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Treatment decision-making of thymic epithelial tumors (TETs) after surgery is based on the pathological stage. Currently, most institutions use both the Masaoka-Koga system and the 8th edition of the tumor, node, metastasis (TNM) classification. Because these two systems separate each stage according to the same concept, namely, the "levels" of tumor extension, precise pathological evaluation of the presence or absence of tumor invasion into stage-defining structures is necessary. This review provides representative pathological snapshots of tumors invading neighboring structures to provide references that might be helpful to readers; the snapshots will cover features that correspond to those of "locally advanced TETs", the topic of this series. Tumor subtype, whether thymoma or thymic carcinoma, is another factor influencing treatment decisions. Accumulating evidence has indicated that most thymomas and thymic carcinomas have biologically distinct features. Representative results were achieved by a study conducted as part of The Cancer Genome Atlas (TCGA) project, and subsequent studies with the help of the TCGA data have further reported on these distinctive features. Here, we also introduce newly recognized features of TETs, mainly focusing on the difference between epithelial-rich thymomas and thymic squamous cell carcinoma. The new (9th) edition of the TNM classification will be launched in January 2024. Therefore, sharing current pathological features of TETs will help readers, not only in their daily practice but also in preparing for the upcoming classification system.

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OBJECTIVES: This study aimed to examine the expression of programmed cell death 1 ligand 2 (PD-L2) in thymoma and thymomatous myasthenia gravis (MG). METHODS: The records of 70 patients with thymoma receiving surgical resection between January 2017 and December 2018 were retrospectively reviewed. Thymoma PD-L2 expression was evaluated by immunohistochemistry staining. Associations between PD-L2 expression and clinicopathologic features were examined. RESULTS: PD-L2 expression was positive in 41 patients (58.6%) and negative in 29 patients (41.4%). Of them, 33 had thymomatous MG. Patients with MG were more likely to be 50 years of age or younger (69.70% vs 35.14%); have more World Health Organization (WHO) type B thymomas (84.85% vs 64.86%); have tumors of smaller size (4.09 ± 2.33 cm vs 6.47 ± 2.42 cm); have positive PD-L2 expression (78.79% vs 40.54%); and have a higher percentage of PD-L2-positive cells, higher PD-L2 expression intensity, and score (all P < .05). Positive PD-L2 expression was associated with more type B thymomas, higher Masaoka-Koga stage, smaller tumor size, ectopic thymus, and MG (all P < .05). Factors significantly associated with MG were age under 50 years, tumor size less than 5 cm, and positive PD-L2 expression (all P < .05). CONCLUSIONS: Thymoma PD-L2 expression is significantly associated with thymomatous MG and WHO histologic types B2 and B3.

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Objective: To describe the clinical features of a cohort of patients with thymic epithelial tumors (TETs) and to analyze their prognostic factors. In particular, we investigated the correlation between the genetic polymorphism of methylenetetrahydrofolate reductase (MTHFR) C667T and the incidence of TETs. Methods: Pathological records were reviewed from the database of the Second Affiliated Hospital of Jiaxing University, from January 2010 to December 2020, and 84 patients with TETs were recruited for this study. Univariate and multivariate analyses were performed to determine the prognostic factors. The genetic polymorphism of MTHFR C667T was examined in the patients with TETs and in a group of healthy individuals. The correlation between MTHFR transcriptional levels and methylation was analyzed using The Cancer Genome Atlas (TCGA) thymoma dataset from the cBioPortal platform. Results: Kaplan-Meier univariate survival analysis showed that sex, age, the maximum tumor diameter, surgery, chemotherapy, radiotherapy, WHO histological classification, Masaoka-Koga stage, and 8th UICC/AJCC TNM staging, were statistically significantly correlated with the prognosis of patients with TETs. The Masaoka-Koga stage and 8th UICC/AJCC TNM staging were strongly correlated with each other in this study (r=0.925, P<0.001). Cox multivariate survival analysis showed that the maximum tumor diameter, Masaoka-Koga stage, and 8th UICC/AJCC TNM staging were independent prognostic factors affecting the overall survival (OS) of patients with TETs (P<0.05). The MTHFR C667T genotype (χ 2 = 7.987, P=0.018) and allele distribution (χ 2 = 5.750, P=0.016) were significantly different between the patients and healthy controls. CT heterozygous and TT homozygous genotypes at this MTHFR polymorphism significantly increased the risk of TETs (odds ratio [OR] =4.721, P=0.008). Kaplan-Meier univariate survival analysis showed that there was no correlation between different genotypes and the prognosis of TETs (CC versus CT + TT, χ2 = 0.003, P=0.959). Finally, a negative correlation between the transcriptional and methylation levels of MTHFR was observed in the TCGA thymoma dataset (r=-0.24, P=0.010). Conclusions: The Masaoka-Koga stage, 8th UICC/AJCC TNM staging, and maximum tumor diameter were independent prognostic factors for TETs. Reduced methylation levels of MTHFR and particular polymorphic variants may contribute to the susceptibility to developing TETs.

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OBJECTIVES: Our goal was to compare the oncological outcomes and efficacy between minimally invasive thymectomy (MIT) and open thymectomy (OT) in patients with early or locally advanced thymoma using a multicentre study database. METHODS: We retrospectively collected data from 1,239 patients who underwent thymectomy between January 2000 and December 2013, as recorded in the database of the Korean Association for Research on Thymus. We compared the postoperative outcomes of the MIT and OT groups using unmatched and propensity score (PS) matched data. RESULTS: We excised the thymoma using MIT and OT in 455 and 784 patients, respectively. We matched 378 patients with Masaoka-Koga stage I or II thymoma by their PS. The operative time, duration of hospital stay and complications were significantly shorter in the MIT group than in the OT group (all P < 0.005). In the PS matched data, the groups did not show significant differences in the 10-year survival rate (87.7% in OT vs 85.5% in MIT, stage II, mean follow-up duration: 12.9 years in OT vs 11.1 years in MIT), recurrence-free survival (94.0% in OT vs 86.4% in MIT) and R0 resection (97.35% in OT and MIT, P = 0.59). CONCLUSIONS: Compared with OT, MIT was associated with shorter operative times, shorter durations of hospital stay and fewer complications. Long-term survival, recurrence-free survival and complete resection were not significantly different between the OT and MIT groups. Our findings may help physicians track the progress of patients with early or locally advanced thymomas and design treatment plans for them.

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BACKGROUND: The length of time for clinical improvement of patients with thymomatous myasthenia gravis (MG) after extended thymectomy is not clear. The purpose of this study was to determine the length of time after thymectomy in patients with thymomatous MG to achieve a 3-point reduction of Quantitative Myasthenia Gravis Score (QMGS), and identify variables associated with a failure to achieve the reduction. METHODS: The records of patients with thymomatous MG who underwent extended thymectomy from January 2005 to December 2018 were retrospectively reviewed. The primary end point was a reduction of 3 points of QMGs and the secondary end point was another reduction of 3 points of QMGs. RESULTS: A total of 481 patients were included in the analysis, the mean age of the patients was 41.63 ± 8.55 years, and approximately 60% were male. The median time to achieve a 3 point decrease in QMGS was 6 months, and the median time to achieve another 3 point decrease was 30 months. Multivariable analysis indicated that age ≥ 42 years and Masaoka-Koga stage > I were associated with a lower probability of achieving a 3 point decrease in QMGS (HR = 0.55 and 0.65, respectively). Likewise, multivariable analysis indicated that age ≥ 42 years and Masaoka-Koga stage > I were associated with a lower probability of achieving a second 3 point decrease in QMGS (HR = 0.53 and 0.53, respectively). CONCLUSIONS: In patients with thymomatous MG who receive thymectomy, age ≥ 42 years and Masaoka-Koga stage > I are associated with a worse prognosis and failure to achieve a 3 point decrease in QMGS.

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BACKGROUND: This meta-analysis aimed to evaluate the incidence of tumor recurrence, postoperative myasthenia gravis, postoperative complications, and overall survival after limited versus total thymectomy for Masaoka stage I and II thymoma. METHODS: A systematic search of the literature was conducted using the PubMed, Embase, MEDLINE, and Cochrane databases to identify relevant studies that compared limited and total thymectomy in Masaoka stage I-II patients. The quality of the included observational studies was assessed using the Newcastle-Ottawa Scale. The results of the meta- analysis were expressed as log-transformed odds ratios (log ORs), with 95% confidence intervals (CIs). RESULTS: Seven observational studies with a total of 2,310 patients were included in the meta-analysis. There was an overall non-significant difference in favor of total thymectomy in terms of tumor recurrence (pooled log OR, 0.40; 95% CI, -0.07 to 0.87; p=0.10; I2=0%) and postoperative myasthenia gravis (pooled log OR, 0.12; 95% CI, -1.08 to 1.32; p=0.85; I2=22.6%). However, an overall non-significant difference was found in favor of limited thymectomy with respect to postoperative complications (pooled log OR, -0.21; 95% CI, -1.08 to 0.66; p=0.64; I2=36.1%) and overall survival (pooled log OR, -0.01; 95% CI, -0.68 to 0.66; p=0.98; I2=47.8%). CONCLUSION: Based on the results of this systematic review and meta-analysis, limited thymectomy as a treatment for stage I and II thymoma shows similar oncologic outcomes to total thymectomy.

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This study was aimed at evaluating the safety and efficacy of hyperthermic intrathoracic chemotherapy in patients with Masaoka stage IVA thymoma. This is a retrospective comparative analysis between two groups of patients who were operated for Masaoka stage IVA thymoma. One group underwent complete parietal pleurectomy whereas other group received hyperthermic intrathoracic chemotherapy after complete pleurectomy. An analysis of all perioperative variables, complications and survival was carried out. A total of 13 patients had stage IVA disease during the study period. Initial 7 patients (March 2012-March 2015) underwent complete parietal pleurectomy, whereas next 6 patients (April 2015-December 2018) had undergone HITHOC after complete parietal pleurectomy. Both groups are comparable in terms of age, co-morbidities, tumor size and duration of symptoms. The duration of surgery and intra-operative blood loss, postoperative ICU stay, duration of ICD and total hospital stay was similar between two groups. The total number of post-operative complications was higher in HITHOC group (5 vs 2), however non-significant (p = 0.10). The median follow-up duration was 63 months in no HITHOC group and 49.5 months in HITHOC group. There was no peri-operative mortality. The overall survival (P = 0.06) and relapse-free survival (P = 0.36) were not significantly different in the both groups. Hyperthermic intrathoracic chemotherapy is a safe and feasible modality with no added morbidity or mortality. Multi-institutional prospective studies with large number of patients are required to accurately assess survival benefit.

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BACKGROUND: To assess the correlation of WHO histological classification and Masaoka-Koga staging system of thymic epithelial tumors (TETs) with prognosis. METHODS: We retrospectively analyzed 83 patients with TETs in the Instituto Nacional de Enfermedades Neoplasicas between 1996 to 2018. We analyzed the clinical stages, histological types and treatment modalities and attempted to determine the impact on overall survival. The data was retrieved from clinical files and reviewed by a pathologist who reclassificated according to the 2004 WHO classification system. The staging was performed with the Masaoka-Koga staging system. Survival curves were constructed with Kaplan-Meir method. RESULTS: There was a total of 83 patients with a median age of 55 years old included in the study. The histological type corresponded to thymoma (T) in 63.8% (n = 53) and to thymic carcinoma (TC) in 36.1%. T were type A, AB, B1, B2 and B3 in 14.4%, 18%, 12%, 3.6%, 7.4% of cases, respectively. The proportion of advanced disease (Masaoka stage III-IV) was high (65%). With a median follow-up of 88.4 months, median overall survival (OS) was 81.6 months for T and 12.3 months for TC (P = 0.01). Univariate analysis showed that sex, histological type, clinical stage and surgery (P = 0.01) were significant independent prognostic factors. On multivariate analysis, histology type and Masaoka-Koga staging had an effect on survival. CONCLUSIONS: The results indicates a clear association between the WHO histological classification and Masaoka-Koga staging system with survival. We found a higher proportion of TETs with advanced disease at diagnosis. Further research are required and collaboration is important to foster knowledge focused on classification and treatment. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: The WHO histological classification, the Masaoka-Koga system and surgery treatment were associated with overall survival. WHAT THIS STUDY ADDS: To determine prognosis factors in TETs.

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BACKGROUND: Accurate thymoma staging via computed tomography (CT) images is difficult even for experienced thoracic doctors. Here we developed a preoperative staging tool differentiating Masaoka-Koga (MK) stage I patients from stage II patients using CT images. METHODS: CT images of 174 thymoma patients were retrospectively selected. Two chest radiologists independently assessed the images. Variables with statistical differences in univariate analysis were adjusted for age, sex, and smoking history in multivariate logical regression to determine independent predictors of the thymoma stage. We established a deep learning (DL) 3D-DenseNet model to distinguish the MK stage I and stage II thymomas. Furthermore, we compared two different methods to label the regions of interest (ROI) in CT images. RESULTS: In routine CT images, there were statistical differences (P<0.05) in contour, necrosis, cystic components, and the degree of enhancement between stage I and II disease. Multivariate logical regression showed that only the degree of enhancement was an independent predictor of the thymoma stage. The area under the receiver operating characteristic curve (AUC) of routine CT images for classifying thymoma as MK stage I or II was low (AUC =0.639). The AUC of the 3D-DenseNet model showed better performance with a higher AUC (0.773). ROIs outlined by segmentation labels performed better (AUC =0.773) than those outlined by bounding box labels (AUC =0.722). CONCLUSIONS: Our DL 3D-DenseNet may aid thymoma stage classification, which may ultimately guide surgical treatment and improve outcomes. Compared with conventional methods, this approach provides improved staging accuracy. Moreover, ROIs labeled by segmentation is more recommendable when the sample size is limited.

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Objectives: Computed tomography (CT) is an important technique for evaluating the condition and prognosis of patients with thymomas, and it provides guidance regarding treatment strategies. However, the correlation between CT imaging features, described using standard report terms, and clinical characteristics, Masaoka-Koga stages, and World Health Organization (WHO) classifications of patients with thymomas has not been described in detail nor has risk factor analysis been conducted. Methods: Overall, 159 patients with thymomas who underwent preoperative contrast-enhanced CT between September 2011 and December 2018 were retrospectively reviewed. We assessed the clinical information, CT imaging features, and pathological findings for each patient. A total of 89 patients were specially used to evaluate postoperative recurrence or metastasis between September 2011 and December 2015 to obtain an appropriate observation period. The relationship between CT imaging features and clinical characteristics, Masaoka-Koga stage, and WHO histological classification were analyzed, and related risk factors based on CT imaging features were identified. Results: CT imaging features did not significantly differ based on sex or age. Some imaging features demonstrated significant differences between the groups with and without related clinical characteristics. Contour (odds ratio [OR] = 3.711, P = 0.005), abutment ≥50% (OR = 4.277, P = 0.02), and adjacent lung abnormalities (OR = 3.916 P = 0.031) were independent risk factors for relapse or metastasis. Among all imaging features, there were significant differences between stage I/II and III/IV lesions in tumor size, calcification, infiltration of surrounding fat, vascular invasion, pleural nodules, elevated hemidiaphragm, and pulmonary nodules. Tumor size (odds ratio = 1.261, P = 0.014), vascular invasion (OR = 2.526, P = 0.023), pleural nodules (OR = 2.22, P = 0.048), and pulmonary nodules (OR = 3.106, P = 0.006) were identified as independent risk factors. Tumor size, contour, internal density, infiltration of surrounding fat, and pleural effusion significantly differed between low- and high-risk thymomas. Tumor size (OR = 1.183, P = 0.048), contour (OR = 2.288, P = 0.003), internal density (OR = 2.192, P = 0.024), and infiltration of surrounding fat (OR = 2.811 P = 0.005) were independent risk factors. Conclusions: Some CT imaging features demonstrated significant correlations with clinical characteristics, Masaoka-Koga clinical stages, and WHO histological classifications in patients with thymomas. Familiarity with CT features identified as independent risk factors for these related clinical characteristics can facilitate preoperative evaluation and treatment management for the patients with thymoma.

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BACKGROUND: The purpose of our study was to investigate the correlation between tumor volume (TV) and each subtype of thymic epithelial tumors (TETs) based on the World Health Organization (WHO) classification and Masaoka staging. METHODS: Sixty-one consecutive patients (45 thymomas and 16 thymic carcinomas) were studied. All were classified according to Masaoka staging: 31 non-invasive TETs (stage I) and 30 invasive TETs (8 stage II, 11 stage III, 3 stage IVa, and 8 stage IVb). TV on computed tomography (CT) were semi-automatically calculated using our software. The correlation of TV with each WHO subtype and Masaoka staging was analyzed using Mann-Whitney U and Scheffe's F test. RESULTS: Thymic carcinoma (mean ± SD, 117.5±143.6 cm3) was significantly larger than thymoma (53.4±78.4 cm3) (P=0.0016). Stage IVb tumor (190.8±156.8 cm3) was significantly larger than stage I (33.1±42.6 cm3) (P<0.05). Invasive TETs were significantly larger than non-invasive TETs (P=0.0016). TV >54.3 cm3 indicated invasive TETs. CONCLUSIONS: TV of invasive TETs may be larger at the time of initial presentation. TV >54.3 cm3 indicates invasive TETs.

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BACKGROUND: The prognostic factors and the efficacy of first-line chemotherapy remain unclear in patients with advanced thymic carcinoma. MATERIALS AND METHODS: We conducted a multi-institutional retrospective study named NEJ023 for patients with advanced thymic carcinoma. All patients without any indication of curative treatment were treated with chemotherapy from 1995 to 2014 at 40 institutions of the North East Japan Study Group. RESULTS: A total of 286 patients with advanced thymic carcinoma were analyzed. First-line chemotherapy included platinum-based doublets in 62.2% of the patients, monotherapy in 3.5%, and other multidrug chemotherapy (e.g., cisplatin, doxorubicin, vincristine, and cyclophosphamide [ADOC]) in 34.3%. The median follow-up period was 55.5 months, and the median overall survival (OS) from the start of first-line chemotherapy was 30.7 months (95% confidence interval, 25.9-35.9 months). There was no significant difference in OS among different first-line chemotherapy regimens (e.g., between carboplatin/paclitaxel and ADOC, median OS: 27.8 vs. 29.9 months). Masaoka-Koga stage IVa and volume reduction surgery were favorable prognostic factors for OS in the multivariate analysis using the Cox proportional hazards model. CONCLUSION: The efficacy of each first-line chemotherapy regimen for advanced thymic carcinoma did not vary significantly. Our results might support the adequacy of the use of carboplatin/paclitaxel as first-line chemotherapy for these patients. IMPLICATIONS FOR PRACTICE: Because of its rarity, there is limited information about prognostic factors and efficacy of chemotherapy in patients with advanced thymic carcinoma. This is the largest data set for those patients treated with chemotherapy. This study suggests there is no significant difference in efficacy between carboplatin/paclitaxel and cisplatin/doxorubicin/vincristine/cyclophosphamide for advanced thymic carcinoma. This result can support the adequacy of the selection of platinum doublets as treatment for those patients, rather than anthracycline-based multidrug regimen.

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