Wentao Fang

Outcome of Multimodality Treatment for 188 Cases of Type B3 Thymoma

Introduction: This study aimed to evaluate the long-term efficacy of multimodality therapy for patients with type B3 thymoma. Methods: A total of 188 consecutive patients with type B3 were treated in our hospital from January 2001 to December 2010. One hundred seventy-seven patients who had been treated with curative intent were retrospectively analyzed. According to World Health Organization Classification, all patients were pathologically confirmed as type B3. Distribution of Masaoka stages I, II, III, and IV was 35 (19.8%), 20(11.3%), 78 (44.1%), and 44 (24.8%), respectively. Myasthenia gravis coexisted in 34% of patients. Results: After a mean follow-up of 49 months (7–135 months), the 10-year overall survival (OS) rates were 65% (89%, 86%, 61%, and 42% in stage I, II, III, and IV, respectively). One hundred five patients patients (102 patients with R0 resection and 3 with complete response after radiotherapy) were analyzed for freedom from recurrence (FFR). The 5- and 10-year FFR rates were 91% and 73% (100%, 94%, 84%, 71% and 100%, 94%, 56%, N/A in stages I, II, III, and IV, respectively. We have no data of stage IV.) TTP was calculated on 72 patients including 57 patients with R+ resection and 15 with partial response or stable disease after radiotherapy. The 5-year time-to-progression (TTP) rates were 33% (41%, 24% in stage III and IV, respectively). Multivariate analysis showed that prognostic factors for OS were the Masaoka stage and adjuvant radiation for patients with stage III and IV. The Masaoka stage and resection margin after surgery had significant effects on FFR and TTP. Conclusion: The type B3 thymoma often presented with the later stages at the diagnosis. The Masaoka stage was closely associated with OS, FFR, and TTP. Resection margin after surgery was related to TTP. Adjuvant radiotherapy may be beneficial to stage III and IV patients in this clinical setting.

Clinicopathological analysis of 241 thymic epithelial tumors—experience in the Shanghai Chest Hospital from 1997–2004

BACKGROUND To assess the correlation of WHO histological classification of thymomas and thymic carcinomas (TCs) with prognosis in recently treated patient cohort compared to a historical one from a single institution. METHODS Retrospective review of clinical charts and histological sections of 241 patients treated during 1997-2004. Univariate and multivariate analysis of associations between risk factors including gender, age, tumor size, myasthenia gravis, WHO histological subtype, Masaoka stage, resection status, (neo-)adjuvant therapies, and survival. RESULTS The 5-year overall survival (OS) of A, AB, B1, B2, B3 thymomas and TCs patients was 100%, 100%, 94%, 80%, 94% and 45%. Five-year progression-free survival (PFS) was 100%, 96%, 78%, 80%, 78% and 39%, respectively. The 5-year OS of patients with Masaoka stage I, II, III and IV thymomas and TCs was 96%, 89%, 59% and 50%. (Neo-)adjuvant therapies were administered more often than in the historical cohort. Tumor-related death mainly occurred in patients with stage III, IV and B2, B3 thymomas and TCs. By univariate analysis, gender, tumor size, myasthenia gravis (MG) status, histotype, Masaoka stage, resection status and treatment were associated with OS. By multivariate analysis, histological subtype, Masaoka stage, and (neo-)adjuvant therapy were revealed as independent prognostic indicators. CONCLUSIONS WHO histological subtype, Masaoka stage and (neo-)adjuvant treatment have remained independent determinants of OS in patients with thymomas and TCs. Compared with the historical cohort during 1969-1996, prognosis of patients with B2, B3 thymomas has improved, which may be partly due to the increased use of adjuvant therapies. Prognosis of patients with TCs remained unsatisfactory, suggesting that neoadjuvant treatment should be tested to improve survival.

The IASLC/ATS/ERS classification of lung adenocarcinoma-a surgical point of view

Adenocarcinoma has become the most common histologic type of lung cancers. Ground glass nodules (GGN), most of them early stage noninvasive or minimally invasive adenocarcinomas (MIA), have been encountered more frequently with the application of computed tomography (CT) screening. The International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) histologic lung adenocarcinoma classification combines radiologic, histologic, clinic, and molecular features to form a diagnostic approach for different subgroups of diseases. One of the major focuses of this new classification is the introduction of adenocarcinoma in situ (AIS) and MIA, to replace the old term of bronchioloalveolar carcinoma (BAC). Not all GGNs are malignant lesions that should be surgically resected upon first presentation. A management approach different to solid nodules has been suggested based on the understanding that these lesions tend to have a more indolent nature. Hasty intervention should be avoided and potential surgical risks, radiation exposure, patient psychology, and socio-economical burden must be balanced comprehensively before surgery is decided upon. In the mean time, surgical issues concerning extent of resection and lymphadenectomy should also be carefully contemplated once intervention is deemed necessary. Extremely good prognosis with a near 100% disease-free survival could be expected when a pure GGN is completely resected. This has led to re-evaluation of sublobar resections, including both segmentectomy and big wedge resection, for small (≤2 cm) less invasive histology (AIS or MIA) appearing as GGN on CT scan. Evidences are accumulating that these limited resections are oncologically equivalent to standard lobectomy. And extensive lymph node dissection may not have additional staging or prognostic benefit. These would add new meaning to the contemporary definition of minimally invasive surgery for lung cancers. Overall, joint effort from a multiple disciplinary team is imperative, and decision making should be based on both anatomical and biological nature of the disease.

Solid predominant histologic subtype and early recurrence predict poor postrecurrence survival in patients with stage I lung adenocarcinoma.

Introduction This study investigated the correlation between histologic predominant pattern and postrecurrence survival (PRS), and identified the clinicopathologic factors influencing PRS in patients with completely resected stage I lung adenocarcinoma. Methods A total of 136 stage I lung adenocarcinoma patients who experienced tumor recurrence after completely resection were included in this study. To analysis the association between histologic predominant pattern and PRS, invasive adenocarcinomas with mixed histologic components were divided into 2 groups: solid and nonsolid group (including lepidic, acinar, papillary, micropapillary) based on the histologic predominant pattern. PRS was analyzed to identify the prognostic predictors using the Kaplan-Meier approach and multivariable Cox models. Results For all stage I invasive adenocarcinoma patients, the majority of postsurgical recurrences occurred within 2 years. Patients with solid predominant histological pattern were associated with unfavorable PRS (HR, 2.40; 95%CI 1.13-5.08, p=.022). There was a significant difference for poor PRS for patients who diagnosed tumor recurrence shorter than 12 months after surgery (HR, 2.34; 95%CI 1.12-4.90, p=.024). Extrathoracic metastasis was associated with poor media PRS in univariable analysis (p =.011), however, there was no significant PRS difference in multivariable analysis (HR, 1.56; 95%CI 0.65-3.73, p=.322) compared with intrathoracic metastasis. Conclusions Solid predominant histologic subtype and recurrence free interval less than 12 months predict worse PRS in patients with stage I lung adenocarcinoma.

Management of Thymic Tumors - Consensus Based on the Chinese Alliance for Research in Thymomas Multi-institutional Retrospective Studies

Thymic tumors are relatively rare malignancies comparing to other solid tumors in the chest (1). Its incidence is estimated to be at 3.93 per 1,000,000, which is about 1/00 of lung cancer and 1/25 of esophageal cancer in China. And it appears to be higher than that reported from North America, which is only 2.14 per 1,000,000 according to the SEER database. However, in the SEER database, the incidence rate was much higher in Asians (3.74 per 1,000,000) than in Caucasians (1.89 per 1,000,000) and close to the data from China. This implicates that there might be some ethnical and generic difference in thymic tumors. In the meantime, both these two registrations record only ‘malignant tumors’ that are clinically advanced diseases. A large part of early stage, low grade lesions are considered ‘benign tumors’ and thus, not registered. Therefore, the actual incidence of thymic tumors is much under-estimated. With the increasing use of screening for other malignancies such as lung cancer, it can be expected that more early stage thymic tumors would be discovered.

Comparison of the Masaoka-Koga staging and the International Association for the Study of Lung Cancer/the International Thymic Malignancies Interest Group proposal for the TNM staging systems based on the Chinese Alliance for Research in Thymomas retrospective database.

BACKGROUND To compare the predictive effect of the Masaoka-Koga staging system and the International Association for the Study of Lung Cancer (IASLC)/the International Thymic Malignancies Interest Group (ITMIG) proposal for the new TNM staging on prognosis of thymic malignancies using the Chinese Alliance for Research in Thymomas (ChART) retrospective database. METHODS From 1992 to 2012, 2,370 patients in ChART database were retrospectively reviewed. Of these, 1,198 patients with complete information on TNM stage, Masaoka-Koga stage, and survival were used for analysis. Cumulative incidence of recurrence (CIR) was assessed in R0 patients. Overall survival (OS) was evaluated both in an R0 resected cohort, as well as in all patients (any R status). CIR and OS were first analyzed according to the Masaoka-Koga staging system. Then, they were compared using the new TNM staging proposal. RESULTS Based on Masaoka-Koga staging system, significant difference was detected in CIR among all stages. However, no survival difference was revealed between stage I and II, or between stage II and III. Stage IV carried the highest risk of recurrence and worst survival. According to the new TNM staging proposal, CIR in T1a was significantly lower comparing to all other T categories (P<0.05) and there is a significant difference in OS between T1a and T1b (P=0.004). T4 had the worst OS comparing to all other T categories. CIR and OS were significantly worse in N (+) than in N0 patients. Significant difference in CIR and OS was detected between M0 and M1b, but not between M0 and M1a. OS was almost always statistically different when comparison was made between stages I-IIIa and stages IIIb-IVb. However, no statistical difference could be detected among stages IIIb to IVb. CONCLUSIONS Compared with Masaoka-Koga staging, the IASLC/ITMIG TNM staging proposal not only describes the extent of tumor invasion but also provides information on lymphatic involvement and tumor dissemination. Further study using prospectively recorded information on the proposed TNM categories would be helpful to better grouping thymic tumors for predicting prognosis and guiding clinical management.

Lymph node metastases in thymic malignancies: a Chinese Alliance for Research in Thymomas retrospective database analysis

OBJECTIVES Lymphatic involvement is believed to be relatively rare in thymic epithelial tumours. The incidence and prognostic significance of nodal metastases are still unclear. The goal of this study was to define the incidence and prognostic relevance of nodal metastasis in patients with thymic epithelial tumours, using a nationwide retrospective database of the Chinese Alliance for Research in Thymomas. METHODS Patients who underwent upfront surgical resection without preoperative therapy were enrolled for the study. The International Thymic Malignancies Interest Group proposal of a new staging system for thymic epithelial tumours was used to redefine the pathological stage. The incidence of nodal metastasis and its relationship with clinicopathological characteristics and its impact on survival were examined accordingly. RESULTS A total of 1617 patients were enrolled in this study. Lymph node metastasis was identified in 35 patients (2.2%). No nodal involvement was found in type A, AB or B1 thymomas. The incidence of nodal metastasis in thymoma (B2/B3) and thymic carcinoma was 1.3% and 7.9%, respectively, and it was most commonly seen in patients with neuroendocrine thymic tumours (16.7%, P < 0.001). According to the primary tumour invasion stage, incidences of nodal metastasis were 0.2% in T1, 6.9% in T2, 8.5% in T3 and 7.4% in T4 tumours (P < 0.001). Gender, pleural or distant metastasis and resection status were also correlated with nodal metastasis (P < 0.05) in univariable analysis. Multivariable analysis revealed that patients with non-thymoma histological characteristics (P < 0.001) and tumours in non-T1 stage (P < 0.001) had significantly greater risk of developing nodal metastasis. The overall survival of patients without nodal metastasis was significantly higher than that of patients with nodal involvement (P < 0.001). Disease-free survival of patients after R0 resection without nodal metastasis was also significantly higher than those with nodal metastasis (P < 0.001). On multivariable analysis, overall survival was significantly associated with histology of the tumour (P = 0.019) and complete resection (P = 0.047), and there was a trend towards significance (P = 0.052) in the association between overall survival and nodal involvement. CONCLUSIONS Lymph node metastasis in low-grade, early stage thymic tumours is a rare phenomenon. However, it is not uncommon in tumours with a higher stage or a higher histological grade, especially in neuroendocrine thymic tumours. Nodal involvement as well as tumour invasion and histological grade may denote worse prognosis. Lymph node dissection may be warranted in selected high-risk patients.

Lymph node metastasis in thymic malignancies: A Chinese multicenter prospective observational study

Objectives To study the incidence and pattern of lymph node metastases in thymic malignancies. Methods This multicenter prospective observational trial with intentional lymph node dissection was carried out by the Chinese Alliance for Research in Thymomas (ChART). Data on patients with thymic tumors without pretreatment were collected prospectively. Results from this prospective study were then compared with those from a previously reported ChART retrospective study. Results Among 275 patients, metastasis was detected in 41 nodes (3.04%) in 15 patients (5.5%). The rate of lymph node metastasis was 2.1% (5/238) in patients with thymomas, 25% (6/24) in those with thymic carcinomas, and 50% (4/8) in those with neuroendocrine tumors (P < .001). The rate of lymph node metastasis in category T1 to T4 tumors was 2.7% (6/222) in T1, 7.7% (1/13) in T2, 18.4% (7/38) in T3, and 50% (1/2) in T4 (P < .001). Nodal involvement was significantly higher compared with the ChART retrospective study (5.5% vs 2.2%; P = .002), although the 2 groups were comparable in terms of tumor stage and histology. Metastasis was found in N1 nodes in 13 patients (86.7%) and in N2 nodes in 8 patients (53.3%); 6 patients (40%) had simultaneous N1/N2 diseases and 6 (40%) had multistation involvement. Based on World Health Organization histological classification and Union for International Cancer Control T category, patients were divided into a low‐risk group (1/192; 0.5%) with T1‐2 and type A‐B2 diseases and a high‐risk group (14/83; 16.9%) of category T3 and above or histology B3 and above tumors for nodal metastasis (P < .001). On multivariate analysis, type B3/thymic carcinoma/neuroendocrine tumors, category T3 or above, and N2 dissection predicted a greater likelihood of finding nodal metastasis. Conclusions Lymph node involvement in thymic malignancies is more common than previously recognized, especially in tumors with aggressive histology and advanced T category. Intentional lymph node dissection increases the detection of nodal involvement and improves accuracy of staging. In selected high‐risk patients, systemic dissection of both N1and N2 nodes should be considered for accurate tumor staging.

The enlightenments from ITMIG Consensus on WHO histological classification of thymoma and thymic carcinoma: refined definitions, histological criteria, and reporting.

The World Health Organization (WHO) histological classification of the thymoma and thymic carcinoma (TC) has been criticized for poor interobserver reproducibility or inconsistencies in the routine pathological diagnosis. The International Thymic Malignancy Interest Group (ITMIG) panel achieved an agreement to maintain the widely accepted WHO framework but to refine historic definitions and histological criteria, and further introduce some new terms with the aim to improve interobserver reproducibility. This review addresses the enlightenments we can get from the ITMIG consensus on the WHO histological classification of the thymoma and TC, which may be helpful for most pathologists.

The application of postoperative chemotherapy in thymic tumors and its prognostic effect

BACKGROUND To study the role of postoperative chemotherapy and its prognostic effect in Masaoka-Koga stage III and IV thymic tumors. METHODS Between 1994 and 2012, 1,700 patients with thymic tumors who underwent surgery without neoadjuvant therapy were enrolled for the study. Among them, 665 patients in Masaoka-Koga stage III and IV were further analyzed to evaluate the clinical value of postoperative chemotherapy. The Kaplan-Meier method was used to obtain the survival curve of the patients divided into different subgroups, and the Cox regression analysis was used to make multivariate analysis on the factors affecting prognosis. A Propensity-Matched Study was used to evaluate the clinical value of chemotherapy. RESULTS Two-hundred and twenty-one patients were treated with postoperative chemotherapy, while the rest 444 cases were not. The two groups showed significant differences (P<0.05) regarding the incidence of myasthenia gravis, World Health Organization (WHO) histological subtypes, pathological staging, resection status and the use of postoperative radiotherapy. WHO type C tumors, incomplete resection, and postoperative radiotherapy were significantly related to increased recurrence and worse survival (P<0.05). Five-year and 10-year disease free survivals (DFS) and recurrence rates in patients who underwent surgery followed by postoperative chemotherapy were 51% and 30%, 46% and 68%, comparing with 73% and 58%, 26% and 40% in patients who had no adjuvant chemotherapy after surgery (P=0.001, P=0.001, respectively). In propensity-matched study, 158 pairs of patients with or without postoperative chemotherapy (316 patients in total) were selected and compared accordingly. Similar 5-year survival rates were detected between the two groups (P=0.332). CONCLUSIONS Pathologically higher grade histology, incomplete resection, and postoperative radiotherapy were found to be associated with worse outcomes in advanced stage thymic tumors. At present, there is no evidence to show that postoperative chemotherapy may help improve prognosis in patients with Masaoka-Koga stage III and IV thymic tumors.