CD73, and A2AR was 4.9%, 2.5%, and 69.2%, in TETs and 0%, 1.7%, and 50.8%, in SCLC. The multivariate analysis showed that CD39 expression was significantly associated with worse disease related survival (hazard ratio [HR], 10.36; 95% confidence interval [CI]: 2.01-53.47; P= .005) and a shorter time-to progression (HR, 11.35; 95% CI, 2.11-61.23; P = .005) in TETs. Other biomarkers were not associated with disease related survival or time to progression in TETs. No biomarker was associated with survival in SCLC.ConclusionArginase-1 was not detectable in TETs and SCLC. Expression of markers in the adenosine pathway were present in both TETs and SCLC. CD39 expression in tumor cells may identify subsets of patients with TETs with an unfavorable prognosis.     

Establishment, characterization and drug sensitivity testing in primary cultures of human thymoma and thymic carcinoma

Thymomas and thymic carcinomas are peculiar epithelial tumors of the anterior mediastinum. They may show aggressive clinical behavior and are a paradigm for the interaction between the tumor and the immune system. So far, adequate functional studies enabling a better understanding of this malignancy have not been performed, since human thymoma/thymic carcinoma cell lines have not been available. Here, the authors describe the establishment, characterization and functional analyses of epithelial cell lines from a Type B1-thymoma and a poorly differentiated thymic carcinoma. By Fluorescence-activated cell sorting (FACS) analyses, both cell lines were aneuploid. The aneuploid cell fraction of the thymic carcinoma cell line was characterized by a high proliferation index of 55.9%, in contrast to a lower proliferation rate of the aneuploid cell fraction of the thymoma (19.7%). Array-based comparative genomic hybridization (aCGH) and conventional cytogenetic analysis of the thymoma revealed only minor imbalances whereas the thymic carcinoma was characterized by a complex karyotype in the hyperdiploid range that was readily defined with multicolor FISH (mFISH). Application of a selective COX-2 inhibitor reduced cell viability in both cell lines in a dose-dependent manner. In conclusion, these first cell lines of a thymoma and a CD5-positive thymic carcinoma are useful tools for further in vitro studies of cellular, molecular and genetic aspects of the disease and for functional tests to evaluate new therapeutic targets.     

Activation of matrix metalloproteinase-2 is correlated with invasiveness in thymic epithelial tumors

BACKGROUND AND OBJECTS: Matrix degradation, which is a critical event in the process of tumor invasion and metastasis, is considered to be caused by the action of proteolytic enzymes. METHODS: We examined the gelatinolytic activity of matrix metalloproteinase (MMP)-9, and the activity of active and inactive forms of MMP-2 in five thymi, five noninvasive thymomas, eight invasive thymomas, and five thymic carcinomas by quantitative gelatinolytic zymography. RESULTS: The gelatinolytic activity of active MMP-2 in five thymi was zero. The mean gelatinolytic activity of active MMP-2 was 0.020 +/- 0.015 in noninvasive thymoma, 0.084 +/- 0.098 in invasive thymoma and 0.246 +/- 0.194 in thymic carcinoma. The gelatinolytic activity of active MMP-2 correlated with the invasiveness of thymic epithelial tumors (Spearman rank correlation: r-value = 0.532). The gelatinolytic activity of active MMP-2 in three thymoma cases with microscopic capsular invasion was the same as that of noninvasive thymoma. When thymoma cases showing microscopic capsular invasion were classified into the "macroscopically noninvasive thymoma" group, the gelatinolytic activity of active MMP-2 correlated with the invasiveness of thymic epithelial tumors (Spearman rank correlation: r-value = 0.621). CONCLUSIONS: The gelatinolytic activity of active MMP-2 significantly correlated with the invasiveness in thymic epithelial tumors. J. Surg. Oncol. 2001;76:169-175.     

The biologic spectrum of thymic epithelial neoplasms: current status and future prospects

Thymoma is the most common anterior mediastinal tumor in adults and is frequently associated with autoimmune disorders such as myasthenia gravis. Thymomas are a diverse group of epithelial neoplasms with a behavioral spectrum that spans the complete clinical gamut from entirely benign to highly aggressive, lethal thymic carcinomas. The biologic behavior seems to depend primarily on the clinical stage at presentation and histologic subtype. This article discusses thymic organogenesis, Masaoka staging, WHO histologic classification of thymoma and thymic carcinoma, and selected molecular characteristics that highlight this diversity. This discussion will further underscore both the similarities and differences between categories of thymic epithelial neoplasms and offer support for the notion that tumor heterogeneity and/or tumor progression may explain the observed clinical variation in behavior. Recommendations are offered for future investigational approaches to further the understanding of the complexity of these tumors.     

A single institutional experience of thymic epithelial tumours over 11 years: clinical features and outcome and implications for future management

Thymic epithelial tumours (TETs), the most common tumour of the anterior mediastinum, are epithelial neoplasms of the thymus with a wide spectrum of morphologic features. We retrospectively analysed clinical features of TET and the correlation of World Health Organisation (WHO) histologic classification and Masaoka staging system with different treatment modalities in 195 patients, from 1995 to 2005. According to the Masaoka's staging system, there were 78 (40.0 %) patients with stage I, 38 (19.5%) with stage II, 41 (21.0%) with stage III, 38 (19.5%) with stage IV. All patients were reclassified according to the WHO criteria as follows: Type A (n=9, 4.6%), AB (n=37, 18.9%), B1 (n=29, 14.8%), B2 (n=48, 24.6%), B3 (n=40, 20.5%), C (n=32, 16.4%). There was a fairly good correlation between Masaoka staging and WHO histotype (P<0.05). However, in multivariate analysis, the tumour stage and WHO histotype were two independent factors separately for predicting overall survival (P<0.001, P<0.001, respectively). Thus, both Masaoka stage and WHO histotype should be considered in risk stratification of therapy for TET patients. Patients with completely resected types B2, B3 and C and adjuvant radiotherapy (n=57) had more favourable disease-free and overall survival as compared with those without adjuvant treatment (n=20) (P=0.015, 0.015, respectively). Given that the predominant sites of recurrence after surgery was pleura/pericardium and lung, and the fact that complete resection was a significant influential factor for survival at log-rank test, an active investigation of newer treatment strategies such as neoadjuvant treatment to improve the resectability and development of optimal adjuvant treatment modality is a high priority especially for those with high-risk for recurrence or in patients with advanced stage disease.     

Genomic clustering analysis identifies molecular subtypes of thymic epithelial tumors independent of World Health Organization histologic type

Further characterization of thymic epithelial tumors (TETs) is needed. Genomic information from 102 evaluable TETs from The Cancer Genome Atlas (TCGA) dataset and from the IU-TAB-1 cell line (type AB thymoma) underwent clustering analysis to identify molecular subtypes of TETs. Six novel molecular subtypes (TH1-TH6) of TETs from the TCGA were identified, and there was no association with WHO histologic subtype. The IU-TAB-1 cell line clustered into the TH4 molecular subtype and in vitro testing of candidate therapeutics was performed. The IU-TAB-1 cell line was noted to be resistant to everolimus (mTORC1 inhibitor) and sensitive to nelfinavir (AKT1 inhibitor) across the endpoints measured. Sensitivity to nelfinavir was due to the IU-TAB-1 cell line’s gain-of function (GOF) mutation in PIK3CA and amplification of genes observed from array comparative genomic hybridization (aCGH), including AURKA, ERBB2, KIT, PDGFRA and PDGFB, that are known upregulate AKT, while resistance to everolimus was primarily driven by upregulation of downstream signaling of KIT, PDGFRA and PDGFB in the presence of mTORC1 inhibition. We present a novel molecular classification of TETs independent of WHO histologic subtype, which may be used for preclinical validation studies of potential candidate therapeutics of interest for this rare disease.     

Novel prognostic groups in thymic epithelial tumors: assessment of risk and therapeutic strategy selection

PURPOSE: To assess the role of multimodality treatment on patients with thymic epithelial tumors (TETs) (i.e., thymomas and thymic squamous cell carcinoma) and to define the prognostic classes according to the Masaoka and World Health Organization histologic classification systems. METHODS AND MATERIALS: Primary surgery was the mainstay of therapy. Extended thymectomy was performed in all cases. The cases were primarily staged according to the Masaoka system. Adjuvant radiotherapy was given to patients diagnosed with Masaoka Stage II, III, and IVA TET. Adjuvant chemotherapy was administered in selected cases. RESULTS: We reviewed the records of 120 patients with TETs, with a mean follow-up of 13.8 years. Of the 120 patients, 98 (81.6%) received adjuvant radiotherapy. Of these 98 patients, Grade 1-2 pulmonary or esophageal toxicity was acute in 12 (12.2%) and late in 8 (8.2%). The median overall survival was 21.6 years. Of the 120 patients, 106 were rediagnosed and reclassified according to the World Health Organization system, and the survival rate was correlated with it. Three different prognostic classes were defined: favorable, Masaoka Stage I and histologic grade A, AB, B1, B2 or Masaoka Stage II and histologic grade A, AB, B1; unfavorable, Stage IV disease or histologic grade C or Stage III and histologic grade B3; intermediate, all other combinations. The 10- and 20-year survival rate was 95% and 81% for the favorable group, 90% and 65% for the intermediate group, and 50% and 0% for the unfavorable group, respectively. Local recurrence, distant recurrence, and tumor-related deaths were also evaluated. CONCLUSION: The analysis of our experience singled out three novel prognostic classes and the assessment of risk identified treatment selection criteria.